Martindale

The .C omplete Drug Reference

Thirty-seventh edition

Edited by
Sean C Sweetman
BPhorm, FRPhormS

(l?P)
London • Chicogo Phormoceutical Pre.ss
Published by Pharmaceutical Press
1 Lombe1h High Street. London SE 1 7JN. UK
1559 SI. Povl Avenve, Gurnee, IL 60031, USA

C> Pharmaceutical Press 2011

(RP) is a rrade mark of Pharmaceurica l Press

Pharmaceurical Press is the publishing division of the Royal Pharmaccutic~l
Society of Great Britain

Fim edition of Martindale: The E.xtra Pharmacopoeia was published in 188.l

Squiu's Companion was incorporated in the twenty-third edition in 1952.

Thirty-seventh edirion published 2011

Printed in Italy by LEGO S.p.A .

ISBN 978 0 85369 933 0

ISSN 0263-5364
All rights reserved. No pan of this publication may be
reproduced, stored in a rctrie,oal sysrcm, or transmiued in any
form or by any means, without the prior wrirten permission of
the copyrighr holder.
The publisher makes no reprcscntarion , cXpress or implied,
with regard ro the accuracy of rhc information comaincd in this
book and shall not be liable, sn far as is permissible b)• law, for
any claim whether in contract or rort for losses arising out of
or in connection with rhe use of rhc book.
The book should be imcrprctcd in light of professional
knowledge and supplemcmcd as necessary by specialised
publications and product lircrarure. The reader should ensure
rhar the information being used is consistent with normal,
gcntrallr accepted healthcare practice.

A catalogue record for this book is available from the British Lib1"ry
 Contents
Preface v
Abbreviations viii
Contracted Names for lons and Groups xi
Atomic Weights of the Elements xiii

Volume A
" Monographs on dc-ugs and ancillary substances

Analgesics Anti-inflammatory Drugs and Antipyretics Cough Suppressants Expectorants Mucolytics and Nasal Decongestants 1686
Anthelmintics 140 Dermatological Drugs and Sunscreens I 716
Antibacterials 166 Disinfectants and Preservatives 1765
Antidementia Drugs 392 Electrolytes 1812
Antidepressants 402 Gases 1834
Antidiabetics 463 Gastrointestinal Drugs 1840
Antiepileptics 507 General Anaesthetics I 935
Antifungals 562
Growth Hormone and its Modulators 1955
Antigout Drugs 600
Immunosuppressants 1968
Antihistamines 611
Lor...al Anaesthetics 2011
Antimalarials 646
Miotics Mydriatics and Antiglaucoma Drugs 2035
Antimigraine Drugs 670
Muscle Relaxants 2050
Antirnyasthenics 684
Neuromuscular Blockers 2064
Antineoplastics 691
Nutritional Agenls and Vitamins 2078
Antiparkinsonian Drugs 875
Obstetric Dmgs 2 164
Anliprotozoals 906
Pesticides and Repellents 218 J
Antivirals 938
Pharmaceutical Excipients 2201
Anxiolytic Sedatives Hypnotics and Anti psychotics 1054
Blood Products Plasma Expanders and Haemostatics 1149 Radiopharrnaceuticals 2256

Bone Modulating D111gs I 193 Sex Hormones and their Modulators 2262

Bronchodilators and Anti-asthma Drugs 1220 Stimulants and Anorectics 2347

Cardiovascular Drugs 1268 Thyroid and Antithyroid Drugs 2365

Chelators Ant idotes and Antagonists I 574 Urological Drugs 2379
Contrast Media 161 I Vaccines Inununoglobulins and Antisera 2406
· Corticosteroids 1628 Miscellaneous Drugs and Other Substances 2453

Volume B
" Preparation$ 2659

0 Directory of Manufacturers 3555

"Multilingual Pharmaceutical Terms 3637

0 General Index 3657

° Cyrillic Index 4113
iii
 Martindale: The Complete Drug Referenee

Editor: Sean C Sweetman, BPhann, FRJ'ham1S

Senior Assistant Editor: Paul S Blake, BPhann, G.-d01pHea.l1hlnfonna1ics, FRPharmS

Assistant Editors: Alison Brayfield, BPhann, MRPhannS

Julie M McGiashan, BPhann, Diplnrae, MRJ'hannS
Gail C Neathercoat, BSc, MRPham1S
Anne V Parsons, BPhann, MRJ>hannS

Staff Editors: Catherine RM Cadart, BPhasm. GradOipHospPhurm, MRPbannS

Kathleen Eager, BPbarm, MRPhannS
Austin C Gibbons, BSe. MSc, MRPharmS
Susan L Handy, BPhann, OipClinPhann
Fauziah T Hashmi, BSc, MSc, MRPhannS
Sue W Ho, BPbarm, MRPbarmS
Joanna A Humm, MPhann. MRPllarm.S
Kelli Kalb, BSc(f'baml), RPh, RPEBC. ACPR
Jean Macpherson. BSc. PaCen, MRPhannS, MCPP
Priya Patel, MPhann. MRPhannS
Sandra C Sutton, BPhann, MSc Med. Ccn Proj Mn11, SAPC(SA)
Gerda W Viedge, BPharm, MIU'bannS

Senior Editorial Assistant: Chlo!: SAJ HatwaJ, BSc, MRes

Editorial Assistant: Elizabeth D King, DipBTECPhannSc

Clerical Assistant: Christine L lskandar

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

Volume A
• Monographs on drugs and ancillary substances

Analgesics Anti-inflammatory Drugs and Aotipyretics Cough Suppressants Expectorants Muco\ytics and Nasal Decongestants 1686
Anthelmintics 140 Dermatological Drugs and Sunscreens 1716
Antibacterials 166 Disinfectants and Preservatives 1765
Antidementia Drugs 392 Electrolytes 1812
Antidepressants 402 Gases 1834
Antidiabctics 463 Gastrointestinal Drugs ·1840
Antiepilcptics 507 General Anaesthetics 1935
Antifungals 562 Growth Hormone and its Modulators 1955
Antigout Drugs 600
Immunosuppressants 1968
Antihistamines 611
Local Anaesthetics 2011
Antimalarials 646
Miotics Mydriatics and Antiglaucorna Drugs 2035
Antimigraine Drugs 670
Muscle Relaxants 2050
Antimyasthenics 684
Neuromuscular Blockers 2064
Antineoplastics 691
Nutritional Agents and Vitamins 2078
Antiparkinsonian Drugs 875
Obstetric Drugs 2164
Antiprotozoals 906
Pesticides and Repellents 2181
Antivirals 938
Pharmaceutical Excipients 220 I
Anxiolytic Sedatives Hypnotics and Antipsychotics 1054
Blood Products Plasma Expanders and Haemostatics 1149 Radiopharmaceuticals 2256

Bone Modulating Drugs 1193 Sex Hormones and their Modulators 2262

Bronchodilators and Anti-asthma Drugs 1220 Stimulants and Anorectics 2347

Cardiovascular Drugs 1268 Thyroid and Antithyroid Drugs 2365

Chelators Antidotes and Antagonists 1574 Urological Drugs 2379

Contrast Media 1611 Vaccines Irnmunoglobulins and Antisera 2406
Corticosteroids 1628 Miscellaneous Drugs and Other Substances 2453

Volume B

• Preparations 2659

• Directory of Manufacturers 3555

• Multilingual Pharmaceutical Terms 3637

• General Index 3657

•Cyrillic Index 4113

IV
Preface

The aim of Martindale is lO provide healthcare professionals with unbiased approved by the relevant regulatory health bodies. Acknowledgement is also
evaluated information on drugs and medicines used throughout the world. It given to information referenced from a number of authoritative sources
therefore has to develop as the body of knowledge on existing drugs grows, new including the British NaJionol Formu/ary, the British National Formulary for
drugs emerge, new preparations are launched, and old preparations are Clrikttn, the British Phannocopoew, the European Pharmacopoeia, the United
abandoned, reformulated, or redefined. It also has to reflect the changing needs Stales National Formulary, and the Ufliled Slates Phannacopeia.
of those practising pharmacy and medicine. We try to ensure that each new Martindale is not a book ofstandards. Inclusion ofa substance or a preparation
edition continues to meet all lhese needs. · is not to be considered as a n:cornmendation for use, nor does it confer any Status
In order to provide more up-to-dale infonnation the interval between the on the substance or preparauon. While considerable efforts have been made to
publication of the printed versions of Manindale has been reduced over check the material in Martindale, the publisher cannot accept any responsibility
successive editions and the book is now produced about every 2 years. For those for errors and omissions. Also the reader is assumed co possess the necessary
who require even more up-to-<late infonnation from Martindale there are various knowledge to interpret the information that Martindale provides.
electronic versions, sections of which are updated more frequently.
Martindale has been continuously expanded since it was first published in
Philosophy and methodology
1883, and lo present all the extra infonnation this edition of Martindale Manindale's uses are as varied as its users. However, our primary aims are:
maintains the recent return to a two-volume publication. l11e first volume • to summarise clinically useful information on all drugs and medicines
contains this preface and the drug monographs, and the second holds the around the world
propriewy preparations and the indexes, as well as manufacturers' contact • to provide accurate, unbiased, reasonably comprehensive, and regularly re-
infonnation. evaluated information in o. concise format
A3 always the contents have been extensively revised, with all the text scanned o to provide a lead-in to the published evidence base from which we derive our
and revalidated where necessary by a team of experienced pharmacists. Over information
240 monogniphs ha~e been added, and 171 removed from the book (abbreviated
information on the latter remains available in the electronic versions). In our In order to achieve the aims specified above, our working practices have to
continuing attempts to improve the usefulness of the book., the chapters on optimise internal knowledge management
Colouring Agents, Nonionic Surfactants, Organic Solvents, Paraffins and MARTINDALE STAFF. Martindale is CWJently produced by a learn of21 people,
Similar Bases, Soaps and Other Anionic Swfuctants, and Stabilising and I g of whom are pharmacists or pharmacy technicians with relevant ~.
Suspending Agents have been amalgamated and with additional material now The team is divided into 5 revising groups each of2 or 3 staff editors, as well as
form the new chapter Pharmaceutical Excipients. 5 assistant editors, I editor-in-daief, a co-ordinator for the processing of
The disease treatmeut reviews, 675 in all and generally located in the chapter information on proprietary medicines, and 3 clerical and suppon Staff. A nwnber
introductioos, have also been revised in order to reflect current trends and of pharmacists work as external evaluators to maintain coverage of non-UK
provide key references. Cross-references t0 these revi~'S appear in the preparations.
monographs of the drugs cited; the reviews can also be accessed via the general Staff editors receive formal !raining in literature evaluation and searching
index. It is hoped that these reviews will be of use to readers who want an techniques, as well as specific, 'on-the-job' ttaining in internal procedures. Each
overview of a panicular disease and its drug trealment and will provide a useful revision team has l'CSPoOSibility for the re-evaluation and update of a particular
starting point for those who want to pursue particular aspects further. group of chapters. Senior editorial staff edit and approve the output ofthe teams.
Martindale contains much nomenclature information intended co assist the Staffarc l'CSPonsible for ongoing data collection as well as the revision process.
reader in identifying a particular drug or compound, and for this edition we have DATA CoLl..ECTION. In order to reduce the amount of formal data collection
again greatly exp~nded our coverage of synonyms, with increased coverage of required at revision, a prospective data~llection roster is in operation. This
Russian synonyms and 'street names' for substances of abuse. Coverage ofATC involves all staff members in hand-searching selected majormedicaljoumals, as
codes has been expanded to include codes assigned to herbal medicines. This well as regular searches of the internet sites of regulatory authorities (EMEA,
edition also carries for the first time the unique ingredient identifiers (UNlls) that FDA, Health Canada, and MHRA). and sources of high-quality systematic
are generated by the joint FDA/USP Substllnce Registration System. reviews and guidelines (such as Oinical Evidence, Cochrane, and NlCE), for
This edition of Martindale also sees the number of graphical representations drug information. In addition, pharmacopoeia!, governmental and WHO
of the chemical structures increased.. publications are hand-searched for information relating to drugs and drug
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 the number of countries covered has again
been increased. For this edition homoeopathic proprietary preparations have also analysis of previous citations, and is reviewed and updated regularly.
been listed at the end of the relevant monographs according to their ingredients. PROPRLETARY PREPARATIONS. The Martindale proprietary preparations team
evaluate licensed product infonuation for 41 countries and regions, in order
Martindale is based on published information and more than 54 500 selected
to maintain the widest possible coverage of drugs in use internationally.
references are included. The amount of drug infonnation now published
Preparation names, manufacturers, ingredients, and licensed uses are included in
elec:uonically has increased significantly since the last printed edition of
Martindale and this edition now includes ·over 3400 citations to material the internal Martindale database for review during the revision proc~ and any
sigiiificant additional infonnation is forwarded to the relevant revision team.
available on the Internet as web pages. Because of the nature of the Internet,
there is no way to guarantee that the material referred to by a URL will remain REvlslON. In order to maintain the quality and cum:ncy of our content, it is
at that location, as many sites are subject to periodic reorgan isalion; additionally, constantly revised and updated. Our revision processes cover both scheduled, in·
the content of Internet documents may change without warning, All URLs iu depth revision of the content of every chapter in the book on a chapter-by-
Martindale are rechecked shonly before publication to ensure that a docwnent 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 sranding
the content of the document was referred to during revalidation. information, the assessment of new collected references for quality and
relevance, and the selective use of search techniques on bibliographic databases
Our objective is to evalua1e the literature, covering important studies,
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 CHECl<INO. Once the material for a given chapter has been re-evaluated and
drug treatment, and their findings and cooclusions are considered in many of our updated it undergoes a rigorous check, designed to ensure not only that all
chapccrs. However, there is also a place for the anecdotal report and die small changes are valid and appropriate, but also tll3t important Points have not been
study, and information from such sources is included where appropriate. In missed.
compiling the text of a Martindale monograph extensive use is made of the EDITING. The chapter is then passed to a member of the senior editorial staff,
drug's licensed product information as published in various countries and who performs a second check and preliminary editing of the data This process
v
vi Preface
is designed to ensure consistency of approach and style, as well as offering an page and in which volume the entry may be found. To improve clarity and the
opportunity to pick up any cnors missed at the first check. Changes and ease oflocation of inde.x entries long chemical names have been omined from
questions are fed back to the revision team in an iterative process that may the index.
involve more than one cycle. Once past its preliminary edit the chapter is se(lt to • CYRll.LIC INDEX (pages 4113-4147). Doth nonproprietary and proprietary
the Editor for a final check and approval, which again may require changes to be names in Russian may be found in Russian alphabetical order in this section.
made and checked, before passing it to the next stage.
KEYING, PROOF-READING, ANO Dos&<:HECKJNO. Once approved by the Editor,
Nomenclature
amendments can be incorporaled into the database, which remains untouched Tm.Es AND SYNONYMS. The title of each monograph is in English, with
until this stage as a security measure. These changes are then proofread for preference usually being given. to [nternational Nonproprietary Names (INN),
errors, corrected if necessary, and any corrections checked. Extensive electronic British Approved Names (BAN). and Uniled States Adopted Names (USAN).
iesting for spelling, style, and fonnat is also carried out at all stages. The These 3 authorities are shown where appropriate. A European Directive
amended chapter then undergoes an independent check of the dose information (92/271EEC) requires the use of Recommended International Nonproprietary
against its recorded sources. This check is performed by a member of staff Names (rINNs) in the labelling of medicinal products throughout member states
outside the original revising and editing team, and is an additional safeguard of the European Community and where the BAN and INN differed in the past
against the inadver(.ent introduction of potentially dangerous dose errors. Once the BAN has been changed to accord with the r!NN. 1be major exception to this
past these stages the data are cleared for release, and can be published in the next convention is the retention 'Of the names adrenaline and noradrenaline, these
update of the Martindale electronic products, and, at appropriate points in the being the teuns used as the titles of the monographs in the European
publishing cycle, in the book- Pharmacopoeia and therefore the official names in the member states. In some
approved names it is now general policy to use 'f' for 'ph' in suJpha, 't' for 'th',
ADDmoNAL CH.ECJ<.S FOR PUBLJCATION. Some additional checks are made and 'i' for 'y'; for this reason entries in alphabetical lists and indexes should be
before publishing a print edition of Martindale. An second independent dose sought in alternative spellings ifthe expected spellings are not found. Inevitably
check of all chapters is made by an external expert, all cross-references are there may be some inconsistencies of style witb older approved names but
revalidaled, and tests of the typesetting and page structure are made. In addition wherever possible the names used for drugs or radicals in Martindale have been
our extensive index is generated and carefully checked for accuracy, order, and altered in accordance with the guidelines on the use of INNs for pharmaceutical
consistency. All URLs are also rechecked at this stage to ensure that they still substances. A table of contracted names for ions and groups used in approved
link to the material cited. names and titles is given on page xi. TNNs. in the four other main official
FEEDBACK. We are always grateful to get feedback from our users and, languages (French, Latin, Russian, and Spanish) have also been included in the
whenever possible, we try to incorporate infonnation or suggestions that list of synonyms where these differ from the English INN. BAN names for
help us to improve Martindale. Anyone wishing to conuuent on the editorial substance combinations and United States Pharmacy Equivalent Names (PEN)
content of Martindale can contact us at the following e-mail address: for dosage forms containing two or more active ingredients are given in the text
martindale@rpsgb.org of the relevant monographs; these names start with the prefix 'Co-•.
This sect.ion also includes names given as synonyms such as commonly used
Arrangement abbreviated names; Latin versions ofthe titles in the European Pharmacopoeia;
VOUJME A:. • MONOGRAPHS ON DRUGS AND A."ICJLLARY SUBSTANCES (pages English, American, and Latin synonyn1s; names used in other languages when
1-2658). This section contains 5930 monographs arranged in 49 chapters. These these may not be readily identifiable; manufilcturers' <Xlde numbers; and chem-
chapters generally bring together monographs on drugs and groups of drugs that ical names. Official titles and synonyms used in the British, European, and US
have similar uses or actions. The introductions of those chapters that describe Pharmacopoeias are given in the section on phannacopoeias where the relevant
drugs used in the management of disease may contain disease treatment pharmacopoeia! substance is described.
reviews-descriptions of those diseases together with reviews of the choice of Graphical representations of the chemical strcuturcs for ovcr4 l 00 of the drugs
treatments.The last chapter in this section consists of a series of monographs are also included.
arranged in the alphabetical order of their main titles. It includes monographs on STREET NAMES. This edition of Martindale once again includes greatly
drugs not easily classified., on hCJbals, and on drugs no longer used clinically but expanded coverage of 'street names' for substances of abuse. Street terms and
still of interest There are also monographs on toxic substances, the effects of other slang names for drugs of abuse are included for guidance only and should
which may require drug therapy. be used with caution. Because of the very nature of their origin they cannot be
VOLUME B: • PREPARATIONS (pages 2659-3554). TI1is section contains over relied upon for definitive identification of a substance. The use of such terms
161 700 proprietary preparations from a range of countries and regions. For this changes rapidly, and can vary between different geographical locations, and any
edition we have covered Argentina, Australia, Austria, Belgium, Brazil, Canada, given name may potentially be applied to more than one substance or even to a
Chile, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong mixture of substances. Furthermore, established or well recognised generic drug
Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Malaysia, Mexico, the names or herbal names have sometimes been misused as sireet terms for
Netherlands, New l.ealand., Norway, Philippines, Poland, Portugal, Russia, completely unrelated substances. In order to enable the reader to distinguish
Singapore, South Africa, Spain, Sweden, Switzerland., Thailand, Turkey, them from better validated synonyms, in the index, such names are included in
Ukraine, the United Arab Emirates, UK, USA, and Venezuela. We have also italics and in quotation marks.
included some proprietary preparations from Japan. The infonnation provided CAS REGISTRY NUMBERS. Chemical Abstracts Service(CAS) registry numbers
includes the proprietary name, the manufacturer or distributor, the active are provided, where available, for each monograph substance to help readers
ingredients with cross-references to the drug monographs, and a summary of the refer to other infonnation systems. Numbers for various forms of the monograph
indications as given by the manufacturer. substance are listed with the variation in fonn given in parentheses.
• DIRECTORY OF MANUFAciuRERS '(pages 3555-3636). In Martindale the ATC CODES. Codes from the Anatomical Therapeutic Chemical (ATC)
names of manufacturers and distributors are abbreviated. Their full names are classification system (see http://www.whocc.no) have been provided, where
given in this directory together with the full address and website if it is available. available, for each monograph substance to help readers refer to other
This directory contains about 15 300 entries. information systems. The codes assigned in the equivalent classification system
for veterinary medicines (ATC Vet~ee httpJ/www.whocc.no/atcvet) and
• MULllUNGUAL PHARMACEUTICAL TERMS (pages 3637-3656). This index herbal medicines have been included where possible.
lists nearly 5600 of the commoner pharmaceutical fonns and routes in 13 major UNll CODES. The unique ingredient identifiers, which are generaled by the joint
European languages. lt is provided as an aid to the non-native speaker in FDA/USP Substance Registration System have been provided, where available.
interpreting packaging, product information, or prescriptions written in another Numbers for various forms of the monbgraph or related substances are listed
language. with the variation in fonn given in parentheses.
• GENER.AL INDEX (pages 3657-41 12). To make fullest use of the contents of
Martindale the general index should always be consulted. The exhaustive index, Atomic and Molecular Weights
prepared from 172 000 entries, includes entries for drugs (approved names, Atomic weights are based on the table of Atomic Weights as revised in 2007 by
synonyms, and chemical names), preparations, pharmacological and therapeutic the Commission on Atomic Weights and lsotopic Abundance, International
groups, and clinical uses (disease treatment reviews). As in previous editions, the Union of Pure and Applied Chemistry (IUPAC) and based on the t2c scale (see
index is arranged alphabetically 'word-by-word' rather than 'letter-by-letter'. page xiii). Molecular weights are given corrected to one place of decimals or to
The index indicates the column in which the relevant entry appears as well as the four significant figures for relative weights of less than ·100.
 P1-eface vii
Phannacopoeias check with the appropriate body. TI1e rules are constantly evolving and the
absence of any indication of restriction in Martindale should not be taken as
The sdected phannacopoeias in which each substance appears are listed. A
absolute confinnation that the substance may legitimately be taken by a
description of the substance and a summary of the pham1aceutical information
competitor.
(see below) that appears in the British, European, or US Pharmacopoeias is also
included. Current copies of the phannacopoeias and their addenda should be Pharmacological and Therapeutic Information
consulted for confirmation and for details of standards.
· Information on adverse effects, treatment of adverse effects, precautions
The phannacopoeias covered include: British. British VeterinCl!J\ Chinese,
(including contra-indications), interactions, phannacokinetics, and uses and
European, French. Gennan, /nJemational, Italian, Japanese, Polish. Spanish,
administration of each substance is provided by concise statements and these
Swiss, United States (including the National Formulary}, and llietnamese. The
may be elaborated and ·expanded by referenced reviews and abstracts from
abbreviations for these pham1acopoeias are included in the list of abbreviations
papers and other publications. This edition contains over 16 400 such abstracts
used in Martindale, see page. viii, which also includes details of the edition and/or
or reviews based on information in an ever widening range of publications.
supplement(s) consulted.
Several countries are parties to the Convention on the Elaboration of a Much information has been found in sources such as World Health
European Phannacopoeia. This means that they must adopt the standards of the Organization publications, goverrunent reports and legislation, and other official
European Pharmacopoeia. These countries are currently Austria, Belgium, and standard publications. Licensed product information and manufacturers'
Bosnia and Herzegovina, .Bulgaria, Croatia, Cyprus, the Czech Republic, literature has been considered in the light of other available information.
Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, The risks of giving drugs in pregnancy are well known and the general
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, the principle is to give a drug only when the benefii to the individual mother
Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak Republic, outweighs the risk to the fetus. Where there is a clear risk it is noted under the
Slovenia, Spain, Sweden, Switzerland, Tw-key, ihe United Kingdom, the Former Precautions or Adverse Effects heading but safety should not be inferred from
Yugoslav Republic of Macedonia, and tl1e Ew-opean Union. Hence the European the absence of a statement for any drug.
Pharmacopoeia is cited in the drug monograph lists of pharmacopoeias rather Some drugs given to the mother are distributed into breast milk and therefore
than these individual national pharmacopoeias. may pose a risk to a breast-fed infant Whenever possible, information has been
Official preparations, mainly from the current British, Ew-opc.an, and US included to help determine the safety of continuing to breast feed while the
Pharmacopoeias, are listed at the end of drug monographs. mother is receiving a particular drug. Safety during breast feeding should not be
inferred from the absence of a statement for any drug.
Pharmaceutical Information
Information on the chemical and physical properties of each substance is given Doses
when it is likely to be ofuse or interest, but only when it is certain that it applies Doses are described under the Uses and Administration heading with as much
to the form of substance being described in the monograph. detail as is necessary and available. Unless otherwise stated the doses represent
PERCENTAGE STRENGTHS. Unless otherwise stated, solutions ofsolids in liquids the average range of quantities which are generally regarded as suitable for
are expressed as percentage w/v, of liquids in liquids as percentage v/v, and of adults when given orally. More information on doses and drug administration
gases in liquids as percentage w/w. may be given in the abstracts or reviews. Unless otherwise specified, glucose
SOLUBILITY. The figures given for solubility in each monograph have generally injection is 5% w/v and sodium chloride injection is 0.9% w/v.
been obtained from the major pharmacopoeias in which the substance is . When doses for children are expressed as a range of quantities within specified
described, but should not be considered absolute. Unless otherwise indicated in age limits, the lower dose applies at the lower age and the higher dose at the
the text, the figures are for solubility at temperatures betWeen 15° and 25°. The higher age.
information usually relates to w/v solubilities but in some ca~es is v/v if the
monograph substance itselfis a liquid. Where solubilities are given in words, the Acknowledgements
following terms describe the indicated solubility ranges:
The Editor gratefully acknowledges the advice and assistance of the many
solubility expens who have suggested amendmcnlS to the text of Martindale. Thanks are
very soluble I in less than I also due to Osquel Barroso, Karen Baxter, Lina Bladh, Thomas Brendler, Larry
freely soluble I in I to I in 10 Callahan, Alessandro Gabbi, Judy van Engeldorp Gastelaars, Spela Godec, Jan
soluble I in 10 to I in 30 Hom, Montserrat Jane, Andrius Kairys, Maria Kouimtzi, Rhoda Lee, Dinesh
sparingly soluble I in 3010' 1in100 Mehta, Carla Oliveira, Frank · Post, Anne Prasad, Olivier Rabin, Kamila
slightly soluble I in 100 to I in 1000 RameSova, Elsa Simon, Gyongyver Soos, Carina Tukukino, Robert Wasilewski,
very slightly soluble I in 1000 to I in 10 000
Frank Switzer, and Paul Weller, for advice and comments on specific issues
practically insoluble I in more than I 0 000 during revision. The Editor is grateful to the many organisations that have helped
in providing information.
STORAGE. Substances and preparations should be stored under conditions which
Martindale staff have been able to call on the expertise of other members
prevent contamination and dinlinish deterioration, and the conditions of storage ·
of the Royal Pharmaceutical Society's staff. In particular the Editor is
given in the text indicate the precautions recommended in specific cases. The
grateful to John Martin and the staff of the British National Formulary, and
term 'a.cool place' is generally used to describe a place in which the temperature
the staff of the library and information department. Thanks are due to Ian
is between 8° and 15°. In general, the storage conditions apply to the monograph
Baxter, Mildred Davis, Sam Driver, Marian Fenton, Eileen Laughton, Rosalind
subst3.flce and not its solutions or preparations.
McLarney, Claire Norton, James O'Reilly, and Susan Shankie for their editorial
·TEMPERATURE. Temperatures are expressed in degrees Celsius (centigrade) tasks. Thanks are also due to Bob Bolick and the staff of the Pharmaceutical
unless otherwise indicated. · Press for their support.
Drugs in Sport The contents of this 3 7th edition were planned, written, checked, indexed,
Wherever possible we have attempted to indicate.those drugs and substances keyed, proofed, and processed by the Martindale staff. The Editor is pleased
that may be subject to restriction in some or all sports, either in their own right, to acknowledge the skills and commitment of all the Martindale staff anil to
or because they are a derivative of a restricted substance or a member of a record his gratitude: to Christine Iskandar for clerical assistance; to Chloe
prohibited group. Proprietary preparations containing such compounds are also Hatwal and Elizabeth King for editorial assistance; to the Staff Editors
mark~ in the preparation section in Volume B. The definitive guide used for
Catherine Cadart, Kathleen Eager, Austin Gibbons, Sue Handy, Fauziah
identit';ing restricted drugs for this edition is the 20 I 0 Prohibited List issued by Hashmi, Sue Ho, Joanna Humm, Kelli Kalb, Jean Macpherson, Priya
the World Anti-Doping Agency (WADA-see www.wada-amaorg). However, Patel, Sandra Sutton, and Gerda Viedge; to the Assistant Editors Alison
these regulations, which are issued annually, are subject to interpretation and Brayfield., Julie McGlashan, Gail Neathercoat, and Anne Parsons; and to the
therapeutic exemption, and may vary from sport to sport; particular sporting Senior Assistant Editor Paul Blake.
authorities may also issue additional restrictions, and competitors should always London October 20 I 0
Abbreviations

For abbreviations of the names of manufacturers or their distributors, see d e-German.

Directory of Manufacturers, page 3555. d.c.-dircct current.
DEFRA- Department for Environment, Food, and Rural Affairs (UK).
ACE-angiotensin-convcrting enzyme. Denm.-Denmark.
AD HD-attention deficit hyperactivity disorder. DH SS-the formu Department of Health and Social Security (UK).
agg.-aggrcgatc (in botanical names~. including 2 or more species which dL-<lecilitre(s).
resemble each other closely. DNA-deoxynbonucleic acid.
AIDS-cquired immunodeficiency syndrome. Do H- Dcpartrnent of Health (UK).
a.m .--ante mer1diem, 'before noon' . DTF-Drug Tariff Forrnulary.
ARC- AIDS-related complex. EC G-<lectrocardiogram.
Arg.-A.rgentina. ECT--elcctrOCOnvulsivc therapy.
ATC-Anatomical Therapeutic Chemical classification. Ecuod.-Ecuador.
AUc-rea under the concentration-time curve. ed.--editor(s) or edited by or edition.
Austrof.- Australia. EEC- European Economic Community, now lhe European Union.
AV-atrioventricular. EEG-<lcctro-encephalogram.
BAN- British Approved Name. e.g.-aempli gratia 'for example'.
BANM-British Approved Name Modified. e l-Greek.
Befg.- Bclgium. EMEA-European Medicines Agency.
BMA- British Medical Association. ENL--ecythema nodosum lcprosum.
BMl-body mass index. es- Spanish.
BNF-British National Formulary. ESRD-end-stage renal disease.
BNFC- British National Formulary for Children. et al.-et al/I, 'and others': for three or more co-authors or co-workers.
b.p.- boiling point. et seq.- and what follows.
BP-British Pharmacopoeia. Unless otherwise specified., BP references arc EU- European Union.
to the 2010 edition. Eur. P.-sce Ph. Eur.
BP(Vet)-British Pharmacopoeia (Veterinary) 2010. Ext. D &. C-designation applied in USA to dyes perrnined for use in
BPC- British Pharmaceutical Codex. external drug and cosmetic preparations.
Br.-British. °F-<lcgrees Fahrenheit.
8raL- Brazil FAC-Food Additives and Contaminants Committee of the former
Bufg.- Bulgaria. Ministty of Agriculture, Fisheries and Food (UK).
BUN-Blood-urea-nitrogen. FAO-Food and Agriculture Organization of the United Nations.
oC-<legrees Celsius (centigrade). Unless ot~ciwise indicated in the text, FAO/WHO--Food and Agriculture Organization of the United Nations
temperatures arc expressed in this thcrmomctnc scale. and the World Health Organization.
Conod.-Canada. FDA-Food and Drug Administration of USA.
CAPD-<:0ntinuous ambulatory peritoneal dialysis. FdAC-Food Advisory Committee of the former Ministty of Agriculture,
CAS-Chemical Abstracts Service. Fisheries and Food (UK).
CCPO-<:<>ntinuous cycle peritoneal dialysis. FD & C-dcsignation applied in USA to dyes permitted for use in foods,
CDC-Centers for Disease Control and Prevenuon (USA) (formerly drugs, and cosmetics.
Centers for Disease Control). FEV 1-forced expiratory volume in I second.
Chin. P.-Chinese Pharmacopoeia 2005. Fin.-Finland.
CHM-Commission on Human Medicines (UK). FIP- FCderation Internationale Pharmaceutiquc.
Cl-Colour lndex. f.p.-'-freczing point.
CMV-eytomegalovirus. FPA-Family Planning Association (UK).
CN5--eentral nervous system. fr-French.
cP-eentipoise(s). Fr.-Francc.
CPMP-Comminec' on Proprietary Medicinal Products of the European fr. P.- Frcnch Phannacopoeia 1982 (Pharmacopec Francaise, X" Edition)
Union. and updates up to 2003.
cs-Czech. g--grarn(s).
CS F-eerebrospinal fluid. Ger.--Gcrrnany.
CSM-Committcc on Safety of Medicines (UK) (now subsumed within the Ger. P.- Gcnnan Pharmacopoeia (Dcutsches Anncibuch, 2007).
Commission on Human Medicines).
GFR-glomcrular filtration rate.
cSt--centistokcs.
G6PD-glucose-6-phosphatc dchydrogcnase.
C;_-Czcch Republic. -
o & C-dcsignation applied io USA to dyes pcnniued for use in drugs and Gr.-Greccc..
HAART-highly active anlirctroviral therapy.
cosmetics.
VIit
 P~eface ;x

Hb-- haemoglobin. ml-millilitre(s).

Hib-Haemophilus injluenzae type b. mm--millimetre(s).
HIV-human immunodeficiency virus. mm2--square millimetre(s}.
HLA-human lymphocyte antigens. mm 3--cubic millimetre(s).
HLB-hydrophilic-lipophilic balance. mmHg-millimetre(s) of mercury.
HRT-honnone replacement therapy. mmol-millimole.
HSE-Health and Safety Executive (UK). mol--mole.
hu-Hungarian. mol. wt-molecular weight.
Hung.-Hungary. Mon.-Monaco.
IARC- Intemational Agency for Research on Cancer. mosmol-m illiosmole.
ibid.-ibidem, 'in the same place (joumal or book)'. m.p.--melting point.
idem-'the same': used for the same authors and titles. MRC-Medical Research Council (UK).
i.e.-id est, 'that is'. MRSA- meticillin-resistant Staphylococcus aureus.
lg-immunoglobulin. µg-microgram(s).
lndon.-Indonesia. µm -micrometre(s).
INN-lntemational Non proprietary Name. N-normal.
INNM-Intemational Nonproprietary Name Modified. n.b.-nota bene, note carefully.
Int. P.- lntemational Pharmacopoeia 4th ed., 2006, and Supplement I, Neth.- Thc Netherlands.
2008. NICE- National Institute for Health and Clinical Excellence (formerly the
IPCS-Internntional Programme on Chemical Safety. National Institute for Clinical Excellence) (UK).
IQ-intelligence quotient. NIH-National Institutes ofHealth (USA).
frl.-Ireland. nl-Dutch.
!SH- Internati onal Society of Hypertension. nm-nanometre(s).
it-Italian. NMDA- N-methyl-o-aspartate.
ft. P.- Italian Pharmacopoeia I Ith ed., 2002 (Farmacopea Ufficiale della NNRTl-non-nuclcoside reverse transcriptase inhibitor.
Repubblica Italians, XI Edizione, 2002). Norw.- Norway.
ltol.- ltaly. NRTl--nucleoside reverse transcriptase inhibitor.
IUD- intra-uterine device. NSAIO--nonstcroidal anti-inflammatory drug.
IUPAC-International Union of Pure and Applied Chemistry. NYHA- New York Heart Association.
IVF-i11-vitro fertilisation. NZ-New Zealand.
J-joulc(s). OP-over proof.
Jpn- Japan. o/w-oil-in-water.
Jpn P.-The Pharn1acopoeia of Japar:i, J5th ed., 2006 and Supplement 1. P-probability.
K-kelvin. Pa-pascal(s).
kcal-kilocalorie(s). Pak.-Pakistan.
kg--kilogram(s). pC0 2--plasma partial pressure (concentration) of carbon dioxide.
kj-kilojoule(s). PaC0 2- arterial plasma partial pressure (concentration) of carbon dioxide.
lb-pound(s) avoirdupois. PEN-Pharmacy Equivalent Name, see page vi.
LOSO- dose lethal to 50% of the specified animals or micro-organisms. pg--picogram(s).
Lf-limes flocculation. pH-the negative logarithm of the hydrogen ion concentration.
It-Lithuanian. Ph. Eur.- European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 to
m -metre(s). 6.8.
m 2--square metre(s). Pharm. Soc. Lab. Rep.-Royal Pharmaceutical Society's Laboratoty
m 3-<:ubic metre(s). Report.
M-molar. Philif>f>.- Philippines.
HAFF-the former Ministry of Agriculture, Fisheries and Food (UK), now PHLS-Public Health Laboratory Service (UK).
Depart.ment of Environment, Food, and Rural Affairs (DEFRA). plNN- Proposed International Nonproprietary Name.
MAOl-monoamine oxidase inhibitor. plNNM- Proposed International Nonproprietary Name Modified.
max.-maximum. pK.-the negative logarithm of the dissociation constant.
MBC--minimum bactericidal concentration. pl-Polish.
MCA- Medicines Control Agency, now MHRA (UK). p.m.--post meridiem, 'afternoon'.
mEq-milliequivalent(s). p02--plasma partial pressure (concentration) of oxygen.
Mex.-Mexico. p3 02-arterial plasma partial pressure (concentration) of oxygen.
mg- miltigram(s). Pol.- Poland.
MHRA- Medicines and Healthcare products Regulatory Agency (UK). Pol. P.-Polisb Pharmacopoeia 6th ed., 2002 (Farmakopea Polska VI, 2002)
MIC-minimum inhibitory concentration. and Supplement 2005.
min- minute. Port.- Portugal.
min.-minimum. ppm-parts per million.
MJ- megajoule(s). PSGB-The Pharmaceutical Society of Great Britain. Now the Royal
x Preface
Pharmaceutical Society. Switz.-Switzerland.
pt-Portuguese. Thai.-Thailand.
PUVA-psoralen with UVA light irradiation. TNF-tumour necrosis factor.
PVC-polyvinyl chloride. THM-traditional herbal medicine.
RCGP-Royal College of General Practitioners (UK). THMP-traditional herbal medicinal product.
RIMA-reversible inhibitor ofmonoamine oxidasc type A. TPN-total parenteral nutrition.
rlNN-Recommended International Nonproprietary Name. Turlc.-Turkey.
rlNNM-Rccommended International Nonproprietary Name Modified. UAE-United Arab Emirates.
RNA-ribonucleic acid. UK-United Kingdom.
RPSGB- The Royal Pharmaceutical Society of Great Britain. Now the
Ukr.-Ukraine.
Royal Pharmaceutical Society
UNICEF-United Nations Children's Fund.
RSV-respiratory syncytial virus.
UP-under proof.
Rus.-Russia.
Urug.-Uruguay.
S. Afr.-South Africa.
SGOT- serum glutamic oxaloacetic transaminase (serum aspartate amino- US and USA-United States of America.
transferase now preferred). USAN-United States Adopted Name.
SGPT-serum glutamic pyruvic transaminase (serum alanine amino- USNF-The United States 'National Forrnulary 28', 2010, and Supplement
transferase now preferred). I.
SI-Statutory Instrument or Systeme International d'Unites (International USP-The United States Pharmacopeia 33, 2010, and Supplement l.
System of Units). UV-ultraviolet.
sic-written exactly as it appears in the original. var.-variety.
SLE-systemic lupus erythematosus. Yenez.-Venezuela.
sp.-species (plural spp.). Viet.- Vietnamese.
sp. gr.-specific gravity. Viet. P.-Vietnamese Pharmacopoeia 2002 (Pharmacopoeia Vietnamica,
Span.-Spanish. Editio III).
Span. P.-Spanish Pharmacopoeia 2nd ed., 2002 (Real Farrnacopoca vol.-volume(s).
Espaiiola, Segunda Edici6n, 2002) and Supplement 2.1.
v/v-volume in volume.
SSRl-selective serotonin reuptake inhibitor.
v/w-volume in weight.
St-stokes.
WHO-World Health Or:ganization.
subsp.-subspecics.
w/o-water-in-oil.
suppl-supplement(s).
sv-Swedish. wt-weight.
Swed.-Sweden. wt per mL-weight per millilitre.
Swiss P.-Swiss Phannacopoeia 2006 (Pharmacopoea Helvetica, 10 w/v-weight in volume.
Ausgabe, Deutsche Ausgabe). w/w-weight in weight.
 C9ritracted Names for Io ns and Gro ups
Convactcd N.Jmc Chemic>.I N.,.,,.,

aCiefurate acetate (ester) and furan-2-carboxylate (ester) crosfuma.ril (2E)-but-2-enedioyl

acealumate roe-hydrogen N-acetylglutmatc cyclamace eyelohexylsulfamatc

aceponate acetate (ester) and propionate (ester) daloxate L-alaninatc (ester) and (S-methyl-2-oxo-t,3-di-
oxol-4-yl)methyl
acetonlde isopropylidenedioxy or propanc-2,2-<liylbis(oxy)
_a _ce_ tu
_ ,.,.
_ ta_ _ _ _ _ _ _ _ _ __ _ _N·."._~tylg l yc ina t_e_ _ _ _ _ _ __ __ daropate ( d aprop ate) N.N-dimcthyl-Jl-alanillate or 3-(dimelhylamino)pro-
panoare
aclbutate acetate (ester) and 2-methylpropanoale (estu)
deanii 2-(dimethylamino)clhyl
acistrate acetate (ester) and stcarate (salt)
decil dccyl
acoxll •cctoxymethyl or (acetyloxy)methyl
defalan des-18 -L-phenylalaninc-insulin
alfosce,.,.te (2R)-2,3-<lihydroxypropyl hydrogen phosphate
detemir tc!tlldccanoyl
alideximer poly((ox)12-hydroxyethane-l, l-<liyl)j (oxy[ I ·
(hydroxymcthyl)cthane-1,2-<liyl)} p1nly 0- dibudina.te 2,6-<li-terr-butylnaphthalene-1 S-disulfonate
ethcrificd with urboxymcthyl croups with
some carboxy groups amide linked to the dibunate 2,6-di-tert-butylnaphlhalcnc-1-sul rona10
te!tllpeptidc residue (glyglyglycyl-vphenyla-
lanylglycyl) dielbate dicyclohc>;ylmcthyl carbonate
amsonate 4,4'..<fiaminostilbcne-2,2'-disulfontte or u·- diftitox N-vmethionyl-387-t.-histidine-388·L·1l1ninc- l -
ethenc-l ,2-diylbis(S-aminobcnicnc-1-sul- 3ss-tox in (Cory11•boct•ri11m dipltth<rloe
fouatc) strain C7) (388-+2'}-p<Otein

anlsatil 2-(4-mcthoxyphcnyl)-2-oxoethyl or p-mctho~y­ 2-(2-hydroxyahoxy)ethyl

phenacyl
diofamine 2,2'-az.ancdiytdicthanol or dicthanolaminc
arbamel 2-(dimethylamino}-2-<>xoethyl or <$ter with
IV.N-dimcthylglycolamide doeosil docosyl
argine dofosfate ocudecyl h)'<irogen pho$phate
aritox ricin A chain-MAB '1nmunotoxinc
ecamate N-elhylcarbamalc
upart
edamine ethane- I ~-di:unine or ethylenediaminc
axetil (RS)-1-aceloxytlhyl or rac-1-(acetyloxy)cthyl
edeta.te ethylcnediamine-./VNN '/V~1e1ra-acctate
be I ox ii bcozyloxy
edisilate (ed isylate) ethane- I ,.2-disulfonate
benetonlde N-benzoyl-2-methyl-jl-alanine (ester) and acc-
lOnick: e nibonatG 4,4'-methy lcnebis(3-hydroxy11aph1h1le11c-2-c.ir-
boxylate) or 4,4'-tnetl1ylenebis(3-hydroxy-2-
besllate (besylace) benz.enesulfonatc naph1hoate) (• pamoate)

betadex ll-cyclodextrin enantate (enanthate) hcplanoate

bezomil (l>enzoyloxy)inethyl enbutate acetate (ester) and bulanoale (ester)

budclate 1ro11s-4-butylcyclohcxanccarboxylale epolamjne 1-pyrrolidinccthanol or 2-(pyrrolidin-1-yl)elh•·

11ol
bunapsllate 3,7-di-t<!n-butylnaphth•lenc- 1,5-<lisulfonate
er bumfne re11-butylamine or 2-mclhylpropan-2-arnlne
b uteprate butyrate (estet) and propionate (ester)
esilate (esylatc) etllanesulfonatc
camsilate (camsylato) camphor-10-sulfonate or (7,7-dimelhyl-2-<>xc>-
bicyclo(2.2.l)heptan-1-yl)methan<$ulfONte estolate propanoate (ester) and dodccyl sulfalc (salt) or
prapionatc dodecyl sulrate
eaproate hcxanoate
etabonate (ethoxycart>onyl)oxy (-ethyl carbonate)
carbesilate 4-sulfobe!W)ltt<
etilsulfate ethyl sulfate
ciclotate (cyclotate) 4·mcthylbicyclo{2.2.2)oct·2-ene-1-carboxylatc
fitmesil (2£,6£)-3,7.11-trimcthyldodcca-2,6, 10-trien-1 •
citexetil (RS}-1-{[(cyctohexyloxy)carbonyl)oxylethyl or yl
rac-1- ([{cyclohcxyloxy)cart>onyl )oll.y )ethyl
fcndlzoate 2-(6-hydroxybiphenyl-l-catbonyl)benzoale
cipionate (cypionate) cycloperuanepropionate or 3·cyclopentylpro-
~noate
fostedatc tetradccyl hydrogen phosphate
rac.N-(4- (2-(bis(cerboxymcthyl)amino)·3-( {2·
furet onidc 1-bcnzofuranc•2-urboxylate (ester) and pro-
Ibis( ca rbox yin eth yl)ain ino) ethy 11(car- pane>2,2-<liylbis(oxy)
boxyn>ethyl)a mi no )propyl l phenyl)th iocar-
bainoyl
1amolenato (6Z,9Z, 12Z)-oetadeca-6,9, I 2-1rie0041c
2-(4-ch loropheno~y)-2-mcthylpropyl
\, gtaraine
closllate (elosylate) 4-chlorobcnzenc- l-sulfonalc
ri glueep tate D-glycero-o-gulo-hepianoate or D-giycel"O·D-
t::. crobefate roe- (3·[(3E)-4-methoxybenzylidenc)-2-(4-med1- gulo-hcptooate
oxyphenyl)cJ1roonan-6-yl phospha1e(2-))
glullslne
Tomacate 2-((6-hydroxy-4-mclhyl-2-oxo-2H-chromcn-7-
yl)oxy]acctate g lutamer g lutaraldehydc polymer

-omesllace 6,7-<lihydroxycoumarin-4-onethancsulfonate or guaeil 2-methoxyphenyl

( 6, 7-d ihydroxy-2-oxo-2H- chro n1 cn- 4-
yl)methancsulfonale hemisuccinate hydrogen butancdioole

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

hexacetonide 3,3-dimethylbutanoete (ester) and propan-2,2- pivoxil (2,2-dimcthyl·l -oxopropoxy)me~1yl or ((2.2·

diylbis(oxy) or 3,3-dimethylbulyrate (ester) domethylpropanoyl)oxy)methyl or (pivaloyl-
and a<:etonide oxy)merhyt

hiben:r:ate (hybenzate) 2{4-hydroxybenzoyl)benz.oate poliglumex [poly(L-gtui.mic 1cid~•·&lutam1te-r-estcr)

-poly(L-gluramic acidly) 0
hydate monohydroehloridc hemi-elhanolate hcmihy-
drate probotate 17-(1-oxobutoxy) (ester) and 21-(1-oxopro-
poxy) (ester) or propionate (ester) and bu·
hydroxynaphtoat e 3-hydroxynaplhalcne>2-<:11boJtylate tyrate (csta)
isetiooate (isethionate) 2-hydroxyethane-l·sulfonate proxetil I ·[(isopropoxycarbonyl)oxy]ethyl or rac-l-
{[(propan-2-yloxy)carbonyt)oxy)crhyl
l;a_urate dodecanoatc
raftime:r (2S,4R,6R,8S.l IS,13S)·l,4,8,ll·tctrakis(hy·
la.uril dodccyl
d r oxymethyl)· 4,6, I I · tri s(ylomcthy l) -
dodc:cyl sulfate 3,S,7,10, 12· pcntaoxarctradecane-I, 14-diyl
la u rilsulfate ( la u ryl sulphate)

li.seti1 ~-lysinatc (ester) and diethyl (es1er) saJicylate 2-hydroxybcn1.0ate

lisicol (N-[(5S}5-carboxy·5{3a,7o., I 2a·ttihydroxy· sesquioleate (9Z)-octadec-9-cnoete(l .S)

5 ~ -cholan- 24-am i do )penry l )carbamoth io-
yl}amino soproxil (((propan-2-yloxy)corbonyl)oxy}mcthyl

lispro 28 8 ·L·lysinc-298 -t.·proline ste.agla.te 2-(oe1adccanoyloxy)lec1atc (mer)

mafenatox cntcrotoxin A (227-alanine) (Slap/rylt>C<XXJU stearate

011rna)
stinopra.te N-acc1ykystcin1tc (oalt) and propanoatc (ester)
medoxomil (5-mcthyl-2-oxo· I ,3·dioxol-4·yl)methyl

3,4,5-trimtlhoxybenzoate succinil 3-c.arboxypropanoyl

megallate

meg:l umine N-methylglucaminc sudotox 248-L·histidine-249·L-mc1hionin ...2SO·t.-

alaninc-25 I +glutamlc acid-248-6 13-cndo-
merpentan 4 ,5-bis(2-mercaptoacctamido) valcric acid or loxin A (Ps1udomonos 011n1ginosu reduced)
(N,N-[ l-(3-oxoprnpyl)cthane-1,2·diyl]bis(2-
sul fanylaccuimida10))(4 .) suleptanate monosodium 8-[merhyl(2-sulfoethyl)amino]·8·
oxooctanoatc or monosodium 7·[me thyl(2-
mertansine tctral..is{(4/IS}4((3-{[(IS}2- sulfonatomcthyl)catbamoyl)hepunoyl
{[( IS,2R,3S,5S,6S, 16E, 18£,20/1,2 1S)· I I -
ehloro-21·hydroxy·I2,20·dimcthoxy- sulfoxylate sul fino mcthyl. monosodium salt
2.5,9, 16-tctramethyl-8,23-dioxo~124-dioxa-
9,22-diazatCtlaeyclo[ I 9.3. I . 1 10·".u-~)he.uco­ tafenat.ox enterotoxin A (Slapll)lloe«cus Dkm.s)
sa-I 0, 12.14(26), 16, 18-pentacn·6-yl]oxy}- I -
methy l-oxoothyl)me1hylam ino }-3-oxopro- tartnte (2R.3R)-2.3·dihydroxybU1anedioatc
pyl)disulfanyl]pent.1n0yl}

mesilate (mesylate) methanesulfunate

tebutate tert-butylacetatc or 3,3-dimethylbutyratc

mete.m bonate 4,4'-methylcnebis(3-methoxynaphthalcnc-2-car- tenoate thiophcne-2-carlxlxylate

boxylate)
t eoc.late 8-ch loro- I ,3-dimethyl-2,6·dioxo-J,6-dihydro-
methonitrate N-mcthyl, nitrate (salt) IH-purin-7·(2H)·ide or 8-ehlorothcophyllin-
ate
m etilsuJfate methyl sulfate
teprosila.te 3-(l .J-di01e1hyl-2,6-dio•o· I ,2,3,6-1ctrahydro-
metiodide N-mcthyl, iodide (sail) 7H-purin-7 -yl)p<opanc-1-sul fonatc

methylbromlde N·methyl, bromide (sail) tidoxil roc-2-(deeyloxy)·3{dodccylsulfonyl)propyl

mofetil 2-(morpholino)dhyl or 2-(morpholin-4-yl)ethyl tiuxet:an N-(4-{(2S)·2·(bis{carboxymcthylpmino}-3-

[(2RS)- {2·(bis(carboxymcthyl)1mino]pro-
napadisil>.te niphthalene-1,S-disulfonate pyl}(carboxymcthyl)amino]propyl}pncnyl)
thiocarbamoyl
napsilate (napsylate) napl>thalent-2-sulfonate
tocoferil rac-(2/1)-2,S,7,8-tctramcthyl·2·[(4R,8/1}4,8, J 2·
nicotinate pyridine·3-<:arboxylate trimethyltridecyl)chromon-6-yl
octil OC1)'1 tofesilate 3-{l ,3-dimerhyl-2,6-dioxo-1,2,3,6-tettahydro·
7 H-purin-7 ·yl)ethane· I ·su.Ifonatc
olamine 2-aminoothanol or cthanolamine

oleate (9ZJ·octadcc-9-cnoatc
tosilate (tosylate) 4-methylbenzene-l·sulronatc or tolucnc-4-sul-
fonate .
'.
oxoglurat e hydrogen 2-oxopentanedioa1e
trlclofenate i,4,S-trichlorophcnolarc
palmitatc hexadecanoale
triflutate trifluoroac.etatc
pamoate 4,4'·mcthylcnebis(3-hydroxy·2·n•phthoatc)
.·.
c~cmbonatc) trioleate (9Z)-octadee-9-a>oatc(3) oc uis((9Z}-ocladcc-9- • "·:
enoateJ j ~.;
pegol ci-(2-ealboxyethyl)-<D-mcthoxypoly(oxyethane·

ocla.:. .,;:. .de--

canoa- tc(-3_)_oc_1n_·_s(_oct_•dee_~an"".._(c-).,.·~- - ·.. '. ~~
0
1,2-diyl)

pendetide N"-(N-[2-( {2-{bis(cuboxyrnethyl)amino]-

cthyl }(carboxymcthyl)ami no )ethyl)-N·( car-
t.nst_·_ea_ra_t_•_ _ _ _ _ _ _ _ _ _ _ _
trolamine
-
2,2',2"-nitrilotrieth•nol or triethan~lamioe
•
r
boxymethyl)glycyl}-N'-(N-alycyl-L-lyrosyl)-
L..lysinc
troxundate [2-(2-cthoxyethoxy)elhoxy)aceutc or 3,6,9-tri- )·.
pent exil (RS)· I ·[(2,2-dimcthylpropanoyl)oxy)e1hyl
undecylate
oxaundecanoate

undccanoate
.
.'! : ..
p he npropionate 3-phcnylpropionate .,
undecyle nate undcc-10-enoate ., ! ' '

pivalate 2,2-dimethylpropanoare (ester) or uimethylace-

uitc va le rate pcntanoate

pivoxetil roc-1-{(2·mcthoxy-2·mcthylpropMOyl)oxy)ethyl xinafoate l-hydroxynaphthalcne-2-carboxylate or 1-hy-

or I{2-mcthoxy-2·methylpropionyloxy)ethyl droxy-2-naphrhoatc
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 0 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 *
56 Barium Ba 137.327 94 Plutonium Pu *
84 Polonium Po *
97 Berkelium Bk *
4 Beryllium Be 9.012182 19 Potassium K 39.0983
83 Bismuth Bi 208.98040 59 Praseodymium ?r 140.90765
107 Boluium Bh * 61 Promethium Pm *
5 Boron B 10.811 91 tProtactinitim 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
58 Cerium Ce 140.116 37 Rubidium Rb 85.4678
44 Ruthenitun Ru 101.07
17
24
Chlorine
Chromium
Cl
Cr
35.453
51.9961 104 Rutherfordium Rf ..
27 Cobalt Co 58.933 195 62 Samarium Sm 150.36
112 Copemicium Cn * 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 Dubniwn Db * 47 Silver Ag 107.8682
66 Dysprosium Dy 162.500
II Sodium Na 22.98976928
99 Einsteinium Es * 38 Strontium Sr 87.62
68 Erbium Er 167.259
63 Europium Eu 151.964 16 Sulfur s 32.065
100 Fennium Fm * 73 Tamalur~ Ta 180.94788
9 Fluorine F 18.9984032 43 Technetium Tc *
87 Francium Fr * 52 Tellurium Te 127.60
64 Gadolinium Gd 15725 65 Terbium Tb 158.92535
31 Galliw11 Ga 69.723 81 Thallium Tl 204.3833
32 Germanium Ge 72.64 90 tThorium Th 232.03806
79 Gold Au 196.966569
69 Thulium Tm 168.93421
72 Hafuium Hf 178.49
Hassium Hs 50 Tm Sn 118.710
108 * 22 Titanium Ti 47.867
2 Helium He 4.002602
67 Holmium Ho 164.93032 74 Tungsten w 183.84
1 Hydrogen H 1.00794 116 Ununhexium Uuh *
49 Indium In 114.818 118 Ununoctium Uoo *
Iodine .. 1 126.90447 u~
53 115 Ununpentium *
77 Iridium Ir 192.217 114 Ununquadium Uuq *
26 Iron Fe 55.845 113 Ununtrium Uut *
36 Krypton Kr 83.798 92 turanium u 238.02891
57 Lanthanum La 138.90547
103 Lawrencium
23 Vanadium v 50.9415
Lr * 54 Xenon Xe 131.293
82 Lead Pb 2072
3 :j:Lithium Li 6.941 70 Ytterbium Yb 173.054
71 Lutetium 174.9668 39 Yttrium y 88.90585
Lu
12 ~gnesium 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 "!here 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 Molybdenuin 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 (t) as they do have a
characteristic terrestrial isotopic composition. Commercially available lithium mmate-
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 A

Monographs on Drugs and Ancillary Substances

Analgesics Anti-inflammatory Drugs and Antipyretics
Aspirin and other salicyla1es. p. I Spec.lie paon stztes. p5 Pancreatic pain. p.9
Ois=e-modifying antjrtieYmatic drugs. p. I Bohaty and reNll colc. p.5 Phantom limb pan p.9
Gold compooods. p.I C¥1Cer p;iin, p.5 Posthe<petic neuralgia. p.9
Nons<eroidal <W11i·inf.amma10ry dtugs. p.I Central post-S1l'Oke pair•. p.6 Sickle-cell crisis, p. l 0
Opioid analgesics. p. I Complex regional pain S)'ldrome, p.6 Triger.Wlal neuralgia. p.10
Paracetamol and other para-amnophenols. p.2 Diabetic nellrcpathy. p.6 lncre.sed Boctt Temperature. p 10
Analge9a and Pain. p.2 Dyvnenormoea. p.7 Fever and h)'pefthermia, p I0
Mus:uloskele141 and )oS1I Olsordets. p. 1 I
a
Choice analgesic. p.2 1-teidac~.p.7
Jwenile idopathic: arlhntJS, p.11
Choice a analgesics in chic!""' p.3 Laooor poin. p.7 0.-.eoartl'.titis. p. I l
. ~ bbcks. p.4 I.ON back pail\ p.8 flheunatoid ar11rl.is. p.12
Patiem<om1d.ed analgesia. p.' l'1)0C7<bl infarctCin pan p.B So't-tissue rf>eumatism. p.13
fl>stopes-a;j,.~ ~ p.~ Nairopathic pain~ p.9 ~tl"ies.p.14
Rubefacieru and lopoul ana~ p.5 ()ro(aoal poin. p.9 ~sdisease. p.I~

The drugs described in this chapter are used mainly in the monoclonal antibodies certolizumab (p.1865), riruxi- ~bed in lhis chaptu ~
the relief of pain, inflammation and, in some cases, fe. mab (p.845), and tocilizumab (p.2549), and the inununo- Accclofenac. p. IS Ketop1orcn. p.76
Acemetacin, p.16 Kctorolac:, p. 77
ver. They can be grouped broadly into one of the cate- suppressants azathioprine (p.1977), ciclosporin (p.1981 ), Alminoprofen, p.19 Lioo(elone, p.81
gories briefly described below. cyclophosphamidc (p. 768), and methotrexate (p.817). Aminophenazonc, p.20 Lonazolsc, p.8 1
Ampiro.xie41m, p.20 Lomoxi<am. p.81
Described in Ihis chapter arc Amtolmctin Guacil, p.20 Loxoprofen, p.81
Atx11acepc. p.14 Eiancrccpc, p.S2 Azapropazon<, p.27 Lwniroco>tib, p.8 l
Aspirin and ot her sallcylates Act~t. p.16 Golimumah, p.65 Bcnduac, p.28 Meclo(enamic acid. p.83
Aspirin and other salicylatcs have analgesic., anti-inOam- Adalimumab. p.16 lnnixiinab. p.72 B<:azydaminc. p.28 Mclerwnic Acid. p.83
matory, and antipyretic properties. Like other NSAIDs Anakinra, p.20 LeRunomid<, p.7'J Beca.aminopropionitrite. Meloxicarn. p.84
(see below) they are inhibitors ofthccnzymeeyclo-oxyge· p29 Mo~hu11ZCne, p.90
nase; however. aspirin (though not the non-acecylated sal- Bromfenac. p.29 Morezo1ac. p.90
icylatcs) irreversibly acctylates the enzyme whciea.s other Gold compounds Bu(cxamac. p.29 Mominunv~. p.90
Gold compounds are used mainly for !heir anti-inflamma- Bumadizon., p.29 Nabumetone, p.95
NSAlDs compete with arnchidonic acid for the active site. Carprofen, p.35 Naprox<I\ p.96
Salicylat es arc used for the relief of mild to moderate pain, tory effect in active progressh•e rheumatoid arthritis and O:leco.xib, p.35 Ne,.rcnoc,p.93
minor fcbrileconditions, and for acule and chronic inflam- progressive juvenile idiopathic arthritis; they may also be Oofcxamide, p.38 Niflumic Acid, p.99
matory disorders such as osteoarthritis, rheumatoid arthri- beneficial in psoriatic arthritis. The mechanism ofaction of Oofczonc,p.38 Nimesulid<. p.99
tis, juvenile idiopathic arthritis, and ankylosing spoodyli- C'lonixin. p.38 Oxaproiin, p.110
gold compounds in rheumatic disorders is as yet unknown. ~xibupto(en. p.41 Oxyphenbtrtazone. p. t 12
tis. Some salicylates are applied topically in rubefacient Pnrecoxib, p.116
For fi.niher discnssion ofthe actions and uses ofgold com- Dexl<etoprofen, p.76
preparations for the reliefof muscular and rheumatic pain. Diclofenac, p.46 Phenazone, p.120
Aspirin also inhibits platelet aggregation and is used in pounds, see Sodium Aurothiomalate, p.127.
Dipyronc, p.51 PhcnylbulaZOnc. p.121
cardiovascular disorders. Non-acetylated salicylates do Described in this chapter are Eltenac, p.52 Piketoprofcn, p. I 22
nol have 1tnliplat~let a~tivity. Auranolin. p.26 Sodium Aurothiomal:ite. Epirizolc, p.S2 Piroxicaon, p. 122
Aurochioglu«><', p.27 1~12;
Etodoloc, p.54 Pronopror<n, p. 123
For further discussion of the actions and uses of sali- Aurocioprol. p.27 Sodium A11ro11osulf31c. Etofenamatc, p.SS Proglun>etacin, p. 123
cylates, sec Aspirin, p.21. Gold Kcntuwe, p.65 p.129
E1oriroxib, p.SS Propyph<nazom-, p.124
Felbinac, p.56 rroquuon..p.124
D=ribcd on mis c:hlp<cr ore F<nbufcn, p.57 Raini(<mlOllC, p.124
Aloxiprin.p.19 Lithium Salicylotc, p..81 fcnoprofen, p.Si Rofecoxib, p.12S
A lumin1um Aspirin. p.20 Lysine Aspirin. p.82 Nonsteroidal anti-inflammatory drugs F<ntiozac. p.62 Sulindoc,p.131
Ammonium S.hc:ylal<, Ma~um s.Jic:.ylotc, Nonsteroidal anti-inflammatory drugs (NSAIDs) are a fepradioo~ p.62 Suproft:n. p.133
p.20 p.83 group of structurally unrelated organic acids that have an- Fcp1uonc, p.62 Suxibuione, p.133
Amyl Sah<ylotc, p.20 Mclhyl 611J01isalic)lalc. rirOCOXJb, p.62 Tcnoxia.m. p.133
Aspirin, p.ll p.89
algesic, anti-inflammatory, and antipyretic properties (sec Floc:tafcnine. p.6) Tcpoxolil\ p.134
Bomyl S1hcybl1e. p.29 Methyl Salicylatc, p.89 p. I00). NSAIDs are inhibitors oftlic enzyme cyclo-oxyge- Flufcnamic Acid, p.6) Tctridaminc,p.134
c.rt....... late C.lcium, Morpholinc Salicylate, nase, and so directly inhibit the biosynthesis of prosuglan- flunixin, p.63 Tiopro(enic Acid. p.134
p.35 p.95 din's ond thromboxanes from arachidonic acid (see flurtipro(en, p.63 Tia.ramide, p.134
Choline M•~'nCsium Salamidacetic Acid. p.126 Glucameticin, p.64 Totrcnamic Acid. p.135
Trisalicylo1.. p.37 Solicylamide, p.126
p.2607). There are 2 forms of cyclo-oxygenase (COX), Ibuprofen, p.66 Tolm<tin, p.135
Choline Solicylaic, p.37 Salix, p.126 COX- I, which is the constitutive fonn of the enzyme, and lbuproxam, p.69 Valdt."Coxib. p.138
Diethylamine Salicylluc. Salo!, p.126 COX-2, which is the fom1 induced in the 1>rescnce of in- lndometacin, p.69 Vcdapiofo1, p.13S
p.49 Salsalale. p.126 nammation. Inhibition ofCOX-2 is therefon: thought to be lsonixin, p.75 Zohoprofen, p. IJ8
Oifluuisol, p.49 Sodium Salicyla1c. p.129 K<buzone, p.76
Edten7.omid<, p.54 Sodium Thiosolicylote,
responsible for at least some of the analgesic, anti-inflam-
Ethyl Solicylote, p.$4 . p.129 matory. and antipyretic properties ofNSAJDs whereas in-
fos(osal, p.64 Thurfyl Salicylate, p. I )4 hibition of COX- I is thought to produce some ofthcirt0x- Opioid analgesics
Cil)'col Sahcylatc. p.64 Trolamin. Sali<ylalc. ic effects, particularly those on the gastrointestinal tract. Opioid analgesics include the opium alkaloids morphine
lmidazole S.hcyllll<. p.137 and codeine: and thdr derivatives as well as ~-ynthetic ~b­
p.69
Most NSAIDsavailable for clinical use inhibit both COX-
! and COX-2. althougb some ~loctive COX-2 inhibitors stances with agonisi, partial agonist, or mixed agonist and
such as celecoxib arc also marketed. antagonist activity al opioid receptors (see p. I05). The
Disease-modifying antirheumatic drugs tcnn opiate analgesics refers only to those opioids derived
NSAJDs are used for the relief of mild to moderate pain. fi'om opium, or their scmisynthetic congeners. The term
Disea~-modifying antirheiiniatic drugs (DMARDs) have
minor febrile conditions, and for acute and chronic intlam- narcotic analgesics bas legal connotations and is no longer
anti-inf1amma1ory 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
cytokines. They are used in the treatment of rheuonatoid 1is, juvenile idiopathic arthritis, and ankylosing spondyli-
Most opioids are used as analgesics, and morphine is the
arthritis and juvenile idiopathic a1thritis; some are also of tis. Indometacin and some olhcr NSAIDs arc used lo close standard against which all other opioid analgesics are com-
benefit in ankylosing spondylitis and psoriatic arthrilis. patent ductus arteriosus in premarure neonates. Some pared. Opioids such as codeine are used in the treatment of
Many DMARDs also possess other therapeutic properties NSAIDs are applied topically for the relief of muscular less severe pain, and are oflen combined with non-opioid
and are used in non-rheumatic conditions. The DMARD a11d rheumatic pain.and some are used in ophthalmic prep- analgesics such as aspirin, other NSAJDs, or paracetamol.
gold is referred to below; other DMARDs include sul- arations for ocular inOammatory disorders. Aspirin (see More potent opioids such as morphine arc used in severe
fasalo:.::ine (p.1928), penicillamine (p.1 598), the antimalar- above) is considered to be an NSAID, although it also has acute and chronic po in. including cancer pain. Some opio-
ials chloroquine (p.652) and bydroxychloroquine (p.657), other properties. ids such as codeine, morphine, and diamorphine are al!:O
All cross-references refer to entries in Volume A
2 Analgesics Anti-inflammatory Drugs and Antipyretics
used as antirussives, although the latter two arc usually re- respond to low intensity or innocuous stimuli; central sensiti- niques such as acupuncture, spinal cord stimulation,
served for use in terminal lung disease. Some opioid analg- sation also occurs. Pain associated with tissue damage hence and tra nscu taneous electrical nerve stimulation
esics such as fentanyl and its congeners are used mainly as results in increased sensitivity ofthe sensory system so that the °(TENS) arc also used.
adjuncts to anaesthesia; some of these may also be used in pain can OCCI.- in the absence of a clear stimulus. Pain that oc-
higher doses as the sole anaesthetic drug. cur$ due to a stimulus that does nol us\llllly provoke pain is 0 G<:ncral references to pain and iis mana1:emen1.
tenned ol/odynio; this applies to conditions such as sunburn, I. Mclzac.k R. \Vafl PO. P.a1n mech1nisms: a new 1hcnry. S<ienc~
Some opioids are rarely if ever u~ as analgesics and are l96S; ISO: 971-9.
.described elsewhere; they include the antirussives dex- inflammation, and trauma that may result in sensitisation of 2. Jntcmational Association fot the Srudy of Pain. Clas.sification of
tromethOJphan (p.1694) and pholcodinc (p.1710), and the the skin. Hypero/gesio is defined as an inaeased response to a chronic pain: descriptions of chronic r-in syndromes and defi·
slimulus lhat is usually painful. Hyperoes~ia is an increased nitions of pain terms. Poin 1986; (suppl 3 ~ S l-SllS.
antidiarrbocals dipheno'(ylate (p.1875) and lopcramidc 3. Lewis KS,., ot. Elfcct of U1Jlgcsie tre•tnlcnt on the physiolog-
scnsiti>~ty to s1imulation, excluding the special senses and in- tct:I conscquence.s of acutt patn. Am J Hrup Pltorm 1994; S1:
(p.1893).
cludes allodynia and hypcralgcsia. Hyperpothia is character- lS39-S-4.
Opioids ean produce physical dependence and withdrawal ised by an abnonnally painful reaction 10 a Slimulus. particu- 4. Lotscr JD, Mclzack R. Pain: 1n 4"'crview. Ll11JUI 1999; 3S3:
symptoms if suddenly stopped. They are also subject to larly a repetitive stimulus, and may occur with allodynia, 1607-9.
abuse. S. Ashburn MA, S1aau: PS. Mana,gement of chronic pain. LtlJJc-el
hypc111lgcsia, or hypcraCSlhesia. 1999; 353: l 86S-9.
Described in this chaplcr MC 6. Woolf<:J. Mannjon RJ. Ncuropathic pain: 1c1iology, symptoms.
Pain is often classified as being acute or chronic in na- mechanisms., and ma111gcmenl. Lanett 1999i 35.J: 1959-64,
Alfcnlallil, p.I 7 Lcvocctylmethodol, p.80
Anileridine, p.21 Lcvomcthadone, p.80 ture. 7. C.rr DB. Goudas LC. Acute pain. L<»tell t999; 353: 20Sl-8.
8. C.rvcro F, Laird JM. Viscorol poin. lonc11 1999; 35.l: 2145-&.
BuprenO<phine, p.30 Levorphanol, p.80 • Acute pain is associated with trauma or disease and 9. American Soc;iety of Ancs11lcsiologists Task Force on Acute
Butorphanol, p.33 Mepta7-inol, p.8S usually has a well-deftned location, character, and Pain Man3g-cmcnt. Pni.c1icc guidcline1 for acute pain manage·
Carfenlanil. p.3S MtO»done, p.86 mc'u in the perioperati\'e senina: an updated report by 1hc
Codeine, p.38 Morphine, p.90 timing. It is accompanied by symptoms ofautonom- American Society of Anc.sthcsiotogim Task Force on Acute
Oextromoramide, p.41 Nalb<Jphinc, p.9S ic hyperactivity such as la.chycardia, hypertension, Pain Man1gemenL Anesihuiolow 2004; 100: 1573-81. Also
Oexaoprnpoxyphene, p.4 I Ni<omorphine, p.99 availJbfc at: hnp:l/www.as.ahq.org/publicationsAndSuvicesl
Diamorphinc, p.43 Opium, p.109
sweating, and mydriasis. pain.pdr (ac:ccsscd 23/06i08)
10. Gordon DB. et ol. American Pain Socie1y recommendations for
Oihydn>a>deinc, p.SO Oxyoodonc, p. I JO • Chronic pa in is usually regarded as pain lasting improving the: quality of acute and c::anoer pain m&na&cmcnt.:
Dipipaoonc, p.S I Oxymorphonc, p.111 more than a few months. It may not be clearly asso- Am«icm Pain ~iety Q.»>J;1y of Ca~ Task Foree. Atdt tntun
Ernbuti3mide, p.52 Papavamim, p. J()I) M•d 2005; 165: l S74-80. Also l\'li l1blc II: http://
Ethoheplarine, p.S4 Penw.ocinc, p.117 ciated with trauma or disease or may peISist after the archinte.a.rna-assn.orglcci/rcpr1nt/l 6S/l '1,/J S74 (1ccuscd
Elhylmo<phine, p.S4 Pethidine, p. I l 8 initial injury has healed; its localisation, character, 2JJ06/0&)
Elorphine, p.S6 Pinrnmide, p.122 11. Spacek A. Modem concepls or.cute and chronic pain man.agc-
and timing are more vague than with acute pain. Fur- ment. Biom<4 Pbarmaco1h<r 2006; 60: 329-JS.
Ftn131lyl. p.58 Rtmifcnunil, p. l 24
Hydrochloridos of Mixed Sufmtanil, p. I 29 thennore, as the autonomic nervous system adapts, 12. !'!:~~~1~:$~~~tACJ~:12oQ1;'~~~a~:f!m.Ms to pain man-
Opium Alkaloids, p.109 Tapen1adol, p, l 33 the signs of autonomic hyperactivity associated with 13. European As.sociation ofUrolOJ.Y. Guidelines on pat.in manage ..
Hydrocodonc, p.6S Tilidine, p. 135 acute pain disappear. Some fonns of pain regarded mc.n1 (is.sued March 2007). Av:ul:abJe 11:
Hydromorphone, p.66 Tr•m•dol, p. J36
as being chronic may consist of intenninent attacks htlp://www.uroweb.org/fileadmin/user upload/Guidelines/
2 l_P1in_Management_:!007 .pclr (oece.sed 23/06/08)
Ketobemidonc, p.76 Trimcpcridine, p.137
ofpain followed by relatively long pain-free periods. 14. Brcnmn f-1 CJ al. Pain maim1g.ement: • f\indamcnual human right
llnuth Anolg 2001; I OS: 205-2 1.
Patients with chronic pain have physical, psycholog-
is. ~aJ7~~d~~f's~:r:1~~~Gu~~:1i~: f:l~~~io~~:i.r~~"~al:
1
Paracetamol and other para-aminophenols ical, social, and functional deterioration which con-
Paraceiamol is the principal para-aminophcnol derivative f~~i;:j_~r>-anacslhesiology doctors. Eur J AnautMs;o/ 2007;
tributes towards exacerbation of the pain.
in use. Acet.anilidc and phenacetin have generally been re-
placed by safer analgesics. Propacetamol is hydrolysed to Physiologically, pain may be divided into nociceptive 16. Manehika.ntiL. ~,al. Evidence.-bascd inicrvcntional pain man-
llgtmenl: principles. problems. potcnt•al and applications. Porn
paracetamol in the plasma. pain and neuropathic pain. PhyJicion 2007; 10: 329-56.
Paracetamol has analgesic and antipyrclic properties and • Nociceptive pain follows activation of nociceptOIS
17. Cawky 0. Brn..:11 M l. M>nagement or pain. Br J Horp M<d
2009; 70: 197-201.
weak anti-inflammatory activity. The mechanism ofanalg- by noic.ious stimuli as described above but is not as-
esic action remains to be fully elucidated, but may be due sociated with injury to peripheral nerves or the CNS.
to inhibition of prostaglandin synthesis both centrally and Choice of analgesic
It may be somatic or visceral, depending on which Paracetamol and NSAJDs are the first choice analgesics
peripherally. Paracetamol is used for the relief of mild to
receptors or nerves are involved. Somatic pain is for treating mild to moderate pain and arc also used in
moderate pain nod minor febrile conditions.
usually well localised and may be described as deep- moderate to severe pain to potenliatc the effects ofopioids.
Described in this cliaplcr.,,,
Aoctanilide, p.16 Phcnace1in, p.120
ly located, sharp or dull, nagging, stabbing, throb- They are suitable for use in acute or chronic pain. Effective
Paracetamol, p.112 PfO!lOCCWllOI, p. I 24 bing, or pressure-like. Visceral pain is generally less reliefof acute pain can be achieved with oral NSA!Ds and
localised and more diffuse than somatic pain and with paracetamol (particularly in combination with an opi-
Analgesia and Pain may be referred 10 remote areas of the body. De- oid-see below). Dependence and tolerance are not a
Pain is defined by the International Association for the pending on the siructure involved it is variously de- problem with non-opioid analgesics but they have a rather
flat dose-response curve: as the dose is increased, the in-
Study of Pain as 'an unpleasant sensory and emotional scribed as deeply located, aching, nagging, cramp-
crease in pain relief may be quite small. Aspirin and other
experience associated with actual or potential tissue ing, or pressing and may be accompanied by nausea non-selective NSAIDs inhibit blood platelet function, ad-
damage, or described in terms of such damage.' and vomiting. Nociceptive pain usually responds 10 versely affect the gastrointeslinal tracl, and can precipitate
Under norm31 cin:umstinces pain is the result ofstimulation of treatment with conventional analgesics. hypersensitivity reactions including asthma. The risk of
peripheral receptors that tn111smi1 impulses through pain path- • Pain resulting from damage or dysfunction of pe- severe upper gastrointestinal adveJSC effects may be less
ways to the brain. Pain rcceptOrs or nociceptors are oftwo ba· ripheral ncrvcs/receplors or of the CNS is known as with selective inhibitors of eyclo-oxygenase-2 (COX-2)
sic l)lpCS: neuropathic pain (or neurogenic pain). The tenn such as the coxibs, but their use has been greatly restricted
• medronoheot naptors have a high stimulation threshold by concerns about serious cardiovascular effects. Para-
covers sympathetically maintained pain including
and respond to intense or potentially damaging noxious cetamol does not have the haematological or gastrointesti-
causalgia and reflex sympathetic dystrophy, and nal adverse effects of aspirin but large doses can produce
stimuli. These receptors arc as.~ociated with rapidly con-
ducling, thinly myelinated A6 fibres, and their stimulation painful conditions such as postherpelic and trigemi- severe or sometimes fatal hcpatotoxicity. Giving paraceta-
produces rapid sharp localised p~in that serves to activate nal neuralgia, and diabetic neuropathy. Ncuropalhic mol with an NSA ID improves analgesia.
withdrawal reflexes pain associated with centra l nervous 1iss\te, such as For the treatment of moderate or moderate lo severe opio-
• polymodal naciceptors respond lo mechanical, them1al, or in central post-stroke pain (the thalamic syndrome) id-sensitive pain codeine is the traditional choice; allema-
chemical insults. These receptors are also activated by cel- is referred to as central pain. The clinical signs of 1ives include dihydrocodeine and tramadol. They are of-
lular comJl<lnenls that arc released after tissue damage. neuropalhic pain can vary greatly. Some of the more ten given with non-0pioid analgesics. Combinations of
Their impulses are transmitted slowly along unmyelinated common features include heightened pain sensitivity codeine with paracetamol al full doses produce a small but
C type fibres and produce dull, aching. and poorly localised and sensations of superficial burning or stabbing significant increase in analgesia compared with paraceta-
pain with a slower onsel (lancinating) pain. The pain may be associated with mol alone and are one of the mOSl effective options for
Nerve libres from nociceplors tcmuna1e in the dorsal root of acute pain, but the incidence of adverse effects increases
areas of sensory deficit or some fonn of autonomic
the spinal cord before uansmissioo by ascending pathways to with repeated use. Combinations of dcxlropropoxyphene
instability. Neuropathic pain responds poorly IO con- with paracetamol or aspirin are no more effective in acute
the bra.in. There have been many theories on the proc:es:sing of
pain signals at the spinal level but the 'gate theoty' proposed ventional analgesics and can be difficult to treat. pain than the non-Opioid alone; efficacy in chronic pain is
by Mel;zacl; and Wall is one of the best known. This lheo<y Early treatment of pain is important as unrelieved unclear and advesse effects may become troublesome. The
pnsrulates that the trwmission of impulses to the brain is pain can have profound psychological effects on the EM£A has recommended that oil dcx1ropropoxyphene-
modulated by a gate mechanism in the substantia gelatinosa. patient, and acute pain that is poorly managed initially con1aining preparations be no longer available in the EU
Stimulation of small fibres opens the gate and facilitates trans- can degenerate into chronic pain, which may prove to because of the risk of toxicity in ovcrdosage; such prepa-
mission whereas stimulation of large fibres, which nonnally rations may remain on the market in other countries.
be much more difficult to treat It is imponant to assess
carry non-painful sensory input, can close the gate and inliibit More potent opioids such :is morphine are mainly used in
transmission. Traosmission also appears 10 be modulated by and treat the mental and emotional aspects of the pain
the treatment of severe acute non-malignant pain and can-
several other mechanisms which can influence the sensitivity as well as its physical aspects. Although drug therapy
cer pain (sec below). Their use in chronic non-malignant
of the g;ite. is a mainstay of pain treatment (sec Choice of Analge- pain is somewhat conlTOversial bcalusc of fears ofpsycho-
Inflammatory mediators such as bradykinin, hisla.mine, serot- sic, below), physical methods such as physiotherapy logical dependence and respiratory depression. However,
Clllin, and prostaglandins produced in response to tissue dam- (including massage and the application of heat and in practice such problems rarely occur and those fears
age can produce peripheral sensitisation so that receptors cold), surgery, and nervous system stimulation tech- should not prevent patients being given effective analgesic
All cross-references refer lo entries in Volume A
 Analgesics Anti-inflammatory D11Jgs and Antipyretics 3
tl1erapy. Opioids may also be of value in neuropad1ic pain Miscellaneous drugs. After the discovery that epidural or since it was widely believed that neonates were incapable
in some palienis. intrathecal injection of opioids can produce effective of feeling pain.
Morphine is the opioid of cl.1oice in severe pain. It is ab- analgesia many other drugs have been tried by these Non-opioid analgesics are used in i11fa11ts t111d chiltlre11,
sorbed when given orally and has a short half-life so that routes, either alone or with opioids or local ana~thetics, either alone for minor pain or as an adjunct to opioid analg-
the use of immediate-release oral preparations offers a but their role, if any, in the management of pain is wiclear. esics in severe pain,4'6 (they can reduce opioid require-
flexible means of dosage titration in, for example, pallia- Some, such as clonidinc and ketamine, also appear to have ments.'-' perhaps by up to 40%5). Paraceiamol is frequent-
tive care. Once initial pain relief has been achieved, use of analgesic properties whe.n given by other routes, and keta· ly used but it lacks any anti-inflammatory effect NSAIDs
a modified-release preparation every 12 or 24 hours is mine may be useful in reducing opioid requirements. such as ibuprofen are useful for minor pain,4" especially
more convenient for maintenance of analgesia in severe Some antiarrhythmics (including systemic lidocaine) may when associated with inflammation or trauma. T1lC use of
chronic pain. II may also be given parcntcraUy (e.g. for be effective in chronic neuropalhic pain, but must be used aspirin is greatly restricted by its association with Reyc's
control of acute severe pain in emergency departments or with extreme caution. The use of antipsychotics, such as syndrome.
in paticnt-comrolled analgesia-see also below), or rectal- the phenothiazines. as adjuvant analgesics is controversial; The opioids are still the mainst.ay of analgesia for moder-
ly or transdermally, where there would be problems with levomepromazine is sometimes used as an adjunct in pal- ate to severe pain in paediatric patients, and morphine is
the oral route. liative care. tl1e standard against which the others are compared. It is
Occasionally other oploids may be useful. Switching to See below for discussions of the use of patient-controllod given intravenously for rapid relief of severe pain (for ex-
an alternative opioid may be effective in patients who have analgesia. and rubefacicnts and topical analgesics. Neivc ample after bums, fractures or other injuries), and is titrat-
inadequate pain control or intolerable adverse effects with blocks are discussed under Pain, on p.2014. ed to achieve a suitable analgesic dose."6.8.Y Where intra-
morphine. Methadone (which also acts as an NMDA an- References. venous access is not readily achievable, oral morphine
tagonist) or oxycodone have a longer duration of action I. S:iwynok J. Ph:1m1acologicil rationale for the clinical use of may be given but its onset is slower and less predictable;
than morphine, but it should be noted that melhadone, etffcln<. On.gs 199S; 49: S7-SO. some favour intranasal diamorphine as an alternative to in-
2. Watson CP. The 1TC3tmenl or neuropathic s»in: 11ntidepttisants
which has a long half-life, should not be given more lhan ind opio1ds. C/i11 J Pain 2000; 16 (wppl): S49..SSS travenous morphine.• Continuous intravenous morphine
twice daily when used long tenn because of the risk or pro- 3. Curatulu M, Svclicic. G Orvg combinations in p3un uca1mtnl: a infusion with or without initial loading doses has become
gressive CNS depression and overdosagc. A rapid onset of rC\lirw of the published evidence :and a medlOd for finding th~ popular for postope!11tive pain relief.'' but titration of the
op1imal comb1nauon. Best PraCI Ra c1;,, A1KJC'Jlht.siol 2002~
action is provided by alfentanil and fentanyl but use of 16: S07-19. infusion rate is necessary to achieve a balance betwee'1 an-
pethidine is no longer recommended. Diamorphine or hy- 4. Mc:Qu:ty HJ. Ncuropalhic: ptin: cvidt11CC' m:mc:rs. £"" J Pnm algesia and respiratory depression (particular care is need-
dromorphone may be preferred to morphine when the 2002: 6 ("'ppl A): II-I&. ed in neonates, see below). Subcutaneous infusions of
S. Anonfmous. Acute pain (Ba~icr Exlra. issued Februal)'
parenteral route has to be used because they are more sol- morphine have also been used,s mostly for the reliefofiec-
uble and can be give.n in a smaller volume. Tramadol, LOOu!r~:d~!~i~~~~~~;:Ct.J~~i)c.vk/bandolier/ minal cancer pain in children. Intramuscular injections arc
which may impair respiratory and gaslrointestinal function 6. B•ll1n1ync JC, M•o J. Opioid lhenlpy for chronic pain. N £1>1/ painfuJ8• 11 and therefore probably only suitable for short·
J Mtd2003; 349: 1943-Sl.
less than other opioids at equianalgesic doses. is also of tenn use. Fentanyl has also been wide~ used for short·
benefit in neuropathic pain. 7. ::i~k:~!1,;.:S~~~:;;p!~He!~~~ ~~'2003:ol: 'f"~~rhie tenn analgesia in surgical procedures, ·9• 11 • 1 ~ and other
8. McQu.oy 1-i . Pai" and its conltol (iSS\lcd Isl January, 2004). opioids such as buprenorphine, hydromorphone, oxyco-
Adverse cffec1s of opioids include sedation, nausea, vom- Av11il11ble a1: hltp:/lwww.medicine.ox.ac.uklbandolicrlboo1h/
iting, constipation, and, most seriously, respiratory depres- p•iopag/wisdom/C 13.hinil (accessed 26111/09) done, and tramadol have been given.s Patient-controlled
sion. Tolerance generally develops to all of these effects !), The CoUcgc or Emergency Medicine. Clinical EfTcc1ivencss analgesia using morphine (see below) has been tried in
Commiuee guideline for the managt'ment of p1in in 11duhs children.
except constipation, which may be prevented by regular (2004). Available al: hup://www.collcmcrgcn<ymcd.ac.uk/asp/
use of laxatives. doc:11mcn1.asp?t0•4t93 (accessed 26111109) Morphine has also been given 10 children by the epidural
10 A11at N, ~101. Systemic IKlocainein pain dut' 10 pe.riphcr•I nen·c: route;9 experience with the intrathecal route is more limit·
Some other groups of drugs have significant roles in pain inj11ry1nd prcdicton ofrespons<. N<uro/1>gy2004; 62: 218-2S.
management either alone or as analgesic adjuvants. 11 . Qui&lcr, C. Opioid' switchin~ ro improve pain relief and drug ed. Other methods of opioid drug delivery of possible val-
1ok:r1btlity. Available •n The:""Cochrane 0.1abase of Systematic ue in paediatric anal~esia include transmucosal,7·12 na-
Subantidepressant doses of tricyclic antidepressants Reviews; ls.sue J. Chichuter: John Wiley: 200.t (accessed sal,'.& and transdennal .io dosage.
(usually amitripl)lline) are considered to be useful in re- 2~1).
fractory cluonic pain, including ncuropathic pain of the t2 R11hm<n JP, et al. The rote ofinlralll<cal dnip 1ft !he 1r..11Mnl Cancer pain in children may be tteatcd using the analgesic
of 1cu1c pain. A,..,th .~nolg 200~; tot (5Uppl): S30-SO. ladder scheme described under C:inccr Pain (see below).
burning. dysaesthetic type such as postherpetic neuralgia 13. Avs1nli1n and New Zc-aland College or Al\leslhcli.sis and fac>
and diabetic neuropathy; shooting pain has also been re- uJty or Piin Medi('inc. Aculc 1>1in management: S<"ic:-ntirtc cvi· bl.baled nitrous oxide and oxygen mix1ures may be useful
ported to respond. 111ey may be used in addition to con- dcncc. 2nd ed. 200S. A'-"ailable 3t: hllp:!/www.1nzc~.edu.;1u/ for preliminary pain relief and short, painful proce-
ventional analgesics, notably in the treatment of cancer ;~~;~;),/books·:and-publications/:icu1cp1in.pdf (acCC$$cd dures.<.J.9,11
pain of mixed aetiology.111ere is linlc evidence for benefil 14. Ei.s.cnbcrJ E. et al. Efficacy and sorety of opioid 1~onists in the Local anaesthetics are especially sui1able for lhe manage-
in acute puin although musculoskele1al pain has some- 1rc:ument ofncuropathic pain ofnoom.ali~ant origin: 1ys1cma1 .. ment of acute pain in day-care situations. Single injections
ic l'C\'icw ond meu1-an;:ilysis of randormud eon1rollcd trial$,
times responded. Amitriptyline has also been found to be JAMA 200S; 293: 3043-52. given by the epidural route arc oflen used to provide analg-
useful for tension-type he;idache and for the prophylaxis of IS. Davis MP, t:I ol. Controversies in pham1aco1hcnipy of ~in m:.n. esia during and after surgery. Con1inuous epidural infu-
migraine. The role of other antidepressants in the treat· agcment /..tmer.1 (}l;oo/ 2005; 6: 69~704 . sions of local anaesthclics have also been used. However,
16. Nicholas MK, c1 al. Using opioids wi1h pcrsistin¥ nollCrrnccr
ment ofneuropathic pain is less clear although venlafaxine pain: o biopsychosocial pcrspcc11ve. C/111 J Palu 2006; 21: simpler teclmiques such as wound infiltration or peripheral
may be useful. IS7--t6. nerve blocks can also provide effective analgesia for some
17 McQuay HJ, Moore R.A. Do:se-respon.st in di~cl comparisons procedures and are free of the problems of lower limb
Antiepileptics (often carbarnazcpine and, more recently,
gabapentin and prcgabatin) have been found useful in the ~:.=>' i:~~,:~p!~~~~~~0Sec,~,.nc;,r:~:c~l:J~~~;; weakness or urinary retention associate~ with caudal
relief of neuropathic pain, especially w'heo there is a stab- 271-$ blocks.s.&,9.ll Application of eutectic creams (sec Swface
18- Knodco\"":) H. f>appog3llo M. Adjuv:ine anal1csics. Anc.s1h~1iol Anaesthesia, p.2027) containing lidocainc with prilocainc
bing (lancinating) element, as in trigeminal neuralgia; Cli• 2007; 25: nS-116.
there have also been reports of efficacy in the treatment of l9. Tame-he$ E. t'I al. Acute pain in adulisadmiued to the: tmtrgrn· to intact skin, to produce surface anaesthesia, may be suf-
diabetic neuropathy and for migyaine prophylaxis. ~~.:~::s.d;,~~oI:;;~:;.~?;~;;~~j~ or abbreviated ficient for some minor painful procedures in chil-
drcn.i..10.12
Beozodiaupincs and other muscle relaxants such as ba· 20. AUSlra1;111 and New Zc:aland Collete of Anat1thc1is1s and Fae·
clofen or dantrolene are useful for relieving painful museI.: u1ty of P:tin Medicine. Aculc p1in managCl1'1C111: "icntifie cvi· Ketamine is used in outpatients for brief, painful procc-
spasm in acute or chronic conditions. dcncc. Update to 2nd t-d. Dccc-nlbcr 2007. Av1ilablc 11: http:// dW'CS such as fracture reduction and to provide immobility
www.1:1nzca.cd u.a u/rcsourcc: s/books· 11 nd-pu bl ic 11 ions/ for repair of facial lacerations in young children.6•12·i:; The
Bone modu lating drugs such as calcitonin and bisphos· acu1ep:iin_upd>1c.pdr(occe.. cd 23/06/08)
21. Guin~on J, Cf al. Rcccn1 adlfanccs in 1he pharmacolo;icol u1an- emergence reactions that limit its use in adults are less
phonat~ may be usel\Jl in cancer pain arising from hone ctg(.tncnt of pl'in. Drr1gs 2001; 67: 2 12 1-,;. common in children,12 and can be ameliorated by benzodi-
metastases (see below) but have a slow onset ofllclion and ll. Gh~roor VL. Cl al. Jntrnthccal dru' lherory ror Ions-term p;1in azcpines.8·11
are second choice to NSAIDs. Bisphosphonatcs may manag:cmcnl. Am J H~o/1li-S.vs1 Phnrm 2001; 64: 2447-61.
cause an initial transient increase in bone pain. 23. Seidel S. er of. Amipsychotics for acute and chronic ~in in Most 11eo11a1es requiring analgesia and receiving respira-
~.1~~!~·; 1;~:~~b~ 'C~~~~!~:r J~h~'te~:;;o~grs'(~:~~s~eed
3 tory support can be managed witl1an infusion of morphine
Caffeine has been used with the aim of enhancing the ct~ but in neonates who are breathing spontaneously there is a
26111/09).
fects of non-opioid and opioid analgesics but is of debata- 24. Vc«lu 8. ('/ Ctl. AmCdcpicssanlS for 1hc 1ratment of chronic substantial risk of respiratory depression. Morphine has
ble benefit There are similar doubts about whether caf- p•in. Drugs 200S: 68: 2611-32. been used in such neonates9 but should be limited to those
feine enhnnces the effect of erg0tamine in the treatment of lS. Britit.h Pain Society. lnltathtcal dNI dehvery r0t 1hc manait-
mc::nt or pain and spastie:ity in aduhs: reco-1nmcnd.1tions ror best under intensive care, as for c."<amplc after major surgery
migraine (see Pharmacokinetics, p.675); it may also add to clinical practice (is.sued Augus.1 2008). Available al: htlp:// (see also Intensive Cate. p. I059). Fcntanyl citrate1and co-
gastrointestinal adverse effects and in large doses can il5Clf ~;;r~)tishp.ainsocicty.orglbook_1ttd_main. pdf (accessed deine phosphate have also been used in neonates. Sucrose
cause headache. and other sweet taSting solutions ha\'e been shov.n to re-
l6. Barbtr JB. Gibson SJ. TreatnlCnl or chronic non-malignant pain
Corticosteroids have produced improvement, oflco sub- in the elderly: safety considcr:uions. Dms Safory 2009: Jl: duce physiologic and behavioural indicatoI> of stress and
stantial, in ncuropathic pain. They can also relieve head· ~57-7~.
27. British Pain Society. Opioids for pcrsistem p:ain: good pr3clicc
pain in neonates undergoing painful procedures10 although
ache caused by raised intracranial pressuream.I refractory (i:.sued fanuuy :!0 10). Avait1bJc a1: there had been some doubt expressed over whether this in-
pain caused by bone metastases, and have the added bene- http:J/www.brilishpainsociety.org/book_opioid_main.pdf (ac- dicates effective analgesia. 14 TI1e Ameiican Academy of
fits of increasing well-being and appetite. ce•scd lS/04/tO) Pediatrics has suggeMod that oral sucrose together wilh
Some inhalational anaesthetics are used in subanaes1hct- other non-pharmacological methods such as swaddling
ic doses as inhalation analgesics for acute pain. In particu- Choice of analges.ics in children should be used for minor routine procedures; topical local
lar, nillous oxide is given witl1 oxygen for pain relief in Pain has often been undertreated in infants and children anaesthetics may be used for tnorc painful procedures such
obstetrics and during dental and od1cr procedures, and in because of fears of rcspirato1y depression. cardiovascular as venepunclw'C if titne pennies. Opioids should be tbe ba-
emergency management. lsollurane, cnfiurane, and in collap5e, depressed levels of consciousness, and addiction sis or postoperative analgesia after major surgery in the ab-
some countries mcthoxyf1UI3ne or trichloroethylene have with potent opioid analgesics. Assessment of pain is also a sence of regional anaesthesia; a rapidly acting opioid such
been used similarly. problem in children of all agesH and it is not that long as fe.ntanyl is advocated, together with infiltration of the
4 Analgesics Ant i-inflammatory Drugs and Antipyretics
site with a local anaesthetic where time pennits, for inser- improvement in analgcsia;6.7 There is also a greater risk of sive surgery usually require parenteral opioids or local an-
tion of a chest drain.15 Similar recommendations for pain- adverse effects, including rcspiiatory depression.2 .3.7 Jt re· algesic techniques such as regional block, sometimes .in
ful procedures in neonates have been made by an interna- mains to be seen if there is any advantage with the more combination.3
tional consensus group. 16 sophistieatcd devices that can be programmed 10 adjust the • Opioid analgesics, in particular morphine, are the
The use of analgesic adjuvants (see Choice ofAnalgesic, background infusion according to the frequency of the bo- mainstay of treatment for moderate to severe postoper-
above) has also been advocated in some childrcn. 17 lus demands.6. 7
ative pain. 3 Opioid dose should be individually titrated;
l. Amaiun Academy of Pediatrics rnd Canadian Paediatric Soci• Most of the common opioids have been used successfully they may be given by several roules, bu! intravenous
cry. Prevention and management of pain and stress in the nc. for PCA.2 Morphine remains the gold standard, and fenta-
onate. Pedit1tric:1 2000; JOS: "454-6 1. Also available at: doses give more predictable results than intramuscular
hnp:l/aappolicy.aappublica.tions .org/cgi/rcprintlpediatrics; JOS/ nyl, hl'lromorphone, or tramadol are widely used alterna- or subcutaneous doses and are widely favoured.2,3,IOIn-
2/454.pdf (accessed 2 3/06/08) tives. .3 Use of pethidine is no longer advised because of travenous patient-controlled analgesia (see above) is
2. American Ac.ademy of Pediatrics Comminec <m P~ychosocia l the risk of accumulation of its toxic metabolite, norpethi-
ASpeGlS of Child and Family Health, American Pain Society now a standard method of management for postopera-
Task Force on Pain in Infants, Children, and Adolescents. The dine.2 Drugs with very short (remifentanil) or very long tive pain.3·4 Where it is unavailable, intramuscular or
a~sessment and management of acute pain in infants, children, (methadone) half-lives may be less suitable for use. subcutaneous dosage every 2 hours as needed for 24 to
and adolc:scenls. Pedlatrics 2001; 108: 793-7. Also available al:
http://pedi3trics.aappublicatioos.orglcgi/rcprintll08/31793.pdf Although generally perceived as safer lhan conventional 72 hours, followed by conversion to an oral analgesic
(accessed 23/06/08) opioid analgesia, occasional serious adverse effects and fa- regimen, may be an alternative.' Careful monitoring for
3. Maurice SC. er of. Emergency analgesia in the paediatric popu.. ta.lities have resulted from errors in progr.unming, or in-
l:>tion (.Pin J): currcril pr:1ctice 3ni perspectives. Emcrg Med J potential adverse effects, in particular respiratory de-
2002; 19: 4-7. correct or inappropriate use (including operation by per· pression, is needed.3
4. The College of Emergency Medicine. Clinical Effec:ti"eness sons other than the patient). These risks can be minimised
Committee guidellnc for the mar:agcmcnt of poin in children by safety features built into the PCA device itself, and by Opioids injected centrally via the _epidural and intrnthe-
(May2010). cal routes provide effective regiona'. analgesia2,4 •10 (and
Avai lable at : ht1p://secure.collc mergencymed.ac.ukh1.sp/ the develofiment of standard protocols for the usc of the
documcntasp?IDft4682 (accessed 20/08110) technique. may be more effective than intravenous opioids, 11 al-
S. Morton NS. Management of poMopcrative pain in children. though whether this improves the ultimate outcome is
Arch Di< Child Educ Proct Ed2001; 92: cpl~pl9. Most experience rel ales to the use ofthe intravenous route. unclear'). Morphine is the opioid most commonly given
6. Atkinson P, et al. Paln ma1111gement and sedation for children in However, epidural PCA is also used. It appears to be as centrally, but others such as fentanyl, which is more lip-
the emergency department. BMJ20{19~ 339: I074-.9. effective, or more effective, than intravenous PCA,2.3 al-
7. Berde CB. Selhna NF. Analgesics for the uea1ment of pain in id soluble, may be preferable in the ease of epidural in-
children. N Eng/J Med2002; 347: 1094- 1103. though it may not be suitable in all cases, and carries addi- jection. The epidural and intratheca I routes have also
8. Maurice SC, et of. Emergency analgesia in lhe paediatric popu- tional risks to do with the placement of the epidural cathe-
Jation (pan JI): phannaoo l ogi~t r.iethods or pain relief. Emerg ter.3 Epidural PCA generally produces analgesia with a been used for patient-controlled analgesia.
MedJ2002; 19: 101-S. Oral opioids may not be suitable in the immediate post-
9. Aldec Hey Royal Liverpool Children's N HS Trust Guidelines combination of a lipid-soluble opioid such as fentanyl or
on 1he m3nagemenl of pain in chiidren. 1s1 ed, 1998. A\'ai1abJe sufentanil plus a long-acting local anaesthetic such as operative period, but oral regimens are generally pre-
at: hHp://painsC'lurccbook.cal;>drs1pps55.pdf (accessed bupivacaine or ropivacaine; the optimum combination has ferred if the patient can swallow and gastrointestinal
23/06/08)
10. Zcmps.ky WT: et al. Reliefofpnio and anxiety in pediatric pa- yet to be defined.)·3 Jn addition, unlike intravenous PCA, function has recovered.1•3 Tramadol is useful in patients
1ients in emergency medical system$. Pediatrics 2004~ 114: the usc of a background infusion is reconunended. undergoing minor or intermediate surgery.3
1348-56. .
11. Harvey AJ, Monon NS. Management of procedural pain in chi I· Other routes have been investirited, including inttaoasa1 7 Management of postoperative pain in patients who have
dren. Arch Dis Child Educ Procr fd2007: 91: ep2~p26. and, in particular, !rnnsdermal .s PCA. An iontophoretic been receiving long-tenn opioids before surgery may be
12. Krauss B. Green SM. Sedation and an3lgesia ror procedures in patient-<:<>ntrolled delivery system for traosdermal fenra- particularly difficult.3• 12 Baseline requirements should
cl>ildr<.n. N Engl J Med 2000; 34?: 938-45. nyl that allowed PCA to be given in a non-invasive manner
13. Howes MC. Kcraminc for paediatric sedationfanalgcsia in the be calculated for each patient, but may go up or dov.n
e mergency department Emcrg M<d J 2004: 21: 27S-SO. was available;8•9 however, this was withdrav.n from the after surgery; typically, at least 50%ofthe baseline dose
14. Slevens B, t i of. Sucrose for analgesia in nrwb<.>m infants un- market because of a defective delivery system. will be needed postoperatively, with additional opioids
dergoing painful procedures. Ava·lablc in The Cochrane Data·
base of Sysicm:ahc Reviews; Issue 3. Chichester. John Wiley; Although it is not always considered in terms of PCA, in- titrated according to pain requirements. Such patients
2004 (acGC$sed 23/06/08). haled nitrous oxide in oxygen also has a long history of may thus require larger than nonnal doses of opioids to
JS. American Academy of Pedia1rics Committee on Fccus and New- effective use as a patient-controlled analgesic during child- be given, and a balanced multimodal approach to analg-
born 3nd Stclion on Surgery, Can~dian Paediatric Society Fetus
and Newborn Commitlcc. Prevention and management of pain birth; opioid PCA may not be suitable for such pain al- esia is particularly important.1 2
in the neonate: in update. Pl!diatn°cs 2006; 118: 223 1- U. Cor· though local anaesthetics have been usod with satisfactol'y • NSAJDs and paracetamol are u.ieful analgesic ad-
rection. ibid. 2001~ 119: 425. results.'°
Also avoitable a1: http://pedi:nrics.aappubhca1ions.org/cgi/ juncts that can improve pain relief,3 but are not suitable
reprinl/1I8/S/223 I .pdf (acccsS<:d ZJ/06/08) J. Walder D, et ol. Efficacy and safety of patient·controHed opioid alone after major surgery. 2 After minor or intermediate
16. Anand KJ; International Evidence-Based Group for Neonatal anaJge:sia for acule pos1opcra1h·e pain: a quantitative systemalic
Pain. Consensus ~tcmenl for tht: prevention and management review. Acto Anoe<rhesiol ScQnd200l; 4S: 79S-804. surgery an oral regimen of paracetamol plus an NSAID
of pain in the newborn. Arch Ped;otr Adolc~c Med 2001; 155: 2. Gr~ss JA. Palicnt-conirollcd analgesia. An~sth Anofg 2005; JOl such as naproxcn may be adequate, with oxycodone or
113-80. Also available at: hnp:t/archpedi.ama·usn.org/cgi.I (suppl): S44-S6 I. tramadol being given for breakthrough paio. 3 NSA!Ds
rcpriol/1SS/2/173.pdf (accessed 23/06/08) 3. Momeni M, er al. Patienc-controllcd analgesia in the manage-
J7. Chambliss CR. ct of. The assc:ssmenl and management ofchron- ment of postoperative pain. D,.ugs 2006; 66: 232)-37.
can be used effectively with other drugs, and use of an
ic pain in chi1dten.. Poediotr Drugs 2002; 4: 737-46. NSAJD with an opioid after major surgery enables the
4. Hudcova J, Cl al, Patient controlled opioid analgesia versus con-
ventional opioid analgesia for pos1operativc pain. Available in dose of the opioid to be reduced wilhout loss of analge-
The Cochrane Database of Systematic Rc...; ews; Issue 4. Chich- sic effect. 1• 5•16 However, tl1e risk of gastric ulceration,
Nerve blocks ester: John W iley; 2006 (accessed 23/06/0&).
For a discussion of the use of nerve blocks in the manage- 5. Bainbridge 0 , ff ol. Patient.controlled versus nurse contcolled
0
impaired coagulation, and reduced renal function may
ment of pain, see under PaiJ1, p.2014. aoolgcsia after c:ardi0c surgery-a meta-analysis. Can J Anaes1h limit the use of NSAJDs in some patients,3•10 and the
2006: 53: 492-9. potential cardiovascular effects of the selective inhibi-
6. Mac inlyre PE. Safety and effic:acy of p:itient-<::Ontrolled analge- tors of cyclo-oxygenase-2 (COX-2) have also been a
Patient-cont rolled analgesia sia. Br J Anoesth 200 1; 81: 36-46.
7. Lehmann KA. Recent developments jn patient·contro11cd anal- cause of great concern.3
Patient-controlled analgesia (PCA) involves the use of au- gesia. J Pa;n Symptom Manuge 200S: 29 (suppl): S72-S89.
tomated delivery systems that enable patients to receive Diclofenac, flurbiprofcn, ketoprofen, ketorolac, lomox-
3. Sinalra R. The fcntanyl HCI pa1ien1-controlled transdermal sys-
doses of an analgesic on demand. The technique is now tem (PCTS): an allernative 10 intravenous pa1icnt•corurolted an · icam, and naproxen are among the NSA!Ds used for
widely favoured in the management of acute pain, 1·3 and algesia in the postoperative setting. cu,, Phtrrmoco/t.inet 2005; postoperative pain; the COX-2 inhibitors including
44 (suppl J); 1-Q. parccoxib have also been used. Diclofenac, ketoprofen,
appears to produce slightly better analgesia, and greater 9. Eberhart L. ·rhc ~afcty and tolerability of the fcnt;myl HCI ion-
patient acceptance, than comentional analgesic meth- tophoreiic transch:rmal sy'$tem: an alternative 10 currcntty avail- ketorolac, and parccoxib may be given by injection, and
ods.4.l It has been used successfully in children as young able analgC"sic modalities. J Opioid Manog 2001; 3: 249-56. a parenteral fonnulation of parncetamol is available in
as 4 years, and in elderly patients.6 Most experience relates to. van der Vyver M, et ol. P:uient·controlled epidural analgesia some countries.
versus continuous infusion for labour analgesia: a mcta ~ analy·
to systems using intravenous opioids. sis. Br J Anoesth 2002; 89: 459-6~. • Infiltration oflocal anaesthetics atthe site ofoperation
Initial analgesia must be established by giving the patient is a simple method of preventing postoperative wound
bolus doses of the analgesic, to achieve effective blood pain. 1·• Central nerve blocks obiair.ed witl1 epidural or
concentrations.l,3 In the simplest type of PCA the patient Postoperative analgesia
intrathcx:al local anaesthetics produce excellent analge-
is then able to self-administer a small fixed dose on de- Pain relief after surgery has often been inadequate and it is
sia,1.2.• although again, whether this improves outcome
mand; further doses are not permitted until a pre-pro- now recogi1ised that pain control should be adjusted for
each patient and each situation .1·3 Multimodal regimens, is unclear. 2.3 Insertion of a catheter during the operation
grammed lockout interval has expired. TI1e demand dose allows subsequent infusion or bolus injection. 10 Howev-
should be large enough to produce an appreciable analge- using several classes of analgesic, and ideally more than
one route, are now generally favoured.3·5 Pre-operative er, there may be complications related to botl1 the proce-
sic effect, but not large enough to lead readily to toxic con- dure and the drugs used (see also Adverse Effects of
centrations; the lockout period should also be long enough evaluation of the patient,2-4 and frequent assessment of
pain intensity after surgery (both to allow appropriate an- Ceorral Block, p.20 JI). Local anaestl1etics arc rarely
for the maximum analgesic effect to be felt before another used alone, as a mixture of an opioid and a local anaes-
dose is pennined, and should therefore relate to the speed algesia, and to dlltect possible complications)3 are funda-
mental. Evidence-based procedure-specific guidelines thetic produces effective analgesia using relatively
of onset of action of the drug.2 Some devices allow the smaller doses of each drug.10 Such combinations are
dose to be given as a short infusion2 to reduce adverse ef- have been issued.6•7 Giving pain control on a preventative
basis (pre-emptive analgesia) has been recommended, and also used in patient-<:antrolled epidural analgesia (see
fcx:ts associated with high peak concentrations of opioids.
may be more effec1ive than conventional management, at above).
In another comroooly used me\hod, sometimes described
as patient-augmented analgesia, the patient is given a con- least for some regimens, although results have varied. S,9 • There is growing interest in the use of analgesic adju-
tinuous background infusion which is supplemented by Patients undergoing minor surgery can be adequately man- vants, including antiepileptic~ such as gabapcntin or
self-administered bolus doses. 2 •3·6 However, with this aged with oral analgesics, such as pardcetamol, NSAIDs, pregabalin,13 or the NMDA antagonist ketamine, 14•15 to
method patients may receive J10re opioids without any tnunadol, and oxycodone. Those undergoing more exten- modulate opioid dosage and efficacy for postoperative
All cross-references refer 10 entries in Volume A
 Analgesics Anti-infl2mmatory Drugs and Antipyretics 5
pain. (ror funhct discussion of analgesic adjuvants see Local anaesthetics are sometimes included in topical malignancies, but in up to three-quarters of those with ad-
Choice of Analgesic, above.) preparations used for the relief of puinful skin ond muscu- vanced disease.
I. Shan.a AB. 0An TJ. Optimiiing poscopcntivt pain m11.nas:emcnt loskeletal disorders. Pain relief involves the treaunent of the cause of the pain
io lhc ambul;1tory pauent.. Druv 2003. ,3, 8SS-67. Application of heat to the skin can also help to relieve pain as well as treatment of the pain itself, together with expla-
2. Rosenquist RW, Rosenberg J. Unittd St.alts Ve1crans Adminis- and melted hard paraffin has been used in w!IX baths as an nation, reassurance, and supportive care to improve any
tra1ion Postoperative pain guidelines. Rrg An~sth Pain Med
2000: U: 279-88. Also available at: adjunct to physiotherapy for painful joints and sprains. mental and social complicating factors. TI1e mainstay of
http://www.oqp.mcd.v:a.gov/cps/PA IN.IPA IN_ bue .h1m (oc· Wann kaolin pouhices have also been used as a means of cancer pain management is drug treatment with non-opio-
cessed 23~6!08)
applying heat for pain relief. id or opioid analgesics, or both together, plus adjuvant an-
3. Myld PS. Power I. Chnic1I update: poS'lOptt'ati\.~ an.alicsia.
lancer 2007; 369: 110-12. 1. ArgoITCE. Topical "&Cnts ro, the 1reatmcntofchronic 1>1in. C1ll'r algesics if necessary. A small proponion of patients (about
4. American Society of AMSthesio l ogin~ Task Force on Acu\e Pofo Heodoch. Rep 2006; 10: 11-19. I0 to 20"/o) may have pain that responds poorly or not at all
Pain M:tn:.gtmtnL f>tactiec g-uidclines rot DCUIC pain ma.n~gc­ 2. S:i..,..')'nok J. Top.cal and peripherally acling: a.n.algc1tcs. Phanno~
col R<v 2003; SS: 1-20.
to opioid analgesics given at tolerable doses, e.g. neuro-
menl in the pcriopc-raih·ir: setting: an updated report by the
AmcriC11n Socie1y or Ancsrhesiolog.ists Task Force on Acute 3. Manhcws P, t-1 al. Topia:I rubefacien1s for acute and chronic pain pathic pain resulting from nerve deSIJUction or compres-
P>in M•no;tmenL Ancsthniolt>gv 2004; 100: 1573-81. Also in adults. A\•t:ihiblc: in The Cochrane o~uab.asc ofS)'$lcnutic Re:- sion, incident bone pain, pancreatic pain, and muscle
:atailab1c at: h11p://www.as:ahq.org/publ1c111ionsAndServiccs/ views~ lnue 3. Chichuter: John Wiley; 2009 (accc:ucd
spasm.
p1in.pdr(1cc<sscd 23/06/08) 26111/09).
S. Elia N. ~ ul. Docs inultimodlll a.n1l1cs&a with aeelaminophc.n, • . Mason (.., el ( If. Sysicmllic rev~ of topical caps;i.icin for 1hc Jn die management of cancer pain the aim is to achieve
nonsteroidal :intlinfl:.1mm:uory dNp. or selective cyc1ooxyg<:n· treatment of chronic pg.;n. BAU 2004; 328: 991"""4. adequate continuous pain relief with the minimum or ad-
o~t-2 inhibiLQn. and paticnt•COtmolled analgesia morphine offer S. Mason L. et al. Topical NSAIDs for chronic mu5culoskc1ctol YClSC effects and this calls for appropriate assessment of
edventa~s over morphine alone? MeUi-•natyscS of randomized pain: systematic review and me\l·INl~i~ BMC Musculoskrlrt
trials. AM>thuiolo:r 2005; 103: 1296-1304. Disortl~ ~ 5: 28. A'- :.ihtblc: at: http:ll'A-ww.biomedcentral.coinJ
1 the intensity and quality of pain, and regular monitoring of
6. The PROSPECT Wor1cina Group. PROSPECT: procedure spe- 14 71-2474/S/28 (OCCC1$Cd 23/06/08) the treatment. Guidelines for !be reliefof cancer pain, pub-
c ific poSlopentivc pain m3nagement. Available at: 6. Massey T,ct al. TOPJCll NSAID&for acute pein in adults.. Avail. lished by WHO in 19861 and revised in 1996,2 arc widely
h:tp:l/www.pos\Oj)pail\.0<8 (a«essed 26111/09) able in The Coduane Oatab;:ise of Sysl'-mattc Reviews; Issue 6.
or
7. Associatioo P1cdialric Anaqtheti.sts. Oood prar.tice in post- ChichoMer: Joh11 W.ley; 2010 ( acccmd 20/08110) endorsed by ~cialists in pain relief and the care of the
opet:llivc and J'lrocedunl pain (iasucd 200S). Av~il2ble 2t: tenninally i113' despite some questions aboot the robust-
h11p·//www.bri1ishp.ainsoc-it.ly.or1/book_1pa_p1rtJ.pdf (ac- ness of supponing studics.1 Subsequent guidelines issued
cc.ssed I 5/0411 0} Specific pain states by the Scottish Intercollegiate Guidelines Network8 in
8 Ona CK..S, el al. The efficacy or preemptive analgesia (or acute
posiopenti"·e pain mantgemcnt: :11 meta-.analysis. Am!sth Anolg Biliary and renal colic. Gallstones (see Ursodeoxy- 2008 and the British Pain Socicty9 in 2010, and the annu-
200~; 100: 7S7- 73.
cholic Acid, p.2647) or Olhcr biliary disorders that result in ally updated guidelines of the US National Compfellen-
9. Orapc S. TramU MR. Do we need prcmipti\·e anal~sl111 ror the sive Cancer Netwotlc (NCCN)10 are also available. Specif-
trcatmcnl of po.saopctativc pain? Btll l'roct Res Clin A110,JllH1- obslruction of the bile ducts may produce biliary col.ic.
ic guidelines for die relief of cancer pain in children have
siol 2001; 21: Sl-<13. Morphine may relieve the accompanying pain, but as it
10. Brown AK.~ ol. Sttattcies (or postoptr1.tive pail\ rN~cmcnt. also been published. 11
can also produce spasm of the sphincter ofOddi it can raise
Bes1 Pro~t Rn CJlnAnuCb,hesiol 2004; 18: 70)-17. intrabiliary pressure and exacerbate the pain. It is therefore Treatment should be given regularly, orally ifpossible, and
11. Block BM. Cl al. Etrteacyofpostopef3ti\'e eridure1 anal:fl:ia: a should follow the accepted three-step ' analgesic lad-
m<ta·•nolysiL JAMA 2003; 290: 24SS-03. usually recommended that morphine and its derivatives
12. JamC':S C, Wijljams JE4 How should posiopen11ive. pa.in ift pa.. should either be avoided in patients with biliary disorders der' .1.l This approach is often described as treatment 'by
11e11u on lon~·l<nn opioids bt m.>naaed? Br J 11.,p Mb/ 2006; or that they should be given with an antispasmodic. Histor- mouth, by the clock, and by the ladder'. Regular dosage
67: soo. mther than treatment as required aims to prevent pain re-
ically, pethidine has been regarded as a more suitable
13 QQhl JB. 1r nl. 'Protective premtdicuion': an optior1 wic.h emerging and to minimise the expectation of pain. The an·
pbaptnlin :ind rchncd druas'? A tt"'iew of gahapcntin and pre· choioe because it was thought 10 have Jess smooth muscle
gibalin in the 1rc.11mcn1 ot'pos..c>ptnrive pain. Aclo AnfJt.srh._ activity than morphine; however, this has been questioned. algesic ladder consists of 3 stages, treatment beginning at
siol Sctmd2004; 48: 1130-<I. Prostaglandins have 3lso been implicated in the aetiology step I and progressing lo step 3 if pain is uncontrolled or
14. S1.11>ramaniam K. ~t al. Ke1uminc as adjuvant analscsic LO opio· increases. The stages are as follows:
ids: a qu.antit~i'#C end qualitative S)'Stcrn11ic review. A1umh An~ of biliary colic and NSA!Ds such as diclofenac or ketoro-
olg 2004: 99: 482-95. lac have been successfillly used to relieve the pain.1•3 An- I. a non-opioid analgesic such as aspirin, other
15. Bell RF, tt al. PeriopcnliYc kc1amin¢ fOI' acute pos,&operotive timuscarinic antispasmodics have been aied for their ac- NSAIDs, or paracetamol; an adjuvant (sec below) may
pain, Avai11bl¢ in The Cochr.sn~ Otital-ase or Sys:~ma1ic Re·- tion oo biliary smooth muscle and the sphincter of Oddi. also be given if necessary to taeklespecific pain or asso-
views; Jnuc L Chichester: John Wiley; 1006 (accessed
23/06/08). Urctcral obstruction, such as in the formation and passage ciated symptoms
of renal calculi (see p.2383). produces painful renal or 2. an opioid analgesic such as codeine, dihyclrooodeine,
urcterol colic.+4 The acute pain of renal or ureter.ii colic or tramadol plus a non-opioid analgesic; an adjuvant
Rubefacients a nd topical analgesia has been traditionally relieved using opioid analgesics may also be given
Substances applied topically can relieve local pain through such as pethidine that were thought to have a minimal ef-
several different mechanisms.' Rubefacients or cowitcr- 3. a potent opioid analgesic such as oral morphine; a
fect on smooth muscle, although lllOlphine has also been non-opioid analgesic may also be given, as may an ad-
irritan1s can relieve superficial or dcq>-seated local pain used.'6 However, opioids, and especially pethidine, are
probably by producing counter stimulation, which accord- juvant.
particularly associated with nausea and vomiting, 5·1 and Combining analgesics with different phacmacological ac-
ing to the 'gate theory' of pain (sec Analgesia and Pain, NSAlDs arc increasingly used in their place; they appear
ahove) helps to inhibit the transmission of pain signals. 1ions can produce additive or synergistic increases in
to be at leasl comparable with the opioids in tenns of effi- o.nalgesia but only one analgesic from each of the 3 groups
Their topical application produces hyperaemia or irritation cacy.•·1 111ey can be given intramuscularly, intravenously,
of the skin and they are used alone or as an adjunct to mas- (non-<ipioid, less potent opioid, po1en1 opioid) should be
orally, and rectally, although the best route is unclear.5.8 Di- used at the same time.
sage in rhc management of a variety of painful muscu- clofonac sodium given intramuscular16 is recommended
loskel.:tal condilions.1 Some are also 1raditionally used in as first-line treannent by some authors. Parenteral keioro- Evidence to support the choice of analgesic is often
preparations for the symptomatic relief of minor peripher- lac also seems to be effective. 5 The use of intranasal scanty. A systematic review12 found some evidence of
al vascular disorders such as chilblains. Substances com- desmopressin has also been studied.4·l benefit from the use ofNSAJDs 10 treat cancer pain, and
monly used in r ubefacient preparations include nicotinate supponed their use in mild pain (WHO step I), but there
I. Aktivi.adis EA,('/ ol. Treatment ofbihary colic wilh diclofeMc:
and salicylate compounds, essential oils, capsicum, solu- a randon1iud, double-blind, placcbo-QM\uuUcd l:iludy. CttllJt>~11- was little to suppon the choice of one NSAID over anoth-
tions of ammonia, camphor, and nonivamide. However, a rerolof.v 1997; 113: 225- -31. er, and little evidence for the addition of an opioid to an
systematic review3 concluded that the evidence did not 2. Dula OJ, #I al. A pro!>pective study companns im kctorolac wilh NSAID in moderate pain (WHO step 2).
im mtperidinc in the trea.hncnt of acute biliary colic. J £metg
support the use of rubefacient preparations containing sal- M•d2001; 10: 121-1. Jn moderate to seve1·e pain (WHO step 3), morphine is
icylate compounds for acute musculoskeletal pain. and 3. HenderSon SO. a al. CompArison of intr•\·enou:s kctOfolac ind generally held to be the opioid of choice;5 alternatives in-
suggested that their effic:icy compnred poorly with topical mcpcridine in the m:-a1mcnl or bil iary colic. J Eu~rg },kd2002: clude fen1anyl, hydrocodone, and oxycodone.5.S.•0 Mixed
NSAlDs for chronic musculoskeletal pain; no evidence 23: 237-4 1. •
°"· Shokc:it AA. Rc:nal cohc: new concepts related to pathophysiol- opioid agonist-antagonists may precipitate withdrawal
was found to support the use of rubefacicnt preparat.ions ogy, diagnoiis and uc1tmcnl. U1rr Opi11 Urot 2002; I2; 263-9. symptoms in opioid-dependent patients; opioids with long
containing other substances. Capsaicin, which is one of S. Heid F. Jnge J, The trt::tlmtnl of pain in urology. BJU lttt 2002~ half-lives (such as methadone or levo1phanol) are also less
the active ingredients of capsicum, is used ~lone as a topi- 9t: 48 1-8. suitable for treatment than pure opioid agonists with less
cal analgesic in a range of painful conditions. including 6. Writh4 r J, e1 Q/, Man.,ging acute renal colic ocross the prin1ary-
sccondaty ctirc intcrracc: a ptthv.-ay of c.arc bJ.SOO on ~vidcncc prolonged actions..•0 In patients who do not achieve effec-
neurop:uhic p:lin 3ud rheumatic disorders; its benefits arc •nd con..nsu•. BM./ 2002; 31S: 1408-12. tive analgesia al an acceptable level ofadverse effects with
modest though it may be useful in some patients.4 It does 7. Hofdptc A. Pollock T. Non-stcro1d2.I 1nt1-inOammatory druss one opioid, opioid rotation, switching 10 an alternative
not rely on vasodilatation in the skin and it is therefore not (NSAIOS) versus opioid$ in 1hc truuncnt of acute ren:sl colic. opioid at an equivalent dose, may enable pain con-
considered to be a traditional counter-irritant. :\vailablc in The Cochrane Da\lbase: ofSystcma-tic Rcvicw1: lli·
sue I. Chidl....r. John Wiley; 20CM <accessed lJ/06/08). rro1.s.10.11
Some NSA£Ds have been used topically in 1be u-eatment 8. Lte C. et of. Rtteal Of intnwenous non·steroidtl anti·inn:1mm•· The optimal route for use is oral dosage. For best e!Tect,
of soft-tissue injuries and inOanunatory musculoskeletal tory drugs in acu1c ru.I colic. Emtrg MedJ 2005; 21: 65l-4.
both conventional (for dose tilr3tion) and modified-release
conditions, although this route does not necessarily avoid Cance r pain. The pain cancer patients have may be (for maintenance) dosage fom1s are required. The Europe-
the adverse effects of systemic treat ment. There is acute, chronic, or in1ennittent. It may result from rumour an Association for Palliative Care (EAl'C) suggests5 that
evidenc;eS.6 to suggest that topical NSAIDs are more effec- involvement of the viscera and extension into soft tissues, the simplest method of dose titration is with conventional
tive than placebo. tumour-induced nerve compression a11d injury, raised in- morphine dosage every 4 hours, and the same dose for
O ther agents used as topical analgesics include com- traeranial pressure, or bone metastases. Pain may also arise bccakthrough pain. TI1is 'rescue· dose may be given as of-
pounds such as ethyl chloride and the halogenated hydro- as a result of adverse effects of treatment, or from a con- ten as required, up to hourly. 111e tot.al daily dose of mor-
carbon propellants; their evnpora1ion produces an intense current disease, and may be exacerbated by emotional or phine should be reviewed each day and 1he regular dose
cold that numbs the tissues. Transdennal clonidine has mental changes. Many patients will have more than one adjusted to take account of the amount needed for break-
been used in the treatment of chronic pain. Ke1amine also type of pai!). There may also be exacerbations due to through pain. If pain returns consistently before the next
appears to have some local analgesic effect when applied movement (incident pain) or worsening ofcancer. pain oc- dose is due the regular dose should be increased. Conven-
topically. 1 curs in about a quarter of patients with newly diagnosed tional formulations do not generally need to be given more
6 A nalgesics Anti-inflammatory Drugs and Antipyretics
uflen than every 4 hours, and modified-release products as should antiemetic therapy; sedation and nausea usually C omplex regional pain syn drome. Complex re·
should be given according to the intended duration of the become less marked as treatment progresses,s and warront gional pain syndrome (CR.PS) is a regional, post-traumatic
preparation (usually every 12 or 24 hours). Patients stabi- reassessment if they persist for longer than a week. 1 Con- ° neuropathic pain that generally affects the limbs. CRPS
lised on regular oral morphine require continued access to cerns about respiratory depression and dependence should bas also been referred to as reflex sympathetic dystrophy,
a rescue dose for lxeakihrough pain. For patients taking not be allowed to interfere with appropriate treatment: pa- post-traumatic dystrophy, causalgia, Sudeck's atrophy,
conventional morphine preparations every 4 hours, a dou- tients whose pain ameliorates can generally reduce and and shoulder-hand syndrome. Causalgja has also been
ble dose at bedtime is effective to prevent pain disrurt>ing stop opioid treatment without difficulty. s used to describe the burning pain that follows a penetrating
sleep. I. WHO. c-., poin r<li<f. Gene,·o: WHO, 1986.
l . WUO Concv f"'I• rdk/. 2nd ed. Gcnc'-a: WHO, 1996.
injwy. Historically, it was considered that the pain was
Similar recommendations arc given by the NCCN. 10 They 3. Amcric111 Soc1rty of An..lhcsiologim T•sk force on Pam
maintained by the sympathetic nervous system and the
advise that the oral rescue dose for breakthrough pain M1n.a4emtnl. Conca Pam Section. Practic-e @uidelines for an· tenn 'reflex sympathetic dystrophy' was commonly used
should be calculated as l 0 to 20"/o of the total 24-hour re- """"&•mtnt.
cer P.lln Anesthesiology 1996; 84: 120-$7. Also to describe the syndrome (although recent srudies have
av111tb1t 11: hup://'NWW. a ~hq.orgtpublicalionsAndScn1cu/ shown that the sympathetic nervous system is not always
quirement; this may then be increased by 50 to IOO''lo in cancer.html (acc:cssc<I 23/06l08)
patients who still have increased pain, with hourly reas- 4. Portcnoy RK, Lesage P. Management of cancer pain. J,onctr involved). However, the temlS given above are now con-
sessment of efficacy and adve~ effects. If inadequate re- 1999; 353: I69S- 1700. sidered to be inappropriate and CRPS is now broadly clas-
S. H1111ks GW, 11 al. Expert Working Group of Ille Research Ntl·
sponse is still seen after 2 or 3 cycles, a change of route work of tile European A5sotiation for falliati\'c Care. Morphine sified as:
(e.g. intravenous titration) may be considered. and elcem1tivc opioids in cancer pain: the EAPC rccommcnda· • Type I: (previously reflex sympathetic dystrophy)
If patients are unable to take morphine orally the EAPC lions. Br J Ca11c«r 2001; 84: 587-93. Also J\!::tilable at: hup:J/ which develops after tissue trauma, such as that accom-
www.eepcnct.org/download/forPublicationsfBJC_Enalish.pdf
considers the preferred alternative route to be subcutane- (accessed 23/06/08) panying myocardial infarction, stroke, bums, frostbite,
ous,s and the NCCN suggests either continuous garenteral 6. European Society for Medic.al Oncology GuideJines T3sk Force. fractures, and shoulder or limb injury, but where there is
infusion, intravenous, or subcuianeous dosage. 1 There is !~~r~~:~';a~l.i~:! ~:~~~~a:~(!u~;I ~: i'SJ~ij$: no identifiable nerve lesion
no indicatioo for intramuscular morphine for cancer pain Also avaitable 11: hnp://annonc.oxfordjoumals.org/cgilrt.prinll • Type II: (previously causalgia) which develops after
since subcutaneous dosage is simpler and less painfuI.5 In l6/•vppl_l /i&J.pdf(1«esscd 23/06.'0S) trauma to a major peripheral nerve
7. Mcrcodanlc S, l'ulfaro f . World H..lth Orgoniution gvidcli•u
the UK diamorphine hydrochloride is often preferred to for c111CU p11n: 1 ruppni..I. A•• Onco/ 200S; 16 (•uppl 4): Clinically the two subsets arc ideotical o.nd typical symp-
mmphine sulfate for parenteral use because it is more sol- iv132-iv13S. toms include pain, allodynia, and byperalgesia; as the syn-
uble and allows a smaller dose volume. Hydromorphone &. Sconish lnttrcollrcgiatc Guidelines Nc1v;-ork. Control of pain in drome becomes chronic, trophic changes to the bone, mus·
1duhs with c:Ulccr: a national clinical guideline (iS'SUCd No"e:m·
hydrochloride is an alternative to diamOJphine. bcr 2001). An iloble at: hllp://ww•·.sign .1c. vk/ pdfl cles, and skin may occur. Sympathetic dysfunction may
Epidural or intrathecal opioids, either by injection or infu- SIGN106.pdf(ooc:cssed 2611tl09) also be present Jf the pain is relieved by a sympathetic
9. British Pa.n Society. Cancer pain management (is.sued January
sion, have been used when conventional routes have 20•0), Available 11: http://www.britishpainsoc:ictv.ors/ block (see below), this pain is regarded as 'sympathetical-
failed. 10.14 Some advocate the use of these routes because book_~ncer_pain.pdf(accustd 20/04110) • ly-maintained', ifnot it is known as 'sympathetically-inde-
smaller doses may produce analgesia equivalent to that of 10. National Comp.-chcnsivc Cancer Network. Clinical prac1kc pendent' pain.
guidelines in onc.o1ogy: adult cancer pain (version l.2010).
larger doses given orally or parenterally, although there Availablo 11: hnp:/lwww.ncxn.orgfprofcssiomlslphyaician..alsl The treatment of CRPS is difficult especially in chronic
has been little conclusive e\1idence for a lower incidence of POF/paln.pdf(a«tsS<d 16/08110) disorders and is usually aimed at pain control and restoring
adverse effects or a better quality of analgesia. I l · ~~ l~j.fQ:'J99r.'n rttliefo,1dpo/liot~"'-e co1·e in children. Gene· limb function. The cornerstone of treatment is physiother-
The buccal, sublingual, and nebulised routes have been in· 12. McNicol E. er of. NSAIDS or parace1amol. alone or combined apy, with pain relief provided in order to allow physical
vestigated, but these are not recommended for morphine with opioid.s. (or eancer pain. Available in The Cnchrane Data· exercise. Patients with mild disease may not requite pain
base of S)•s.cmatic Reviews; Issue 2. Chichester; John Wiley:
because there is no current evidence of clinical advantage 200S (accessed 23/06/08). management; those with moderate pain should be tried
over com·entional rou!Cs.s However, buprenorphine is giv- 13. Vielhabcr A," of. Advances in cancer pain management. H~­ with a tricyclic antidepressant, an antiepileptic such as
en sublingually and may be a useful alternative in patients motol On<ol C/i" Nor1b Am 2002; 16: S27-4 I. gabapentin, or a less potent opioid. Oral or intravenous bis-
with dysphagia, although experience of loog-tenn use in 14. =~~~· =:;~b~C:~~~~ c:r!i%c:.~~~ phospbonates have also produced some promising results.
cancer pain is limited. Transdermal opioids are an alcema- with pain dlH: to cancer. Available in The Cochr"Jne Database. of A sympathetic nerve block with bretylium or perhaps a lo-
tive to oral morphine in patients whose pain and opioid re- Syskmllic Reviews; Issue 2. Chicheslcr. Jolin Wiley; 200S (••· cal anaesthetic may be useful in carefully selected patients
ecucd 23.'06!08)
quirements are s1able.u.1o Buprenorphine or fentanyl can 1S. Skaer TL Practice guidelines for uan:sdermal opioids in mali1· with sympathetically-maintained pain; those who do not
be given via a transdennal system that provides continu- nanl poin. Dnlp 2004; 64: 2629-3&. rcspood to a sympathetic nerve block may be given an epi-
ous and controlled deliveiy for up to 72 hours. Calculating 16. Zc:ppctclla G. Ribeiro MDC. Opioids (or lhe management of dural block. Other methods that have been tried in refrac-
bre~kthrou1h (tpisodic) pain in cancer paliuits. Available in
an appropriate conversion regimen for trdilsfec of patients The.Cochrane: O"abasc of Systematic Reviews; Issue 1. Chich· tory pain include spinal cord stimulation and intrathecal
from oral or parenteral therapy to transderrnal can be difli· ester: John Wiley; 2006 (accessed 2711 t/09). baclofen or opioids. There are small studies or anecdotal
17. ~~~:U~i!;,~, ~~d:~;~1 ;7:~~ics in cancer pain manage·
cull, IS but the NCCN suggests lhat the totll daily require-
ment of oral morphine is equivalent to about 2000 times
5 reports of the use of a variety of other drugs and in1erven-
1ions.
20. Pa cs FM, Serafini AN. Sys.temic metabolic radiophannn.c:euticel
the hourly dose of transdermal fentanyl. 10 Oral transmu- therapy in 1he trea1mcn1 or meta~1a1ic OOne pain . .'Wtmln Nucl References.
cosal dosage fonns 10•16 and an inlrnnasal spray offentanyl MedlOIO: 40: 89- 104.
J. Kingery WS. A critical review of controlled cliniciil 1rials for
are also available for the management of breakthrough Central post-stroke pain. Central pain is a neuropa01· peripheral neuropalhic poiin and complex rcaional pain syn-
dromct. Pain 1991; 73: 123-39.
cancer pain. ic pain arising from lesions of the CNS. 1 ~ Pain following 2. Baron R. Wasner G. Complex rcaionol pein )yndromcs. Curr
Automated delivery systems for self-administration of a cerebrovascular accident has been referred to as thalamic Pain Headache Rep 2001; 5: 114-23.
parenteral analgesics (patient-controlled analgesia) have syndrome but is now commonly known as central posl· 3. Sc:hott GD. Reflex sympa1hc1ie dystrophy. J Nturol NtNros11rg
Psychiatry2001; 71: 291- $.
been used to administer opioid analgesics (see above). stroke pain and may arise not only from classical stroke •· Rho R.H, et ol. Comp1ex ~tional pain syndrome. Mayo Clin
Adjuvant drugs that may be necessary at any stage in- but also from surgery or trauma to the bead. 1be pain, P""' 2002; 77: 174-80.
which has been described as burning, stabbing, and ach- S. 'Wasner~ ti of. Complex rcg.ional/ain l)'ndromc-diagnostic,
clude antidepressants, antiepileptics, and class I an- medianismo, CNS in\001'-enttlll 10 lhenpy Spino/ Cord 2003;
tiarrhythmics for neuropathic pain, corticosteroids for ing, may be mild to intolerable and occurs spontaneously 4t: 61- 7S.
nerve compression and headache resulting from raised in- or in response to a mild stimulus. 6. Hord ED, Oakl•nder AL. C<>mplcx rtcional pain syndrome: a
roicw of tvidence-supponed trcatmenl cp<ions. Cwrr Pni.n
tracranial pressure, and muscle relaxants for muscle As in other types of neuropathic pain, whether opioid an- H<odo<l1< Rep 2003; 7: 188-96.
spasm. Radiotherapy and radioisotopes such as strontium- algesics can be of benefit is con1roversial: it has been sug- 7. Chai B, Ou:rtja GP. Complex rqional p1in syndrome: a review.
89 may be of use when the bone pain of meiastases is un- gesled that the value of conventional opioids such as high· J Posrgrad .\ltd 2004: SO: 300-7.
8. Harden RN. Pharmaoothcrapy or complex reaional pain syn·
responsive to analgesics.20 Bone modulating drugs such as dose morphine is modest, but that NMDA receplor antag- drome. Am J Ph)4 M•d Rehobil 200S; S4 (suppl): Sl7- S2S.
calcitonin and bisphosphonates may be of additional ben· onis1s such as methadone may be of more benefit. 2 Keta- 9. Quiscl A. et ol. Complex regiC1nal pain syndrome: which trcat-
efit but have a slow onset of action and bisphosphonates mine, anotl1er NMDA antagonist, may also be of value. me1lls show promise? J Foni Proct 2005~ 54: S99- 603.
10. Cepeda MS, er al. Loul antsthc1ic 5ympo1ho1ic blockade for
may cause an initial transient increase in pain. Corticoster· Conventional management of central post-stroke pain in-
oids have been used as an alternative to NSA!Ds in refrac- volves lhe use of antidepressants such as amitriptyline and Oa~~::, ':f~~:!.:=:rc ile~=t;:!i~~~;~~~~~ ~~~r~
tory bone pain but long-term use should be avoided. Nerve anticpilcptics including larnotrigine or gabapcntin. Early lty; 200S (accessed 23I06/0S).
JI. Sharma A, ti al. Advances in trcatmeni or complex regional
blocks with local anaesthetics or ncurolytic solutions may peripheral sympathetic blockade may produce temporary pain 'yndrome: recent insi&hU on 1 pcrplexin1 disc11sc. Curr
benefit a few patients, in particular those with sympatheti- relief in some eases. Mexiletinc may be of use in patients 0p;,.,1..,,.,,huio/2006; 19: $66-72.
cally maintained pain or specific localised pain (see under with refractory pain; it has often been given with ami· 12. RowboOl.a:m MC. Pban"Mcologic 1nanq.emcnt of complex re~
gional pain syndrome. C/in J Pain 2006; ll: 42S-9.
Pain, p.2014). Topical local anaesthetics or NS."'1Ds may triptyline. Oral or intrathecal baclofen may be tried. Trans- 1
also be ofuse in some patients.10 Physiotherapy and relax- cutaneous electrical nerve stimulation (TENS) may occa· Il . !',:~S::r~~!~~:~"::'::;!,°:r! m~~'1!:j Pa~c=f;;
alioo techniques may be useful for painful muscle spasm. sionally be of help but some advocate brain or spinal cord 438-42.
14. AJbazu R, ~'al. Complex regional p.1in Jyndromc: a review.
The addition of an NMDA antagonist such as dextrometh- stimulation. Suigjcal treatment generally gives disappoint· Ann Iii.re Sorg 2008; 12: 297-306.
olJ)han or ketamine to conventional analgesic regimens ingresuhs. IS. Hsu ES. Practical management of complex rcaional pain syn--
has been tried with some success in patients with refracto- I. Bowsher D. The management of central post-Stroke pain. Post· drome. Am J Tk.-2009: 16: l47-S4.
ry pain.'l Adjuvant therapy shou ld be fully explored be- grad Mr<IJ 199S; 71: S9S~.
2. Bow,her D. Central po41·Sl.roke ('lhalarnicsyndrome') and other D iabetic neuropathy. Sensory polyneuropathy, a com-
fore moving on to the next 'rung' of the treatment ladder eenltol pains. ,f., J Hosp Po/liar Core 1999; 16: 593- 7. plication ofdiabetes mellitus, is tbe commonest of the neu-
or increasing the dosage of an opioid analgesic.'7 For fur- 3. Fruc A, ti of. Pharmocologic 1rcatment of central post-·s1roke ropathies producing neuropathic pain. The pain mainly
ther details of analgesic adjuvo.nts, see Choice of Analge- pain. Clln J Pain 2006; 22: 2S2-60.
4. Canovcro S. Donicalii V. Central pain syndrome: elucidation of
manifests as a burning sensation, sometimes accompanied
sic, above. genesis and trutmcnl. Expert Rev N~urother 2001; 1: I48S- 97. by shooting, or aching pain. Painful neuropathy may ben-
Management of cancer pain also requires monitoring to S. Kumar B, "of. Central poststrokc pain: a review of palhophysi· efit from optimal diabetic control (see under Diabetic
prevent and reduce adverse effects of therapy, particularly OIOJy •nd 1reauncn1. A"Wh Analg 2009; !08: I 64S-S7. Complications, p.467). Non-opioid analgesics such as as-
6. Klit H, t-1 ol. Central post•strokc pain: clinical charac~ristic.s..
of opioids. Appropriate bowel regimes to manage consti- ~~~~ysiotoa.y, and management. Lonc~t Nu,ol 2009~ 8:
pirin or other NSAIDs, or paracetamol may be tried, al-
pation should be started at the same time as opioid therapy, though neuropalhic pain is often rcsiS1ant to conventional
All cross-references refer lo cntric:-s in Volume A
 Analgesics Anti-inflammato1y Drugs and Antipyretics 7
analgesics, and the treatment of painful diabetic neuropa- idence of benefit from other therapies such as magnesium Epidural analgesia witl1.a local anaeslhelic is now con-
thy is generally as for pos1he1]'.letic newalgia (see below). or vitamin Eis considered to be weaker. J.S.9 sidered the gold standard for treatment and provides the
Relief may be obtained using tricyclic antidepressants and Secondary dysmenorrhoea is associated with various other most effective pain relief during labour.9·12· 1• Medical in·
the BNF 59 considers amitriptyline and nortriptyline to be disorders such as endomeoiosis, and treatment is mainly dications may include a history of malignant hyperther-
the drugs of choice. SSR!s have been tried but studies sug- aimed at the underlying cause. mia, certain cardiovascular or respirntory disorders, or pre--
gest that they are ineffective or less effective than tricyclic I. l,.(!fehvre ~at ol. Society ofObstetricians and Gyn:>ecologi~lS of eclampsia, but the primary indication is the pacient's desire
antidepressants. Duloxetine, a serotonin and noradrenaline Canada. SOGt clini<:al pr.setice guidelines no. 169. Dcccmbe.r for pain relief.9.13 Bupivacaine is one of the local anacs-
reuptake inhibitor, is licensed for use in diabetic neuropa- JOOS: Prim:i:ry dysmenorrl1ea consensus guideline. J Obs1<rt (i) .. thecics most ofien used in epidural analgesia; others in-
noC!col Cnn 2005; 27: 1117-30.
tby. Antiepileptics such as carbamazepine, gabapentin, Also ;:1vailablc at: h11p:!/www.sogc.org/guidelint"si public/ clude ropivacaine and lidocaine."
phenytoin. and pregabalin can be used to control any I69E·CPG·D..,ember2005.pdf (acce5'ed 23106/0S) Epidural block has few contra-indications and serious ad-
shooting or stabbing components of the pain; lamotrigine 2. Zhang WY, Ll Wan Po A. Efficacy of minor analgesics in prima· verse event~ are rare. Nonetheless, ii has been associated
and topiramate are also under investigation. Antiarrhyth- ry dysmenorrhoea: a systemaric review. Br J Obstct Gynotcof
1998: 105: 780-9. with an increased risk of prolonged second-stage labour,
mics such as lidocauJe given intravenously or mexiletine 3. Marjoribunks J, et ol. Nmlstcroidal an1i-inOamma1ory drugs for forceps delivery, and caesarean section9· 13· 14 (although
given orally have beeo shown to be effective against some primary dysmcnorrhoca. Available ln The Cocbr:u'c D"3tabasc of meta-analysis8 and a systematic review14 refute the latter),
components of the pain. Topical application of capsaicin Systematic Reviews; ls~uc 4. Chichesler: John Wiley: 2003 (ac.
cessed 23/06I08). and it may not improve macemal experience of childbiJ1h.
or lidocaine may have some effect. Neuropathic pain may 4. French L. OysmenOHhea in adolescenls: diagnosis and treat· Many centres stop epidural analgesia for the second stage
respond partially to some opioid analgesics, such as meth- ment. Pediatr Drugs 2008; 10: 1-7. of labour to recuce the incidence of forceps delivery but
adone, oxycodone, and tramadol, aud they may be of use 5. Ha.rel z. Dysmcoorrhea in adolesce-nts. Ann N }' Acod Sci 2008~ substantive evidence for this is lacking. 15 Central blocks
when ot'1er treatments are ineffeccive. Transcutaneous 1135: 185-95.
6. Morrow C, Naumburg EH. Oysmenorrhea. Prim Cort 2009; 36: may also produce adverse effects including shivering,
electrical nerve stimulation (TENS} may also be tried. 19- 32. pose-puncture headache, and hypotension (for further de-
References. 7, Wong CL. <:I ol. Or3t contraceptive pill for primary dysmcnor- . tails of the adverse effects of and precautions for epidural
I. Je11sen PG. Larson JR. Manc:se:mc:nt (If pain fol di:tbt:lic neurop- thOC'-a. Available in Tht: Cochrane Database of Systcmati-c Re· block, see p.2011 and p.2012, respectively). Occa.5ionally
:ithy. Drup· AgitJg 2001: JS: 737-49. views; Issue 4. Chichcste1: John Wiley: 2009 (accessed
2 Boul!o.i AJ. TrcAtmcn1s for diabetic nevrop:athy. Curr Diob Rep 27/11/09). epidural local anaesthecic does not produce adequate
200J: J: J27-:l2. 8-. rtoctor ML., Murphy PA. Herbal and dictar)' therapies for prima· analgesia due co patchy or incomplele block.
ty and se<:ondary dysmenonhoca. Av~ilab l c in Th.e Cochnrne
3. ~~~bC:!~:fno~~~';b~c~~;e~66~~~;~~~~~-iabetic neuropa- Datab01Se of Systematic; Reviews; Issue 2. Chichester: John Wi· Some of the adverse effects associated wi1h epidural analg-
4. Llewelyn JG The diabetic neurop;tehiC$; types. diagnosis and Icy; 2001 (occcssed 23/06108). esia are associated with the motor block and profound an-
inannscmenl. J Neural A'emvsurg Psychiatry 2003; 74 (suppl 9. rtoctor M, Farquh:>t C. Diagnosi~ and management of dysmcn- algesia resulting from traditional techniques using rela-
U): iilS-iil9. O<rhoto. BMJ 2006; 332: I 134-ll. tively high concentrations of local anaesthelic. There has
$. Vinik A. Use: of anticpilcpcic; drugs in Che treatment of chronic
~infu l diabe1ie neutopathy. JC/in E11docri110/ Metab 2005~ 90: Headache. Aspirin and other NSAIDs, or paracetamol d1erefore been an increasing trend to the use oflower-dose
4936-45. .. ., are often tried first for the symptomatic treatment of vari- techniques. Altl1ough opioid analgesics are not particular-
6. Argoff CE. e1 al. Cons.ens.us guidelines: lrea1men1 pl::inning and
optiom. Diabetic peripheral nl!uropatbic paio. M<1yo Clin Proc ous types of headache including migraine (p.670) and ten- ly effeccive for labour analgesia when given systemically
2006; 81(suppl4): St:!--525. sion-type headache (p.671). NSA!Ds may also be effec- (see above), addition ofa small amount of an opioid to epi-
7. Wong M·C, et o!. Effects of treatments for symptoms of painful tive for lhe prophylaxis of migrnine, although they are not dural solutions enables effective analgesia to be achieved
diabetii: neurnpathy: system1uic review. Abridged version: BMJ with lower concentracions of local anaesthetic, and with
·2007: 33S: 87-90. Full version: hHp:l/www.bmj.com/cgi/ considered first-line options. 9 12 16 17
rcprinti:l35n6 J0/87 (accessed 23/ll6I08) Opioid analgesics such as codeine are sometimes included less motor block; · · • however, the incidence ofpruri-
8. ChQongMS. Hester J. Diabetic painful ncuropuhy: current and tus (a known effect of opioids) is greater than wilh a local
fu1urc lnatmcnt options. Dn1gs 2001; 67: S69-SS. Correction. in oral compound analgesic preparations used in the initial 8
ibid.; 1702. treatment of migraine or cension-type headache, but are anaesthetic alone.' l11ere is no standard combination of
9. Ziegler D. fajnful diabetic ncuropathy: treatment ~nd future as- local anaesthe1ic and opioid, although one large srudy used
best avoided, especially in patienls who have frequenc at-
pects. Dia/),i.s ,llerab Res Re>' 2008: 24 (suppl I): SS2-SS7. bupivacaiJ1e 0.1% with fentanyl 2 micrograms/mL.16 Suf-
tacks.
i 0. Tav:tkoli M, ~1 al. Pathophysiology and treatmie:nt of painful di- entanil is also widely used with either bupivacaine18 or
abetic neurop:uhy. Curr· Pllln Htadochc Rep 2008; Jl: l92-7.
I J. Dubinsky R.M. Miyasaki J. Asscssmcn1:c0icacyoftranseutane- labour pain. It is important to assess the adverse effects, ropivacaine. T~ epidural use of other adjuvants such as
ous elcelrle nef\te sli1nuta1ion in the trealmenl ofp<>in in ncuro- on both the mother and che fe1us, when selecting any meth- clonidine and neostigmine is also being studied.' 9 Low-
logic disordcts (an evidence.based review): rep0rt of the Ther· od for the management oflabour pain. Non-phannacolog- dose techniques are the basis of so-called 'ambulatory' or
apcutlcs a:nd Technology Assessment Subcommittee of the
ical methods of pain relief may include relaxation tech- 'wall<ing' epidural management, allhough it is unclear to
~~~~~~~~~f:~~~~::~,:~,~~~~ro~:~:~B~ ~i;;,"~t113
1
niques, transcutaneous e!ectrical nerve stimulation what extent this mobility improves ouccomes or patient
(•ccesstd 07/09it 0) (TENS) (which is popular with patients, although 1here is satisfaction.'°
Dysmenorrhoea. DysmenotThoea is painful menstrua- no robust evidence ofbenefit1}, and various other comple- Once an initial block is eslablished, additional analgesia
tion. The primary fonn arises from uterine contractions mentary therapies: of the latter, chere is some evidence of can be provided through a catheter by intem1ittent 'top-up'
produced by release of prostaglandins from the endometri- benefit witli the use of acupuncture and hypnosis.2 Water doses or by a conlinuous epidwal infusion; a combination
um in the luteal phase of the menstrual cycle. For this rea- immersion (use of a binning pool) du1ing the first stage of of the two methods fom1s the basis of some types of pa-
son, d11Jgs that inhibit ovulation or prostaglandin produc- labour has been shown to reduce reported maternal pain.3 tient-controlled epidural analgesia.
cion are often effective treacments. 1NSA IOs inhibit cyclo- Subcutaneous or intradermal injection of sterile water into Another method ofreducina the adverse effects oftradi-
oxygenase (prostaglandin synthetase) and are usually the the back has also been used for the relief of low back pain tionul epidural techniques iS to combine a spinal block,
drugs of first choice. 1"6 111ey are taken at the onset of dis- during labour.'-~ which is quick acting bul not long lasLing enough to be
comfort and continued for a few days while symptoms However, at some point during labour many women will used alone for analgesia in labour, wilh epidural delivery.
~rsist. Those most cocrunonly used have included aspirin, request some sort of pharmacological analge$ia. Although studies have reported superior pain relief' 7 with
diflunisal, flurbiprofen, ibuprofen, indometacin, ketopro- The inhalational anaesthetic nitrous oxide, given witl1 ox- such combined spinal-epidural analgesia, a systematic
fen, mefenamic acid, naproxen, and piroxicam. Theoreci- ygen, is suitable for self-administration and is com!llonly review IS considered that there was no overall benefit with
cally, mefenan1ic acid bas the advantage of inhibiting both used to relieve labour pain. It is relatively safe and can pro- the technique when compared with low-dose epidural
the synthesis and the peripheml action of prostaglandins, duce substantial analgesia in most patients.6 Other inhala- techniques, although onset of analgesia was faster.
but clinical studies have not consistently shown fenamates tional analgesics such as isoflurane or sevoflurane are also The use of spinal blocks in obstetrics has been more com-
to be more effective than other cyclo-oxygenase inhibitors. sometimes used7 (see Choice of Analgesic, above). monly associated with anaesthesia and management of
Paracelamol has also been given for pain relief. A system- Opioid analgesics have been given systemically in lhe postoperacive pain in caesarean section.' 2 Spinal blocks
atic review~ comparing several of these dmgs concluded management oflabour pain for many years, although they with local anaesthetics have a greater tendency to produce
that ibuprofen appeared to have the best risk-benefit racio do not appear to provide adequate analgesia in most pa- bypotension and headache than epidural blocks (for fur-
in dysmenorrhoea and was the preferred analgesic; cients at a tolerable dosage. s.9 There is no clear evidence to lher delails of the adverse effects of and precaulions for
naproxen, mefenamic acid, and aspirin were also effective, favour one opioid over anoll1er. 10 Mo1phine is considered spinal bloek, see p.2011 aod p.2012, respectively).
but the limited data on paracetamol did not show such unsuitable.' and che wides! experience has been with pethi- Pudenda I nerve blocks with lidocaine followed by a local
clear benefits. Another such review considered that there dine.7.IO However, its efficacy has been queried,7·'° and its anaeslhetic given into the perineum provide pain relief
was insuff-icient evidence to detennine which NSAID use has declined in many countries.' Fentanyl and its de- during labour." However, 1he technique of pa.racervical
should be preferred.3 rivatives sufentanil and alfentani l have been used, particu- local anaeslhetic block is now lar<6Cly of historic interest in
Patients who fail co respond to analgesics may benefit larly when ,\liven as intravenous patient.controlled analge- labour analgesia" be.::ause of reports of fetal arrhythmias,
from the use of progestogens either alone for part of the sia (PCA ),' but ii is not clear that they have any great acidosis, and asphyxia and isolaced repo11S of fetal death.
cycle or more usually with oestrogens in the fonn ofcom- advantages, and as with other opioids they may cross the Local anaestl1e1'cs have l:x.>en applied topically for perine-
bined oral contraceptive preparations. L ..6 A systematic placenta and produce respiratory depression and other ad- a! pain caused by tearing or episiotomy in wo~en w!10
review7 found limited evidence of pain improvement wich verse effects in the newborn. The use of the very short- have given birth. However, a systematic review-2 consid-
the use of such preparations for primary dysmenonhoea; acting opioid remifentanil for PCA during labour has been ered tl1at the evidence of cfticacy was not compelling.
however, the authors noted a paucity of studies, and that inves1igated, with some bcoefiL 11 but although ii is less
the included studies were of variable quality aod had me1h- I. Caffoll 0. tJ nl. Tn:in!;Cut.'lntou~ eleclric3J nerve slimulation in
likely to produce effects on neonatal respira6on ii is not labour pain: a systenrn1ic 1·cvicw. Br J Olme1 G.vnuecol 1997~
odological flaws. clear that the degree of supervision required to guard 104: I 69-75.
Antispasmodic drugs such as hyoscine butylbromide are against unacceptable respiratory depression in the molher 2. Srnilh CA. e1 oJ. Complementary and ahtm3livc therapies for
pain managc111n11 in l:l~our. Available in.The Cochrane ~313•
included in some preparations promoted for the relief of can be widely achieved on busy labour wards. 7 Nalbu- base of Systcmicic Rc\'1ews; Issue 4, Ch1chc$.1<.T: John W1ky;
spasm associated with dysmenorrhoea but the BNF 59 phine has heen used in some countries because of iL~ 2006 (accc=d 23106/08).
considers 1hat they do not generally provide significant re- mixed agonist/ancagonist action.' although there does not 3. Cluett ER. er of. Immersion in water in pregnancy, labour and
lief. There is limited evidence8 that vitamin B1 may beef- binh ... A\'ailable in The Cochrane Dalabasc of Sy~tematic Re·
seem to be clear evidence that it conveys any substantial vic\\.·s; ls.sue 1. Chicl\ester: John Wilt'y: 2002 (::iccessed
fective and some considcr1 thal it may be wonh trying; ev- benetil. 23106/0S).
8 Analgesics Anti-inflammatory Drugs and Antipyretics
4. Milrtcnsson L, Wallin G. Labour pi:>in tre;;:iled with culancous in- ous electrical oerve stimulation (TENS), massage, trac- 15. Koes BW. tU al. Diag11osis and treatmcn1 orsefo1ica. BJ\l.12001;
jcc1ions of sterile w3tcr; a randomi!Cd controlled lrial. Br .I Ob-
tion, specific back exercises, or lumbar supfort are 334: 1313-17.
srer Gynocco/ 1999; 106: 6ll-7. 16. Gibso;"t JN. Waddell G. Surgical interventlcms for lumbar disc
s. Bahasadri s. Cl ol. Subcutaneous s•crile waler injection ro. la- beneficiat. 1.2,4.i i.i 4 However, in the UK, NICE recom- prolapse. Available in The Cochrane D:tuibasc or Systematic
bour pain: a randomised controlled ttial. A11...1 NZ J Ohs1e1 Gy- mends offering acupuncrure, manual therapy, or a struc- Reviews; Issue 2. Chic:heslcr: John Wiley; 2007 (accessed
nu•col 2006; 46: 102-6. tured exercise programme as part of the treatment regimen 23/06/08).
6. Rosen MA. Nilrous oxide for relief of 1abor pain: a systcm:itjc 17. Annon C, et al. Assessment: use of epidural steroid injeci.ions
review. Am.I Ob.<t<r Gynccol 2002; 186 (suppl 1): SI 10-Sl26. for persistent or recurrent non-specific acute or chronic to ire.at radicular lumbosacral pain: report or lhc: Therap«itics
7. BruyCre M, Mercier FJ. Altematives 3 ranalgtsie pCridurale au lower back pain. Moreover, patient expectations of benefit and Technology Assessment Subcommittee of the American
cours du 1r;ivail. Ann Fr Ancsth Rccnim 200$; 24: 1375- 82. Academy ofNeurology. Neurology 2007; 68: 723:-9. A•so avail·
8. Halpern SH. et of. Effect o( epidural vs parentcraJ opioid anal- from different therapies may influence outcomes, and this
able at: http:/lwww.ncurology.org/cgi/reprint/68/I On23.pdr
gesia in the progress of labor. JtlMA 1998: 280: 2105-10. should be taken into consideration.2 (accessed 24/06/08)
9. Goctzl LM. ctol. American College of Obstetricians and Gync· Sciatica usually resolves with conservative management 18. Airaksincn 0, e1 ol, COST Bl3 Working Group on Guidelines
cologists. ACOG Practioc Bullclin. Clinical management guide· ror Chronic Low Back Pain. Chapter 4. European guidelines ror
lines for obstetric-ian·gynecologists number 36. July 2002: ob.. including analgesics and continued activity; however, if the management of chronic nonspecific low back pain. Eur
stetric analgc.sia and anesthesia. Obslt!I Gynttcol 2002; 100: sciatic pain persists for longer than 6 to 8 weeks, surgery Spine J 2006; IS (suppl 2): Sl92-S300. Also •vailablc at:
177-91. may be indicated.15 Dissolution of the disc by injection of http://www.backpaincuropc.org/wcblfilcsf\l.'G2 _Guidelines.pdf
JO. Bricker L. Lavender T. Parentecal opioids for labor pain relier: (accessed 23106/08)
a systcm3tic review. Am J Obsrc1 G)~nccol 2002; 186 (svppJ 1): enzymes (chemonucleolysis) such as chymopapain orcol-
S94-SI09. 19. Staal JB. et of. Jnjcc1ion therapy for su~c\lc and chronic: low-
lagenase has been used as an effective alternative to sur- back pain. Available in The Coc:hrane Daubase of Sys1ema1ic
11. Evron S. et of. Rernifentanil : a no,:el systemic analgesic for la·
bor pain. AntJTh Anolg 2005; I 00: 133-8. . . gery, but concerns about its safety have Jed to a decline in Reviews; Issue 3. Chichester: John Wiley; 2008 (accessed
12. Findley J. Chamberfain G ABC of labour c.are. Rehcf of pam. use, and discectomy is often preferred. 16 27/11/09).
BMJ 1999; 318: 927-30. Epidural injections of corticosteroids, using either the cau- 20. Priest TD. Hoggart B. Chronic p3in: mecharisms and trcatmcnl.
J3. Eltzs.chig HK, c1 of. Regional ancstbesia and analgesia for labor Curr Opin PhtJrmocol 2002; 2: 310- l 5.
and delivery. N Engl J Med2003; 348: 319-32. dal or lumbar route, have been given to patients with sciat- 21. Urquhart D, et al. Antidepressants for noa-specific low back
14. Anim-Somuah M, Ct ol. Epidural versus non-epidural or no 1m· ica; any relief is temporary only, the evidence of a benefit pain. A\•ailable in The Cochrane Database of Systematic Re-
algesi3 in labour. Available in The Cochrane D:i.tabase of Sys..
tematic Review~; ls..~ue 4. Chiche~er: John Wiley; 2005 (ac· is conflicting, and their use is no longer recommended.15·17 views; fssuc J. Chichester: John WHey; 2008 (accessed
23/06/08).
ccsscd 23/06108). There is no evidence of benefit in patients with non-specif- 22. Gibson JN, W3ddell G Surgery for degcnera1ivc lumbar spond·
J5. Torv3ldscn S, et al. Discorninuation orepidural am1l.gcsi~ la1e in ic acute or chronic back pain; 1•4 ·8,18·19 however, it cannot ylosis. Available in The Cochrane Oat.abase of Sysrematic Re·
labour for reducing the adverse delivery outcomes associated "'icws; Issue 4. Chichester: John Wiley; 2005 (occ·esscd
with epidural analgesia. Available ii The Cochrane Database or be ruled out that some types of injection therapy may be
23i06/08).
Systematic Reviews; Tssue 4. Chichestet: John Wiley; 2004 (ac.. effective in some subgroups of palients. 19 23. Khadilkal' A. et al. Transcutaneous eJec1rica.I nerve stimulation
ccssed 23/06108). About 2 to 7% of patients with acute lower back pain go (TENS) for chronic low bac.k pain. Availal:Je in The Cochrane
0

16. Comp3rativc Obstetric Mobile Epidural Trial (COM£T) Study

Group UK. Effect of low.dos~ mobile versus .tradition3J cpidu~­ on 10 develop chronic pain,4 and in the majority of cases, DatabHe of Systematic Re.viev.·s; Issue 3. Chichester: John Wi-
ley; 2005 (accessed 2.3/06/08).
al techniques on mode of dehvery: a randomised controlled tn- the source of the pain cannot be identified. Chronic pain is
al. Lancer 2001 ; 358: 19-23. 24. Dubinsky RM, Miyasaki J. Assessment:effi:acy ofttansculane..
J7. Comparative Obstelrit Mobile Epidur~ l Tri31 (C~MET) .~tudy not necessarily the same as prolonged acute back pain and ous electric nerve stimulation in Lhe treatme:nt of pain in neuro-
Group UK. Randomiz.cd controlled trial companng tr3d1uonal treatment is difticult. Conservative treatment is as for logic disorders (an evidence-based review): report Qf the Tht:r·
with two "mobile" epidural 1cc.hniq11es: anesthetic and analgesic acute pain (see above);1.2. 5.is.io tricyclic antidepressants apculics and TC'chnology Assessment Suhc:omminee nf lhe
American Academy of Neurology. Ne11rolou 2010; 74: 173-6.
efficacy. Anesthesiology 2002; 97: l $67-7$.
18. Simmons SW. et al. Combined spinal-epidural versus epidural may also be tried1'3·5•8•1s.2o although a systematic review Also available at: http://W\vw,neurology.org/tgi/reprinl.l74/2/l ?3
analgesia in Jabour. Available in The Cochninc Da1abasc of Sys- found the evidence of benefit to be lacking. 21 Topical ap- (accessed 07/0911 O)
cematic Reviews; Issue 3. Chic hc~ter: John Wiley; 2007 {aC· plication ofcapsaicin may be considered for short-term re-
c:es,se<I 23/06108). . Myocar dial infarction pain. The severe pain of acute
19. Roclants F, et ol. Epidural admin;;tn1tion of ncostigmine and lief.18 Surgery may be indicated for disc disease (see myocardial infarction is located in the retrostemal area
clonidine to induce labor ilnR1gesia: t-valuation of efficacy and above) or spondylosis,22 although it is not recommended with radiation to the anns, neck, jaw, and epigastrium. Pain
Joe.al 3ncsthetic-sparing effect. Ants1heslology 2005; 102: for non-specific chronic back pain until conservative treat-
1205-10. reliefis ofbenefit not only in its own right but also because
20. Roberts CL~ el al. Impact of first-s.age ambulation on mode of ments have been tried for at least 2 years. 18 Epidural corti- pain may cause adverse haemodynamic effects such as in-
deli,·ery among women with epidural aMlgcsia. Aus: N ZJ Ob· costeroids, intra-articular corticosteroid injections, local creases in blood pressure, heart rate, and stroke volume.
srcr Gynoecol 2004; 44: 489-94. facet nerve blocks, trigger point injections, and spinal cord
21. Rosen MA. Paraecrvic;al block for labor analgesia: a brief his· Although early treatment of the myocardial infarction
toric review. Am J Obiter Gy11uo/ 2002; 186 (suppl I): stimulation also lack evidence of efficacy. 18 Other meth- (p.1294) may relieve pain dramatically, opioid analgesics
Sl27-Sl30. ods that may be tried for intractable chronic back pain in- are tbe first-line treatment for pain and should be given in·
22. Hedayali H, et nl, Topically applied anaesthe1ics for tr-uting clude multidisciplinary physical and psychological ap-
perinea! posin after childbirlh. Avaifable ill The Cochrane ~a.ta~ !ravenously as soon as possible, that is before hospital ad-
b.'.lsc of Sys1ema1ic Reviews: Issue 2. Chichester. John Wiley; proaches; 1·3·8·14·1 8 evidence for TENS, massage, mission, to patients with suspected infarction. 1.. Opioids
2005 (accessed 23/06/08). acupuncture, laser therap£, and traction is either equivocal can also help to reduce anxiety. An inhaled mixture of ni·
Low back pain. Low back pain (sometimes referred to or scant, however. 1·18.10;2: •24 trous oxide and oxygen has sometimes been used 10 pro-
as lumbago), is a common complaint but only a small per· 1. Koes BW, et of. Diagnosis and treinment or low back pain. BMJ vide pain relief before arrival in hospital; sublingual glyc-
2006; 332: 1430-'I.
centage of patients suffer from a recognised organic dis- 2. Chou R, cl al. Diagnosis and treatment of low b3ck pain: a joint eryl trinitrate or an alternative fast-acting nitrate may also
ease, most frequently disc disease. Jn pati.:nts with a lum- clinic.al practice guideline from the American College of Physi· be given.
bar disc prolapse or herniation, the rupture of one of the cians and 1hc American Pain Society. Ann Intern Med 2007;
147: 478-91. Correction. ibid. 2008; 148: 247-8. Available ai: Diamorphine or morphine given by slow intravenous in-
fibrocartilagenous intervertebral d iscs can exert pressure hup:l/""'v.'w.annals.org/cgi/Jeprint/147171478.pdr (:accessed jection have generally been the opioids of choice, partly
on spinal nerve roots and produce a condition character· 23/06108) because of a better haemodyn~mic profile, but pethidine
iscd by severe and often acute pain radiating from the back 3. Wilson JF. Amcric,an College of Physicians. Jn lhc clinic: low
back pain. Ann /nrern Mcd2008; 148: ITCS-l-JTCS-16. AIM> has also been used. An intravenous mtiemetic such as
along the distribution of the nerves affected (radiculopa- av3ilitble -.1: h up://www.annis ls.org/cgilr~prinl/ l 48i9/ITCS· l .pdf metocloprarnide or, if left ventricular fonction is not com-
thy). The sciatic nerve may be involved and patients have (>tcme<I I 5/08108) promised, cyclizine, should also be given. The intramus-
pain (sciatica), usually in one leg along the typical dis!ri- 4. ''an Tuldcr M, el al. COST D 13 Working Group on Guidelines
for t.hc Management of Acute Low Back Pain in Primary Care. cular route should only be used if venous access is unob-
bution of the nerve. Non-specific back pain (back pain of Ch.apter 3. Europctin guidelines for the menitgcmcnt of v.culc tainable since ii is relatively ineffective in shocked
unknown origin) is usually.self-limitin~ with a good prog- nonspecific low back pAin in primary care. E11r Spine J2006; lS patients, complicates the enzymatic assessment of the inf-
nosis, although recurrence 1s common. •3 Back pam is con- (suppl 2): SJ69-Sl91.
Also available o.t: http:!/www.backpaincurope.or:lfwebtfiles/ arction, and may result in large haematc·mas when patients
sidered to be acute ifit lasts for less than 6 weeks, subacute WG I _Guidelines.pdf (accessed 23/06/08) are given thrombolytics. Alternative analgesics include
if it lasts for 6 to 12 weeks, or chronic ifit persists for more 5. Chou R, HufTm3n LH. Medications for acute and chronic low nalbuphine or buprenorphine, although the latter may not
than 12 weeks.4 back pain: a review oflhe evidence (or ;m American r3in Soc.::i-
ety/American College of Physicians clinical pr~cticc guideline. produce pain relief as quickly as diamorphine. The cardio-
Treatment for acute back pain should be given early to Ann Intern Med 2007: 147: SOS-14. vascular effects of pentazocine make it unsuitable for use
prevent the condition becoming chronic. For simple back 6. Mens JMA. The use ofmcdic01lion in Jow OOck p.i.in. Best Prac1 during or after myocardial infarction. Selective cyclo-oxy-
pain (in the absence of nerve root symptoms or signs of Res Clin Rherm:uto/ 200S; 19: 609-21.
7. Roelofs PDDM. et ol. Non-steroidal anti·inOammatory drugs genase-2 (COX-2) inhibitors and non·selective NSA!Ds
serious spinal pathology) parace1amol should be tried first for low back pain. Avail:ibk in The Cochrane 011.1;ib3sc of Sys- (other than aspirin) should not be used in patients with
NSAIDs are probably more effective,2•5 but are associated 1cmo1ic Reviews; Issue I. Chichcslcr: John Wiley; 2008 {ac- acute myocardial infarction because of their known cardi-
cessed 21107/0g).
with a higher frequency of advc-rse effects and should be ovascular risks5 (see Thrombotic Events under Adverse
reserved for those in whom paracetamol is ineffective.2·4-8 S. National Collaborating Ccnlrc for Primary Care/NICE. Low
00.ck p<1in: c<1rly managemenl of persistent non-specific low Effects ofNSAIDs, p.100).
If these treatments fail, muscle relaxants, including ba- back pain-foll guideline (issued May 2009). Available at: I. Getshlick AH . The ac:utc m3.nagement of myocatdial infan.aion.
clofen or tizanidine, may be added to therafy, although ad- http://www.nicc.org.uk/nicemedia/pdf/CG8&fullguidelinc.pdf Br Med Bu/1200 1; 59: 89-112.
verse effects may limit their usefulness; ·6·9·10 benzod i- (•ccesscd 27'11109) 2. Anlman· EM, eta/. ACCJAHA guidelines for the m3Mgcmcnt of
9. Deyo R.A, Weinstein JN. Low OOck rxtin. N E,,g/ J Med 2001:
azepines such as diazepam (which should only be given 344: 363-70. paticnls wilh S1'-clcvacion rnyocurdi3l inforction: a report of .the
for a short period because of the risk of dependence)2 are JO. ,.an Tuldcr MW, ct al. Muscle rel:J.xants for non-specific low· Americaii College or Cardiology/Ame.r;can Heart AssociAtion
Task force on Praclicc Guidelines (Wri1ing Commince 10 Revise
among the most effective muscle relaxants, but d1ere is lit- back pain. Available in The Cochrane Database of Systematic
Reviews; Issue 4. Chichcs1cr: John Wiley; 2003 (acce~scd the J999 Guidelines for the Managcmen1 of Patients With Acute
tle comparative evidence, and s.Jme suggest that they act 23/06/08). Myocardia1 l n(arction). Exccu1ivc summary: Circu/atio? 2~04:
mainly as sedatives.6 Opioids have moderate benefits in 11. Ehtlich GE. Low back poin. Bull W/10 2003; 81: 671-6. 110: 58&-636. Correction. ibid. 2005; Ill: 2013. Full guulclones
12. Hagen KB, el al. Bed rest fol' acute low..back pain and sciatica . 3vailr;,blc a1; http:/fcirc.ahajournals.org/cgi/rcprint/1 J0/9/c82.pdf
.severe or disabling pain not reiieved by paracetamol or Available in The Cochrane Database of Systematic Review1'; Js.- (3ccessed 23106/08)
NSAIDs,1 .5°6 •8 but again should only be used in the short suc 4. Chichester: John Wiley; 2004 (aeocsscd 23/06108). l . Anderson JL, cl ol ACC/AHA 2007 guidelines for 1.hc manage ..
term.1·8 There is strong evidence that remaining active 13. French SD, er ol. Superficial heat or cold for low back pain. mentor p3tienls wi1h unstable angina/non--ST-clevat1on my<?C-ar-
speeds recovery and reduces the risk of chronicily, even if A\'ail3ble in The CochrMe Database ofSystem3tic Rtviews; Is- dial infirc1ion: a rcpon of 1he American College of Card1olo-
sue I. Chichester: John Wiley; 2006 (accessed 231'06/08). gy/Ainetican Heart Association Task Force on Practice
pain or discomfort is caused; be<l rest delays recovery and 14.Chou R, Huffman LH. Nonphannacologic 1herapics for acuce Guidelines (Wri1ing Committee to Revise the 200~ Guidelines
is not recommended.1.3.4•9 .JJ.i 2 Othernon-pham1acological and chronic low back rxtin: a review or the evidence ror an for the Man;1gcmcn1 of Patien1s Wilh Unstable Ang:ina/Non-ST-
approaches that have evidence of a benefit include topical American Pain Society/American College of Physicians clinical Elevation Myocardial lnr:irction). Circnla1io11 2007; 116:
heat wraps and spinal manipula1io11. 1•2.4.S.l 3.i 4 There is lit- practice guideJinc. An11 /111em Med 2007; 14 7: 492- 504. Also cl48-c304. .
available at: hup://www.annals.orsfcgiireprinlfl47/7/492.pdf Full guidelines available at: http://circ.ahajournals.ortt/cg.i/
tle or no clinical evidence that acupuncture, transcutane- (acce<se<l 24/06108) reprinVI 1617/el48.pdf(accesse<l 23106!08)

All cross-references refer to entries in Volume A

 Analgesics Anti-ir.flammato1y Drugs and Antipyretics 9
4. Van de Werr i:. t•r ul. l't'lot Tuk Foree on ;he Man:.genlC:nt of ST· for several months to avoid pain recurrence on withdrawal. may also be of usc.1-4 From a review7ofstudies investigat-
Sc:1m1enl Elevo1ion Acu1e M'yoca1di1l Cnfarction of the Europe:;m Psychological t.reatmcn1S can also be helpful. 8oculil1um A ing the effect of regional anaesthesia in prc\cnting phan-
Society of Cardiolo;.y. M1n.a:<mtnt of acute myocardial infa~
1ion in palicnts presenting with pasist~n~ ST-scs111cn1 elevation. toxin has Ileen tried fo,. the relief of facial pain associated tom limb pain in patienrs undergoing lo'<''Cr-limb amputa-
Eur Htorr J 2008: 29: 2909-4$. with some disorders of the orofacial muscles. tion it appeared that epidural blockade started before and
Alt.0 a"ail1ble at: h11p://cu1·hcanj.o,,;ford)OUmol.s.orgiconlc:nl·"'19/ continuing for the d11I11tion of surgciy or for several days
23f29!l9. ful ~pdr-html (occessed 2~110) References.
5. Anunan EM." al. 2007 focused updMe of lhe ACOAHA 2004 I. \'ic.hrs E~. Coo.sins MJ. N'urop1th1c orofacial p:tin part 2- after amputation confet:rcd more protection from long-
auidelinrs for the: m~nagement ofpatients with ST+eJ~,·Qtion my· dta;nostic prOC:CdurC-$, Uetln1ent JUidehr\C.S and Cl\SC repons.. term pain than blockade begun late intra-operatively oc
~r.t rdial infarcbon: 1 rcpono( 1he American College ofCal'diol· Attst EndodJ2000; 26: S~l . postoperatively. However, a randomised, double-blind,
ogy!Amerlc:an Ht>:an Associ:ition Task force o., Pr.Jccicc Guldc- l. List T, ct al. .Pharrnacoloaic inlc,...·cntions in the 1rc:nmcn1 of
linc.$;. Circttlannn 2008; It?: 2l'6-329. tcmporomandihul.ar chsordcrs. a1ypical facial pain. and buming controlled study8 failed to show any balcfit of pre-emptive
Also available 11: hn.p;//circ.ah11journals.orgn:11/rtprint/ mouth syndrome~ a qualhativt' sysu~ matic TC\iew. J Oro/« P<1i11 analgesia usin~ epidural blockade in such patients. A sub-
CIRCU L.~T I ONAliA . I 07.1SS209.pdr (occcsscd 23/06/08) i ooJ; 17: 301-10. sequent revic>1. that included this study concluded tliat the
3. L.:"'i' MA, ' ' ol. Management o r neuropalhte orofacial p:iin. pre-emptive use of epidural block was oflimitcd success.
Neuropath ic pain syndromes. TI1e definition and Oro! Sing Oral M<dOral Pathol Oro/ Radi<>I Eodt>t/2007: ti~
characteristics of neuropathic pain are 'described under (suppl I): S32.cl-SJ2.e24. I. Wonan SW. n al. Phantom pain and scnsa1ion•mong 8ri1ish ...cc...
4. PaHon LL, er ol. Mana.gc:mcnt of bum ins mouth syndrome: sys.. oran ampuieu Br J Anaesth 1997; 78: 652-9.
Analgesia and Pain, above. Treatment can be difficult and t.em11ic re\•iew :ind manas:emcru. recommendations. Oral Surg 2. Nikolai><• I., .lenocn TS. Phanlom Iinib pain. BrJ Anoes1h 200 I;
is best undertaken in specialist pain clinics, since neW'O- Oral Med Oro/ Pn1hol Oral Rad/()/ E1ulod 2001; I 03 (•uppl t): 87: 107-16.
pathic pain often responds poody to conventional analge- S39.cl-SJ9.c 13. 3. Halbcrl J, tU ol. f'oltdcnU" ror the optimal m1magcment of KUU:
5. Mingucz Serra MP. cl ol. Ph•rm1co~I treatment of bum in& and chronic phantom pain; a sysccmalic n:vicw. Clln J Poin
sies. •-s The painful disorders characterised by neuropathic mouth syndrome: • review and update. M<4 0.-01 Polo/ Orn/ Cir 2002; 18: 84-92.
pain (either as the predominant form of pain or as one Bt>C:GIW01; 12: £299-£304. 4. Flor H. Phanlom·fl mh pain: cbllractcrisliC$, causes, and Uttt-
component of the overall pain) discussed in this section 6. Sardella A. An UP'"'o.dgtc view on bwnin:. mouth syndrome. man. Lo«~t Nt11rol 2002~ t: 182- 9.
are: Mlncn>o Sloolotol 2007; 56: 327-35. 5. Manchibnti L. Sina,h V. Managing phamom pah,, P<1in PltJ-,i-
cion 2004: 7: 36S-75.
• Central Post-stroke Pain Pancreatic pain. Pain in pancreatitis (p.2592) can be se- 6. W1ffen P. d ol. Di:1g.nostic and 1re:i.tme:nt 1s.suia in post3mputa-
• Complex Regional Paio Syndromes vere and may require opioid analgesics. Concerns over the lion pain after landmine injury. PoF11 Mtd 2006; 7 (suppl 2):
long-te1m use of opioids in non-ma lignant pain should not S209-S212.
• Diabetic Neuropathy 7. Katz J. Prevention of pb1nto.n limb pain hy regional a.nacsth.c.sia.
• Phantom Limb Pain prevent the patient being given effective analgesia which Lnncet 1997; 349: 5t9-20.
may be achieved by following the general principles rec- 8. Nikolajscn L. e1 ol. Randomised trial of epidural bupiv1ca1ne
• Posthcrpctic Neuralgia and morphine in pre\'Cn\ion ofst\lmp and phantom pain in k>'t\'Cr·
ommended by the WHO for treatment of cancer pain (see
• Trigeminal Neuralgia above); this involves giving non-opioid analgesics such as limb amputa1ion. Lim«t 1991; 350: 1353-7. ·
I, \lf.daloun A. et al. Therapeutic m1nagcmcn1 of chronic neun>· NSAIDs for mild attacks, with or without antispasmodics
p:nhic pain: an e.x.1mina11on of pharmacologtc tre:at.mcnt Attn N Postherpetic neuralgia. About 10"/o of patients who
Y Acod S<l 2006: 1088: t64-86. such asantimuscarioics, and progressing to 'weak' opioids have had acute herpes 20Ster still have neuropathic pain
2. Jackson KC. Phanntcothcrapy (or ncuropa1hic pain. Pafn Proct such as codeine. and 'strong' opioids including morphine, resulting from peripheral nerve injury one month or more
2006; 6: 27-ll. according to the severity of pain. after the rash has healed. The elderly are the most susocp-
3. Cruccu a Trc:itment of painful neuroptuhy. Curr Opln N~.1.rOI
2007; 20: Sl 1-5. There has been some controversy about the appropriate tible. The affected area (commonly head, neck, and limbs)
•. Dworkin RH. et of. Pharmaco&oaic manaaemcnt of ncuropathic choice of opioid: traditionally, morphine and its deriva- is extremely sensitive to any stimuli; even the pressure of
p~in. ev1dt:nCC"-based recommcndlll~-.n.$. Pa fo 2007; 131: . ti\'Cs have been avoided in favour of pethidine, in the belief clolhing can produce wibcarable pain. Spontaneous remis-
2:>7- 51.
S. Moulin OE. et al. Pharmacolo,tal minascmcnt o f chronic nc-u-
that they are more likely to cause spasm of the sphincter of sion occurs in many patients within a few months. Howev-
ropathic pain-consensus '°1alcmen1 and guj<fclincs fronl the C-1- Oddi. However, the evidence supporting this bas been er, in a small percentage of patients the pain can last for
n2dian Pain Socic•y. Pohl Rr1 J.folf"R2007: 12: 13-2 9. questioned. Some suggest that K-receptor agonists such as several years.
6. NJCE.. Spinal cord 11imulation (orclvontc pain of ncuropathic or oxycodone may be of value. In addition, there is some ev-
i ~c haemic origin: Ttthno,ogy Appraisal Guidance 159 (is~ed
Attempts have been made to prevent the development of
Oclober 2001). Avaihablc :n: hup:l/www.nice.ors.ukJnieemedi31 idence that pancreatic pain may have a ncuropathic cle- poslherpc1ic nturalgia. An early meta-analysis' concluded
pd ITTA IS9CuMl:ince.pdf (ac<csscd 25/11109) ment, and the use of an antiepileptic such as gabapentir., or that, if started within 72 hours of the onset of rnsh, aciclo-
1. Beuon M , et al New appro.tthcs to the pharmacothcnpyof ncu- an SSRJ such as paroxetine, may be considered for pain vir might reduce the incidence of residual pain at 6 months
rop:uhic pa.in. £.~n Rev Oin Pltarmncol 2008:; I: 683-93. syndromes associated with chronic pancreatitis.
S. Freynhet;en R. Scnnl!:lt Ml. Diagnosis ind n\anagcmcnt of nc:u- in some patients. A more recent systematic rcview2 found
ropathic pnin. Abridged \CJ"fion; BMJ 2009; 339: 391-5. Fun Analgesics arc gj\'Ql before meals to help to alleviate the tliat oral aciclovir or famciclovir did nOI have a signifil:llnt
\t'rsion : hllp://www.brnj.com/cgilcontc-nt/ful1/339/:Augl 2_ 11 postprandial e.uccrbat:ion of pain. They should be given effect on the incidence of postherpctic neuralgia 4 or 6
b3002?view-long&pmi.,.t96750Sl (•ecessed 2611 1/09)
on a regular basis and doses titTated for each patient. Pan- months after the onset of rash when compared with place-
Orofacial pain. Orofacial pain may arise from many dis- creatic extracts may case the pain but arc otheiwisc re- bo. It is, however, generally agreed that antiviral treatment
orders so i1S effective management depends veiy much on served for those with symptomatic rnalabsorption. Coeliac does reduce the duration of postherpetic neuralgia.l-S Epi-
the correct identification and treatment of any underlying plexus block has been used for the relief or severe intrac- dural injection of methylprednisolone with bupi\'acaine
cause, which may incl ude: table pain in some jl<1tients with chronic pancreatiti s: it has has been shown to reduce short-term pa in from herpes
• dental disease also been used similarly in patients with cancer of the pan- zosttt, but wns ineffective in preventing postherpetic neu-
• cluster headache (p.6 70) creas. However, the benefits of such a block are unclear. ralgia in the longer tenn,6 and evidence of the preventive
' References. value of corticosteroids is gencrally lacking.'
• migraine (p.6i0)
I. TI1umpson OR. :'iat"cotic anal&esic cffccu on the- sphincter of Various treatments have been tried once neuralgia devcl-
• lrigeminal neuralgia (see below) Oddi: a review of~ dala and ttlcnpcutic implications in llc1t· ops.3·S.S-is l11e value of conventional analgesics is limited
• sinusitis (p.208) in,g pancrca1itf$. A• J <As1rw1u1rol 200 1~ 96: 1266-72.
2. Khalid A. Whitco.ub DC. Conserv:lli\'e ll'i:illm<.!nt of chronic because of the ncurOJl"thic character of the pain although
• car disease such as otitis media (p.196) pancreatilis. £11r J Go11tV>Cn1~ Hcpatol 2002~ 14: 943-9. opioid analgesics have been used in refractory cases (sec
• giant cell artcritis (p.1641) 3. El Kamar FO. fl ol. Metastatic pancreatic unc:ct: crntrtingsttal· below). Low-dose tricyclics such as amitriptylinc, or in
cgics in chcmo1he.rapy and palliatiTe care. a,,cologf,st 2003; 8: particular nonriptylinc, have been widely used for treat·
• anewysms 1'-34.
• neoplasms 4. Mi1<bcll RMS,., ul. Poncr<:a1i1is. LI"'"' 2003; 361: 144 7--SS. mcnt, and appear to be ofbcocfir in about hal f of all cascs:s
S. St•hl C. « ol. Managjns pain in chronic ptncr11ti1is: therapeutic ho\\'Cvcr, the antiepileptics gabapcntin and pregabalin may
In the 1reatment of de11tal pain, analgesics arc used judi- value of Opioid 1rcalmcnt J Poht Polliot Corr: Plsormocntl1er now be preferred, and gabapcntin is licensed for this indi-
ciot1sly as a temporary measure until the underlying cause 2007; 21: 63- S. cation in some counuies. A comparative srudy has sug-
has been effectively managed. Paracetamol or aspirin or 6. Ccyhan GO. et ol. Pincreatic pain, 0411 Pt'O('t Ra Cli" Gwu'O.. gested that gabar.;ntin is as effccti'<-e as nortriptyline and
~lll~rcl 2008: 22: 31-44,
other NSAlDs a1e adequate for most purposes. Opioid an· better tolerated.1 Topical lidocaine has also been licensed
1, G~chago C, OraganO"V ~V. l,11in m3 n~g.emcnt '" dvoioc pancre 4

algesics are relatively ineffective and are rarely needed. ulitis. WOr/dJOoJ11Wt1ltro/2008: 14: 31 37-48. for treatment of postherpetic neuralgia, but the evidence
Burning mouth syndrome (stomatodynia; glossodynia) is &. Crud~ n i RA. Jain S. hnc:rcatic pain: a mini l'cview. Pon<~o1ol· for such use has been questioned. 17 However, il is likely to
Ot;J' 2008; 8: 230-5.
characterised by a burning sensation or other dysaesthcsias be better tolcrattd than the o~r main topical alternative,
of the oral mucosa in the absence of specific oral lesions. Phantom limb pain. Phantom limb pain is associated capsaicin.s Opioids, including methadone, morphine, and
11 is often aocompanied by xcrostomia and altered taste. with an amputated limb and is more common when there oxycodone, arc usually rcscrvcd for calienrs who Jail to
Those treatments for which thel'e is the best evidence of has been severe pre-amputation pain. It is frequently a respond to tricyclics or gabapcntin.1 Nerve blocks and
efficacy include topical therapy with clonazcpam, system- mixrurc ofneuropathic and other types of pain. Manage- surgical techniques may provide temponuy pain relief, but
ic treatment with thioctic acid, SSR!s, or amisulpridc, and ment maybcdifficull 1-6 but in a survey of war veteran am- results have generally been disappointing. Transcutancous
cognitive therapy. Other treatments that may produce putees, for those "'ho took any form oftreatment for phan- electrical nerve stimulation (TENS) has also beeu tried.
some benefit include capsaicin used topically or systcn1i- tom limb pain, conventional analgesics such as NSAJOs or Topical preparations of aspirin or indometacin, have
cally, topical lidocainc, or systemic therapy with other paracetamol with or without opioid analgesics were re- shown some promise.
antidepres.•ants. ported as being satisfactoiy.1The use of the WHO analge- I. Jackson JL. t1 al The tt1'1m of 1rea1iog herptS ZOS\Cf ~th oul
Jn addition, a large number of patients have a type of facial sic ladder, as in cancer pain (see p.5) may guide the choice acy..:luvir in prncntift! po)1hcrpctic ncur111i11: a meta-an.alJ$is.
Ao-.:/o Jt>ICl'n ~d 1997; 157: 909- 12.
pain of w1known cause which is typically exacerbated by of analgesic;6 although the u.~ of opioids has been ques- 2 Liq. al ol. Antiviral treatment for preventing poslh:crpctj~ neu4

SIICSS and can develop into a chronic debilitating disorder. tioned in what is essentially a neuropathic pain syndrome, nl11a. A"1ai1eblc in The Cochnnc Oatebasc of Systcmauc Re-
Many patients with such idiopathic facial pain respond to many consider tliem of potential value in phantom limb views; Issue 2. ChicbCJ.tcr: John Wiley; 2009 (acccssc:d
27111!09).
non-opioid analgesics, explanation, and reassurance. Anti· pain.M Transcutan eous electrical nerve stimulation 3 Alper BS, Lewis PR. Docs vcauncnt of acute hcrpC$ zosLcr ptc·
depressants such as the tricyclics are often of value. Antie- (TENS) was another method used by some and considered YCnt °"shorten poslhcrpclic ncunlgia? J Fom Prac.1 2000; .C9:
pileptics, including carl>ama7.cpine and sodium valproate, to be at least as effective as other thetapies.1Tricyclic anti- 25;-64.
and the oral lidocaine analogue mexiletine have been used depressants and anticpilcptics may be of help for the ncu- 4. Pan1ilio L\1. ~ ol. Current manttgcmcnl of postherpcdc ne u~l­
gia. N..rotoi 2002. 8: 339-SO.
as adjuncts to the tricyclics. Topical lrealment with capsa- ropathic components of the pain1·4 and some reliefmay be 5. Tyrins SK . Manascmcnt.o f hc~$ zos.tcr and posthcrpc1ic ncu..
icin has also been tried. Treatment needs to be continued obtained with sympathetic blocks. Intravenous kctamine ral;11. J A• ANNI D<rmofol 2001: 57 (suppl): Sl36--S 142.
 l 0 Analgesics Anti-inflammatory Drugs and Antipyretics
6. van Wijck AJM," al. The PINE S1udy or epidun.I stt:roids ;md 11 . Grun,, R, ~'of. Pr"ctlc.11 managcme111of pain In sickling disor·
local anac1lhc1ics 'o prevent postherpetlc ncuralgi1: a ran· dm. rch DIJ Child 1993; 69: 256-9.
control. ll is caused by ex1e111al factors such as injwy 10 the
domised eonlrolled 1n1l. "1nu1 2006, 361: 219-2•. 12. van Been EJ, ~I nl. Pac;ent..controllcd analttlll 'crAJJ conLinu· hypothalamus, heat stroke following dcfcc1ive heat loss
7. He L a al. Cortico11eroids (or pocvenlina po.thcrp<1ic ..,.,.,.1. ou1 inru..ton of morphine during \-UU-UCClush·c crisis in 1icklc (as occurs in dehydration or excessive heat production fol.
gia. A"*~ll>lc 1n The Coe/Iran< 01llba.. of Sy>1t:mllic Re-
=~;suc I Ch1chcuer· John Wiler~ 2008 (access.cd
~I,':= a r>ndom1ud C<>Olrolled lri1L 4• J HDlalOI 200i; lowing strenuous activities), exccuive dosage of some
13 Jacobson SJ.~ ol kandonuscd trial of en! .-pl\111< for po>r>- dru&$. oc a reaction to certain drugs such as anaesthetics
&. Collins SL.. -1 •I Antidqiressaats 1.nd en11cottwlsaots for dia-
betic ......_thy and posll><rpcllc neunl111· 1 quan~ll1M sys-
or
tls~'f°' 11<kle<cll d-incbildrcn t...... 1997: 350: (malignan1 hypcrthennia, p.2060) or an1ipsychotics (ncu-
lcmatic rcvtew.J /#out Sy,.ptom Mo~ 2000, Jt: -449-58. roleptic malignant syndrome, p. 1075). Underlying thcr-
9. Jolin.son R. P11nck 0, eels. Rccommcnd11iom ltom 1hc ln1cm1· Trigeminal neuralgia. Trigeminal neuralgia (tic dou· morcgulatory defects may be a particul31' problem in sed-
tional Herpu Manaae.mtnl Forum m1n11tment sirattgics entary elderly subjects.
workshop: improvins the m1n1icmcn1 of YViceHa. herpes lo~reux) is a neuropathic pain characterised by sudden,
zoster and zostcr·asociated pti1n (1uued November 2002). brief, sharp. agonisu1& episodic pain in the distribution of Whenever possible the underlying cause of fe,·er should
Anilablut; hap-J,,.'WW.ihmf....,t.illr1r)"'-lnl>Mn 11.pdf
(acc=cd 2JIO&'oc) - one or more braocha of the fifth aanial nerve. There may be identified and trcatcd.1 Body tempcrat~C$ up to 41° arc
I 0. Johnsm RW, 0-kin RH Trn1mm1 o( herpes zmtcund past· be several episodes (lasting SC\U31 seconds or minutes) 1 relatively hannless2 and it is not clear if there is any value
hcrperic .....,,.. l/tll 2003; 326; 741-50 day over a number of"'eeks, followed by a pain-free inter- in l.TCaling fever al lower tcmperalUrCS, I but some ll'OUJlS
II. Oworlcin RH, Schmad<r KE. Tru1m<n1 and pm..,,lK>n ofpos1· may be more vulnerable, such as young children, pregnant
herpctic ncurolaia. Chn lnft<1 O/J 2003; 36: 177-82. va I thal may last for weeks or years. Trigeminal neuralgia
12. Ou~insky ~· "' "'· Praaicc partnleter~ rrcatmcn1 ofposthcr- g~ncrally has a 'trigger zone' in which even a very light women, or patienlS who &fC already dehydrated or mal-
pet.c neurolt;tt-an evtdct1c:e-based rcpon or1he Quality Stand- stimulus such as n draug/11 of air produces pain. In some nourished or those with cardiac, respiratory, or neurologi-
ards Subcommiucc o ( the American ACldemy of Neurology. cal diseases.
959~5 . Al>O 1v1i11ble al:
Neurology 2004; 63: cases finn pressure a.pplicd around bu1 no110 the zone it·
~~=lw.neuroloay.ors/<11/reprlnll6J/6/959 (accused ~~fmay.help lo relieve pain. Trigeminal neuralgia may be Both physical means and ao1ipyrctics may be used 10 re-
1d1opath1c or may be secondary lo nerve compression duce body temperature in feYcr. Maintainin& an adequate
I J . 00..glu MW, a ol. Tolerability of 1muncn
. ts f0< pOSlherpai<:
nC11nlp 0.-"1Softl)'2004: 21: 1217-33 (such as that caused by a rumour), facial injwy, or multiple Ouid intake is imponant. Fanning. removal of clOlhing
14. Dainty P Prevc:no;oo ond m<dicat ...,,•pmco1 ofposthcrpctic sclerosis. and tepid sponging arc often uscd,1·3 but they do noc ,.,;.
..,...Jg;.. Br J Hosp Mtd 2001: '9: 275-1 The management of trigen1inal neuralgia is distioc:t from d\Jce the set-point of the hypothalamus, and lead IO shivC1'-
15. Sampathkumar P, <1ol Horpcstomr (lh1nalo1)and pOSlhorpo•·

·=
ic nourolgia. "'1>'0 Cl•• Proc 2009; M: 274--80. 01.ber forms of ncwopathic pain. Carbamucpinc is the ing (rigor) Ol'other advcrsccffectsas the body 1nes10 meet
16. °".'ndra K, •• o/ Oobopenlin Y<nUS nortrif.1ylin< in pos1·hcr· ~g o_fchoice and inirially may produce sa1jsfactory pain the raised set·poin1, and their value is 1hercfore questiona-
~:G"J~~r~::r,~~:'ti.:.~.:!.1~ ~1;
1
rehcf m 70% or more of patients, although inacasing)y ble; i •..s similarly, cold baths should not be used as they
)~. large doses may be requilcd.1.a Ifpain relief 1s inadoquaie may aaually increase body lempcra.rurc by inducing vaso-
pCljc .-,.L
17. Ku liq W,., ol Topical ltdocaioc for IN irtatman of postbtr·
Avatbblo in The Codnnc Oaubas< ofSysta'6-
~;-.~...: 1..... 2. O.iches<cr John Witoy; 2ocn 1-c1
phenytoin or baclofcn may be added IO carbamucpine
therapy; these~ may also be used alone in patients in·
constnction, and the risks of a cold-induced prcssor re-
sponse should be borne in mind. Anlipyretics 1ppear most-
tolerant of carbarnazcpme.' Other antiepileptics such as ly 10 help rerum the sct·point 1empcraturc to normal by
Sickle.cell crisis. The management of pain ofsickle-cell gabapentin, lamotrigine, oxcarba?cpine, valproa1e, and inhibiting central synthesis ind release of proslaglandin
clon~pam have also been used in patients intolerant of. ~. which mediates 1he effect of endogenous pyrogens in
crisis that can occur in sick.le-cell disease (p.115 l) is simi·
lar to that of other forms of acu1e pain. The pain of mild or resistant to, carbamazcpine.1-6,s Evidence for the value the hypolhalamus.6 This mechanism cannot lower 1he
crises may be controlled using oral analgesics such as pa· ofnon-aniiepilepticdrugs in lrigeminal ncumlgia is mostly body lempcrarure below normal, and an1ipyrelics are inef·
poor.9 fcctive against raised body 1empcrature not associated
racemmol, an NSAID, codeine, or dihydrocodcinc. Partial
agonist and antagonist opioids such as bup'enorphine are ln some patients drug therapy eventually fails to control \vith fever.
not recommended to treat acute pain before transfer to hos- the pain or produces unacccp1able ad\la'Se effcctS and in- Chok-e ofan1ipyreric in children has been widely debated.
pital.1 Crises ~ere enough to need hospital admission vasive proccdwcs become necessary. These may include The drugs IDOSl commonly used an: par1cctamol 111d ibu·
usually require the use ofmore potent parenteral opioid an· the selective destruc:uon of pain bearing nerve fibres with profen; salicylates (including aspirin) are generally contra-
algcsics bu1 NSAlDs may be useful as an adjunc1 for bone 11dio&cquency thcrmocoagulation, instillation ofglycerol indica1cd because of the possible link beiwcen their use
pain. ln most centres, morphine is the opioid ofchoice for (although the efficacy and safety ofthe procedure is debat· and the development of Reye 's syndrome. A systematic
moderate to se\'m: pain. Some patients appear 10 prefer able), giimma kmfe 11dialion, and microvascular decom- review7 found inconsiS1cnt evidence 10 support the use of
pc!hiclinc bu1 many clmicians24 avoid its use if possilile as pression of the trigcminal nerve root. :uu pancctamol to reduce fever in children, since the number
amtro1 of pain ~ be inadequaic and doses of pe!hidinc I ~sltaJM Tr.,.,...,lnnnfPa-/'ri•l>MlC4r<l997;4: of .reliable studies was too low to be sure that 1t was effec-
needed 10 manage crises can lead to accumul.ation of its tive. Although studicsh3ve fowid 1hat ibuprofen was supc-
2. Jofl"roy A. •• ol Tniem1n1l neuralgia: J*1hG!Jhystoqy and noc to paracetamol in 1enns of both efficacy and dwation
ncuroexcilatory mc1abolitc norpcth1dine and precipitate ttHlm•n~ Acta 'll••IOI l«lt 2001; 101: 2~5
seiiures (see also Effccis on !he Nervous SyslCm, p.J 18). ) , Nurmi~o TJ, Eldridj;c PR. Tngcmin• I "°"'"l1ia-pa11tophysi· of acuon, some of the doses of paracetamol 1verc below
UK guidelines'" recommend that pethidine should only be ology, d1a111os11 and current treatmcnrs.. BrJ Ann1111f, 200 1: 87: those recommended in the UK and NICE did not consider
used in exccp1ional circums1anees such as in patients hy·
11 7-32. ~tal either drug had a significant advantage over the other. 1
4. Ro1..en TO. Anticpilcpllc drugs in the management or
cluster A ltema1ion of 1he 1wo may be more effec1ive than cilher
pcrsensilive lo other opioids. Diamorphine, fentanyl, hy· ~),•~;1:Sll~ 1rigcml111I n••rol&i'- Headocht 2001: ~ I (suppl
dromorphone, and mcth~one have been used as altema· elonel.9 but again this is controversial. '·•.U·1 1.u
th-es to morphine. Nalbuphinc may also be suitable. 10 As 5. Sindnlp SH. lens<• TS. P'lllU'IMCO<lterapy of maenun1I neurol· Anlipyrelics should no! be given IO all children wi1b fever,
the dose of opioid required to control the pain can ' 111Y
a•• CflnJPoin 2002, JI: 21-7.
but only to those in obvious discomfort or dtstrCSS because
6 Sc:nn.n1 SJ. ~ tll. Trlpm1naJ ncural£ia. Oral S.,,'I Orol M«f
considerably, noc only during each episode but also from Oro/ Potlool Orol llod'.o/ E"4t/2005; 100: 527- 31 of the fever or associated symptoms such as headache or
one episode lo another and belwccn individu:il palicnlS, 1 Ucnnetlo L. n al Tnae.m1nal no.aral.gia md ns man11cmcN. myalgi:i. •.•.s.i2 It has been su~$cd lh:ll the use ofantipy-
patient-Gontrolled analgesia (see above) may be ofhelp io Abndred version· IMJ 2007; 334: 201-5 full version; f'Clics mighl prolong infection, and that in severe infection
h11p:11..ww.bmj.com/c11/rcprinll334nS861201 pelf (•cc•ssed
manage the pain once initial pain relief has been oblained 23/06.01) 1he use of antipyretics might increase monahly;n WHO
with Joa.dins doses of parentcr1I opioids;•·11 •12 opioids ('"ONtllo Ci "•Ior 1ri,cmlf'QI.--••or.
l'nclJU the di"COOSlic eval11a1ioo has1>recommcodcd tha1 in developing counlries antipyret·
used have included morphine and fcntanyl. The use of 1.nd tralmcn1 neunJ_gia (111 e-vidc:ncc•bucd re-. ic:s should not be given rounncly to children with fever but
continuous epidur1l analgesia with local anaesthetics •iew)-<'opon of lh< Qulrty Sl>n<l•rds S\lbcorrun111ee lh< or should be reserved for those with severe discomfort or
A - 0 . Acodomy ofN.-qy and the European fcdont-
alone or with opioids has beeii tried. However, a ran- of Nevroloatal Sonettc~ N••rology200S; 71: lll}JJO. h•gh fcYer. In !he UK. the Joint Committee on \ollccmarion
domised sludy13 of morphine for the ruanagemen1 of se- 9 He L. " ol l\0<>-•n<1Cp1lopb< drup fo.. trraominol ne.nliia. and lmmWlisation recommends Antipyretic therapy to treat
vere painful sickle-cell crises in childfcn showed that onl Av1.i111ble: in The Cochnnt ~tabasc ofSy'Stcm.atic Reviews; Js. posl·immunisation fever developing after some vaccines.
out J. Chlchos1er: John Wiley: 2006 (•«•md 2)/06/08)
modified-release morphine was a safe and.effective al1er- However, if the fever persists after the seoond dose of a111i-
native to conlinuous intmvenous morphine. Inhalation ofa pyre1ic medical advice should be sought
Increased Body Temperature
mixture of nitrous oxide nod oxy~cn may be a useful Anlipyrctics have also been given as propl~y/a.tis against
analgesic during transfer to hospital. ·' The hypothalamus is the centre of the thermoregulalo· fcbnlc convulsions, especially in those wi1h a history of
I. Report_of a wotkrn& .-111 or lhc SWw:tina Medical Ad.-isory ry system 3nd 1s rcsp0nsible for maimaining the body such seizures or in •hose with epilepsy. However, antipy-
Committee on dcUt ctll, th.alass:1tm«1 end Olhtr haemogJobin· temperature at a set poi111 (known as the set-point rctic thcraPY does ll(J( appear to prevent recurrence of fe-
opz<bies. London: HMSO. 1993
2. P>ylc 81,aol To>ici1yofnorpclhid1nc u1'1Cklc cell crisis. BAU 1cmpcrature) which is normally 37•_ Mechanisms !hat brile convulsions (p.513).'·'<.u There is also hllle to sup-
1m30•: 101-9 produce or conserve body heat include passive heat port 1he use of antipyretics for pfophylAxis of posl-
3. Davies SC, Onl L. Mtnoiemcnl of p1hcnll "'"h side to cell dis-
caso. BMJ 1997: llS: 65~. absorption from the environmen1, peripheral vasocon- inununisalioo fever. Furthcnnorc, there is )ll'Chminary ev-
4 . Vijay v. rt ttl Tl.c 1natilhcti11•s rott: 1n ac.vlc stckle cell cris&S. striction, and thcnnogcnic processes such as metabolic idence thal, although effective in preventing fever, prophy-
BrJAnaut4199l;lt: 82M. lactic paracetamol can reduce antibody response lo the
reactions and shivering. Heal loss is achieved mainly
S. ;;:,,~f,. t:.,,,~:;~ :~i~J• 11<-lk cell c!isr2sc. through S"'C1t1ng and peripheral vasodilatation. Vari- VllCCine. 16 Routine use m:iy no< beJustified although some
6. ~ fto!~:~111ne111 oh1dtlo an p.ia. pifar. ous states may lead 10 an abnormal increase in body have suggested offerin& it to infams at higher risk of sei-
zures receiving diphthcria-tetanus·pcrtussis oc polio im-
7. Stinson J, N'tscr 0 hrn lll3na,....,,. in chrldrtn wn Pdcle cdt temperature.
discas~. Pn<d•atr Drop 2003; S: 22941 . munisation.17
8. Sickle Cell SocJCty Sund1«is f0< the cllniul core ohduhs willt Recommendations for mana\cment of fc\/Cr in adullS are
sickle cell d!seuc In 1~e UK (issued 2001). Available a1:
~Zf.~9)"'·••cklc«ll &oc101y.orsfpdf/Corellook.pdr (accessed
Fever and hyperthermia similar 10 thoseforchi ldren.2· al1hough salicylatcs such as
As mcn1ioncd above, body temperature is nonnally resu- aspirin 111ay also be used.
9. Recs DC.~' ol. Dritish Commince for SLtindards in Haematuh>- laletl by the hypoU1alamus. Fever(pyrcxia) is a controlled
11· Guidelines for lhc m1n1;cmcnt of &he acu1c painful crisis in Hypcrthermia may produce body temperatures arealer
Stclde cell disuse Br J HIN..,,rol 200J; 120: 7•'-S2. increase in body 1cmpcrature due to an elevated hvpotha· lhan 41°. Tiiese high ten1penirurcs arc life-lhrcatening and
Also •viii.bit 11· hUp;//\Ww"W bc5hl'*idclinu.com1pdf/ lamic set-point tempcrarure. Common reasons for this need to be lowered immediately. Anlip)Tetics arc ineffec-
sicklccdldiseHc_OSOJ pdf (>cccucd 23!06101) if!Cludc infect.ions, 1nOamma1ory disorders, neoplastic
to 8uchaNn ID • ., .t Oli'01d selcclH>11 d•rtna &ockl• cell pain cri· tive since the high tempcnlturcs arc a rcsuh oftbennoreg-
sis arad jts impt(;l on the ckwlopmen1 or aceic chut syndrome. disease, and some drug treatment. Hypertltermia (by· ulatory failure. One of the most rapid and effective means
P«l'wor BloodC.0,,_ 2005; 4S: 716-24 pcrpyre:..ia) implies a disrurbancc of 1hcrmorcgulatory of cooling is to immerse the paticn1 in very cold water but
All cross-re(crcnces refer lo enlrics in Volume A
 Analgesics Anti-inflammato1y Drugs and Antipyretics ll
core temperature should be monitored to avoid inducing of the sLJUctures that surround a joint. For a discussion the severe growth retardation that is often seen.1 Topical
hypothe:·mia. 18 Evaporative cooling methods may be of the management oflow back pain, see above. treatment with glucoconicoids and mydriatics may be
more ef!icient. 19 Intravenous or ;nrraperitoneal adminis- neecled for eye disease.1
tration ofcool fluids, gast1ic lavage or enemas with ice wa. Physiothernpy <11d occupational 1herapy are also important
tcr have also been used. 1s.w juvenile idiopathic arthritis
components of disease management, and surgery may be
Wnen hyperthermia is associatecl wi1h muscle rigidity and Juvenile idiopa1hic arthritis (juvenile chronic arthritis) is a needed in selected cases.'
fuhninant hypem1etabolism of skeletal muscle, as in the term used to describe a clinically heterogeneous group of I. R.avelli A, Martini A. Juvtnilt idiopathic.arthritis.. lortt:U 2(107:
neurolep1ic malignant syndrome and malignant hyperther· idiopathic arthritides occurring in children under I 6 years 369: 767-78.
mia, temperature reductions may be obtained using the of age; subtypes include systemic arthritis. oligoarthritis ~. Haines KA. Ju"·~nile idiopJ1hic ::inhrilis: thcr:ipies ill 1he 21 M
(panicularly oflegjoints), and polyarthritis, either positive century. Bull Nru Hosp J1 Dis 2001; 6$: 20S-I I.
muscle relaxant dantrolene. There is also anecdotal evi- 3. Soulh\vood TR, Sier IS. Juvenile idiopathic :uihritis. In: Adeba-
dence that dantrolene may produce beneficial effects for or negative for rheumatoid factor. 1·> jo A. ed. ABC of Rh<!umutofogy. 4th ed. Chi~heSlt'r: Wilcy-
Treatment involves many of the same drugs used for rhcu· Bl3okwell, 2010: S5-97.
the treaunent of similar symptoms resulting.from poison· 4. Cron RQ. Current lrca1mcn1 for chronic arthritis in childhood.
ing with various agents. Mowever, dantrolene·is not an ef- matoid anhritis in adults (see below), although there may Curr Opin PtdlDtr 2002; 1~: 684-7.
fective treatment for all types ofhyperthenniil and rigidity be limited evidence for their use in children.1·11Appropri- S. Wilkin.son N, era/. Biologic lhcrapics for juvenile arthritis. Arch
ate management will depend on the subtype of disease, but Dis Child 2003, 88: 186-91.
aocompanying poisoning. Altl1ough dantrolene has been 6. Cleary AG, et cl. lnlra·articular con.icos1eroid injections in ju-
tried in patients witl1 heat stroke, there is no'evidence that there is no definitive consensus on the drugs of choice. venile idioputhK:: arthri1is. Arr:h Dis Child 1003; 88: 192-6.
it affects outcome.21 In severe cases ofhypertherrnia when • The NSAJDs have been a mainstay of treatment for 7. Ramanan AV. er of. Use of metho1rexate in juveni le idiopathic
neuromuscular hyperactivity may also impair ventilation, many years, and continue lo be important. 1·2 Most chil- arthriti~. Arch Dis Child 2003; 88: 197-200.
8. Wedderburn LR, et ol. Autologous haemalopoietic stem oell
a neuron:uscular blocker has been used, although suxame- dren begin therapy with an NSAID, 1 and they may be transplantation in juvenile idiopaEhic arlhtitis. A,.c:h Dis Child
thonium is best avoided as it can itself precipitate malig- particul?rlY useful in oligoarthritis. 2 Naproxen, ibupro- 2003: 88: 201-;,
nant hypertherrnia. fen, or indometacin are among the most often used. 1As- 9. Hashkcs PJ. (...axer RM. Medical trea1111cntofju\'enile idiop::nh-
ie anhri1;s. JAMA 2005: 294: 1671-84.
I. N~ti ona l CQllal;>oratin' Centre fQr Womell '$ ~d Chi14r(:n '$ pirin is now rarely prcscribed,9 althoug!i in many juve· IO. lleresford MW. llaikl•m EM. New advances in !he managemrnt
HC'81thlNlCE. Feverish illness in C'hildren: assessment and ini- nile idiopathic arthritis remains one of its few licensed ofjuvenile idiop~thic a11hri1is-1: non· biological lhefapy. :frch
tialm~r1agcmem in children younger t.han S }'Cars (issued May D;s Child £due Proct Ed2009; 94: 144-SO.
20(}?). A\'ail3ble 31: hnp://www.nice.org.uk/niccmedialpdfl indications in children. 1(. Acres ford MW, Aaildam €.M. New advances in the management
CG47Gu;dooce.pdf(aettsse<l 23/06/08) · ·' • Intra-articular injections of a corticosteroid (often tri· of ju\'cnilc idiopalhic arthritis-2: lhc era of biological$. :f1\;h
2. Plaisance Kl, Mackowiak PA. Antipyrctic therapy: physiologic o;s Child£d11cPro~1Ed1009; 94: 151-6.
rationa!e, diagnostic implica1ions, and clinic.al consequenc·C$. amcinolone hexacetonide) are rapidly effective, and
I:2. Thornton J, er n( Systematic re\•iew of crfec1ivenes~ ofbispho.s-
Areldr.1em Med 1000; 160: 44?-56. ·· well tolerated, and are often used in oligoanhritis willi, phonald in lre4!lmenl of low bone mineral tknsity and rr.sgility
3. Mercmikwu M. Oyo·lta A. Physical methods fa< treating t'h-er or ins<ead of, NSAlDs;1·>.6010 they may reduce the devel- fractures in juvenile idiop3thic 3rthritis. Arch Dis Child 2006;
in children. Available in "rllc Cochrane Oatab3se of Systematic
Rcvic,..s; l»uc :?. Chichester: John Wiley; 2003 (:iccessed opment of defom1ity secondary to contractw:e. 1 They 91: 7Sl-61.
23i06iC08). . also have a role in the management of disease flare in
4. AnonymOu5. When the child has a fev~r. Drug Ther Bull 2008~ patients already taking second-line drugs, although it is Osteoarthritis
46: J7.-20.
S. El·Rad'li ASM. Why is tht: cv i dcnc~ not affecting the prnc1ice unclear whether multiple .intra-articular injections Osteoarthritis is the clinical and patl1ological outcome of a
offeve; manageinen1? Arch Dis Child2008; 93: 918-20. would be preferable to systen1ic co1ticosteroids in pa- range of disorders <hat cause structural and functional fail-
6. Aronoff OM. Nidson EG. Antipyrctics: mcchanisn\ of eclion tients with polyarthritis.6 ure ofsynovial joints. It is charncterised by involvement of
and clinic<1l us~ in fe,·e1 Sl1ppression. Am 1 Med2001; Jll:
304··15. Moderate or high-dose systemic corticosteroids 'are tl1e entire joint, Nith Joss and erosion of articular cartilage,
7. f\tcrcmikwu M, Oyo·lla A. Paracc1.amol for trcatin' fever in more generally reserved for patients with systemic ar- subchondral bone changes, meniscal degeneration, mild to
childre:1. Av3ilable in The Cochrane Database of Sys1ematic
Revit\fS; Issue 2. ChicheSl(r: John Wiley: 2001 (accessed thritis whose disease is not controlled by NSA!Ds. In moderate synovial inflammation, and outgrowth of bone
23/06iCS). other subtypes, the adverse effects of sys1emic tl1erapy and cartilage at the joint margins (osteophytes). These
&. Sarrell EM. e1 al. Anupyretic 1rea1mcnt in young children with are likely to outweigh the benefits. A course oflow-dose changes result in pain, stilfoess (especially after inactivity)
fever: icc1aminophcn. ibuprofen, or both Jhen»ling in a rind· and reduced mobility, although patients with changes
omized, double·blind study. Arch P~diatr AdolesC' Med 2006; prednisone might be considered for reduction of pain
160: 197-202. and stiffness in patients with severe polyarthritis who characteristic of osteoarthritis are often asymptomatic. In·
9. Hay AD. e1 al. Paracctamo1 plus ibuprofen ror the ucatment of are unresponsive to other drugs, or awaiting response to crea~cd loading of the joint, and mechanical factors such
fever in children (PITCH): randomised conlrolled tri31.
Abridged version: BMJ 2008; 337: 729- 33. Full \•ersicn: slow-acting second-line treatments.' as misalignment and muscle weakness, co11tribllle to joim
http:f,\..ww.bmj.<.-omlcgi/n;prinl/33 7/stp02_2la J302 {ac\;~ss..xj • The second-I ine treaonent of choice in children with damage and loss of function. The joints most often affect-
!4i12/C9) Corrccl;on. ibi:I. 2009; 339: 510. persistent active artluitis is methotrexate. 1·3•7•9 .io Like ed arc hands, hips, and knees.
HJ. H:\}' AD.~' nl. Antip}'r-etic drugs for children. BMJ2006: 333:
4-S. several other second-line drugs it is of less benefit in Current treatment for osteoanhritis is not curative, and
I I. Weight AD. Lh:bch £L. Ahcn1~ting tullipyrcli1,;s for fever rtduc• systemic arthritis than in polyarthritis or refracto1y oli- management is largely concerned with relief of pain and
lion in ;:hildren: :m unfounded prae(iec p~sscd down to parents
from pc:diatrici<1ns. Cli11 P~tliarr (Pliila) 2007; 46: 146-SO. gom1hritis.9 Improvement may take up to 12 weeks to maintenance ofjoint function. 1•6
I~. Russ~ll FM.~' 111. Evidence on 1hc use of parocetanlol in (ebdlc be seen.1 Physical methods of treatment may be preferred initially,
children. 8111/ WHO 2003; 1)1: '.>67- n. and include physiotherapy, heat and cold d1erapy, exercis-
13. Shaim f. Antipyrc1ics in severe sepsis. lancer 1995; 345: 338.
• The so-called biological therapies have become in·
14. Joint \\'Otking Group of the Research Unit of 1hc Royal C('ll!cgc creasingly important in managing more severe or refrac- es, splinting, correction of misalignment, and weight re-
of Phvsicians and the British Pacdi~lric Associ::ition. Guidelines tory forms of juvenile idiopathic anluitis. J.J.5•9• 11 The duction in the obese.1·8 Acupuncture may also be tried, and
for th'to mclna~emenr of com•ulsions with fever. B...1.J 1991; 303: Th'F inhibitor etanercept, which is licensed for paediat- appears to be of benefit in improving pain and functional-
634-6. Also :vaifoblc at: hup:/lwww.pubmcdt"entral.nih.!ovi
picrt!'1'11ler.fc3i '!:tr1id• I 67 l I J5&b1t\blypc=pdf (a cc css~d ric use in many countries, produces excellent responses ity in knee ostecanhritis.9 Transcutaneous electrical nerve
24/06!C8) in many patients with polyanhritis, J'articularly those stimulation (TENS) may also be of benefit; however, a
IS. Uhari M. N al. Effect of nect:i1ninophen :tnd of low intermittent
doses of dincpam on prevention of recurrences of febrile sei-
who are rheumatoid-factor positive. Like methotrex- systematic review10 was found lo be inconclusive due to
zun:s. J /'~Jiurr 199S; 126: 991-5. ale, it may be less effective in those with systemic juve- the inclusion of small and poor studies.
16. Prymula R. ,., al. Effect of prophylo.etic p'1r-:icc1a1t1ol udminis1ro· nile idiopathic arthritis.~.1 1 Infliximab, although unli- For the management ofpain, paracetamol is recommcndod
lion ar time of vaccination on febrile rcactioos ~nd antibody re-
sponse~. in t.:hildren: 1w·o upcn-l!'ht:I. ramJ.,mised controlled tri-
censed, also seems to be of benefil,1·3.9·11 and may be as the drug offirsl choi~-e. 1 ·6.S Despite its benefits paraceta·
:ils. la1•ce1 2009; 374: 1339-50. ~ · more effective than etanercept in the treatment of asso- mol has been shown to be less effective than an NSAID in
17. AnQny1nous. ProphylAc:ic paracetamol wi1h childhood immuni- ciated uveitis.2 Other drugs that have been rried with patients with osteoanbritis, 11 and the latter may therefore
sation? Drug Titer 8t1111990; 28: ll~.
18. Simon HB. H)'}-~rlhcrmia. N Eng/J Med 1993i 329: ~$3-7. some evidence of benefit include abatacept, adalimum- be considered as an alternative first-line trcatrnent. 2 _.
19. Slovis CM. Hypenhenni•. N £,,g/ J Med 1994; 3~0: 218-19. ab, tocilizumab, and anakinra; 11·9•11 there is some evi- However, the possibility of cardiovascular, gastrointesti·
20. Duthie OJR. Hc:iHelated illness. Lo11ce1 1998~ 3S!: 1329-:lO. dence that the latter, an interleukin-I receptor antago- nal, or renal toxicity with NSAIO treatment should be con-
21. Bouchcma A. Knochel JP. Heal ~lrokc. N Engl J Med1002; 346:
197&-88. nist, may be more effective than the TNF inhibitors in sidered as its use is in a largely elderly group of patients; it
22. Nabulsi M. ls combining, or alternating nntipyrctic; therapy more tre3ling patients with systemic arthritis.2 (Abatacept and is generally advised that a low-dose NSAID should only
beneficial than mono1herapy for fe hrilc children? DMJ 2010; adalimumab are now licensed in some countries for pae- be added or substituted in patients witl1 an in3dequate re-
340: 92-4.
diatric use in active disease). sponse to paracetamol alone,~A-6 and the long-term use
• Many other drugs have been tried in juvenile idiopath· needed for osteoarthritis management may be problemat-
Musculoskeletal and Joint Disorders ic. r:
ic anhritis, often on the basis of efficacy in adults. Sul-
The rheumatic disorders are painful disorders affect-
fasalazine may be of benefit in late-onset oli11,oartl1rilis 1 ln order to reduce the risk of gastrointestinal toxicity with
ing mainly the joints and related structures of the mus- but adverse effects are often troublesome.9 ·ro Concern NSAJDs, use of a gastroprotective drug such as a proton
culoskeletal system, but there may also be widespread about adverse effects may also have limited the use of pump inhibitor or misoprostol has been recommellded.1·6·8
involvement of other systems. The tenn arthritis is cytotoxic and immunosuppressant drugs other than Cardiovascular safety is a particular concern with NSA!Ds
used when the disease is largely confined·to the joints. methotrexate, and there are few controlled studies,9 al- such as cclecoxib that are selective inhibitors of cyclo-ox-
Some of the most common fonns of artluitis are dis- though benefit has been repo1ted with leflunomide in ygenasc-2 (COX-2); U1eir use is limited to those patients
cussed in this section and these include rheumatoid ar· polyarticular disease. 1•9 •10 TI1alidomide has been sug- considered to be at high risk of developing serious gas-
thritis, osteoarthritis, juvenile idiopathic arthritis, and gested-for treatment-resistant systemicaithritis. 1 Jn very trointestinal problems if given a non-selective NSAID and
the spondyloa11luopathies such as ankylosing spond· severe unremitting disease, autologous bone marrow who do not ba\>e pre-existing cardiova:;cular risk factors
ylitis. Other conditions that are associated with arthritis transplantation has been tried. u.s-io (see Effects on die Gastrointestinal Tract, p.101). The use
Drug treatment aimed at rhe complications of disease, of topical NSAIDs has also been advocated,•,6.S although a
and which are discussed elsewhere include gout
rather than tl1e disease process itself, may be needed. 1l1ere meta-analysis" in 2004 found little evidence oflong-tenn
(p.600) ~nd SLE (p. I 652). is some evidence that bisphosphonates may be useful in benefit.
The names soft-tissue rheumatism (sec below) and controlling low bone mineral density and fragility frac- lo patients in whom paracetamol and/or NSAJDs are inef-
non-articular rheumatism have been used to de- tures associated with juvenile idiopathic arthritis. 1·12 fective or not tolerated, addition of an opioid analgesic
scribe some painful conditions associated witlt disease Growth hormone has also been widely used to moderate may be appropriate;2.l.S.6,S.i 4 codeine or dihydroc-Odeine
12 Analgesics Anti-inflammatory Drugs and Antipyretics
are often used as combinations with paracetamol, and 16. Brandt KO, ti ttl. EfTec:i.s of doxycyeline~es.sion of oste- facients may provide slight relief of pain but their role, if
there is evidence of benefit with tramadol, but more potent oarthritis: results of a randomized. placebo-controlled, d(\ubte-
blind trial. Arthritis Rheum 2005; 52: 201S-2S. any, is unclear.
opioids such as hydrocodone, oxycodone, transdermal 17. Iqbal I, Fleischmann R. Treatment of ostoo;:,rthritis with anakin- Once the diagnosis is confirmed and severity and progres-
fentanyl, or morphine, may have a role in a selected sub· ra. Curr Rhtumotol Rep 2007; 9: 31-5.
18. Cicero AF. Laghi L. Aclivity and potential role or licofclone in sion of the disease have been assessed, introduction of a
group of patients.14 the mDnagement of osteo:irthritis. Clin Inter.• Aging 2007; 2: disease-modify ing antirheumatic drug (DMARD)
The anthraquinone derivative diacerein has been widely 73-9. should take place as early as possible.1·3,l Although opin-
19. Arron 6. Oood)·ear-Smith F. Corticosteroid injections for <'k.5le-
used in some countries, and appears to produce a small but 03rthri1is of the knee: meta·i)n.,Jysis. BMJ 2004; 328: 869- 70. ions vary, there is an increasing trend to aggressive man·
consistent benefit in the treatment of osteoarthritis.15 T".f.s 20. Bellamy N, et al. lntrasrticuls r corticos1croid for treatment of agement in early disease, with tight control of the disease
ical capsaicin also produces wme relief of pain. 1•4 ·8 osteoarthritis <tf the knee. Available in The Cochrane Database
of Systematic Revjcws: Issue 2. Chichester: John Wiley; 2006
process."7· 10
There are some interesting data16 to suggest that doxycy- (accessed 23/06/08). Available DMARDs include antimalarials (hydroxychlo·
cline may have a favourable effect on the progression of 21. LoGH,etol. Intra-articular hy.aluronic acid in trcalmenl of knee roquine), sulfasalazine, gold compounds (auranofin, sodi-
osteoarthritis, which rnig)lt open the way for the develop- osteo3rt.hritis: a met.1.-analysis. JAAU 2003; 290: 311 S-21 .
22. Bellamy N. et al. Viscosupplement.ation for rhe 1rea1mcnt of o~­ um aurothiomalate), penicillaminc, conventional immu-
ment of disease-modifying drugs. Experimental therapies teoanhritis of the knee. A\•ailable in The Cochrdnc Database of nosuppressants (methotrexate, azatl1ioprine, ciclosporin,
include anakinra 17 and the combined cyclo-oxygen- Systematic Reviews; lss\1c 2. Chichester: John Wiley; 2006 (ac- cycloph05phamide, and lellunomide), and so-called bio·
asellipoxygenase inhibitor licofelone. 18 cessed 23/06/08).
23. Rossnagel K, er al. Klinischc Wirksamkch 'r'On Hagcbuttcnpul- logical ther.1pies, including the TNF-a inhibitois (adali·
Systemic corticosteroids have no place in the management vcr bci Pat.ienten mit Atthtose: ei.nc systcmatische Uber.;icht. mumab, etanercept, golimumab, and inlliximab). co-stim·
ofostcoarthritis. lntra·articular injection ofa corticosteroid MMW Fomch' Mcd2001; 149: 5t-6. ulation blockers (abatacept), interleukin-I receptor
24. ChrislCO$CJl R.. Cl al. Symptom:nic effic,cy orOYOCDdO·Soybean
produces short-term relief of pain and inflamma- unsap0nifiabJes (ASU) in osteoarthritis (OA) patients: a mcla- antagonists (anakinra), and B-cell-targeted antibodies
tion,2-1.6,8,l9.20 and may be useful for acute exacerbations. ana.lysisor randomitcd controlled trials. Osteoartliri1is Carri- (rituximab). It is thought that most DMARDs inhibit the
/age 2008; 16: 399-408.
Triamcinolone hexacetonide appears to be more effective 25. Clegg DO, et al. Glucns.aminc, chondroitin sulfate, and the l\\'O release or activity of cytokines involved in maintaining tl1e
than bctarnethasone.20 There may also be some benefit in combination for painful knee osteoarthritis. N Engl J Med inflammatory process, although other actions may also
from intra-articular injection of hyaiuronic acid, to im- 2006; 354: 79S-ll08. contribute. Since any therapeutic effcc1 may not be appar·
prove the viscosity and elasticity oftbe synovial fluid; 21 ·n
26. Towheed TE. et of. Glucosamine rherapy for treating osteo3r-
1hri1is. Available in Tne Cochrane Database of Systematic Re· ent for 4 to 6 months, treatment should continue for at least
improvement may be longer lasting than with intra-articu- vi ews; Issue 2 . Chichester: John Wiley; 2005 (accessed 6 months before considered ineffective.
lar corticosteroids.20 23106!08).
27. Towhecd TE, Anast.assiades T. Glucosarnine therapy for osic- There is evidence of disease-modifying effect for mcth-
Alternative and complementary therapies have been wide- oarthritis: an updalc. J Rhcumotol 2001; 34: 1787-90. otrexate, sulfasalazine, lellunornidc, and intramuscular
ly used in osteoarthritis.2 PowdCTed rose hip has been re- 28. Reichenbach S. et al. Meca-ana1ysis: chondroi,in for osteoar- gold, with less compelling data for hydroxychloroquine,
ported to be ofbenefit,2 l as has amixtureofunsaponifiable
thritis of the knee or hip. Ann Intern Me.<12001; 146: SS0-90.
29. Anhritis Restl.rch Campaign. Complemen1.1ry and 3Jtema1ive °"
penicillamine, oral gold, ciclosporin, and azathioprine. 1 16
fractions from avocado and soya oils (avocado-soybean mcdicinf:s for the 1rca1ment of rheumatoid anh1itis, osteoorthri- Concerns about toxicity or efficacy mean that gold com-
unsaponifiables; ASU).24 Particular attention has focused ti.s and fibromyalg.ia (issued February 2009).
Avai lable at: htlp ://www.arthritisrcsea rchuk .org/F il e~/
pounds and penicillamine seem now to be less widely
on the use of oral glucosarnine and chondroitin. Results, used. There is good evidence of the efficacy of the 1NF-a
however, have been ambiguous:ll-28 overall it is not clear f.~~fJfO;~~~~r1~~~~~~~e~O~~~~~}i vc%20mcdieines_ inhibitors,l.6.IO,t6-l9 and some in favour of anakinra,"·19
to what extent these therapies h~ve a benefit over placebo, 30. Rutjes AWS, et al. S-Adcnosylmclhioninc (ot osteoanhriti.s of but good evidence of an effect of other biological therapies
the knee or hip. Available in The Cochrane Database of Sy~tcm­
but there is some evidence that combined h'eatment may atic Reviews; Issue 4. Chiehestcr: John Wiley; 2009 (accessed on disease progression is currently scanty, althoug)l clini-
be useful in the subset of patients with moderate to severe l l/12109). cal benefit has been found with, for example, abatacept
knee pain. 2l Evidence for chondroitin seems particularly and rituximab.6.l7,l9.20
weak.-:is An evidence-based report29 by the Arthritis Re- Rheumatoid arthritis The choice ofDMARD to begin treatment is based on the
search Campaign in the UK of27 alternative and comple· Rheumatoid arthritis is a common chronic systemic in- risk/benefit ratio, with the antimalarial hydroxychloro·
mentary medicines used for osteoarthritis, including ASU, flammatory disease that results in progressive disability quine an option in mild disease, and sulfasalazineor mcth·
capsaicin, chondroitin, glucosarnine, and rose hip, found and increased mortality. Early disease is characterised ob'exate preferred in those with moderate to severe dis·
topical eapsaicin to be the most effective and that ademe- mainly by inflammation of the synovium (the inner mem- case, or judged likely to progress. 10 Methotrexate has
tionine, the active derivative of methionine, may also be brane of the capsule of synovial joints); as the disease become the DM.'\RD of first choice in the majority of pa-
effective; evidence for the efficacy of glucosamine was in- progresses the patient suffers destruction of cartilage and ticnts.'.2·'-10 Subcutaneous or intramuscular methotrexate
conclusive. However, a systematic review30 of ademetio· bone. Exb'a-articular features commonly include general may be an option in patients who caMot be satisfactorily
nine therapy for osteoarthritis of the knee or hip was found malaise, fatigue, weight loss, fever, and anaemia. More SC· managed with weekly oral dosage. I.JU Addition of sul·
to be inconclusive and routine use was not recommended. vere disease may be associated with vasculitis, pericardi- fasalazine, hydroxychloroquine, or both may bea suitable
Surgery, including joint replacement, is of great benefit to tis, pleurisy, pleural effusion, pulmonary interstitial fibro- option in patients refractory to optimal methotrexate ther-
patients with severe osteoarthritis that cannot be effective- sis, peripheral ncuropathics, subcutaneous and pulmonary apy, 1·10 and addition of corticosteroids or leflunomide are
ly managed by physical or medical therapy.2.0.8 nodules, scleritis, and Sjogren's syndrome. Palindromic also options, although evidence for combining methotrcx·
I. Felson OT. Ostro:irthritis or the knee. N Engl J M~tl 2006; 3S4: rheumatism is characterised by repeated episodes ofarthri- ate with ciclosporin is not entirely convincing. 10 At what
$41-8. Corrcciion. ibid.; 2520. tis and periarthritis without fever; the joints appear normal stage biological therapies are to be recommended remains
2. Hunter DJ, Felson OT. O>tcoanhri1is. BMJ2006; 332: 639-42. between attacks. a matter of debate. In the UK, official recommendations
3. Lane NE. Clinical prnctice. Osteoinhriti$ of the hip. N Engl J are still that TNF-a inhibitors should be reserved for pa·
Med 2007; 357: 1413-21. The severity and course of rheumatoid arthritis varies
4. Hunter OJ. American College or Physicians. In the dinic: ostc- greatly between patients. Some have brief attacks with lit- tients who have failed treatment with two conventional
('13r1hrili!'. Ann Intern Med 2007; 147: ITC8-1 -rfC8-16. AlsCJ tle or no disease progression, but the majority will have DMARDs,"·21 but others pennit earlier introduction, for
avail:iblc at: hup:l/Y.";vw.annal.s.oflVcgilreprinl./147/3/ITC8-f .pdf examp le after failure of the first conventional
(accessed 24106/08) slowly progressive joint destruction and deformity despite
;, American College of Rhcumatology Subcommiucc on Osteoar- intermittent relapses and remissions; a few patients may DMARD. 17.22.23 Other classes of biological therapy are
thritis Guidelines. Recommendatjons for the medic.al m:magc- have very severe and rapidly progressive disease. Because likely to be reserved for patients in whom TNF·a inhibi·
mcnt ofosteoarthritis ofthc hip andknee: 2000 update. Ar1hritis tors are ineffective or contrd·indicated. as is currently the
Rheum 2000; 43: 1905- 15. irreversible joint damage occurs early in the course of dis-
Also available at: hup:/J\l.'ww.rhcumalology.org/public:i.tions/ ease, rapid diagnosis and institution ofb'eatmcnt aimed at case with abatacept•.23 and riniximab."20•23.2•
guidclincs/03-mg.mt/o!l·mg.mt.asp t.ncce5sed 23/06!08) preventing progression is crucial.14 Although there is no There is also some evidence in favour of beginning thera-
6. BycrS Kr3us V, Doheny M. Oste<larthritis. In: Adebajo A. ed. py with a combination of DMAROs, and su~uently
ABC of RlteumOlology 4th ed. Ci-.ichcstcr: Wiley.. Blackwell. cure, remission or substantial slowing of the disease proc-
2010: 51-8. ess is increasingly seen as an achievable goal in the major- 'stepping down' once conb'OI is achieved. 1·l,6.io.i .26 In·
7. Brosseau L. et al. Thcrmolherapy for 1rca1ment of os1eoarthri1is. ity of patients.•·6 • deed, N1CE7 in the UK recommends using a combination
Available in The Cochrane Datibue ofSystcmalic Reviews~ Is· ofDMARDs (including methotrexatc ind at least one oth·
sue 4. Chichester: John Wi Icy; 2003 (oe<esscd 23!06t08). The choice of drugs for relief of pain depends upon the
S. N111ional Collaborating Centre fo1 Chronic Conditions/NICE.
7
severity of symptoms. NJCE recommends using analge- er conventional DMARD, plus short·tenn corticosteroids)
Osteoarthritis: national clinical gu·delinc for care and manage- sics such as paracetamol, codeine, or combination prepa· as first-line treatment, ideally within 3 months of the onset
ment in adults (is sued February 2008). Available at : of persistent symptoms. The large, muhiccnb'e BeSt study
http:/lwww.nicc.org.uklnieemcdia/pdflCGOS9ful1Guidcl inc.pdf rations in patients with inadequate pain control, to poten-
(accessed 22!07/08) tially reduce 1heir need for long-term treatment with found that although initial combination therapy (mcth·
9. ScharfH-P. et al. Acupuncture ancl knee os1eoanhri1is: a three- NSA!Os. Nevertheless, most patients prefer an NSAID; ob'exate and infliximab, or methotrexate, sulfasaluine,
anned randomized trial. Ann /nrerR Mtd 2006; 145: 12-20. although these arc thought to have an advantage because and tapered hig)l-<lose prednisone) prcxluced earlier clini-
10. Ru1jer AWS, ct al. Tninscutantou~ cicelrostimulation for ostc-
oanhritis of the knee. Available in Th..: Cochr11ne ·oa1abase of of their anti-inflammatory effects, thec.linical evidence for cal improvement and less progression ofjoint damage, the
Systematic Reviews; Issue 4. Chichester: John Wiley; 2009 (ac- this has been questioned.8 There is little apparent differ- ultimate clinical improvement was similar in patients as-
cessed 14112109). ence between the various NSAIDs in terms of anti-inflam- signed to sequential monotherapy or 'step-up' therapyP
11. Towhccd TE, et ol. Acetaminophen for osteoarthritis. Available There is a concern that combination therafsy may expose
jn The Cochrane Database of S)slcmatic Re\·icws; Jssue 1. matory activity, but patient responses vary widely. When
Chichester: John Wiley; 2006 (acoossed 23/06108). starting an NSAID the dose is gradually increased to the patients to an increased risk of toxicity, 5 althoug)l the
12. Bjordal JM, et ol. Non·stetoidal tnti-infla:nmatory druss. in· recommended maximum over I to 2 weeks; if the re. BcStstudy did not find this to be thecase.27 Combinations
cludins cyclcroxyttenasc,..2 inhibitors. in osteouthritie knee ofTNF·a inhibitors with other biological response modi·
pain: mcta·-analysis of randomised placebo controlled trials. sponse is inadequate after a tolal of about 4 weeks, or if
8A:£/ 2004; 329: 1317-20. adverse effects are intolerable, other NSA!Ds are tried. In fiers such as anakinra or abatacept are not advisable, be-
cause of on increased risk of serious infection.6•17
13
· ~;:f; f~ ~~eE1~~~:{~0t~~~!~~~~ts~;:!.~~~~~~i~:ra~z the light ofconcerns about cardiovascular safety, treatment
with COX-2 inhibitors such as celecoxib is limited to those Since rheumatoid arthritis is a chronic disease, b'eatment
domised controlled trfals. /JMJ 2004; 329: 32~ .
14. Goodwin JL~ et al. The use of opioids in the Liealmenl of oste- patients considered to be at hig)l risk ofdeveloping serious may need to be very prolonged, but evidence of the long-
oarthri1is: when, why, and how? C11rr PoinH~otloche Rep 1005; gastrointestinal problems if given a non-selective NSAlD term tolerability and efficacy ofDMARDs is patchy. Stud·
9: 390-8. and who do not have pre-existing cardiovascular risk ies have suggested that many OMARDs are stopped after
15. Fidctix TSA. et al. Diaccrcin ror oStcoanhritis.. Available in Tnc
Cochrane Da13base of Systematic Reviews~ ls.sue 1. Chichester: factors9 (see Effects on the Gastrointestinal Tract, p.101). a few years, usually because of a decline in efficacy rather
John Wiley; 2006 (accessed 23/06!08). Topical analgesics such as NSA1Ds or capsaicin, or rube- than adverse events.18
All cross-references refer to cntnes in Volume A
 Analgesics Anti-inflammatory Drugs and Antipyretics 13
Addition of corticosteroids lO Dlv!ARD therapy may be 6. Smolen JS.~' nl. Nrw t~r;:ipics for lrU\Ul(.tl\ or rhwm;noid tr• J6. Mc-Carey OW, tt nl. Trial or A1orv:uta1in in Rhe\una1oid Arthri·
useful in early disease 10 control synovi1is, or as bridging th.ri1is. Laue.c l 2001; 370: 1$6 1-74. 1is (TARA); dNbl<-blind. randomised ploeebo-conuoll•d tri:ll.
1. National Collabotnioe Centre- for Ch•onic Condihon)ofNICE. Lnnc<rf 2004; 363: 2015-21.
therapy when starting or increasing OMA RDs. since they Rheumatoid arthritis: nitional clinic:il 1uid~linc for m~n:tacmcnc 37. Vroom F, ~'al. Oisnsc.modifyi~ arnithcurn~1ic dru&s i:> J,ttg·
produce rapid symptomatic conirol.10 Although they pro- and treatment in aduhs (issued February 2009)..~vai11bte at: nancy: cu runt sa.aru.s t!nd implie:3uons for th< fulurc. Dntf $/Jfe.
duce bone loss, this may be outweished (al least short- hnp:i/www.t1icc.org.uk!niccmcdi1/pdrJCG79FullGuidclinc.pdr ry2006: 29: 1145-63.
(•«cssed 15112!09) Jl. Ooldins A. e1 ol. Rhwm:.totd at\hritis and reproduction. Rhl:Nm
term) by their beneficial effects on the disease pr~: S. Witneckc T. Goaschc PC. Paracetamol versus nonstef'Otd.:il Di> Clin ~rhAm?001; 33: 319-43, vi-vii.
there is good evidence that adding a conicosteroid to treat- anti-inOammatory drus;s for rhcunt11oid Df'lhrilt1 Av1i1J.blc in
ment reooces the progression ofjoint crosion.:!9 Short- and The Cochtanie Oata.baR ofSy$1c1iu1ic Rc~ws.; rssuc I. Chach·
cs<«: John W-~cy: 2004 {accessed 23J06/08). Soft-tissue l'heumatism
moderate-tcm1 intennittent use of relatively low doses has 9. MHRA. Upch:cd advice on 11oc ..re1yof sel<cti,.. COX-2 inhib-
therefore been suggested (nol exceeding the equivalent of itors.. Message from ProfcuorG Duff, Cb1irman ofConuniu~ Soft-tissue rheumatism includes conditions such as:
15 mg of prcdnisolone daily).30.ll However, prolonged on Sofc<y of Medici..., (inued I i1h Fcbivaty, 200S). A"'ilobl< • bursitis (e.g. housemaid's knee)
therapy is associated with significant adverse effeds and ~\=L~fO:CNa!~:C·l>No~Slt~~:.~:~~~,?O:,c:.~~~; • fasciitis
long-tern use is not usually considered justified,•0 except Lates<Rdc...d C=<....S 23/06i0lll • fibromyalgia (fibrositis, muscular rheumatism, myofas-
in a select group of patients with established disease where lO. Luqmani R.. tt al. British Socic-ty for Rhcuna1oloay and Bri1ish cial pain)
Hc~hh Proicssion&I$ in Rhti.imalok>g.y g.uidtHne f04' lhc m~n­
nll other treatment options (including biological ag,emcm or rheumatoid artt-,rilis (the first twO years). Rht.111110-- • frozen shoulder
DMARDs) have been tried.7 ln1ra-articular injec1ion is tolugy (Oxfon/) 2006: 4S: t 16i-9. Full auidcline ovailablc a1:
hup:i!thcunu1ology.oxfO<djoum:il•.oriteai/d11a/1«12 I Sa/DCI/ I • humeral epicondylitis (e.g. tennis or golfer's elbow)
recommended for acute narcs, and may be panicularly ef- (aecessed :?.3/06/08)
fective when combined with aggressive DMARD thera- • sprains and strains
Il . Felson OT. er al. The comparative etr1cacy and 1oxicity orsec-
py. •a ond-line drugs in rheumatoid anhri1i1. Arthritis R"twn 1990; • tendinitis
33: 1449-61. • tenosynovitis
There is little good evidence lo support most o_tber drugs 12. Felson OT.~' ol. Use of shorc-tcm1 cniac-y/\oxicily tradcotrs to
tried in rheumatoid arthritis. Mcta-ana lysis' 2 has con- sclccc second-line dru~s in rheumatoid a11hri1is: a met.unalysis • Tie12e's syndrome
finncd that tetracyclines, and in particular minocycline, of published clinical tools. Ar1hritls Rheum 1992~ JS: 1I17-,2S. Inflamed or displaced tissue may al~-o impinge on nearby
13. Capell HA, <t ol. Second line (disease modlfyina) 1rea1men1 in
can produce some reduction in disease activity; erTeclS on rhcurnatoid 3nhritis: which drug for which p121icn1? Am1 Rh"um nerv~ and produce compression neuropathies such as car-
serological markers nppear 10 be more marked than clini- Dis 1993; S2: 421-$. pal tunnel syndrome.
cal improvements in lender nnd swollen joints. The effecLS 14. Tugwell P. ln1ema1ional con5ensus recommcndctions on cy· Some forms of soft-tissue rheumatism respond to selective
dosporin use in rheuin~noid arthritis. Dmg.t 1995; SO: 48-56.
may be greater in patients with early disease; minocycline I5. Cush JJ. e1 al. US consensus guidelines for the use of (')'• rest of the afli:cted region, massage, splinting, or applica-
has been recommendcd2l for those with low disease activ- closporin A in cheumatoid arthrilis. J Rheumntol 1999; l6: tion of heat, cold, or rubefacienLS. 1·3 Exercise is of value in
ity. Much research has been conducted into immunomod- II ?6-86.
16. Oonahue KE."' ol. Systematic- review: companuive cffcc1ivc· neck pain,l.4 fibromyalgia,5" 0 and frozen shoulder, 11 but
ulators and immunothcrapy. Although alternative immu- nC:$S and harms of di$CUC-modifying mnlicadon.s ror rheuma- its benefit in epicondylitis is unclear.•
nosuppr:ssants such as rnycophcnolate mofetil and toid arthritis. Amr lnren1 Med2008; 148: 124-34, For patients wilh epicondylitis oral or topical NSAIDs
tacrolimus have been tried. most interest in recent years 17. Furst OE. e1 al. Updated consensus s•:uernent on biologic.:i.I
agents for lhe lrca\mcnt or rheumatic diseucs, 2007. Atm may offer short-term pain relief, but it is unclear if they are
has surroonde<l new biological therapies. The interleukin- Rh~um Dis 2001; 66 (s.uppl 3): iii2-iii22. Correction. Ibid. 2008: effective in producing longer term benefit. 3·4 They arc of
6 recept<r antagonist locilizumab is given with mcthotrex- 67: 280. unknown benefit in froz.en shoulder, 11 and are not thought
atc for th: treatment of moderate to severe active rheuma- IS. NICE. Adalimumab. etanecccpt and in0ixi1nab for 1hc tru1mcnt
of rheumatoid arthritis (inucd October 2001). Available a1: to be helpful in fibromyalgia,5• 1 ~· 13 although some benefit
toid arthritis in patients who have not responded to, or are ht1p1!www.nice.ori.uk/niccmedi:l/pdlTTll I )Oauidonce.pdf (•c- has been rcponcd with paracetamol and tramadol.uo.12-1 4
intoleran: of, conventional DMARDs or TNF-n inhibitors. e<sse.1 23/06/08)
Corticosteroid injections produce dose-dependent benefit
It may also be given as monothcrapy to patienLS who are 19. Singh JA. et al. Biok>gtcs for rheuma1oid anhriur an ovc:rvicw
of Cochrane reviCW$. Avaibble in The Cochrane Oaiabue of for up to 9 months in shoulder pain such as that associated
unable tc tolerate mcth~xate or in whom mcthotrexate Systematic Rtvic-ws; Issue 4. Chtchcs.iu: John Wiley; 2009 (1<'· with rotator cuff tendinitis or frozen shouldcr,' 5 and oral
would 011erwise be inappropriate. Matrix rnctalloprotcin- cesse.ilS/12/09).
20. NICE. Ri1uximab for the lrcatmcn1 of rheumatoid anhrihs (i_s.. corticosteroids may be of benefit for up to 6 weeks al-
ase inhibitors have proved disappointing, but new TNF·a though it is not clear that benefit is subsequently
sutd August 2007). Anilable 01t: h1tp://www.n1c-c.0rg.uk/
inhibitors such as certoliZ11mab peso!, and modulators of niccmcdia!pcl(ITAl26guidanec.pclf(OC<lessed 23i06/08) maintained 16 (a study 17 in patients with epicondylitis sug-
B-cell finction such as acacicept, belimumab, and cpratu- ll . Ledingham J. Oc1ghtot1 C. Bri1i!h Society for Rhcum11oloey gested that bene:its of corticosteroid injection in this group
2llll1ab are under investigation. In addition, dcnosumab is Si.nchrcls, Guideline$ and Audi< WO<lcing Group. Update on the
British Society for Rhcumatotogy g1.udchncs for prescribing were paradoxically reversed after 6 weeks). Corticosteroid
of interest for iLS potential to control joint destruction.6 D:Fo. blockCTS in adults with thc'umatoMI arthritis (update of injections are often combined with a local anaesthetic; in-
Other rncthod.s of treahnenl that arc being or have been prc,·ioos guidelines or April 200t). RJ1eumaroloKY (0.'if,,,.d)
200S: 44: I S7~3 . jection ofa local anaesthetic alone has been shown to be of
investigated include gene therapy and autologous bone
Also available at: hup:JlrheumalOk>gy.oxfordJOUm:i1s.or&f('gi/ benefit in chronic neck paio.4
mam>w cransplantation. A rheumatoid anhritis vaccine is
also in clinical trials. Induction of tolerance with collagen
ttprinl144f'.JI S7.pclf (accessed 23/Q610l!)
:?2. Me)·cr 0, ti ol. Clinical pnintcc forma1 for choosin; a second·
Botulinum toxin has been tried in epicondylitis18and myo-
and other antigens given orally has also been tried, but re- line disease modifying anli·'thcum::ilic druJ in early rheumatoid fascial pain. 19 There is evidence that nitric oxide plays a
arthriris after failure or 6 months' first'"'lmc DMARD 1hcr1ipy. role in healing ir. p3tients with tendinitis, and topical appli-
sulLS arc reported to be variable. H Juim Bune Spi,,e .20G7; 74: 73-8.
cation of a patch containing glyceryl trinitrate has proved
Many ahemative and herbal therapies have been tried. 23. Saag KG. Cl "'· American CoUegc or Rhcumatoloay 2008 rec·
of benefit in patients with epicondylitis ortendinitis.:!O
Some studies ~uggest tbat addition of fish oils 34 and/or ommendalions for the use of nonbiologic and biolo.ie discHe·
modifyinp. antirheumatic drugs in rheumatoid ar1hr111s. Art/11 ills Fibromyalgia appears to be nssociated with abnormal pain
evening primrose oil to standard antirheumatic tberapy Rheum 2008: S9: ?62- 84.
might help to reduce pain and joint swelling. However, an Also available :11: hup:J/www.theumaiology.org/publicationsf responses, and some consider it a central pain syndrome
evidence-based report35 by the Arthritis Research Cam- guiddioes/rc1.:u1111m:ndations.pdf(acc.csscd IS/12/09) rather than a rheumatic syndrome. There is scrong evi-
24, Smolen JS, e.1 al. Workini!: Group on cite Jliluximab Consensus dence that low-dose tricyclic antidepressants are of benefit
paign in lhe UK of 2 1 altcmativc and complementary Scate.mcnl. Con~cnsus sralemenl on lhe USC or rilu>:im:ib in Pl•
medicines used for rheumatoid arthritis, including colla- tients with rheumatoid ar1hriliS. Aun Rheum Dt1 2001; (i6: in many patients, as is the tricyclic compound cyclobenz-
gen, ever.ing primrose oil, fish oils, and green-lipped mus- 143- 50. Also ov11ilable nt: h11p://nrd.bmj.com/c5i/rcprinl/66/ aprine. Combination of amitriptyline with the SSRI fluox-
21143.pdf(aceessed 24/06/QS) etine also appears beneficial, although SSR!s alone have
sel, only found evidence of efficacy for fish oils. 25. Anonymous. Combination therapy for eQrly rhcun11told 1nhri-
tis. Drug Ther 811112006; 44: 81-S. produced equivocal results; serotonin and noradrenaline
There has been considerable ioterest in the possibility that 26. ROOcns LJ. " of. Early combination disease modifyins rcuptake inhibitors (SNRis) such as duloxetine, milnacip-
slatins such as atorvnsllltin may produce clinical improve- antirhi..'1Jma1ic drug treatment for rhcunHlloid ar1hrhfs. Mtd J ran, or vcnlafaxi1c have also been reported to be of value.
menLS, albeit modest, in symptoms of rheumatoid arthri· Ausr 2006; 184: 122-S.
27. Gockoop-Ruitc-rman YPM. ~'al. Comparison of treouncnl Al fat · A me1a-Hnalysi~ 1 of antidepressants (the aforementioned
tis,36 as well as in any accompanying cardiovascular risk cgies in early rheumatoid arthrit is~ QI. Hnd~miicd trial. A;;n ,,,. dn1g groups and MAO!s) in the treatment offibromyalgia
factors. tem Med ?007; 146: 406-1S. found strong evidence for their efficacy in reducing pain,
The importance of managing eomorbidity in paticnLS with 28. C:i~ll H. Long1nm maintcMnce therapy with disease mocH(y.
sleep disturbances, and depressed mood, and improving
rheumatcid arthritis has been emphasised;1 in panicular
ing: anlirheum:aric drugs. J kluminntol 2002; 19 (suppl 66):
38-43. health-related quality of life; however, effect sizes were
infection (espccially pulmonary infection), cardiovascular 29. Kirwan JR. tt al. Effe~s er 'Jucoconicoid.s on radioloaicat pro-- small. Nevertheless, the authors suggested using shon-
disease, :ind osteoporosis require appropriate management 9_rc.ssion in rheumatoid arlhntis. Anil.1blc 1n The-Cochrane D>
i'abasc: uf$)'5lcma.1ic Rcvie-WJ: luuc I. Chkhcstcr. Jol\n Wiley. tcnn amitriptyline (based on effect size) and duloxetine
and actio~ to reduce risk factors. 2007 (atttsS<d 23J06/08~ (OOscd on number of patients studied) for the treamient of
The crcacment of rheumatoid anhritis during. preo.,n~ncy J.0. Gousche- PC. Joh.lnsea HX . ShOf'l·IC't"m low-dost' conicosttr· pain and sleep disturbances. nie antiepilepties pregabalin
presents its own problems; some of the most effective otds vs placebo and nons1er0Jd1l antiinfl=imrnalOt) druas in
rftcumatoid anhri1is. A,·ai1ab-lc in TM Cochnnc ntt~bHc of and gabopcntin 1ave been shown to be of benefit in con-
DMARDs such as methotrexatc and lcflunomidc have ter- Sy,,emaiic Reviews; Issue I. Ctu<hol<r. John Wiley; 200S (11<' trolled studies.S.1>.S.10.1?-1• Ouloxetine, milnacipran, and
atogenic properties, and for others, including the biologi- cased 23IOM>8). prcgabalin are now licensed in some countries for the treat·
cal therapies, there is linlc cvidcncc.37.31 Hydrox)'l::hloro- 3 I. Criswell LA. ct al. Modcntc--tcnn. low-~osc corticostcrotds for
rhnnn~1otd arthritis. A,·aitable in TM Coclvanc ~tlbasc of mcnt of fibromyalgia. Alternative and complementary
quine, an:I perhaps azathioprinc and sulfasalazinc, may be Sys1em:uie Review•; ll$Vc J . ChicheSICr: John Wiley: 1998 (le• therapies have been tried; 11 however, an evidence-based
relatively safe to use, but it is important 10 wcish benefit ce...rl 23/06.'08). report" by lhe Arthritis Research ~~paign in ~1e UK.of
agllinst ri;k for each individual case.37 32. St0-ne M. "al. Should 1ctracydinc triea1mtn1 be uStd mort ex-
tensively for rheumatoid arthritis? MC1.lln:alys1s dc:mon.SU'lilCl 4 such therapies, including ademeoonine (the acuve deriv-
I. O'Dell JR. Thcrapcuuc Jlratt;ics fOf ~umatoid arthritis.. N clinical benefit with reduction in disca.w echv1ty. J Rltemrt01ol ative of me1hionine) and topical capsaicin, found no evi-
Engl J Mtd2004: JSO: 2591-1602. 2003; 30! 2112-22. dence of efficacy.
1. Doan T ~1auarolli E. Rhtum11oid 1nhri1,.: an ov('r\t\c;w u(nc:w 33. Toussirot EA. Ora.I tolerance in 1he treatment orthcum1101d '1· 0

:md cmer;tnc lhcrap•et. J Clio Phormocol 200S: 4S: 751-62. thritis. C11rr Or11R Tc,.geD /liflomm .4/lcrgJ• 2002; I: '4S- 52. Surgery may bc ofbcnefit in some conditions ~uch as cpi-
3. Nurmnll.-imed t.fr. DiJktn1ns BAC. Efficacy. tolcnibiliry and 34. Cit-land LG. et ol. The role or Cii;:h otls in the lrcatmcnt or l"hcu· condylitis and pJssibly shoulder pain.3•4 Surgical decom-
C051 effc:c1ivene$S Q( dhct1l.:·mud1fying llllirhcuntaliC dn.lttS m•toid anhrhis. Drtigs 2003: 63: 84S-S3. pression is also the definilive treatment for carpal tu1mel
and bic1og.ic agents 111 rheum:itoid :irthrhis. Dn1gt 2005; 65: lS. An.hritis Re:sc.oarch Campai¥n.. Cumph:mcnt.r)' ;1nd oltcmative
661 -94. inc:dicincs for lhc treit1nent or rhcum;uoid l rthrhis, os1coanhri· syndrome 2} alt10ugh there is also evidence of benefit
4. Khm:!iku.i L, at al. Rhcu1n11oid anhritis. U111NI 2009; 373: tis ~nd fibromyalgia (iss.ued February 2009). from splin~ing2·2' and local corticosteroid injcction2.2l (al-
6S9~72. Available at: hup:i/www . ar1l1ritisrcscarchuk.or~/filu/
S. ~mery r. 'fttatmcnt of rheumatoid u1hri1i~. BMJ 2006: 331: Coin pie me nt ary%20a ndV112 Oa Itcr na Ii ve% 2Orned1 einc:s_ though bcncfi1 ma);'. not be long term, and the procedure
I S2-~. 110120101 S•33 l.pclf (•«<$$Cd 08/04!10) can-ies some risks- 6). A systematic review 27 concluded
14 Analgesics Anti-inflammatory Drugs and Antipyretics
chat surgical treatment was significantly beuer than tis. but not for spinal symptoms. TIIC efficacy of most other 16.Zochlins J, et al. 'ASscssment in AS' lniem.:nional Working
Group. European League Against Rhcumalism. ASAS/El:LAR
splinting for symptomatic relief of carpal tunnel syn- DMARDs used in rheumatoid arthritis (see above) re-
drome. However, further study is needed to determine ifit mains to be shown. However, the TNF-a inhibitors adali- ~~~;:,e'*;~o;s ~~~ ~~";r~:~~~~~n!r~:~~~~~:Y~:~
is better than cortieosteroid injection or for patients with mumab, etanercept, and infliximab improve spinal pain, ht1p://ard.bmj.comicgiireprinV65/4/~~2.p<lf(accesscd 23l06/08)
J7. Anonymous. New drugs for peripheral joint psoria1ic an.hri1is.
mild symptoms. Oral corticosteroids and uluasound have function, and peripheral joint disease. They produce rapid D111g Tlier Bu/12006: 44: 1-5.
also shown benefit in patients with carpal tunnel syn- benefit (usually witllin I 2 weeks) although most patients 18. NICE. Ela.nercept and infliximab for lhc treatment of adults
drome.24 relapse once they arc withdrawn. Treatment with a TNF-a
~tGf. ~~a~:fa~~~:;s~J~t:!~~fc~~:~~~)n~~~~~:~:1~d i
5 1
I. Reveille JO. Sofl·tls.,uc rhcutna1is1n: diagnosis and lrcalmCnl inhibitor should be considered in patients with active dis-
AmJ Med 1997; 101 (suppl IA): 23S-29S. TA J04guidancc.pdf (•cccs.•<d 23/06/08)
ease despite conventional treatments. There is some evi- 19. NICE. Ad3limumab (or the trea1mcnl of pSQria1ic anhritis
l . Shipley M, Wise E. P"in rn the wris1 and hand. In: Adcbajo A,
ed. ABC ~fRhtumo1ology. 41h td. Okhel!>tcr: Wilty·Blackwell, dence that early intervention may produce beuer remission (Technology Appraisal 12S, issued AuguSl 2007). Available at:
2010: s-11. rates, but il is yet unknown if this results in longer-tasting http://www.nicc.org.uk/niccmcdialpdITTA 12Sgu1dancc.pdf (ac:·
3. Buchbinder R. Mi1chell C. P11in in cM neck, shoulder and ann. ccsscd 23106108)
remission on withdrawal. Evidence is mostly lacking for 20. Furst DE. tt al. Upd.a•ed consensus statcmcru on biological
Jn: Adcbajo A, ed. ABC of Rhc11ma1ol<rt0•· 4lh ed. Chich.,tcr:
Wiley-Olockwcll, 2010: 1~-20. other biological therapies, but no marked benefit has been ae:ents for the ueatmcn1 of rhcum;11ic: dise:ases, 2007. A11n
4. van Tulder M, ~of Rc.pc1it1n 1tr1m injury. /..,cmc~t 2007; 369: seen in conflicting studies wilh the interleukin- I receptor Rl1Wm Dis 2007; 66 (suppl 3): iii2-iii22. Correction. Ibid. 2008:
181S--22. antagonist anakiora. 67: 280.
S. Fo11<lh K0. Oran JT. Managcm<nt or fibromyalgia: "ht a..c 21. Braun J, Sicper J. Ankylosing spondylitis. lancet 2007: 349:
the bnt treatment choicea1Dr"p2002: 61: S17-92. Psoriatic arthritis (or psoriatic anhropathy) is an inflam- 1379-90.
6. Ooldenberi OJ.. tf ol Monaacment of fibromyalJi• syndrome. matozy seronegative arthritis occuning in patients with 22. Pham T. et ol. Club Rhumatisme.s et Inflammation (CRl/SFR).
JAMA 2004; 292: 2388-9S. Rttcmmc:ndations of the French Society for Rheuma.tology re..
7. Busch Al, e1 of. Excrclsc for trcatina fibromyalgja syndrome. psoriasis. In some patients the spine may be involved gardin' TNFa. 1nta1onis1 therapy in patients with ankylosin&
A\•ailablc 1n The Cochrane Oa•abase of Systematic Reviews: Is.. when the condition may be indistinguishable from anky- spondylitis or psori.atie anhritis: 2007 update.Joint Bone Spi~
S41e 4. Chic:hestcr. John Wiley. 200? (acccucd 16112!09). losing spondylitis. Less frequently some patients have a 2007; 74: 63µ6.
8. Ibo S<l. e• ol Un4crsundins lhc fibromy•lsi• syndrome. Psy- 23 Moksymowydo WP. Updat< on lh< treaancnt o( onkylosing
d•ophormaco/ IMI 2007; 40: 24~7. form of symmetrical arthritis resembling rheumatoid ar- spondylilis. 17tu Clin Risk Monqg 2007; 3: I 12S--33.
9. Goldenbers OL. Muftidisctphnary m..Uhtin in lhc treatment thritis. The psoriasis (p.1123) and the arthritis usually re- 24, Ravindran V, a ol.. A S)'Sletnatic review and me.ta-analysis of
of fib<Omyalaia. J Clm Ps)'dlio1t)' 2008; 69 (suppl 2): l~. quire separate trcaunent. Treatment of the arthritis is ini- tffic.acy and coxicity of disuse modifying anti-rheumatic: drugs
I 0 Suud R. Pltannacofosical lrnlm<nl ortibromyalgia syndrome: tially as for ankylosing spondyliiis with NSAIDs and and biologie:al .agc:nt.s for- psorialic .anhrili.s.. Ann Rltt1111t Dis
new developments. Drup 2010: 70: 1-14. 1008; 67: SSS--9.
II. DiasR,<10/. Frozcnlllo<llder. 8W200S;JJI: 14S~. physical lheiapy. If these methods fail treatmem with a 2S. Cioulieb A,.,ol. Ouicklincs of care for th< ma112iemen1 o(pso-
11. O•uv.· OJ. Pharmacoth<rapy for potienls with libromyalgia. J DMARD may be instituted, although chloroquine and hy- n.asis and psoriatic arthritis: Scclion 2. Psotiatic arthritis: aver·
Clin Psychiatry 2008; 69 (suppl 2): 2s--9. droxychloroquine should be avoided since they may pre• view and JUidclino. or care for treatrnenl ._.;th an emphasis on
13. Abeln M, n ol. Updale on libromytlsia therapy. Am J M<d lhc biologics. J Am A.cod Dermotol 200&: 58: SS I~.
2003: 121 : SSs--61. cipitate skin reactions (see Psoriatic Arthritis, p.654). 26. NJCE. Adalimumab. ctancrccpt and infliximab fOf' ankyJoslng
There is most evidence 10 support the use of sulfasalazine
~:C.kj:'~h~icp~u':!i~:::~, ';.i~~~~, fo,:T~~!
14 0 spondyh1is: Technology Appraisal 143 (issued May 2008).
·
Rheumotol10fn; 11: 499-SI I .
or methotrexate. Leflunomide may be effective but is like- ~~~!~~~ida~~:c.~'l{~:=~·~~~~·uk/niccmcdia/pdf/
IS. Arroll B, Qood)-e::u-Smuh F. Conicosteroid iqjections (or pain- ly to be restricted by its toxicity and prolonged half-life. 27. K<1t A, Inman R. Sp0ndyloanllriticles. Jn: Adebojo A, ed. ABC
ful shoulder: a met,..nalysis. Br J 011• Proct 200S; 55: 224-8. Ciclosporin is also restric1ed by its toxicity. As in ankylos- of R/,.umo1olof:Y. 4th ed. Chichester: Wiley-Blackwell, 2010:
16. Buchbinder R. et ol. Oral steroid.I for adhesive c•psuli1is. A\·ail- ing spondylitis, however, si!lllifteant benefit has now been 19 $4,
able in The Cochrane Da&:il>asc ot'Sys1e.ma1ie Reviews; Issue 4.
Chichesrer: John Wiley: 2006 (occes><d 23/06108). found with the TNF-n inhibitors, and trea!ment with these
17. Bisset L, er nl. Mobilis.tuion wilh movement and exercise. coni- is recommended in patients with active disease despite St ill's disease
costeroid inl'cction, or wail and see ror tennis elbow: ran- treatment with NSAIDs and/or DMARDs. In the UK,
domis<d tria . Abridged. version: BMJ 2006; 333: 939-41. Full Adult-onset Still's disea5e is a syndrome characterised by
version: ht1p:/l'""~•.bmj.com/cgilrep<int/33317S7S/939 .p<lf(•c­ etanercept or adalimumab are preferred to infliximab, but high fever, with body temperature classically spiking daily
ccmd 23/06/08) treatment should be individualised; a monoclonal antibody or twice daily, an evanescent pink maculopapular rash, and
I8. Wong SM, tt al. Treatment of la1cnil 1icondylitis with botuli· such as adalimumab or infliximab is advocated by others
num toxin: a randomiz.cd, doublc:·blin , placcbo·controlfcd lri· artl1ritis (usually oligoarthritis initially). It is most common
al. Ann /ntem Med200S; 143: 793-7. in patients who also have inflammatozy bowel disease. in patients aged 16 to 35 years.
19. Q<rama E, ct ul, A double· blind, con,,ollcd study or booulinum There is some suggestion that alefacepl may also be of
to:< in A in chronic myofucial p.1in. NturolOKJ' 2006; 67: 241-S. benefit in psoriatic arthritis. Systemic corticosteroids have Treatment bas traditionally relied on NSA!Ds, corticoster-
20. Murrell GAC. U1ing nilric oxide 10 1rc1t ltndinopathy. Br J
little or no place in rhe management of psoriatic arthritis. oids, and immunosuppres.<:ants or other Df\1ARDs similar
Spor1s Mcd2007: 41: 227-31. to those used in rheumatoid arthritis (above). 1•3 A trial of
21. ~~':~!1:':~;;:.•at:i~i!.'s~~~nro:N~jiji~~~98-2;~ anti· Reactive arthr itis (aseptic arthritis) is characterised by
sterile synovitis following I t.o 4 weeks after an infection,
NSAIDs is worthwhile in patients with mild disease, but
22. Arthritis Rcsca..ch Campeian. Compl<mentary ond oltcmative most patients cannot be managed with NSAIDs alone.2.l
medicines for the 1rca1men1 of rheuma1oid arthritis. ~ac.oanhri­ most commonly of the gastrointestinal or genito-urinary Corticosreroids may be needed for initial therapy if mani-
tis ond libromyalgia (is11oed February 2009). tract. fatra-artic.ular features involving the slOn, eyes, or festations arc severe, but will eventually be needed in
Avaitable at: http:l/www.arthritisrcsurchuk.or"files/
Complemcntar)'%20and%201l1crna1ive%20mcd1cincs_ geni10-urinary tract may or may not be present. Reactive about 800/o of cases.2 Dll1ARDs (generally metho!rcxate)
110120101~4331.pdf (accessed 0&/04/10) arthritis is also a feature of Reiter 's syndrome. Reactive are introduced when corticosteroid therapy fails 10 control
23. Bbnd !DP. Carpal tuonel syndrome. BM.I 2007; llS: 343-6. arthritis is treated with physical therapy and NSAlDs and, the disease or when their adverse effects become problem-
2-4. O'Connor D. el ol. Non-suraical 1rc.a1men1 (ottle:r lhan steroid ifindicated, intra-articular injections of cortieosteroids; the
injection) for carpal 1unnel syndrome. A,·11lable in 'The Co- atic. Most patients wilt respond to methotrexate although
dvanc Oat.abase of S)'ilctnahC Rcvte~: ISSW: I. Qichcs.t.er. role ofantibacterials is less certain (see Bone and Joint In- liver function must be closely monitored. The value ofoth-
Jol>n Woky; 2003 (><<n>cd 2l/06/08). fections, p.173). er DMARDs is uncertain. Intravenous immunoglobulin is
2S. Manhel1 S. ~' ol. loa111 conicos1uoid injmion for c~l tunncl
S)-ndrome. Available in The Cochrane Oat11»sc of Syu.c.m.atic References. also frequently tried, although supporting evidence is lack-
Reviews; Issue 2. Chichester: John Wiley: 2007 (accessed I. Jcnes G. et al lntenbllions for 1rea1ing psoria1ic anhri1is ing.U
23106108). AY'llilable in The Cochrane Database ofSysicmatic Reviews; I'°"
~6. Gooch CL. Minen OJ. Tre:allMl'll or carp.al Nnnel syndrotDe: IS .,.. 3. Chichester: John Wiley: 2000 (accessed 23J06/0S). The TNF-a inhibitors have also been tricd.JJ but results
rhere a rote for local coniCOiilm>id injcctlOtl? llturfJlt>ty 2005; 2. Khan MA. Update on spMdyloanhropathics. Ann lnttm Mtd have been ~ariahle.~ Thm is, however, some e~;dence
64: 2006-7. ?002; 136: 896-907.
~I. Verdugo RJ. et al. Surgical wrsus non.surgical 11Ca1mcnt for
that interlwkin-1 and intcrleukin-6 play a role in patho-
;. Le~ RZ Veale DJ. Management of spondyl~nhro-pathy: new
carp>I tunnel syndromo. Available 1n The Cochrane Dat>baS< or phnnacologic•I 1r..1ment opriOM. Dmgs 2002: 62: 2349-S9. genesis of the condition, and there have been a few reports
Systt:matic: Reviews.; lss-ue 4, Chichesltr: John Wiley: 2008 (K· 4. Sicptt J, ~t al. Ankylosin$ spondyliti.\: an ovcoiew. Ann Rht11m of dramatic improvement with aoakinra (an interleukin-I
e<ssed I 6/l ll09). Dis 2002: 61 (suppl Ill): 1ii~iiil 8. receptor antagonist) in resistant disease, while tocilizumab
S. v1n du IJont-Dru.insnu. IE. ct al. Treatment of ankylasing (an interleukin-6 receptor antagonist) has also been sug-
Spondyloarth ropathies t;:X~!i!o~~~2~~ <:t>isr: S6~~~o~';c drug.c. c1;,, gested as an investigational d~rapy.2)
The spondyloarthropathies are a group of scroncgaiive ar- 6. 8rockba.1lk J, Gladman 0 . Oia.._ruiosis ind management of psori· The name Stilt's disease has also been used rather incon-
thritides which include ankylosing spondylilis, psorialic atic arthritis. Drug$2002; 62: 2447-57.
1. Kyle S. ~I ol. British Society for Rhcumacology Standards sistently to describe some types ofjuvenile idiopathic ar-
arthrilis, arthritis associated with inflammatory bowel dis- Ouidclints Audit Working Group. Guideline for anli·T'NF·o. thritis (above).
orders (enteropathic arthritis), and arthritis assocfoted with therapy in psoriotic arthritis. Rheumorolos:y (0~/ord) 2005; 44: I. Eflhi1nio11 P, Gcoray S. P11hogenc~t~ and man3gcment of adu1l·
infection as in reactive arthri1is (aseptic arthritis). 390-7. Corrections. ibid.~ 569 :md 701. Also av3ilablc ••: onset SLitl's disease. S~min .•rthrftis Rheum 2006; 36: 144-$2.
htlp:l/rhcum<itOlug.y.u>.:fordjoumals.org/cg.i/rcprint/44/JJ)90.pdr
Ankylosing spondylitis is characterised by arthritis of the (accused 23/06108) 2. Poucho• J. llow ain ~ impruvc 1rn: 111an.agcmcn1 ofaduh·onset
spine and sacroiliac joints and sometimes there is also 8. Kcal A. et ul. Brilish Society for Rhcuma1ology Standards. Still's disc11c? Joh11 IJ01r1Spina2007; 74: I I 7-J9.
Guidelines and Audil Working Group. BSR guidelines for pre- ) . KonU'.Jas A, EOhimiou P. Aduli.cmscl S1ill's dise.3se: pathogen-
asymmetrical peripheral involvement. Males under 40 esis, clinical m1niftsu11ions And thtraptutic ~dva n ce..fl. TJrugs
scribing TNF·a bJockcrS in aduhs with anky1osing spol'ldylitis.
years of age are mainly affected. The Aim of management Rh~mnot0logy (0~/ord) 2005; 44: 939-47. Also avftilablc at: 2008: 68: 319-33?.
of the disease is to reduce pain and sliffiless and lo prevent ht1p:~IW\~\\'.rhc:uma1ology. 01g.u k/g uidclincs!guidc l ines_as/
spine and joint deformity, which is accomplished using a tnrgu1dchnc_os (accessed 23/06/08)
9. Glad.nan OD. Traditional and newer thcnpeutic op•ions ror
combination of active physical therapy and drug therapy. psoriatic anhritis: an c,·idcnce-bascd review. Drugs 2005; 6S:
Exercises are used 10 strengthen muscles and 10 maintain a 1223-38. Abatace pt (SAN. USAN. 1tNN)
good posrure and range of movement in joints. NSA!Ds I0. Boulos P1 <f al. Pharm;ac:olQiial trc;itmcnt of 3nkylosing ipond-
ylitis: a systcmalic review. Dn,g~ 200S; 6S: 211 J-27. Abat~ceptum: BMS· 188667; CTLA4·1g. I·25-oncostalin M (hu-
are used to relieve pain and inflammation, thus allowing I I. Revoilfe JO. Amell FC. Spondyloanhrilis: updale on pathogen· man precursor) fusion protein with CT\.A-1 (antigen} (t..Jman)
the exercises to be performed; they do not influence the csi• • nd management. Am J Med 200S; 118: S92-603. f!M>n protein w~h m~bulin GI (human heavy chain frat;-
progression of the disease. Some patients may need to add 12. Petcrsel DL, S1gal t.H. Reactive anhritis. /nfect Dil C/lnNor1/1
ment), bimolecular (116-+ 1~6')-dtSUlftde.
Am 200S; 19: 863-83.
other non-opioid analgesics such as paracetamol for addi-
13. L.e•risalo--Rc.po M. Reaaive irthritis. Sc.ondJ Rheumotol 2005: A6aTauem
tional pain contrOL Systemic cortioos1eroids arc rarely in- l•: 2Sl-9.
dicated but intra-articular injections of corticosteroids may 14. Gordon KB. Ruderman EM. The trtaunent ofpsoriuis•nd pso- CAS- 332348·12·6.
be beneficial when one or IWO peripheral joints are severe- rialu: arthritis: an interdiscipli.n:ary approach. J Am Acad Orr- ATC - L04AA24
ly alfected. The disease-modifying antirheumatic drug '"'""' 2006; S4 (suppl 2): S8S--S91. ATC Vet - QL04AA24 .
(DMARO) sutfasalazine is of benefit for peripheral arthri- IS. :,:i=·,,~~~i~~;sSS~~S~>na!emcnt of anl<y- UNll - 7DOY867S97
All cross-references refer to entries in Volume A
 Abatacept/Aceclofenac 15
Adverse Effects and Precautions have been found in the synovium of patients with rheu- Aceclofenac (MN. rlNN)
Reactions commonly occur w itl1in I how of starting an matoid arthritis. Abatacep! is described as a biological Act!clofenac: Aceclofenaco: Aceclofenacum; Aceldofenak: Acek-
infusion of abatacept. The most frequently reported in- disease-modifying sntirheumatic drug (DMARD). lorer.ak; Aceldofenakas: A>eklofcnil4ld<i: Asel<lorenak [o-(2.6·
fusion events are dizziness, headache, and hyperten- Abatacept is used in the treatment of moderate to se- Dichloroanmno)pheoyl}acotate glyco41' ~cid ester; 2·(2.6·Dichlo-
sion; hypotension and dyspnoea occur less commonly. roanalino)pli<fl)'la<etoX'µ.cetic acid.
vere active rheumatoid arthritis (below). In the UK, it
Other acute events include nausea, flushing, pruritus, h;e<A<*'HaK
is licensed for use in patients who have had an inade-
rash, and wheezing. Most events are usually mild to quate response to at least one other DMARD, includ- c,.HnCl2NO, = 35~.2.
CAS - 89796-99-6.
moderate although stopping treannent may be neces- ing mcthotrcxate or a TNF inhibitor; in the USA, it is ATC-MOIA816; M02M25.
sary in a few patients. licensed for use in early disease. In the UK, abatacept ATC Ve: - QMOIA6!6: QM02M25.
Other common adverse effects include headache, na- is licensed for use with methocrexate; however, in the UMI - RPK779R03H
sopharyngitis, nausea, dyspepsia, diarrhoea, dizziness, USA it may be given alone or with other DMARDs
back pain, fatigue, cough, and abnormal liver function (but see Interactions, above).
values. Antibodies to abatacept may develop and ana- ~O....._,,,,COOH
Abataccpt is given by intravenous infusion over a peri-
phylaxis or anaphylactic reactions have been reported
rarely. Uncommon adverse reactions include paracs-
od of 30 minutes in the following doses, based on
body-weight: ~ NH)\ ..
thesia, thrombocytopenia, and leucopenia. • 500 mg for patients weighing less than 60 kg Cl~CI
Infections arc frequent i11 patients treated with abata-
cept and most often affect the respiratory and urinary
tracts. More serious infections such as pnewnonia, sep-
sis, cellulitis, bronchitis, diverticulitis, and acute
pyelonephritis have also been rarely associated with
• 750 mg for those weighing 60 to I 00 kg
• I g for those over I 00 kg
The dose is repeated at 2 and 4 weeks, then every 4
weeks thereafter. If a response to treatmen! is not seen
v
Pharmacopoeias. In £11r. (sec p.vii).
within 6 months, the benefits of continuing abatacept Ph. Eur. 6.8 (Acedo(enac). A while or almost while, cryStalline
abatacept treatment; some of these infections have powder. Practically in.soluble in water; soluble in alcohol; freely
been fatal. TTeatment should be stopped in patients may need to be considered. soluble in ac:<!onc. Store in ainight con11incrs. PrOlect from lighL
who develop a serious infection. Since immunosup- For the use of abatacept in children, and recommended Adverse Effects and Treatment
pressive therapy has been associated with progressive doses, sec below. As for NSAJOs in general. p. I00.
multi focal leukoencephalopathy (PML) treatment with Abatacept is also being studied for other auto-immune Hypersensitivity. l.cuooc:ytoclastic vasculitis, a type Ill hyper-
abatacept should be discontinued if.neurological diseases such as inflammatory bowel disease, psoriatic sensitivity reaciion, has been reponed after therapy with ace-
symptoms suggestive of PML occu'r during use. arthritis, and SLE. clofenac.13 Anaphylaxis has also occurred.3
Abatacept shou ld not be given to patients with severe I. EpcJdc F. Boada L. l..eukocytoclaslic v11Sculi1is and hernoptysis
Administration in children. Abatacept is licensed in the after tre:ument '"ilh :i.cecloftn1c. "'"' Pltormoco1her 1995: 29:
and uncootrollt:d infections such as sepsis and oppor- tre:itment ofmoderate to severe, active juvenile idiopnthic anhri· 116S.
tunistic infections. JI should be used with caution in pa- tis io children ascd 6 years and above; it may be used alone or 2. Morros R. ti ol. Hypcrscnsilivity vuculiti5 related lo acc-
tients with a history of recurrent infections, with under- wi1h methotrexate. The dose is calculated uccording to body- clofen:ic. Br J Rlwrm101ol 1991: 36: 503-4.
weight and is given as an intravenous infusion over 30 minutes; l. Rojas-Hijazo B, et al. An~phyl1c«ic rc~ ction after aceclotenac
lying conditions that may predispose to infections, or chose weisbins less lhan 75 kg should be given JO m&'kg initial- intake. AlleiJV•2006; 61: lll.
with chronic, latent, or localised infections. Patients ly, while he~vicr children may rc<:eive d>e appropriate adult dose Precautions
should be screened for latent tuberculosis before start- (see ~bove). Doses should be repeated ot 2 and 4 weeks, and then As for NSAIDs in general, p.102.
ing treatment; those testing positive should be treated every 4 weeks thcttofter. Aoeclofcnac should be ovoidcd in patients with moderate Lose-
with standard chemoprophylaxis before beginning Rheumatoid arthritis. Refemiccs to the use or aba111cep1 in \'fte renal impainne:nt.
abatacept rheumatoid arthritist·•O (p.12) one! juvenile idiopathic orthriris 11 Interactions
(p.11 ). In the UK, ab3111ccpt is licensed for~ treatment orrhcu· For interactions associaled with NSA!Os, see p.103.
Some disease-modifying antirheumatic drugs have matoid arthritis in patients with an inadoquatc response to Stand·
been associated with hepatitis B reactivation; licensed ard disease-modifying antirhcumatic drugs. Although NICE Phannacokinetics
product information for abatacept recomtnends screen- docs nOI recommend such use because its oost-effccchoncss was Aoeclorenac is well absorbed from the gllSlrointestinal tract and
ing for viral hepatitis before starting treatment. qucstionablc, 12 it rewmmcnds that those curmitly caking abata- peak plasma cone<.-ntrations oocur l to 3 hours after an oral dose.
cep1 should continue on therapy w1til it is considered appropriate Aceclofenac is more than" 99".4 bound to plasma proteins. The
Adverse effects of abatacept are more frequent in pa- tOSlOp. plasma-elimination half:life is about 4 houn. About two-lhirds
tients with chronic obstructive pulmonary disease and I. Kremer JM. et nl. Trcaitmcnt ofrtieumatoid arthritis by sclcc;tive ofa dose is excreted in the urine, mainly ns hydroxymetabolites.
may include a worsening of their respiratory symp- Inhibition ofT-c.<:11 :ictiva1ion with fusion pro1cin CTl.A4JQ.. N Asmall amount is converted lo diclofenac.
Eng/JM"12003;349: 1907-15.
toms. 2. Ocnovcse MC. ef of. Atxltacept for rhellm:uoid anhritis rcfrnc.. Ofl h3s been suggested' Lhot low concenlrotions or diclofen3c. o
tnry to tumor necrosis factor« iflhibilion. N Engl J M_.d 2005;. minor melabolile, may account for some of die actions of ace·
Carcinogenkity. The role or abatacept in the onset or malig- 353: l 114-23 . Correction. ibid; l)l I. clofe~c.
nancies such as lymphotna in humans is not known. ~. Kri:mcr JM. ~I ol. Effects of abalaccpt in p~titt1 I J with n1cth· I. HinzB.c10/.Accclorcnac:~ircsc:ycloox)'gCna.5e 1 asar~suhof
04rex1tc-rcsi~tan1 ac:tio:(: rt:..c,u11ataid arthritis: a randumiud 1ri·
ln placebo-controlled studies th• o""rall frequency ofmalignan· >I Am1 /n1<7n MM2006; 144: S6S-76.
limited but sustained biouansfotma1ion to dictoft::n3C. CJ;,, Pltor-
ties in patients treated with ab:11acepc compared \\ilh ~who 4. Wcinblalt M. ~' nl. Safety of the- setecuvc. eostimullbon modtr "'°""' ""' 2003; 74: 222-35.
received placebo was similar (1.4% and t.1%, respe<:1ivcly). lator 1Ntac:q>e. in thewn3toi<l arthritis P"'~ ro..~ivin1 bxk· Uses and Administration
However. there "ere mon: eases oflung cancer and lymphoi~ gr«ind biologic: and nonbiolQ!fc dliease•modifyina antirhcv- Aceclofenac, a pbenylaccttc acid deriva1h-e, is an NSAID (sec
in those givat obatacepc. In studies in n1ia_ increases in lympho- ma1tc dru_g;s.: a one-ycaT midomittd. ptacet.ec>ntrolled study. p.103) related to diclof"enac (p.46). It is used in the management
h1/1ri1is Rimm 2006; 54: 2807-16.
mas and mamm1ry ll•nours have been flOled, allhough these in- of osreoanhrilis, rheumatoid arthritis, and ankytosing spondyli·
aea.scs hove nOI been seen in some studies with.Oll1er mominols. 5. ~~~~~i::~~n~«~~~~:~~~~~:-~7~-ra."a~cwnenl or tis, in usual oral dost.-s or I00 mg twice daily. Reduced dosC$
6. Pollard LC. Inhibiting cos~imuJttory :11c:tiv1tion o(T cells: 1 vi- should be used in paticncs with l><patic impainnent, see below.
Interactions able trettmcntoplion for rhcuina1oi<t onhricis? Dt·ugs 2007; ~7:
t-9. OReviews.
Live vaccines should not be given with obatacept, or 1. Lundquis1 l. Aba1acc:pl: a novel lher.apy 1ppro\'cd for dlC treat· 1. Dooley M. tttJI. Accclofcn1c:;. reapprais,al of its use in 1hc m.&n·
within 3 months of slopping it, as it~ eflect on vaccine mcnt or p:t1icnts with rheumall:lid a11hritis. Adv T11~rapy 2007; agemtnl of rain l'.ll'Jd rhCU11HUiC di'°C3SC. lJrugs 200 1; 61:
24: 333-45. . 1351-78.
efficacy or the risk of infection transmission is un- 8. Russ<ll AS. et al. Ab:naccp1 i mprove~ bmh the physical ar>d 2. Rcg,instcr JV, tt ol Comment posilionncr l'actdof~ouc au .5cin
known. l11e use ofTNF inhibitors with abataccpl may m~ntal heahh of patienu with rhc:um;itoid :111hritis who hnvc in· de l'arunal thtupcutiqnc deJ. pathologies ost~o-a rticu lttircs
adequate resp0n5e: to metho1rcxAte 1rc,ument. Am, Rhf11m Dis chrflniquc-s? Rttv Mi!d lit!BC! 2001; !\6: 484-S.
increase the risk of serious infections (see under lnflix- 2007; 66: I 89-94.
9. Bruce SP, Boyce EG. Update 01\ aba1ac(pt: a selective c:ostimu·
3. Lci:rand E. l\c:cc:lofcnac in the- mana:emcm of in113.mmatory
imab, p. 74); such combinations are not recommended. p;Jin. E.1i/Nr1 Ophr Plmrmoco,ltw11' 2004; S: 1)47-57.
lation modulator for rf\e\una1oid ard'mtis. llJtn Pll<Jr11,aco1lu:r
Many of the serious infections reported have occurred 2007; 41: I IS3-62. 4. Lee J. eta!. Formulotion or1n1croc1T\ul:sion systCms for 1r~nsdc:r·
in patients also receiving immunosuppressive therapy 10. Maxwt11 L. Sl11ah JA. AbaJaccpt fur rh1.:mn;11uid 1nhriti). Avail- m:al dellvuy of utctortn1c. Arch Pharm Re1 200S; 18:
able i" The Coc:hr3.T'le Databnc ofSrs-ttnJ.tic Rnlews; Issue ~. 1097-1102.
(see also above). Use with anakinra or rituximab is also Chidleslcr: John Wile~; 2009 tac......S 14/12!09). Administration in hepatic impairment. The initial onl
not recommended because of insufficient evidenc:e to 11. Ruperto N. ~1 al. Pudiatric Rhcumaitoloa:y lNtemuiOtUI Trills
dose of aceclorcnac should be reduced to 100 mg daily in pa·
assess safety. Orpni%3tion (PRINTO). Pcdi>tnc Rheumatology Coll>bon-
1ive Study Group tPRCSG). AhllAC'P' 1n childr<11 "'ilh1u-ilt 1ie11ts with bepatio impainnent.
idiopolhi< trtlvitis: • r.o.ndorniscd, double-blind, ptac<bo-<on- Preparations
troll.:d ,.,;,hdrawal trial. umw 2008; 372: 383-91.
Pharmacokinet:ics J2. NICE. Ab1111acept for 1he treauncnt a( rhcuma101d arthritis: Proprie~y Preparations (details •.,, given in Volume B)
Abatacept is reported lo have linear phormocokin~tics Technology Appraisal Guidltnce 14 I (l.,ucd April 2008). Al"f" ~ fldi.: ~· fol: BiofeNc: 8rOJ.: Cocollant; Prollarwt Chilo:
at usual dosages. After repeated intravenous doses, its Available a1: hnp:l/www.nict.ors.uk/niccmcdia/pd(/ Airtatt: Oenm.: a.rant. Fin" 81W"C1nt; Fr.: Unrex: Ge...: Beolena~ Gr.:
TA I4 lguid3ncc.rdf (ac«sscd 31110/081 Ace<ioruc; Mina. S.Olenoc Froelopon: lo,.,,: ~: Hung.: Al'.,mn;
mean terminal half-life is about 13 days. Remac Indio: Ace<tcc Nrc.t~ Mo-JOI'< Zoo"Odol: Ital: Anal: Gt""'°' r_.r.
Studies in 011imols suggest that abatacept is distributed
Preparations <WIC: M ex.: Sri"'""' Neth.: e.ore.,.c. Norw.: Bamnt. Philipp.: Clilnl!a.
Port.: A<rut Biofcn.lc: Rus.: Alrul (A>j)Ta.~ Spain: Actocen: Airtal; Artal
Proprietary Preparations (details a~ given in Volume B)
into breast milk. Ari.: OrenOa:. Austrol.: Orenc~: Aunrlo: Otcnc11: Chile: ~noa: Ci.: Oifu<rem. fak'.ot Ge~ S•neint; Swed.: Barcant: Switz.: Locomnt:
Oreneta; Oenm.: Orenc•i: Fr.: Ortnc&a: Ger.: Orencia: Gr.: Orer.cia.; Turk.: Sioltnoc VAf: Ace<lofar: UK: f're>OtVCX Venc..: Alrt.111: ~I·
Hunt" ObXia: Ir/" °"""1.: Ito/.: Orcntia: Ntth.: Orenoa: Norw" CX-
n:.....
Uses and Administration eoaa; NZ: O"....aa; Pol.: 0..ncia: Por<.: a--;,.; Spain: 0..ncia; Swed" Multi·ingredient: lndlo: Kinechne P: K.nt<"..ine·MR1: MOVOl\·MR:
Abatacept, a fusion protein, is a cO-stimu lation blocker. 0..,,.,.; Swia.: Ofeocia: UK: o.-;;a: USA: o...nc;.. Mo.<ll>-P. :Z.rodd·MR: Ztr"Odol·P
It prevents the activation of T-cclls; activated T-cclls

The S)mbol t del!Oles a preparation no long"r fonnuly marketed

16 Analgesics Anti-inflammatory Drugs and Antipyretics
Acemetacin (81iN.11NN) Preparations TNF receptois. It also modulates biological responses
Acemetacina: Acemetacine: Acemctacinum; AsemelaSin: Bay-r- Proprietary Preparations (de1ails .,. given in Volume B) that are induced or regulated by TNF. Elevaled levels
4975: lndometasinin Glikolik Ash Esteri: TVX- 1322. 0-[(1-p- Homoeopactt1c: Fr.: Neuroqnes:ne: Neth..: Neuroc~ . ofTNF have been found in the affected tissues and flu-
Chlorobcnzoyl-5-methoxy-2-methylindol-3-yl)acetyl)gfycofic ac- ids of patients with rheumatoid arthritis (below), anky-
id. losing spondylitis (see Spondyloarthropathies, below),
AueMe1a<fM Actarit (t!NI\? psoriatic arthritis (see Spondyloarthropathies, below},
CNH 18CIN06 ~ 15.8. = Actantum: MS.932. (p-Acetamidoohenyf',acctic acid plaque psoriasis (below), and Crohn's disease (see In·
CAS - 5316~-05-9. Al<npKT flammatory Bowel Disease, below). Adalimwnab is
ATC - MOIA611.
ATC Ve: - Q.MOIA61 I.
= 193.2.
C 1oH11N01 described as a biological disease-modifying antirheu-
CAS - 18699-02-0. matic drog(DMARD).
UN/I - 5V I 4 I XK28X. UNll - HW58635 I RZ.
Adalimumab is used in the treatment of moderate to
severe, active rheumatoid arthritis and active and
progressive psoriatic arthritis. In the UK, it is li-
censed for use in patients who have had an inadequate
response to standard DMARDs, although in severe
progressive rheumatoid arthritis it may be used in pa-
tients not previously treated with methotrexate; in the
Profile USA, it is licensed for use in early disease. Adalimum-
Actarit is reported to be a diseasc-modifyingantirlleumatic drug. ab is also used in lhe trea1ment of active a nkylosing
Pharmacopoeias. In Eur. (seep.vii) and Jpn. It has been i:jven in the treatment ofmeumatoid 8'1hrilis in a usu- spondylitis: UK licensed product infol11lation recom-
Ph. Eur. 6.8 (Acemetacin). A yellow OT greenish-yellow, crys- al Of31doseofI00 mg lhree limes daily. mends that it should only be used in patients with se-
talline powder. It exbibilS polymorphism. Practically insoluble in Adverse effects. A photosensitivity reaction developed in a vere disease wbo have had an inadequate response to
water; slightly soluble in anhydrous alcohol; soluble in acetone. 52-ycar-old woman one mooth after starting actaril and doxycy· conventional treatment; however, in the USA it may be
Protect &om light. clinc. 1 Phocopoteh tests for both drug$ were only positive for the
patche$ conraining adariL used in early disease. For all the above indications, it is
Adverse Effects, Treatment, and Precautions given by subcutaneous injection in a dose of 40 mg
As forNSAJDs in general, p.100. I. Kawacb A. tt ol. PhotOSitnsifrvity due to acta.rit. Conl(l(;I O.'ma-
tltl• 1997; 36: 17S- 6. every other week. In the treatment of rheumatoid ar-
Interactions Use. References. thritis, UK licensed product infonnation recommends
For interactions associated wi1h NSAJDs, see p.103. I. Nakamura lf, ~'al. Clinical effects of :tctarit in rhcurnatoid er- that ad.alimumab should be given with methotrexate,
Phannacokinetics lhriti,s: improvement of ea.rly disease 1cth·ity mediated by reduc- although monotherapy may be used where treatment
Aceme1acin is well absoroed ancr or.al dosage. Its major metab- tion or SC'Nm concentr.nions of nitric ox id~. Clin £,,p Rhe&1ma10/
2000; 18: 445-SO. with methotrexate would be inappropriate. When used
olite is indometacin (p.69) which, ~.fter repealed doses, is present
at higher concenlrations than those of acemetacin. Acemetacin is Pre parations as monotherapy in rheumatoid arthritis, some patients
bound to plasma proteinsto a sligh1ly )CSS(.Tex1crit than indomcl· Proprietary Preparations (details are given in \l:>lume Fl) may benefit from increasing the dose 10 40 mg every
acin. It is eliminated via both the liver and the kidneys. Jpn:M.,.....:Orcl week. Clinical response is usually achieved within 12
Uses and Administration weeks of treatment.
AccmeJacin. a glycolic acid esler ofindomeJaCin, is an NSAID Adalimumab is used in the treatment of moderate to
(p.103). Its pharmacological activity is due 10 both accmcl3Cio
and its majormclabolite, indomcracm (p.69). Acemetacin is used Adalimumab (BAN. USM( rtNNJ severe, active Crobn's disease unresponsive to con-
in rlleumatoid arthritis, osteoarthnl!S, and low back pain, and for Adalimumabum: 02E7; LU-200134. lrmuloglollulin GI (hu- ventional treatment; it may also be used in patients who
postoperative poin and inllammarion. Usual oral doses are 120 to man monoclonal 02E7 heavy ch2in anti-lunan tumor necrosis have relapsed while taking infliximab. Patients may be
l 80 mg daily in divided doses. Acemcracin is eliminated by bolb factor). disulfide with human monoclonal D2E71<-<hain. dimer given an initial dose of 160 mg on day I (given as four
hepatic and renal routes, although pharmacokinetics are not af- 40-mg injections in one day or two 40-mg injections
fected by moderate renal or hepatic impainncnl and appear lo be AAal.""')'Ma6
unchanged in the elderly. CAS - 331731-18-1. daily for 2 consecutive days), followed by 80 mg two
O References.
ATC - L04A804. weeks later (day 15). After a futthcr two weeks (day
ATC Vet - QL04AB04. 29), a maintenance dose of 40 mg every other week
1. Jones RW, et ol. Comparati\'c pharrnacokint:.tics of ~ceinetacin in
young subjects and elderly pa1icnts, Br J C/111 Phormacol 1991; UN/I - FYSOT7F84 2. may be started. There is a high risk of adverse effects
3 1: 543-5. associated with the above induction dose, consequent-
2. Hazkm:m 8, Bernstein RM. Acemcracin in 1hc long-rcnn thcrr,:, Adve rse Effects, Treatment, and Precau·
py of rheumatoid 11nhrilis. Curr Mad Rr.s Opin 1993: 13:
ly, in those who do not require a more rapid response to
119-26. tions therapy, UK licensed product information advises that
3. Chou CT, Tsai YY. A doubk·blind, randomized, controUcd pu- As for lnfliximab, p.72. a lower dose of SO mg may be given initially, followed
alld group study cvaluatinc tM cff.caicy and s.afcty or :tccmc1-
acin for the m•nagemen-1 of ostcoenhntis. Int J Clin Pharm«.ol Injection site reactions including erythema, itching, by 40 mg 2 weeks later; thereafter, usual maintenance
Ra 2002; 22: 1-6. pain, and swelling are the most common adverse reac· doses may be given. A clinical response is usually seen
•. lttb BF, ., al. Behandluoc dtt Oonu1hrosc: Wiriuamlccit und tions with adalimumab; however, most reactions arc within 12 weeks of starting treatment; those patients
VcrulsJichkeit von retard1e-rtcm A«mcucjn im Verglcich zu
Celecoxib. Orthopod• 2~; 33: 103~ I. mild and do not result in drug withdrawal. Other com· who relapse while on adalimumab may benefit from
Preparations mon reactions include headache, rashes, back pain, hy· increasing the maintenance dose lo 40 mg every week.
Proprietary Preparations (details arc given in \Illume B) pertcnsion, paraesthesias, increased alkaline phosphate In the treatment of moderate to severe chronic plaque
Aurtrfo: IU-oeutrop: CL: Ranlu6t Ger.: Accmetldoc; Rontudl: Gr.: Gai-ne- levels, and cough. psoriasis in patients unresponsive to, or intolerant of,
,Pr: R.ntudal: Huni-: Rani~ ho/.: Ac~: Solartt: /pn: F\aolucfj:
Mox.: RanUJC!it Phllfpp" llantud,f: Pol.: llantudd: Port.: Ra.otudil; Sporn: Autoantibodies to adalimumab have been detected. conventional systemic therapy including phototherapy,
e.pledolt; Oldanl: Switr.: n..,.:
Turk.: Ranlud;t UK: ~ Vonex.: the recommended initial dose ofadalimumab is 80 mg
Mosunotf: Prone>< Interactions
Multi-ingredient Arc.: A.Jcatcf'I fOf"te; R.uc~t.en Prednis.o!ona.
subcutaneously; this may be followed by a mainte·
As for Jnfliximab, p.74. nance dose of 40 mg subcutaneously on alternate
Methotrexatc is reported to reduce the clearance of weeks, starting I week after the initial dose. A clinical
Acetanilide
adalimumab by up to 44% but licensed product infor- response is usually seen within 16 weeks of Starting
mation for the latter states that dosage adjusunent for trtatment.
Acetanilida: Antifebrin. N-Pheny1acetamide. either drug docs not appear to be necessary.
At<mjie6pv.t< Aue~ For the uses of adalimumab in children, and recom-
C 8 H,NO = I 35 2. Pharmacokinetics mended doses, see below.
C'\S - 103-84-4. Adalimumab is reported to have linear phannacokinct- Administration in children. Adalimumab is used in the treat·
UNll - SP86R356CC ment of active polyarticulor jll'-cnilc idiopalh!C mthritis in chil·
ics at usual dosages. After subcutaneous injection peak
concentrations are reached in about 3 to 8 days and bio- dren. In the UK. i1 is licensed for use in tho!C aged 13 yean and
older who have had an inadcqualc response to stand:lrd di~
availability is estimated to be 64%. The mean terminal modifying antimeumatic druS' (DMARDs); adalimumob in •
half-life is about 2 weeks. dose of 40 mg is given by subcutaneous injection every other
O References.
week. Licensed product informa1ion also reconimcnds that it
should be given with mcthotrcxote, ahhough monotherapy may
I. Ncs1oro\' I. Clinical phannaeokinctics of tumor •l«rosis factor be used where treatment with me01otrcxatc is inappropriate.
an1asonim. J Rh•11motol 200S; 74 (suppl): 13-18.
Pharmacopoeias. In Ft: lo the USA, adalimumab is licensed for use in children as young
Uses and Administration as 4 ycan old to reduce the signs and syrnp1oms of moderately to
Profile Adalimumab is a recombinant human monoclonal severely active disease; the dose is calculated according to body- -
AceJanilide, a para-aminophenol derivative related to paraccra- weight and is given subcutaneously; those weighing IS kg to less
mol (p.112), ha• analgesic and antip)'l'etic properties. ii was re- TNF antibody that binds specifically to TNF·a and lhan 30 kg should be given 20 mg every other week, while heav-
placed by safer analgesics. blocks its interaction with endogenous cell-surface ier children may receive 40 mg every otl1d' "eek.
Al I cross-references refer to entries in Volume A
 Acernetacin/Alfentanil Hydrochlo1ide 17
lnflammatori• bowel disease. Adalimumab is used in rhe 1
~:!~~~ ~d~·1fi n'~'m':~~~~~~~a~~fc~1~~~~~~:~~i~l~~~~;urt~:
1
managemem ofC'rohn ·s disea,c'·4 (p. I 846). including in parienrs 1. Aifentani! Hydroii:Moiride
who are i1110Jeram ot: or relapse on, infliximah treatment.;. io lt 1oid arth1i1is: resuhs frotll a 6-mouth lon~itudin:il. observ::itioo· (aANM. USAN. rlNN!v1) @
al, multi<..~mrc scud)'. .411n Rheum Dis 2006: 6S: t 379-83.
has a lso ~een tried 1n the trcatmen1 of ulcerative colilis 12. Cvetkovic RS. Sc0t1 U. Ad:ilimumab: ;> te~itw of i1s use in
(p. 1846)-" Alfentaniilihydroldoridi; Alfentanil. chlomydrate d": AJfcntan:I Hid-
~~~~ ~te11cs , .. ith rheunuuoid arthritis. BioDrugs 2006; 20:
I. Hzn:i.uer SB. q/ al. Hmn<>n anti-tumor necrosis factor mono~ 3 rokloJii•·: Affentaoil-hidroklocid; Alfentani-hydrcchlor;d; Alfen-
tar.ilhydrok!Olid: .~fentanili h)•drochlor;dum; Nfentanilio hidro-
clon~I antibody (adalimumab) in Crohn"s disease: t1H! CLAS- 13. Cheu Y-F. c1 ti/. NHS Health Te<:hnology Assessment P10-
SIC-I trial. Gas11'0Cntf1"0logr 2006; 130: 323-33. gramme. A sys1cma1ic review of the dfectivcness of adalimum- ci'Jcricas; Hidrodorui"O de alfentanilo; R-39209. N-{1·[2·(~­
2. Sandborn WJ. <"t ,,/. Adalimumab for main,cnancc 1rcatml!nt or ab. Ct:lnl!rcc-pt and infliximab for the ltC3lnlC.IH of rheumatoid Ethyl-5-oxo-2-tE:tJ-a:zo:1n-l-yi)etl1y~-4-(methoxymethyi)-~ -pip-
Crohn's d!s:ase: results of the CLASSIC JI trial. Gui 2007; %: arthritis in adults and an economic e\•atuation of lheir <'0St-ef-
1232-9. frc1ivcncss <issued November 2006). A\•ailable at: http:// endyl}propionaniide hydrochloride.
3. Colombe! JF. "' '-''· Ad:tlintumub for mainlenancc or c linical re- w·ww.hta.itc.uk/fullmooo.lmon 1042.pdf (:iccessed 31/10/08) AA~Tai t\111'.(l f1tAPOXt10p11A
sponse and remission in patients with Crohn's disease: 1h~ 14. Burmester GR. ct of. Adalimumab ~.lo:'>e and in combination
CHARM 1rial. Gastroemerologl' 2007; 132: 52-65. C ;,H 32N,03.H Ci = 453.0.
with diseasl!'-modifying antirhcutnatic drugs fof the trcatme:.nt of
4. Pioske>GL. Lyseng·WiJlian\Son KA. Adalimumab: in Crohn 's rheumalold anhri1is in clini(.al practice: the Research in Aclive CA5 - 71195-58-9 (alfenrnnil): 69049-06·5 (oni>ydrcus
dise:tst. /JioDrugs 2001: 21: 125-32. Rheumatoid Arthritis. (RcAct) lrial. An11 Rftcum D;$ 2007: 66: al(enranil hydrochloride); ?0879-28-b (al(entanil hydro·
5. Colom!>el J.f. 1:1 al. Adalimumab for the treatment of fis.1ulall in 732-9. ch!~ride monohrdrme).
p::i1ienH wi1h Crohn'sdisease. C1112009; 58: 940-8.
6. Colom't>cl J-F, el al. Comp.a.ri!>on of two adalimumab treatmenl
I5. Bombardicri S. et nl. Re~.c;irch in Active RheumcitoicJ Anhrilis ATC - NOIAH02.
s...:hedule suatcgie:S fot' moch::ratt.>-t~:!cverc Crohn'i;; disease: rc-
(ReAcr) Stud)' Graup. Effec1ivcncss ofadalimumab fOC' rheuma-
loid 3rth.ritis in p~1ienlS wilh o h istory or TNF-Mtagonist thera- ATC Vet - QNO I AH02.
s.ults from lhc CHARM trial. Am J Gos1roe11tuo/ 2009: 104:
1170-9. py in cJinicat practice. Rhemnntolog)' (0l./OJ'1i) 2007; 46: UNfl - I IS92GOTIW
7. Sandbom W J. et al. An open-label s-tudy of the human ami-TNF
1191-9.
monoclonal antibody :idalimumab in subjects with prior loss Q( I 6. NICE. Adalimumab. etancrccpt and inniximab fo,, ~he <rea1menr
response or in1olernnce to infl iximab for Crohn'sd~ose. Am .J of rhtonH'ltold arlhritis: Technology Appraisal Guid<in« 130
GoSll'OMft:rol 2004; 99: I 984-9. (issued Oclober 2007). Available al: http://www. nice.org.uk/
8. Pap:Jdaki$ KA. et al. Safety and effic3cy of odalimumab {D2E7) nicc:mcdia/pdrtTA IJOguidance.pclf (accessed 0)/11/08)
in (.'roltn's dis~a~ r:ttit;nt~ wilh ;!n au~nn~tcd response to iof- 17. Lovell DJ, tu <11. Pedialrlc Rheuma.tQIQg)' Collat>9rn\iye: Study
liximo>b. Am J Gas1ro~n1erol2005; 100: 75-9. Group. Pediatric Rhcumatology International Trials Organisa-
9. Peyrin-Biroulec L, et nl. Adalimum.3b 1n:Jin1cnancc thef;>py fM tion. Adalimunlab with or wi1hout me1hotrcxa1e in jUvcni1e
Cl'l)hn 's. diseai;e wilh imolern n~e ()r 10~1 response 10 inffo; im3b: rheumatoid anhriiis. N Engl J Med 2008; 3S9: 8 10-20.
anope11-labcl SlUd)'.AiimMt Phurnuit:o/Ther2001: ~S: 675-SO.
10. S:rndbc·rn WJ, et nl. Adalimumob induction 1her:Jpy ror Crohn Spondyloarthropathies. Rcfcrcnces•·ll to the use of adalimu-
dise:>~e prcviou~Jy treated with. infl'iiimab: a r~ndomized trial. mab in ankylosing spondyliris and psoria1ic arthritis (p. I 4).
An,, /11.1trn M~tl2001; 146: 829-38.
I. Chew A -L, et al. Successful lrc:itmem o( stvere psori~sis nnd
I J. Peyrin·Biroolct L. el al. Adalimumab induction therapy for u l- psoria1ic arthritis wi1h adillimumAb. /)r J De1·nio1012004: 1 S I : (al(enranil)
~~~~~·:.fa0~:1li~t~~~ ~~~~~~G~,~:~:!:c~i1~{ ~Ji:"f]~~~~~'.
1 492~.
2. Me:1s.c i>J. e1ol. Adalimumab for 1he ircatmenl of pa1ients with
Psor iasis. Adalimumab is used in the treatment of plaque moderately to severely ac1ive psoriatic arthri1is: results ofa dou- Pharmacopoeias. In Ew: (seep. ,-ii) ond US.
psoriasis'~ (p.1723). ble-blind, randomized, p1Rccbo-con1rol lcd trial . A1·thrilis Ph. Eur. 6.8 (Alfentanij Hydrcchloride). A white or ab11os1 white
Rheum 2005~ 52: 3~79-89.
I. Oordoll KB. et ul. C linical response to adalimumab 1rcatmcnt in powder. Freely soluble in water, in alcohol, and in methyl alco-
patients with moderate to severe psori:isi.s: double·blind. ra1ld· 3. \•an dcr Hcijde O. e1 al. ATLAS Study Group. Efficacy and safe-
ty of ad:Jl imumab in patients wilh an.kylosing spondyli1is: rc- hol. Protect from light.
omizcd co n1rollcd trial and open-label extension stud}'. J Am USP 33 (Alfenuni! Hydrochloride). A whire to almost white
ActJd Dtm101012006: SS: 598-606. suhs of a multiccnler, randomitcd, double·blind, placebo-eon-
2. Papoms:i.l:i M, e1ol. Adalimurnab for severe psoriasis :ind pso•i- crollcC trial. Ar1hritil Rheum 2006; S4: 2J36-46. powder. Soluble in water; freely soluble in alcohol, in chloro-
4, ~~'Of;~:~. ~~~~t1· Ad11limumab: in psoriatic anhrhis. Drugs
3tic anhritis: 30 opcn-la~ I Sludy in 30 p:nitnts prevlously trC:Jt-
ed with other hialogic.s.. J Am Acad Dt:l'mlJtol 2007; 57: 269-75. 4 fonn, und in methyl alcohol; sparingly soluble in acetone. Store
in airtig_ht contait¥:rs.
l. Menter A, et al. Adaliinumab therapy for moderate to severe 5. Gladm;m DD, et of. Adolimuinab imprO\•es joint-related ;rnd
psoriasis: a r.mdomii.cd, controlled ph;isc Ill uial. J Am Acod skin-related functional impairment in patil!nlS wi1h psorintic ar-
Dl'n11f1MI 2008: 58: 106-15. 1hritis: patient-reported ou1come!-ofthc Adalimumab Effohive- Dependenc:e and Withdrawal
4. Revicki D, e1 al. lmp~cl ofadalimum3b treatment on he11Jlh-re- ncss in Psoria1ie Archritis Trial. Ann Rlre11111 Dis 2007: 66: As for Opioid Analgesics, p. I05.
latcd qteli1y of life (Ind other patiem-reponed ou1co:nes: resuhs 163-8.
rron1 o> 16-wcek tandomizcd controlled lri.JI in pz.tfonts with 6. Gladman DD, ct nf. Adalimumab for long-tenn treatm ent of
moder3te to severe plaque psoriasis. 81• J D.:rmotol 2008; I 58: psori~uic anhrilis: forty-eight week data from lhe tldalimumab Adverse Effects and Treatment
549-51. effectiveness in pstlriatic anhritis trial. Arthritis Rheum 2007: As for Opioid Analgesics in general, p. l 06, and for
S. Saural J.U, ~t ul. CHAMPION Study Jnvc;Stigators. Efficacy and 56: 476-88.
s3fely r<'sults from the randomized connollOO comp<ir<ltive SlUdy 7. Genovese: MC, flt ul. M02-570 Study Group. $:Jfcty and cfficac:y Fentanyl, p.58.
oradaliinum3b vs. methotrexatt: \'!t placebo in paticnls with rso· of adal imumab in treatment of patiems with plSOriatic arthritis Effects on the cardiovascular system. Sinus arrost had
riasis. fkJ Dermoto/2008; 158: 55~6. who hld fai led disease modifying ;.ntirheumatic drug therapy. .f
6. NICE. Adali11lu111a:b for 1hc treatment of aduhs with psoriasis: Rhtmnatol 2007; l4: 1040-50. Corre<'tion. ibid. ; 1439. occurrcd 1 durin~ iniubation in 2 patients given alfentanil
T e chnolosy Appraisal Guid:lncc J46 (issued June 200&). 8 . Davis JC. e.1 al. Health-rela1ed quality of life outcomes in pa- 30 micrograms/kg.
Available at: hllp :J/www.nicc.ors.uk/niccmedia/pdf/ tienis wilh acti\•e ankylosing spondylith• treated with ;>dalimu· I. Mar)'niak JK. Bishop VA. Sinus nrres1 aflcr alrcnumir. Br J
TA 146Guidance.pdf\accessed 25107/08) mab: rcsuhs fr<'m a r;:mdomized controlled study. Ar•th,.i:is Anoe.1th 1937; 5): 390- 1.
/lhc11m 2007~ 57: 1050-7.
Rheumatoid arthritis. References to the use of adalimumab 9. NICE. Ada1imumab for 1hc l'rcatme:nt o( psoriatic a11l1r-itis:
Efiects on mental function. Like fenlllnyl, aifent3nil 7.5 or
in rheumatoid arrbritis 1•1• (p.12) and juvenile idiopathic Technology ApJ)raisal Guidance 125 (issued Ausust 1001). IS micrograms/kg intra.veno~ly had no cffccr on memory in
arthririsn (p.11). .4.vai lablc at: http://www.n icc.org. uk!n icemcdia/pdfl healthy subjecls.1 In anothl!r ~tudy impairment of memory for
1. den Sr~cdc r AA. <:t of. Lon1Merm ~mi -1un1our necrosis factor TAl2Sgu;d,nce.pdf (accesS<d 03111/08) new facts did occw· 2 hours after o per3lion in patknts anaesthe-
alpha ntonothcrapy in rheum-itoid inhritis: effect on 1•00ioJogi- 10. Mcleod C, t:I nl. NHS Heahh Techool<'lg)' Assessmcm Pro- tised with alfent:nil 7.5 micrograms/kg, bttf not in those give11
C<'l I eou-st and prognostic value of markers (Ifcartilage turnover gramme. Adalimumab. c1ancrccpl and inOiximab fof 1he tre.i1- fentany1;2 meU1ohe."\.ital might have contributed to the impair-
and c:ridothelial ~tth•ation . Ann Rheum Dis 2002: 61; 31 1-18. men1 of :inkylosing spondylitis: 3 sys1cmatic review aod eco·
2. Rau R. Adalimumah (a fully human anti-tumour nccr0sis factor nomic (valuation (i$Sucd August 2007). Av3 il 2bte at: meot.
:tlpha ntOJ_l~d ona l _3 ~1~body) in the trcatm~nt 0(2ctive rheum;:,.. http://www.hta.ac.ukffullmooo/mon 1128.pdf (accessed t. Scamman FL. e1til. V.eiHil:Jtory a1ld mc1nal elTects (I( alfentanil
toid anhrms: the inma.I results of five trials. :fnn Rhe11111 o;s :WtOIOS) and fen1~nyl. Ac1a Amuwheslo/ Scand 1984; 28: 63-7.
2002: 61 (suppl 2): 70-3. 11. NICC.::. Adalimumab, clancrce:pl and inniximab for ankylosing 2. Kennedy DJ. O~g TW. A lft'n1:mil and memory runc1ion: ~ cc-m-
3. Weinbb.tt ME. rt al. AdaJimumab. a fully human anti-tumor spo1ldylitis: Technology Appraisal Guidance 143 (issued May parison with femanyl tor d3y case Tel'miJ13lion of pre~n3ncy. A'1-
necrosi>factor alJ>!la monoclonal a1nibody. for 1hc trc;ument of 1008). Avail;>.bJe ;:n: http://www.nice.org..uklniccmedialpdf'.I aestht>sia 1985; -'O: 537-40.
rheum:toid ar1hn1is in patients laking concomitanc mcthotrcx- TA l 430uidoncc.pdf (acccmd 31/10/08)
atc.: the A RMAL>A tria l. Arlhn)is Rheum 2003; 48: 35-45. Effects on the respiratory system. Alfcnlanil, like other
12. Mease PJ, et ol, Adalimumab for long·term tre~tmenl of psori- opioid agonists, causes dose-related respiratoty depression; it is
4. Furst DE. e1 of. Adalimumab, a fully human anti tumor ne.;rosis alic e rihritis: 2-ycar data from the Adatimumab EfTcctivent:ss in
faetOM!lpha n1onoclonal antibody, ;nd concomi1ant standard Psoriatic Anhritis Trial (ADEPT). Ann Rltcum D;s 2009: 68: significant with doses of more than I mg. Recovery has bc-e11 re;
anlirhe 11 1 n ~1 i c 1hcrapr for 1he trca1mcnr <'f rhc:um)toid anhd1is: 70?-9. po11ed robe fasteraller alfentanil than after fenra11yl (see p.58). 1·•
1·e::sul1s uf STAR (Safety Trial of Adalimumab in Rheumatoid . 1~ibly rcnccting the shorter elimination half-life of alfe11to11il.
1\rthri1is).J Rhcumotol 2003; 30: 256;-1 1. 13. van dct Hcijde 0, If/ of. ATLAS Study Group. AdalimumJb ('f-
5. van de Puue LB, et al. Enieacy :ind s3fety of adalimumab ~
fcc1ivcncss for the treatment or ankylosins, spondylitis i-$ mai11- E"en so, accumulation of atfentanil is possible with large doses
lllt>rlothernpy i1l pa1ien1s with rtieumatoid arthritis for w'hom
1ained for up to 2 years: long·tenn resulls from the ATLAS irial. over :J prolonged ;JCriod. Profound analgesia is accompanied by
Ann Rheum Di.1 2009~ 68: 922-9.
pf~vious disease modifying :tntirheumalic drug: lrcatmcnt hos marked rcspirato1y depression which may persist or recur post-
failed . •4m' Rheum Vi.f 2004~ 63: 508-lb. Uveitis. Adalimum3b has been tried wilh some success in the operatively.
6. Keystone EC', l!I al. R3diogr3phie. clinical, and functional ou1~ 1 2
comes of tn::actnent with ad:il imumtib (n hum:Jn ~mti·1umor treatment of idiopathic uvcitis • (p.1653). Uveiris can also de- Sudden respir•tory arrest usually within an hour after 1he end of
necrosis factor monodooai ~ntibody) i1l pa1ien1s with active velop as a complication of other inflammatory disorders such as alfenranil infusion has been reported in parients who initially ap-
rhe::umatoicJ anhrilis rece:ivjng concomitant me1ho1re>..:11e thera- rhewna1oid arthritis: o-catment with adalimu1nab may improve peared to have made a rapid recovery from anaesrhesia;"5 all re-
py: a n ndomiz_(!d, placebo-controlled, 52-week trio>I. Arthritis ocular symptoms in addition ro its effect on the primal)' disorder. sponded to n·eatn-enl with naloxone. Close monitoring of respi·
Rheum 2004; SO: 1400-1 1.
7. Wick MC. i.!l ol. Ad:i.limumab (Humitu) teslo'fes clinical re- I. Vaiquc:t·Cobfan LB, er "'· Ad<1limumab therapy for chi lc:tho<.>d ration in the initial postoperative period was recommended and
~po nse in p:!lienl.$ with secondory loss or
e:ffic:acy f.-on1 inflisi- uveitis. J Pt>d;a1r 2006; t49: 572-5. lhis was reinforced hy the rnanufacturers;6 factors such a~ hyper-
mab (P..!micodcJ or ctanercept (E:nbrel): results from the 2. Bies1er S. el al. Adalimum;ib in the cherapy or uveiti$ in child - ventilation and the use ofopioid premedical ion might enhance or
STURE 1·cgistry :ii Karolinska University Hospit:sl. Scand J hood. Br J Oph1holmol 2001; 9t: 3t9-24. prolong the respiratory depressant eftecrs ofalfentanil.
Rhe1m14101200S: 34: 353-K ··
I. Andrews CJH. Of ttl. Ven1ila1ory effects during and arter oontin·
S. Navarro-Sarabia F, el nl. Adalimumab for nealing rheumatoid Preparations uous infusion or fentanyl or a lfentanil. Br J A11aesth 1983; 55:
anh1 i1 i~. Available in The Cochran~ Oatab&sl.! ofS)'sh:m:i.tic Rc-
\•iews: Issue 3. Chic:hestct: Johll Wiley; 2005 (3cccsscd Proprietary Prepo:rations (details at'e given in Volume B) 211S- l6S.
13i0610SJ. 2. $c3mm:m Ft , i!t al. Vcntil3l01')' and menlj,( effetu of :ilftnl:i.nil
Arg.: Hu~ra: Austral.: HumWa: Austria: Humira: &etg.: ~ Broz.: and fcntflnyl. A<':o Ant1ts1)1esiol Scand 1984~ 2ii: 63-1.
9. Wcinblan ME, 4!1 ul. Long term effi1.:ucy •md :;.arcty ofadttlimu- Humira Canad.: Humira: Chile: ~ CL: Ht.rn1rn: Denm.: Hu"rir;\:
m:Jb plJs metholrexatc in p:nients with rheuma toid :Jrthritis: Fin.: Humifa; Fr.: Humira: Gtr.: H.xni1-a; Gr.: Hurn~ra.: Trvdex.a: Hong 3. Sebel rs. Cl al. Respiratory depressicm tiller alfcnianil infusiott.
A RMAOA 4 year e;Hmded study. Ann Rhtum Dis 2006; 65: Kong: Hurni-a. Hung.: Hvmira; lrl.: Hi.r'n~i: Israel: Humira; Ital.: Hu:TWa; 8MJ 1984: 289: 1581-2.
753-9. Moloysio: Hui'nir-t: Mex.: Homira: Neth.: Humira: Ttudexat: Norw.: Hu· 4. Krane OD, et nl. Alfontanil and delayed 1tspiralory dc-pression:
10. Brecdwld l~C. (•t ul. TJ1e PREMIER study: a muhicentc:r, r.1nd- m1f'a: NZ: Humira: Pol.: Ht.rnira: Port.: Hurnira: Rus.: Humira (XyMi.tpa); c:1se$ ~audics and review. A,,eirl> Analg 1990; 70: 5!'i7-6J.
omizcd. double-Mind c:linical trial orcomhin.ation 1hcrapy with $.Afr.: H...mira,; Singapore: Humiriil; Spain: Hvmira; Swed.: Humira; S. S1ernlo JEG. Sandin RM. R~um'.·11 1 rcspira1ory depression :if1er
adalimumab plus mcthotrexatc versus mc:thotrcxate a.lone or S~itx.: Hutr6a; Tu rk.: HunW.i;: UK: l-:\U"nira: USA: Humi"a: Venez.: Hu· IOt.1l intravcnOU$ an:Jcslbcsia \•tith propofol and al rcntanit An-
adalimllmab alone in pa1ienl$ with early, aggrcssh1e rheumatoid m1ra. ocs1hrsin 1998~ 53: 378--SI.
arthriti!-who had not had previous m~thotrcxale trco1menl. Ar· 6. Waldron HA, Cookson RF. Respirntory dcp,cssion ;>.Ocr alfon-
tltrifiJ F.l1tum 2006: 5-4: 26-37. wnll infusion. BMJ 1985; 290: 3 19.
The symbol t denotes a preparation no longer actively marketed The symbol ® denotes a substance whose use may be restricted in cenain sports (seep.vii)
18 Analgesics Anti-inflammatory Drugs and Antipyretics
Precautions about 90% protein bound and has a small volume of tanil is prolonged in neonates. See also Hcpa1ic lmpainnen1,
As for Opioid Analgesics in general, p.107. distribu1ion. IL~ terminal elimination half-life is about I below.
lo 2 hours. It is metabolised in the liver; oxidative N- I. Mcistcfman C. e1 al. A c<1mpari50n e>r alrentanil pharm;icokinet·
Children. Alfentanil given to prctcrm infanlS undergoing paral- ics in children and adults. A ntSlh~siology 1987; 66: ll-16.
ysis and mechanical ventilation for respiratory di•'lrCsSsyndrome and 0-dealkylation by the cytochrome P450 isoen- T he elderly. Plasma cleaance of alfentanif ancr a single in1J11-
resulted in a rapid and significant fall in heart rate and blood pres- zymeCYP3A4 leads to inactive metabolites, which are venous dose of 50 microgranWkg was reduced in patient$ more
sure, emphasising that proper evaluation of the pho.nnacological excreted in the urine. Alfentanil crosses the blood- lhan 65 years old when compared with that in healthy young
and clinical effects was nc«.ssary. t adultS. 1 Mean elimination half-life was 137 minutes in lhe elder-
brain barrier and the placenta and has been detected in
The BNFC 2010/11 states that the half-life of alfenianil is pro- ly and SJ minutes in the young adults. \~lumcs of diwibotion
longed in noonates and accumulation is ltkcly with prolonged colostrum.
were similar and it was considered that reduced clearance mig)lt
use; muscle rigidity may occur and the use of inusde relaxants O AlfcnWlil is less lipid-soluble than fcntanyl, but more so than be due to dcaeascd hepatic metabolism in the elderly. In a srudy
may be required. l1'l0f]lhinc. It is highly bowld to plasma proteins, mainly 10 a 1- in male patienlS the terminal tlimina1ion half-life of alfentanil
I. MarlowN, ~Jal. Hazards 0(1nal&esi1 (or newborn infants.. Arch acid glycoprotcin. Decreased lipid solubilily can be cxpcacd to increased with age, althouglt cle:irance ~ noc signifieanlly af-
DisCMldl988;63: t293. limit penetration of the blood-brain barrier when compared wi!lt fecled.2 In P"lients given alfentanil I microgram/kg per minute
The elderly. EEG changes suucsted that elderly patients had fcnWlyi, but the 111ajori1y of unbound alfent1nil is unionised and by continuous intravenous infusion during orthopaedic surgcry,3
increased brain sensitivity to alfcntanil, 1 and that lower doses can rapidly gain accc.<s to the CNS. Alfentanil has a mialler vol- tcnninal haU:life increased linearly with age in those older than
might be indicated in older patients for plwmacodynamic rather ume of distribution than fem.any! and its elimination half-life is 40 years and s1eady-statc volume of distribution was enlarged
than pharmacokinetic reasons. Sec also under Phannacokinctics, shorter. The manufacturers have given values for a three-com- with increasing age; clearance did not correlate significantly with
below. partment pharmacokinclic model with a distribution half-life of age and was though1 to be more variable during a continuous in-
I. Scan JC. Stanski DR. Dccru~cd fcnlanyl and alfcntanil dose re· 0.4 to 3.1 minutes, a redistribution half-life of 4.6 to 2 1.6 min· fusion in long-term surgery than aner a single bolus injection.
quircmcnt$ with age: a simultaneous pMrmacokinctic and ph3r- utes, anti a terminal elimination half-life of 64.1 lo 129.3 minutes Others have reported' lha1 1he effeclS of age on alfentaoil phar-
macodynamic evaluation. J Phormocol Erp Thfr 1987~ 240: after single bolus injections of 50 or 125 micrograms/kg. Accu· macokinctics are dependent on gcnder. In this study total plasma
159-66. mulation is less likely than with fenlanyl, bul can occur after re- clearance decreased and terminal half-life increased with io-
Handling. Avoid oontact wilh the skin and the inhalation ofpar- peated or con1inuous dosage especially in patients with reduced crcnsing age in women, but not in men. It has been suggested that
ticles of alfentanil hydrochloride. clearance. The mean elimination half-life reponed is usually this effect in women may be more dependent on menopausal Sia·
about 90 minutes, but this is rcduc:cd in children and increased in IUS than on age.s
lnOam matory bowel disea n. Patient$ with Crohn's disease the elderly and neonates, in hepatic impainnen~ in the obese, and
required higher doses of alfcntanil than control paticnlS 1 al- lo a StUdy'in ddcrlypatientsplasmacooccntrallOnsofalfentanil
during cardiopulmonary bypass (see below). were peater and the maximum concco1nttioo occumd earlier
lhougb there were no differences in alfentanil phannacolcinctics
between the 2 groops ofpaticnlS. ORcvieW$. wbea alfentanil was injected into the dclt0td musck compared
I. Ge.sink-van der Veer BJ. ti ol. Jnnuence of Crohn's disca$C: on I. Hull CJ. The:ph1rmacokine1K:sofatfent:lnil in man. BrJAnoa1h with injection into the gluteal muscle.
the pharm.acokineiics and pharm1codyn1mics ofalfCnt.anil. Br J 1983: SS (S\lppl 2): IS7S-164S. I. Helmers H, et al. Alfentanil kinetics in •ht cklttly. Cliu P/"1rmO·
Anaesth 1993: 71: 827- 34. 2. Maiher LE. Clinic:al phanna«>kinetics of fentanyl and its newer col Thu 1984; 36: 239-43.
derivatives,. C/ln Pharoracolc;n,, 1983; 8: 4 22-46. 2. Sc:oll JC. Stanslci OR. Ocol"ascd fcntanyl and 1lrenU1nH dose re-
J>ragnancy. UK licensed product information contra-indicates 3. Da\•is PJ, Cook DR. Clinical phanna.cokinetics of the newer in- quircmenu with age: a simultaneous ph1m13cokinctic and phar·
the use of alfentanil in labour, or before clamping of !he cord lra,·enous Anees1hctk agents. Clin Phannocoklntt 1986: I J: macodynamic eva1uation. J Phnrmacol Exp Th•r 1981; 240:
during caesarean section, because placental transfer means there 18-lS. IS9-66.
is a risk of neonatal n:spinuory depression. 4, Bodcnham /\,Park OR. A1fcntanil infusions in pa ticnL~ rcq,uirina
in1cnsivc c.arc. C/ln PhormoctJ/dnet 1988; 15: 2 1 ~26.
3. van Beem H, et al. Pharmaeokinetics oralfentanil dW'ing and
after a fixed r31c infusion, Br J A"'1CSlll 1989; 62: 610-IS.
S. Schol7. J. ttt "'· Clinical ph1nnacokinetK:s of alfcnlanil, fcn11nyl 4. Lcmmcns HJM, el al. Influence ot' age on the pharmacokinetics
Inter actions and surcnUloil. C//n PhDrmocokfne11996; 3l: 275-92. ofalfenlanil: gender dependence. C//n Phormoco/l.ln., 1990; 19:
For interactions associated wilh opioid analgesics, see Administration. CON TINUOUS INTRAVEN OUS I N FU510 H , 416-22.
S. Rubio A. Cox C. Sex, age and 1Jfen11nil pharmacokinetacs. Clin
p.107. Small sludies of alfentanil by continuous intravenous Phormaco*-inef 1991; 21: SL
Drugs that depress the heart or inaeasc vagal tone, infusion 1·l have found phannacokinclic parameters to be sim- 6. Virklcill M. t!I ol. Phannacokincdcs and ctrccc.s of i.m. atrcntanil
ilar to those aner a single bolus injection, bu! with some con- as prt:mcdication for day-cue ophthalmic surstry fn elderly pa·
such as beta blockers and anaesthetic drugs, may pre- flicting results. In 29 patients undergoing orthopaedic surgery ticnts. BrJ Anania t''H: 71: 507-11 .
dispose patienis given alfentanil to develop bradycar- an initial bolus intravenous injection of alfcntanil H epatic impainnent. Total plasma clearance and protein
dia and hypotension. Use of alfentanil with non-vago- 50 micrograms/kg was followed by intravenous infusion of binding of alfentanil were decreased io pa1ien1S with alcoholic
lytic neu romuscular blockers may p roduce I microgiam/k& per minute., eootinued for 44 to 445 minutes; cirrhosis when compared wi1h control subjects. Eliminalion half.
a second bolus injection of 50 microgiams/kg was given im- life was prolonged from 90 lo 219 minu1es in !lte cinhotic pa·
bradycardia and possibly asystole. mediately before incision and an additional bolus injection of ticnts following a single intravenous dose or SO micrograms/kg
The metabolism ofalfcntanil via the cytochrome P450 I mg given if necessary.• The time courtt of the plasma- and was allributcd in part to allcrations in binding sires ofa 1-acid
isoenzyme CYP3A4 may bl! reduced by potent inhibi- alfcntanil concentra1ioo filled a two·compartmcn1al model in glycoprotein.1 '!here mig)ll be different effectS on alfcntanil dis-
tors of this isoenzyme, resulting in a risk of prolonged 26 palieni.s. Terminal half-lives varied widely from 56 to 226 position in pa1ients with non-alcoholic cirrhosis or other liver
minutes (mean 106 minutes), lhe highest values being mainly disordc.s.2 The phannacokinctics ofalfcntanil were apparently
or delayed respiratory depression. Reduced doses of al- in patients over 60 years. There was no sigrtificanl corrcla1ion not affected in children wilh cholcstalie hepatic disease whereas
fentanil may be required if given with a CYP3A4 in- between pharmacokinclic parameter.; a.nd the duration of the cle3r:l.ncc was reduced poslopcralivcly in 3 pa1ienL~ who had
hibitor such as cimc1 idine, diltiazem, erythromycin, infusion or lhc tOlal dose. Plasma clearance and volumes of undergone li\'er transplan1a1ion.l
fluconazole, ilraconaz.ole, ketoconazole, or ritonavir. distribu1ion did no1 correiale significantly with body-weiG)l1 I. Ferrier C, c l al. Alfen1a.nil phtrmacokinclicJ in p11icnt.s wl1h cir·
although s1eady-sta1c volume of distribution was enlarged rhosis. Ane.s1hesiology 198S~ 62: 4S0-4.
Antibacterials. The elimination half-life of alfcntanil was in· with increasing age. The mean es1ima1ed steady-state concen- 2. Bower S. e1 al. Effects of difTe:rcn' hepetic path<"k>aiel on d i s~
creased and clearance decreased when given after a 7-<lay co~ 1ration was 293 nanograms/mL (range 147 to silion of alrcntanil in anaC$the1ized palicnlS. Br J A1taeslh 1992;
of oral erythromydn in hcaldiy subjecls. 1 Prolonged respiratory 636 nanogratnslmL). 68: 462-5.
de1""S5ion has also occwred in a 32-year-old man given alfen- I. Frasen RJ, tt ol. Pharmacoki.n.ctics of the infusion ofaJfcntanil 3. Davis PJ. el of. Ef'Tms of cholc.5tacic hcpaiic disease and chronic
tanil during anaesthesia after 1hrec 1-g clo5es ofcrythromycin in in man. BrJ Anoa1h 1983; 55: 1077-81. renal f1ilure on alfc:ntanil phannxokine1ic1 in children. Antst.h
Anolg 1989; 68: S79-83.
the 24 hows befoce SUJgery.2 In another Sllldyofhcallhy subjcus, 2. Shafer A, ~t ol. ~m1ttokinc:1ic.s 2nd pharmacodynainia of 11·
rhe clearance (three-companmen1 model) of alfentanil was re- fe1n1nil inNsionJ durin_ggener.a.1 anulhC$'3. Ana11t Anolt 1986; Obesity. The pharmaookinctics of alfentarul arc reportedly al·
duced by 70".4 in those given onl rrolt<zndomycin.' 65: 1021-'. tercd in obcsily.' Elimination half-life was 172 minutes in 6
3. Reit.i JA." al. 1bt pharmacokinclics of olfemantl io gynccolo1· obc.5c patients compared with 92 minutes m 7 who were not
Other hepatic enzyme inhibilM and drugs interfering with he· ic surgica• paiient.s. J Cli" Phurmacol 1986: 16: 6().-f.
pa1ic blood flow might also affect the clearance of alfentanil. 4. van Beem H, er al. Ph~rmacoki nd·ics of alfcnlanil durtns and obese. Plasma clearance of alfentanil was also decreased, aJ.
l. Bartkowski RR. et of. Inhibition of alfcn11Jli) metabolism by after a fixed rate inf\Jsion. Br J AttO't.Sth 1989~ 62: 610-1 ~. lhough others2 found tha1 obcsily hod no effect on clearance, but
crythromycin. Clin Phannocol Th,,. 1989; 46: 99-102. Sec The Elderly, below.
1NTllAMt.1 SCt.1LAll.
ii did have a direct relationship with the volume of the ccnlrai
2. llankow~ki RR, McOonocJI TE. Prolonged alfcn1anil effect fol- compartment.
lowing (()'lhromycin adminisu:.1ion. A nts1h~tlulo1Q1 1990; 73: Bums. 11lc volume of dis11ibu1ion and total cleara1icc of alfcn· 1. Bcnllcy JS. ct al. Obesity and alfen1anU ptla1macokine1ics. An·
566-8. tanil were reduced and its elimination half-life prolonged in pa· es1J. Aoolg 1983; 62: 251.
3. Khora.'ich ED, et ol. The role ofc)•tochrome P450 3A4 in alfcn- tic111$ with bwns.1This was due. in part, to raised concentrations 2. M3i1re PO, Cl al. Popufarion ph3rm,cokin.c:tic1 of alfcntanil: the
tanil clearance: implicatlons for intcrindividuaJ variabiliry in dis- av~rage dose--plasma concentration rclat~nship and inle:rindi·
position and pcriopc1ati"c drua interactions. Ant31hesiologv ofa 1..acid glycopro1ein leading to increased prolcin binding.
vidual va1jabili1y in patients. Antst/J6.Slolog;)• 1987; 66: 3-12.
1997; 87: 36- 50. I. Madie A<l ~1 al. Oilposition of alfcntanil in bums p3ricnu:. Br
J A11tm1h 1992, 69: 447-50. Renal impairment. The phannacokindic.s of alfcntanil were
Antifungals. Az.ole antifungals such asjl11ronazo/e., ketocmw- not affected significantly in aduhs 1or children2 with chronic re-
zolc, or _.iconaz<>/1 can inhibil the metabolism of alfentanil. lo Cardiopulmonary bypass. Tiie eliminaiion half-life ofal fen·
tanil incrc:isc:d &om 72 minulcs before cardiopulm003T)' bypass nal faihue. lo another srudyl increased volume of dlSlribution of
a Sllldy,1 giving alfenianil I hour after intnl\'trlOUS or oral fluco- alfentanil at steady state was associated with decreased plasma
nazalc decteaSCd the elcarancc of alfcntanil by 60 :111d 55%, re- to 195 minutes afterwards in S palicnts. 1 This 'V3S anributcd to an
pr~in binding in patients with chronic renal failure.
spectively and increased the mean half-life ofalfentaoil from 1.5 increase in ''Olume of distribution, based in p:ut on o dilution·
induced decrease in plasma protein binding. Othcrr' found IN! I. Van Peer A. el al. AUm1-anil lc:inC1ie5 in renal in.suffic1cncy. Eur
hows 10 2. 7 and 2.5 boon, respeclively. Similarly, another study J Clin Phornracol t9S6; 30: 245-7.
found that giving alfen12nil I hour after oral vorioona:rok de- on Staning cardiopulmonary bypa,ss 1olal scrum concentrations l . Davis PJ, e1 aL I!frects: of cho1'-'t;itic hepatic disease and chronic
creased the clearance of alfen1ani l by 85% and ina-cased the or alfcntanil were halved, mainly because of dilution of a,-acid renal failure on. a.Jfentanil pharmacokiTielia. in chiktrcn. AlftJlh
mean half-life ofaffentanil 10 6.6 hours. g)ycopnoicin and an increase in unbound alfenWlil. Analg J 9S9: 68: 579-83.
J. Palkams VJ, ~t al. The effect of i11trtnnou1 and onl fluconaiole I. Hug CC, ti al. Atrentanil phanmtcokinetics in pa1H:n1S bc:rore 3. Chauvin M, e.r al. Phannacoldnctics or1lfcnt1nil in c.hronic renal
on the pharmacokinctics ond pharmlCOd)'namics or intravenO\lS and after card;opulmonory byp0$s. Ancs1h Anolg 19S3: 62: 266. failure. Anmh Anolg 1987: 66: S3-6.
•lfcntan;J. A1>8'1h Analg 1998: R7: t9(}.4. 2. Kumar K. 11 al. The erreel ofcardiopulmonary bypan on plasma
protein blndin' of alfcntanil. EM J Clin Phom1acol 1988: 35:
2. Saari Tl. er al. Voricon:n.ole, buf l\01 1crbinafinc, m3rkedly re- 47-52. Uses and Administration
duces alfontanil clcural'H:C and prolonp its half-Jifc. C/in Phor- Alfentanil is a shol1-acting opioid analgesic (p. l 08) re-
mocol T'hcr 2006: 80: 502-8. 3. Hynyncn M. Cl ol. Pla.sma conccnlntion 3Jld protein binding or
alfen1anil during high·doJe infusion for eardiac iurgcry. Br J lated to fentanyl (p.60).
An,,.,1h 1994: 72: 571-6.
P harm aco kinetics Children. Alfenianil has been shown to have a shorter elimina- Alfentanil is used in surgical procedures as an analge-
After parenteral doses alfcntanil hydrochloride has a 1ion half-life (about 40 minu1cs) and a smaller volume of distri- sic and adjunct lo general anaesthetics or as a primary
rapid onset and shon duration of action. Alfentanil is bution in children thon in adultS. 1 However, the half-life ofal fen· anaesthetic. It is also used as an analgesic and respira-
All cross-references refer to cntncs in Volume A
 Alfentanil Hydrochloride/Aloxip1in 19
loty depressant in the management of mechanically Alfentanil is also used as an analges ic in patients with first 48 hours after surgery and postopcrativi: opioid dosage
ventilated ratients under intensive care. spomaneo11s respiration receiving monitored anaes- requirements may be less than expe<:tcd. Alrentanil infusion
con1inued into rhc postoperative period allows careful 1i1ra-
Alfentanil is given intravenously as the hydrochloride thesia care; in the USA. an in itial dose of 3 to tion of dosage.
although doses are expressed in tenns of the base. Al- 8 micrograms/kg may be followed by supplementary I. Hull CJ. Ph1eoctlromoc)10t1'a: di1911otis. preopenli'c prcpana-
fentanil hydrochloride 108.8 micrograms is equivalent doses of3 to5 micrograms/kg every 5 to 20 minutes or tion and anaesthetic man.iacmcnr. Br J A11aesth 1986; 58:
14S3-6S.
to about I00 micrograms of alfemanil. A peak effect an infusion of0.25 to I microgram/kg per minute.
Pain. POSTOPERAnvE ANALGC.SJA. Continuous on-demand epi-
maybe seen within 1.5 to 2 minutes of an injection and Administration. Alfeuranil is usuolly giYen by in1Ta\'e11ous in· dural infusions or alrcnlanil 200 micr~rams/hour or rcnranyl
analgesia can be expected to last for up to I 0 minutes; jection 0< infusion, bul hu also boen given intramuscularly, 1.2 20 micrograms/hour provided comparable analgesia 10 mor-
dose supplements are therefore required if it is to be inlf1llhccally.' 0< epidurally (sec Pain, !>!low). phine 200 micrograms/hour in the early postoperative peri-
Arcndl·Nte.lsen L. et M Analgesic cffietcy o( 1m alrcnta.nil. Or J
used for more prolonged surgical procedures. It may be I. A"omh 1990; 6S: 164-8.
od;' alfcntanil (16 minutes) and fenlanyl (13 minulcs) had the
given by continuous intravenous infusion in ventilated 1. Vitkkitl M, 6 nl, Phlirmxokinc1ics and crlCc11 of i.m. 11rera11nil advantage or more rapid onset of analgesia than morphine (44
lll!t prt:mcdication for day.case ophthalmic SUflCfY in ~kterly pa- minutes). However, some considered chat chcrc w3s no over-
patients. tten1s. 81'J Anaesth 1993; 71: SOi-11. all advantage or epidural over intravenous 3lfen1anil either as
Tiie dosage of alfentanil used depends on whether the 3. Hughes DA. Hill DA. lntnth«:al alrtnta.nil wi1h amt without patient-controlled analgesia? or by continuous infusion. l
bupivacainc for analacsia in labout Anaenhe.f io 2000; SS: I. Chrubasik J. et al. Rcllitivc 1n1J1esic potency of epidural (Mt.a.
patient has spontaneous respiration or assisted ventila· 1116-21. nyl. alfcntanil. and morphant in tttatmcnl of postopcrab\IC pain.
tion and on the expected duration ofanaesthesia. Doses Administration in children. Alfcntanil is licensed in 01c UK .in-.1hesiology 1988; 611: 929-33.
are adjusted according to the needs ofthe patient. Chil- for USC in ventilated children during suigicaJ procedures OS an ?. QaU\·in M, l!I ol. EquJvalentt of posioperalive analgesia wilh
patient-controlled in1ravenou.s or epidunil alfcntMil. Antsll1 A,...
dren may require higher or more frequent doses than analgesic and adjunct to general anaesthetic$ 0< as a primary a11- o/g 1993; 76: 12Sl-8.
adults, whereas the elderly or debilitated patients may aes1hc1ic. When used as an adjunct in the maintenance or gen- 3. van den Nicuwrnhuy2en MOO. el ol. EpMlural vs intraYCnous
infusion or al(critanil in the mamgem<nl of postoperative pain
require lower or less frequent doses. Obese patients eral anaesthClb licensed product information Slates that vcnli· follo..-.·•na l a~rotomies. Acta A11oc1thl:1iol Scam/ 1996; 40:
may require doses based on their ideal (lean) body- as la1ed children maybegj'~ the usual in1ravcnousl1y'«tiondoses
for ven1ila1ed aduhs (sec Uses and Administnition. above). 1112-18.
weight. Howcvcr, lhe BNFC 2010/11 suggcs1s I.ha! ncoruiies may be giv- Preparations
\\lhtn used as an adjunct in the mai~tenance of gen- en S to 20 micrograms/kg initially and children aged fiom 1 USP 33: Alfenn rjeaJOfl
nionl.h 10 IS years, IO 10 20 miaogramslkg iniliaUy; supplemcn·
eral anaesthesia the initial licensed dose in the UK is tary doses ofup to I0 micro8J'amslkg may be given. When given Proprteury Preparations (details arc giv~n ln Voturuc: 8)
as follows: A-i.: Brev.ife« Aurttol.: ~ Austria: Rap.fen; Bels.: ~ Stoz.:
by irifaJion lhe BNF' J9 slates thu ventilated children may be /'K=; Rapifen; Conod.: Allc:ni.t. CM., ;Qp;1e,~ c ..: Rapltn: Oenm.:
• in patients with spo111aneo11s respiration, up to given the usual doses os for ventilated adults (see Uses and Ad· fbs>i1tn: Fin.: fla?;r,,,. Fr.: Rapi!M G.,., Rapofer< Gr.: Rapifen: Ho111 Konr:
500 micrograms may be given slowly over about doses ministration, above); the BNF'C10/0IJJ suggest\ that usual adult R.p!en: Huni.: Rapifent: Ir/.: ~ I,,../: Ra,.rcn: ltol.: ~
may be aiven to those aged as youn& as I monrh. The Mu.: Rapii!n: Neth.: R•,.len; Norw.: Rapiflit NZt Rapoleo; Port.:
30 seconds with supplementary doses of BNF'C 20/(1/// also suggests that neonates may be given an ini- Rapilen: S.A(•.: Rlpife.n: Singapore: Rapfli'( Spain: f•n"""I: l.OTife•"
Swed.:~ Swftz.: Rapifen: Turi<.: llapfeJt UK: Rap~en: USA: Alfcr'1a;
250 micrograms tial loadin&doseoflOto SO microgr.11n$/kjo\OCI' IOminutes fol· Venn.:~

• ventilated patients may be given 30 to lowed by infusion at a rate ofO.S to I mierogram.11(g per minute.
50 micr ogra ms/kg with sup pleme nts of Anaesthesia. Alfeniani~ like fentanyl (p.61), appears to pro-
15 micrograms/kg. When given by infusion to venti· duce fewer circulatory changes than morphine and may be pre- Alminoprofen (•"""!
lated patients there is an initial loading dose of 50 to ferred for anaesthetic use, especitlly in cardiovascular swgety. It
is generally considered 10 have a shorter duration or action than Amnoprofene; A!mio oop<o<eo .o: Alminoprolenum 4-[(2-M"thy-
100 micrograms/kg given as a bolus or by infusion fentanyl. It has been used with propofol 10 facili~i lc inrubation, lall)'ljamino)hyd'3tropic ...:d
over 10 minutes, followed by infusion at a rateof0.5 and ror 101.tl inlravcnous anaesthesia. AN.o.4HH00p04>eH
to I microgram/kg per minute For a discussion or the drugs used 10 f.icilitate inrubation and of CnH 17N01 219.3. =
such as alfenranil used 10 control the pn:ssor response CAS - 39718-89.J.
1ypical doses that have been used in the USA are as opioids and the rise of inn-ocular pressure associated with intubation, ATC-MOIAE/6.
follows: sec Anae1.thcsia, p.2064. For reference 10 a Sludy indicating that ATC Vet - QMOIAE I 6.
• for short surgical procedures of less than 1 hour in prctrea1mcn1 with alfcntanil can reduce rhe poin :mociatcd with UN/I - 0255AHR9Gj.
pa1icn1s with spontaneous respiration or assisted injeclion of propofol,scc p.1948.
ventilation, the dose is 8 to 20 micrograms/kg; this CAtsAREAN SECTION. UK liceiued product infonnation contra·
may be followed by supplemental)1 doses of 3 10 caesareanindicates the use or alfen1anil before clamping lbe cord during
seclion because of!he risk of respiratory dcpn:ssion
5 micrograms/kg every 5 to 20 minutes or an infu- in the neonate. A study or alfentanil 30 micrograms/kg in
sion of O.S to I microgram/kg per minute. Alterna- women undefl!oing caesarean section was abandoned af\er
tively pauents with assisted or controlled ventilation massive respiratory depression had occurred in 4 of S neo-
2
may be given an initial dose of 20 lo nate~. Anolhcrs111dy in patients underao1ng elective caesar-
1

50 micrograms/kg, fol lowed by supplementary dos- sponsesean >e<:lion found that although maternal haemodynamic re·
to intubation were minimised when alfentanil
es of 5 to 15 micrograms/kg every 5 to 20 minutes 10 micrograms/kg was given inlnlvenously immediately be- Pharmacopoeas. lnJp11.
• in general surgical procedures in patients with as- fore induction, neon.res in the alfentanil group had lower Ap· Profile
sisted or controlled ventilation, an initial dose of 50 gar scores compared with those in the placebo group. Ahninoproren, a propionic acid derivative related lo ibuprofen
to 75 micrograms/kg may be followed by an infu- However. alfcntanil has bttn used sue<:essfully to minimise (p.66), is an NSAID (p.100). h has been used in onflammalory
haemodyMmie responses to intubation and suo&ery in P"licnlS and rheumatic disordm in oral doses of up lo 900 ong daily.
sion of0.5 to 3 micrograms/kg per minute. lfalfen- with severe cardiovascul:ir disorders undefl!oing caesarean sec-
tanil has been given in anaesthetic doses (sec below) tion."' J\ baby delivered after the successful use or alfentanil Pniparations
Proprietary Preparatic,,. (0.lails •re aiven in Volume BJ
for the induction of anaesthesia, infusion rates may 35 mic:rognunslkg in a mother with scvc:c aonic stenosisl was Fr.:Monolftne.
need to be reduced by 30 to 50% during the first hour apnoeic and unresponsive with poor muselc tone; I.he baby re·
spondcd rapidly to naloxonc. Alfemanil 10 nticrnyams/kg im·
of maintenance mediately before induction aucnuated the cardiovascular re·
Maintenance infusions of alfentanil should be stopped sponse to intubation in patien1s with severe pregnancy-induced Aloxiprin (SAo'lt 11NN)
I0 to 30 minutes before the anticipated end of surgery. hypertension' and was considered a suitable alternative 10 fcnta· A(et.tsalidato de po!roxozlvminio: Nol<sipriin'; A!oxipo'ina;
nyl 2.5 microgmonslkg; no cfl'eet on neono1al mortaliiy could be Aloxip.ine: AloXIJ)fll'OJm
For details of doses in children, see below. attributed to anaesthetic tedinique. However, it bas btcn sug-
AM>KCHnpv.µ
The dose for the induction of anaesthesia in patients gcslcd that 1he use or smaller doses of alrcntanil of CA$ - 901~·67-9.
1.5 micrograms/kg with magpesiu111 sulfate 30 mg/kg ma)' pro-
with assisted ventilation undergoing procedures of at vicle better cardiovascular control! ATC - BOIACi S; NC2BA02.
least 45 minutes is 130 to 245 micrograms/kg, fol- I. lA'uwtr M. ''al.Ph:1nnacokinieties n ph1rmaoodyni.mics of an ATC Vet - QBOIACIS; QN026A02.
lowed by an inhalation anaesthetic or maintenance cq111pownt fcn<anyl and a1rcnl1n1I dote 1n mother :tnd inf:.nt dur· UN/i - 6QT214X4XU.
inscacs;irnnseeli<111. BrJ Anot-~th 1990: 64: 398P-399r.
doses of alfentanil of 0.5 10 1.5 micrograms/kg per 2. Gill T. tt d/.. AlfentaniJ ghic:n imnicdi1tcly before 11\c induction
minute. ' oi anesthesia for elective cuarcan ckliY(ry. Anath Annlg 2000:
Jn the UK, ventilated patients in intensive care may be 3. 90: 1167-n.
Redfern N. ~' ol. Alfcntanil for cai!$ilrcan section complicotcd by
given alfentanil initially at an infusion rate of severe aortic SlettOS•S. a ta5:c ~port Br J An11a1h 1987; 59:
2 mty'hour or a loading dose of 5 mg may be given in 4. Ruul 1309- 12.
CC, RO(:ke DA. Efrcc:u of alfen1anil and rc:nt1ny1 on~
divided doses over l 0 minutes or more slowly ifhypo- tion of nno.cs1hc:si1 in paticnu with severe prcgnnncy·indu«d
tension or bradycardia occur. Thereafter a suitable rate hyp<rl<nilon. BrJ Anaesth 1990; 65: 46$.-74.
Ashton WB. t i al. Aucnuation of lhc: prts'«"r re~ponsc to t~chea l
ofinfusion should be determined for each patient (rates 1ntufftion b)' magnesium sulph3.&c. with ond Wilhout olfentanil in
of0.5 to 10 mty'hour have been used); patients should h)pcrtc:n.si,·c prolcinuric patients: ~oing caesarean stcdon. Pharmacopoeias. In 81:
BrJA_,th 1991: 67: 741-7. BP 20 I0 (Alox:p!in). A polymeric condensation product of alu·
be carefully monitored and the duration of treatment
should not generally exceed 4 days. During continuous PHAEOCHROMOCYTOMA. Alrenl.'lnil does OO( release his1amine minium oxide and aspirin. A line, white or slightly pink powder,
and was of value in the anac.sthctic management of patients odourless or ahnost odourless.11contains1101 less than 7.S%and
infusion additional bolus injections of0.5 to I mg may with phaeoehromocytoma. 1 It has a very rapid onset or action, not more than 8.5% of Aluminium and no1 lcss than 79.0% and
be given if required to provide analgesia for short pain- good vasodilating propcnies. and a relatively shon elimina· not more than S'l .4~. of 101al salicylates, calculated as •Spirin.
ful procedures that may be carried out in intensive care. ti on hat(-life. The.<e patients are often very somnolent for the C,H.04 , both calculated with reference IO the dried substance.
The symbol t denotes a preparation no longer actively marketed
20 Analgesics Anti-inflammatory Drugs and Antipyretics
Prac1ically insoluble in waler, in alcohol, and in elher; sligh1ly Preparations Profile
soluble in chlorofonn. Proprietary Preparations (deiails 31e given in Volume B) /\mtolnielin guacil is an NSAIO (p. 100) tha1 is an ester prodrug
Hunt' Ge-m::id. of1olme1in (p.135). II is used in painful anJ inOa111nia1or:v disor-
Profile ders in oral doses of 600 to 1200 mg daily.
Aloxiprin, a polymeric condcnsa1ion product of alwninium ox· Multi-lniredienl: SroL:G;nebumot. Cz.: DW>)it, Eunalgilt; Huns.: Ar>
ide and aspirin, has actions similar 10 lhose of aspirin (p.21 ); :=;:,"rr~e;;;o.'r,"A~~7';L~~~f ~t,,.,~~ 0 References.
J. Biasi Q Marcolongo R. Effiacia ctollcrtbithldell"amlolmctina
aloxiprin 600 mg is equivalent 10 aboul 500 mg of aspirin. (~)t. Vtnt.r.: Aexidonet·
Aloxiprin has been used as an analscsic and anti-inflammatory guacil nd traua.tnc:nto deU'arn·osi in fut di riac:ubzz.uionc. J.fin~
in musculoskeletal and join! disorders. II has also been used in """'M<d2001;9l: 315-2.l.
2 JaJic Z.. et ol. Gastrointestinal Slfcty or amsohnetin cuac-yl in
the irca1mcnt and pre"cnlion ofthromboembolic disorders. comparison wilh ceJccoxib in Pllicnu with rhtumatoed anhritis.
A mmonium Salicylate
Preparations Clin ExpRhtttmcto/2005; 23: 809- tS.
Sal.olato de ilmO<'lio.
BP 2010: ~ T-.i. Preparations
AMMOHH;,~
Proprietary Preparations (deulib ere Jiv•n in Volume 8)
Proprietary Preparations (d<t11ls 11e givtn in ~lumc B)
ez.,~
=
C 7H 9NOl 155 2. Ito/.: kvc« Ar"""'°" W'•ns
C/\S - 528·9~-9.
Multi.ingredient UK: A.s1<it. UNI/- OT3Ql81657.
A myl S alicylat e
Aluminium A spirin lsoamyl Salicylate; lsopcntyf Salicylate; Salicilato de isoamilo; Sali-
cilato de isopentilo. 3-Methylbutyl 2-t'l)'droxybenzoate.
Acelilsalicilato de alJminio: Aluminum Acetylsalicylate: AJLmi·
• AMW\CaN1U,H/\aT
run Aspirin: AILminum Bis(acctylsalicylate): Aspirin Aluminium.
6is(2·acetoxybenzoolo·O')t'l)'dro><yaluminium. C,,H,.01 = 208.3.
C/\5 - 87-20-7.
At>loMHH"'1 Acrn.p.-..a; Ac""P"'" ANo.."""'" UNI/ - VZ09C30208.
=
C 18H, 5Al09 ~02.3.
Profile
CAS - 23413-80-1.
UNII - E33T505V68. Ammoruum salicylatc is a salicylic acid derivative used topically
in rubefacicnt inpararions similarly 10 methyl salicybte (p.89)
for the relief of pain in musculoslcelelal and joint diso<dcrs.
(fl
Preparations ~O~CH3
Proprietary Prtparations (details arc given in Volume B)
OH 0 CH3
Mutt·i·ingredient: Aultl'Ot.: P.adiin-8t: UK: R.J.OOn.8.

Pharmacopoeias. In Fr.
Ampiroxicam (BAN. rlNN) Profile
Amyl salicylate is a salicylic acid derivative used topically in ru·
Ampiroxicarrum: CP-65703. 4·[ 1-(E'J>oxycarbonyloxy)clhoxy)· bcfacicnl preparations similarly 10 methyl salicyla1e (p.89) for its
Pharmacopoeias. Jn Jp11. 2-meth)'l·Nl·p)'ridyl-2H· I.2·bcnzothiazine-3-carbo><amide I. I· analgesic and a111i-inflamma1ory actions. II has also been used in
Profile 'c:fio><ide. perfumery. ·
Aluminium aspirin is a salicylic acid derivative (see Aspirin, AMnMpot<Cl•l<IM Preparations
p.21)that has been gi"en orally in !he managementoffever,pain,
and musculoskclei.l andjoint disorders.
CioHnNi01S 147.5. = Proprietary Preparations (details arc given in Volume 8)
CAS - 99~64·6•·9.
UNll - OPV32jZ81j. Multi-ingred;cnt: Arz• Alomo ~e: "'-t:mo ~e C:
Preparations
~~=--~-Soi er.ma: Fr.: 8Mne s.rt-Semant
Proprietary Preparations (dcuits an: gh'Cn in ~luonc ll)
Multl-ingred;ent: /ndon" R.cmosalt: S.A(r" ~SA1.

A nakinra (SM< US'IN. rlN'JJ

A m inophenazone (rlNN) Anakinrum: m!L-1 ra: r-metHull-1 ra. Nl·l·methionylmtet'oeulan I
rec:ep:or antlgonisl (t-.Jman 1solorm x reduced).
Amidazoien: Amidopyrine: Amidopyrine-Py1"2midon: Am100-
fenatsont Arrinofenazon: Am1nofenazona: Aminoph<!nazone: AHa•11><pa
Aminop~.enazonl.ITI: Aminopyrinc: 0.methylamino•ntipyrine:
CAS - 143090.92-0.
ATC - L04AC03.
Dimethylamioophenazone. 4-Dimethyfamioo-1.5-dimethyf-2· ATC Ver - QL04AC03.
phenyl-'l·pyratolin· ).one. UN/I - 9013DUQZ8K.
AMH1iOCJ>el•a30H
CllH 11N;O = 231.3. Profile
CA5 - 58-15-J. Ampiroxicnm is M NSAID (p.100) lhal is reported to be 111C13b·
ATC - NOZ880J. olis<:d to piroxicam (p.122). II has been gjven or.illy forlhc relief
ATC Ve1 - QNOZB603.
UNll - 01704YP3M0.
of pain and inll.tnuna1ion panicuWiy in muscu!oskclc:tal diso<·
den suc:h as mcumaioid arthritis :Ind ostco:>rthritis.
Adverse efl'ects. PhOloscnsiti\ity reactions have ocx:UITCd dut·
ing ampiroxicam 1rca1men1.1·l
..
!UOla!"1'7S f'ESAACf'G)f'F I.C"T~P VSL.TIM~ \?C'V'l"l:FY!'OC

Q 1. J<urunllji Y. Amp1ro:c.iam-ind~ed pho10Stnsitivity. Comoc1 Adverse Effects and Precautions

/)cymo1//11 199&. 3~: 293-9. Mild IO moderate injec6on site reactions "'ilh sympcoms of ery-
2. Toyohara A, rt al Ampiro:dcam·induced photosensitivity. Con· thcma, bruising, swelling, and pain arc common wilh anakinra
tact O.rn1ar/1/s 1996; 35: 101-2. particularly in the first monai of1t<•llndlt. 01her common reac·
3. ChishiJd M, ct al. rhotosensitivity due to ampiroxlcam. Dcnn(r· 1ions include headache, nausea, diarriloea, and abdominal pain.
tolaiJY 1m; 195: 409-10. Antibodies 10 anakinra may develop. Allergic reactions such as
Preparations ra~hc. have been reported rarely: if o severe allergic re•ction oc-
P·roprlct:iry P,-epa.rations (dc1ails art: given io Volume B) curs, anakinra should be Stopped and appropriaie treatrncnl giv-
Jpn: l\Jcam. en.
&-rious infections have been reported wilh ana!Onra, particularly
in pa1icnts wilh asthma. These infections 11e mainly bacterial,
A mtolm etin G uacil (tlNNJ such as ccllulitis, pneumonia, and bone and joinl infections.
Pharmacopoeias. Jn It. More rarely, opportunis1ic infCCIions involvint funGJIl, mycobac-
Amtolmetina . ~cilo; Arntolmeti>e Guad. Amtolmetinum terial, ond viral pathogens hove also been seen. Anakinn should
Profile Guaolurn: MEO.IS: ST-679. N-{(l-Melh)'t-S-p-toluoytwrol-2· be slopped in !hose who develop a serious infection. In addition,
Aminophenazone, • pyrazolone derivati\'C, is an NSAlD )l)acety!Ja'ronc o-mcthox)'l>henyf ester. therapy should nol be sta11ed in p:nicnts wilh aclivc infections,
(p.100). but lhe risk ofagranulocytos1s is suf!icicnlly great 10
AMrQl\Mt'TMH ryaW'\I\ including chronic or localiSled inftciions; caution is rCC()lllmcnd-
render it unsuitable for systemic use. Onscl of agnnulocytosis
may be sudden tnd 1D1predici.ble. Aminophcnazonc has b«n =
c,,H2,N20s 120.s. cd in those with a hiSlory of recunenl infections or wilh underly-
ing conditions that may predi5!>0" to infections.
uS<d as salts or complexC$, includina topically os the salicylate. CAS - 87344-06-7.
UNll - 323AOOCR09. A small decrease in absolule nculrOphil count (ANC) is com-
Precautions. ORCINOGfNICITr. Aminophena~one may be monly seen with anakinra 1tealmcn1; however, true neulropcnia
regarded as a polcntial carcino1en because ii has rcacled read· (ANC < I500 celfslnun') is rare. Licensed product infonnalion
ily with nitrous acid to fonn dimclhylnitrosamine. 1 The reac- recommends thal ncultophil counts should be taken before sL1tl·
lion was calalysed by thiocyanal( prcscnl in the saliva partic- ing anakinra and periodically throughout ITCal!nent. UK licensed
ularly in smokers. infonna1ion recommends monthly moni1oring during the first 6
I. Boyland E. Walker SA. Calllysii of the reac1ion of aminopyrine months and then quarterly thereafter: US licensed infonnation
and nilrite by thiocyanate. Arznllmittlf/forsc/Jung 1974; 24: requirt.5 monthly moniloring for the firs! 3 monlhs and then quar-
tt81-4. terly monitoring for a period ofup 10 I year. Anakinra should not
Aminophenawnc has been associated wilh acule
PORPHrRoA.. be staned in patients with neutrOpenia. Small reduelions in the
onacksofporphyria and is considered unsafe in porphyric pa· 1otal while blood cell and platelets coUnt< and a small increase in
tients. eosinophils have also been llOled. AnakiMI is also associated
All cross-references refer to entries in Volume A
 Aluminium Aspirin/Aspirin 21
~- Nuki G. ti ol. LonJ·krm $-afcty a nd m3!ntenan« of chmcal int·
with on increased oncidcncc oflymphoma in patients with rheu-
matoid arthritis. provt:rnc.n1 foU~·tftf trt"atn1en1 wi1h o:m<>l:inra (rCCtWnbinant hu-
Aspirin (SAN)
111~n imcrlcuk1n.. t r«q>1or 1nt1~oni&i) in puicnts with rhcu1na·
For caulion in patients with renal impainnont S<!C under Uses and toid arthrici1: c.-:u:nlion fba.sc of a r.indoniiz.ed, dou.bl~btind. Acetilsaho1ico. i(ido; Acetilsalidio rug!tis: Ac~oc~sav. Ace-
Adminis1ration. below. placcbo..c~ntrolled trial. Arthritis Rl~um 2002: 46: 2838-46. tylsal. Acid: Acetylsaictic Acid: Acet)!sa~9;syra: Acide acetylsal·
4. Flcis:hnuann R..M. ct ol. Anak1nu. 1 rcc.ombinanl human inter- ocylque: Acid!Jm acet'tfsalocylicum; Asetilsabsihk Asit; Asetyyisal-
Effects on the cardiovas<ular system. A 29-yt:<ir-old wom· kukin· l receptor antagonist (r-.mctHult.Jra), in pa l i~nls with isyyll>appo: Kwas acetytosalicylowy. Kyselina acetylsa~ Pol-
an wilh refractory adulH.msel Stilt's disease developed sh<>rtness rheumatohi arthr itis: a lar&c. intcmalional muhic.entcr. placebo·
of breath, which progre$sed to cardiorespiratory failure. 3 C'Onttollcd trial. Ar1hrMs Rlrt1ua 2003: 48: "927-34. oporyna; Saiicyfi< Acid Acetr.e. O.AcctylS<1licylic zcid; 2-Acetoxy·
S. Sctairr MH. Durability and rapidi\y of response to a1,akinrA 1o bcn2oic acid.
months af\er being slatted on anllkinra; 1 although resuscitation pat~nas wilh rheumatoid 1nhn1is. Dntp 2004; 64: 2493-2SOI .
was tried. the patient died. The au~1ors considered that the role of 6. Waugh J, PaTy CM. Anakinia: a re"icw of its U1C in the m11n- l\cnMJl"H
anakinra in this event was unclear, particularly as the patient had agemen: or rheumuoid arthritis. BioDr,,gs ~S; 19: 189-202.
7. Reiff A. Tht use o( 1nakinra in juvenile anhrius. Cnrr Rhe11mo-
=
c,r 00. 1so.2.
shown some evidence of myocardial or pulmonary dysfunction CAS - 50-78-2
before statting the drug. 10/ Rtp 2005; 7: 4:M-40.
&. den Broedtr AA , ~, al. ObRrntional stud)' o.i cfrtcacy. sart:ty, ATC - AOI AD05: 80 IAC06; NOZ6A0l
I. Ruiz PJ. tf 111. Cardix death iD a. pa1icnl with 1dull-onsc1 Stilrs and drua surviYl1 or anakinra in rheumatoid tnhritis paticntS rn
djsc,a.s( lreatcd with the intedeukin I rccepror inhibhur aoakinr.i. ATC Vet - QllOI AD05: QBOIAC06; QN026AOI .
<linicnl8rac1iee. Ann RM.m Dis 2006; 65: 760-2.
Anu Rhtttm DU 2007: 66: 422·3. UN/I - R. f 6<:05Ylb£..
:r::~nds~R~~')';;~,~~1~R~:~~~:,'fOO~~ i~ 'm-~
9 1
Effe<ts on the skin. lnOammalory lesions at injection sites ·
10. Mertens M, SinghJA. Anakmra for rhcum.11itoid arthritis.. A\'ail-
were reponed in S patients after an:ikonrn use. 1 The lesions were ablc in The Coch~ nc Database of Systematic Re views: Issue I .
cl)'lhcmatous, oedematous, painful, and itchy plaq\Jes, and were Chichestcr: John Wile)'; 2009 (IC<eSSCd 20/1 MJ9).
seen within 16 days of starting trelltment Treatment with anok- 11. National Coll•bornting Cenlle f.,. Chroni<: Conditions/NICE.
inra was complclely SIOpPCd in 1 patient and inlemipi..d in 2 oth· Rheumat°'d arthrhis: nalional clinical guideline for manage-
ment and uatmenl in adulls ( i,ssuod Fct>n..ry 2009).
er patients; "~ten n:introduccd, one patient dC'IClopcd abdominal Available at : http: //www. n ice.org. ukl nicemedia/pdf/
pain, dyspnoca, and facial and ~bdomi nal crythema with pruri· CG79Full<iuodtline.pdf (accm cd 20/10/09)
!US. Preparations
A patient with rheumatoid arthritis developed psoriasis 9 months NOTE. The use of the name Aspirin is limi1ed; in soo1c cOUJ1trjes
Prop rietary Prep..rations (details are SiVC11 in 'l.tllume BJ
alicrstaning auakinra therapy;2 the lesions improved significant- Austrot.: IGnen:t; Austria: ~et; Canad.: Kinl!l'tt Cr.: KiNftt O.nm.: ii is A 1rade-marl<-
ly when !he drug was stopped and \\>th topical corticosteroids
and vitamin D therapy.
K......,
t<inetet Fin.: Kincret Fr.: l<itoon:<: G4r~ IG<lcrot: Gr.: lrl.: -
Ital.: Konerot: N eth.: KRret NOfw.: ~t. Pol.: Kinerelt Po~ Kilo<-
Co111poundcd preparations of aspirin may be represented by the
following names:
1. Vil:a AT, ~' al. Adverse cu11ncout l't'actions to snakihra in pa· ... Sf>ain: Ko"""" Swed.: K.,..n UK: t<nore~ USA: K;neret.
• Ccxodaprin (BAN)_,prin SO parts and codeine phosphate
licnts ""·ilh rheumatoid ~n h rilis: c11n;c»p1thotogic.al study <'If five
potients. BrJ Dcrmuto/ 200S; 153: 4t7-23. I pan(w/w)
2. Gonzoilez.-L.Opn. MA. ti ol. Ncw-onw psoriasis foHow;na. trcal· • Co-codaprin (PEN)-aspiriu and codeine phosphate.
ment with lhc .ntcrleukin~ I rtt.ep1or :tnttgonist 1n11tinra. Br J Anile rid ine (BAN. rlNNJ
D en11010/ 200S: I 58: 1146-S. Anileridiir>: Anilerodin; Anileridina; Aoilend'WlC: Anolcridrorn. Ethyl Pharmacopoeias. In Chin.. Eur. (seep.vii). /m.. Jp11, US. and
t -(1·aminophenethyl}-1·phenytpiperidir.e-1<atboxylate. Yiet.
Interactions Ph- Eur. 6.8 (Ac~!salicy!ic Acid; AlpoYI BP 2010). 'Miite or al-
Live vaccines should not be given with anokinra as its-effect on AHW\efl'<Al>'H most white, crysUlline powder or colourless crystals. Slightly
,·accine efficacy or the risk ofinfec1iou 1ransmission is unknown. C11H 2eN202 =
352.S.
CAS - 144-14-9.
Sllluble in water; freely soluble in alcohol. Store in ailtighl con-
The risk of serious infection and ncutropenia is increased when tainers.
an3kinra and etanercepl arc used togtlher (see under lnflixomab, ATC - NOIAH05. USP 33 (Aspitin). White crystals, cnmmonly tubular or needle·
p.74); a similar effect may occur with other TNF antagonists. ATC Vet - Q.NOIAH05. like, or white Cl)~llmc powder; odourless or has a faint odour.
The use of anakinra with etru>erupt or other TNF inhibit0rs is UN/I - 71Q.IA30279 Is statole in dry air; in moist air it gr.idually hydrolyses to salicylic
not recommended. and acetic acids. Soluble I in 300 ofwater, I in S of alcohol, I in
f'harmacokinedcs 17 ofchloroform, nnd I in !Oto 15 ofether; spnringtysoluble in
After subcutaneous doses, peak plasma conccnlntions of anaf.:- abso!Ule cUier. Store in airtight cootainers.
inra occur in 3 10 7 hour•. Its lcnninal half-life is about 4 to 6
hows. Anakinra is excreted mainly in the urine. A dverse Effects and Treatm ent
Uses and Administration Aspirin has many propeitics in common with the
Arulkinrn is a recombinant reccpt0r antagonist of interleukin-I non-aspirin NSAIDs, the adverse effects of which are
(p.2S49). an inflammatory mcdtator fou nd in the plasma and described on p.l 00.
synovial fluid of patients wnh rheumatoid arthritis. Anakinra os
described as a biological disease-modifying antiJheuonotic drug The most common adverse effe<:ts of therapeutic doses
(DMARD). ofaspirin arc gastrointestinal disturbances such as nau-
Anakinra is used for the trcaonent of the signs and syinploms of Pharmacopoeias. In US. sea, dyspepsia, and vomiting. Gastrointestinal symp-
moderate to severely active rl1eumatoid arthritis in patients who USP 3l (Micnane). A white to yellowish-white, odourless or toms may be minimised by giving aspi1in with food.
have had an inadequate response to mcthotrexale or another dis- pmclically odourless, crystalline powder. When expooed lo light
ease-modifying antirheumatic drug (DMARD) alone (but see a.id air ii oxidises and d"rl<cns in colour. It e:.hibits polymor- Irritation of the gastric mucosa with erosion, ulcera-
below). In the UK. it is only licensed for use with mcthotrexale; phism, and oftwoaystallinc fom1s observed, one melts at about tion, haematemcsis, and mclaena may occur. Hista-
however, in lhe USA. it maybe given either aloneorwiU1anoth- 80" and the othcraJ.aboul 89•. Very slightly soluble in waler; sol· mine H?·antagonists, proton pump inhibitors, and
cr DMARD. ahliough not one that inhibits TNF (see lnter.c- ublc I in 2 of alcohol and I in I of chlorofonn; soluble in ether prostaglandin analogues such as misoprostol may be
tions. above). TI1e usual <lose is 100 mg once daily by subcutane- but solutions may be lllfbid. Store in ainigl1l conlaincn. Protect used in the management ofNSAID-induced ulceration
ous injection. TI1e d~ should be given at about the same time from light.
t:achday.
(see Peptic Ulcer Disease, p.1851), including that
Anakinta bas been tried in septic shock 3Ild graft-versus-host dis- Anile ridin'! H ydrochlonde (8AN!.ll, rlNNM) caused by aspirin. Slight blood loss. which is often
ease in transp1111t recipients, but ltSUlls wac disappointing. Aril~. O>loo'hydrate <f: Anilerioono Hydroct-.loridum; Hidro-
asymptomatic, may occur in about 70% of patients; il
Administration in r<!nal impairment. Caution may be ad· donro de ~leridina. is not usually of clinical significance but may, in a few
visable if anakinra is used iu patients with renal impailTllent. A ~J)IW<H<l r >W>OXllOPl'\A patients, cause iron-deficiency anaemia during long-
>1\ldy 1 in patients with varying degrees of renal function indicat·
ed that no dosage adjustment was needed for anokinra in patients
C21._HuN10;.2HCI 425.4. = tcnn lhcrapy. Such occult blood loss is not affected by
CA5 - 126· l Z-5. giving aSpirin with food but may be reduced by use of
with mild or moderate renal impainnent but dosage on alternate UNI/ - 9 t 5Q054DLC. enteric-cooted or other modified-release tablets, H;an-
days appeared advisable in those with severe renal impainncnt. Pharmaco poeias. In US.
US licensed product infonnation 3ISO recommends altemate·<'3y tagonists, or high doses of antacids. Major upper gas-
USP 33 (AAoleridone Hydrodlloride). A white or nearly while
dosing in patients with SC\ ere impairment or end-stage disease odourless crystalline powder. Soluble I in S of w.1tcr and I in 80
trointestinal bleeding occurs rarely.
(~tinine clearance less than 30 mUminule). However, in the Some persons, especially !hose with asthma, chronic
ofalcohol; practically insoluble in chlorofonn and in ether. pH of
UK, licensed product infonnation contra-indicates use in those
with this degree of imp.1inncut.
a 5% solution in water is 2.5 to 3.0. Store in airtight cont:Jiners. urticaria, or chronic rhinitis, exhibit notable hypersen-
Protect from light. sitivity lo aspirin (see also below), which may provoke
Dialysi• docs nol affect anakinra concentrations lo any signifi-
cant <lcgrcc. renctions including urticaria and other skin eruptions,
I. Y:ina B·B. tt of. Pbarmacokine.1ics of IU\Akmra in subjects with
Anileridine Phosphate (8.4NIA llNtW.) angioedema, rhinitis, and severe, even fatal, paroxys-
diO"crcnt fe,·ds of rtnal functlon. C/111 Pl-ormocol T/JeJ-2003: 7-1: Anih!rid~. Phosphate d': An11etidini Plto!plm; fosfato de a11ile- mal bronchospasm and dyspnoea. Persons sensitive to
SS-94. · rid11a.
aspirin often have cross-sensitivity t0 other NSAIDs.
Familial Mediterranean fever. For mention of anakinra hav- .<\>11MCj)~AW>la <I>o<.+aT
ing been tried in familial Meditcrr•ncan fever, see p.606. C22H llN10i.HtP O• = 450.S.
Aspirin increases bleeding time, decreases platelet ad-
Rheumat oid a rthritis. In the UK, anakinra is licensed for the CAS - 4268-37-5. hesiveness, and, in large doses, can cause hypopro-
treatment of rheumMoid arthritis,_,. (p.12) in patients wiU1 an UN/I - 3584484N8V. throm binaemia. It may. cause otlm blood disorders, in-
inadcqu:ile response to mc1hollexa1e alone; however, NICE" Profile cluding thrombocytopenia.
does nol recommend its use except in lite context ofa controlled, Anilendone, a phenylpiperidine derivath•e, is an opioid analgesic Aspirin and other salicylales may cause hepatotoxicity,
long-tenn clinical study. (p.IOS) chemically related to pethidine (p.118) and "ith similar
I. Brc1nih1.n B. ~, ol. Treatment of rtic1.11natoid arthritis with re- a<:tions. It bas been used a.s the hydrochloride in the management particularly in patients with juvenile idiopathic arthritis
combinant human inltrltukin-1 rt"cep1or atua:gonis1. ArthrltiJ of moderate to severe pain. Anilcndine bas also been given by or other connective tissue disorders. In chi ldren the use
Rh'""' 199S:4t: 2196- 220•. injection as the phosphate. of aspirin has been implicaled in some cases ofReye's
2. Coh<::n S1 ct ol. Treatment or rheumatoid arthritiJ with ana.kinra,
a recombinant human in1rrte-ukin· I receptor antag.onisa. in cotn· Preparations syndrome, leading to severe restrictions on the indica-
binatioo with mcthouexate: rcsuhs o( a rwenty four \Yct.k. mu).
0 0
USP 33: Anlcndnc ~<le Tobie!S:Anilcod.ne ~ tions for aspirin thernpy in children_ For further details,
liccnler. r3ndomizcd. double.blind, p1accb<>-controUcd trial Ar-
thritis Hli1!111tt 2002; 46: 6 1.i-24. see Reye's Syndrome, below.
The S) mbol t denotes a preparation no longer actively marl<etcd
22 Analgesics Anti-inflammatory Drugs and Antipyretics
Aspirin given rectally may cause local irritation; 10 aspirin reported lo the CSM bc:twcc:n June 1964 and January tions of3 l l 10 6n microgramslmL. 1 A graded increase in in1cn-
anorectal stenosis has been reported . . 1973. These included 95 reports of blood disorders ( 17 fatal) in- si1y of otolOxicity wilh inc~ng salicylale dose and plasma
cluding 1hrombocytopenia (26; 2 fatal), aplastic anaemia (13; 7 conc.:nu-.stion has been shown.- For example, ar an average 101.11
Mild chronic salicylate intoxication, or salicylism, usu- fatal), and agranulocytosis or pancytopenio (10; 2 faial). Aspirin plasma-salicylate concen1ra1ion of l l 0 micrograms/m I., 1he
ally occurs only aller repeated use of large doses. Sali- has also been associated wi1h haemolytic anaemia in patients bearing loss al any given frequency was about l 2 decibels; such
cylism can also occur following excessive topical ap- with G6J>D deficiency.' ~ deficit mi&h• be relevant 10 patients with pre·exisling hearing
plication of salicylates. Symptoms include dizziness, 1. Cuthben MF. Adverse reactions 10 non·sterold1l 1n1irtieumac\c 1mpainnen1.-
drugs. Curr Med R~r Opin 1974; 2: 600-9. 1. Mongan E, al ol. Tinnitus as an indicition of thcrnpeutic M:rnm
tinnitus, deafness, sweating, nausea and vomiting, 2. Magee r, Becley L. Oru,g..induced blood dyscrasias. Phol'm J salicylak levels.JAMA 1973; 2 26: 142-5.
headache, and confusion, and may be controlled by re- 1991: 246: 396-7. 2. Day RO, et al. Concentration-response rclalionships for t'.tli-
ducing the dosage. Tmnitus can occur at the plasma Effects on the cardiovascular system. Salicylalc poisoning cylatc·induccd ototoxicity in normal voluniccrs. g,. J Clin Phor.
may resull in cardiovascular collapse bul deiails of such cases m•col 1989; 28: 69S-702.
concentrations of 150 to 300 microgramslmL required
for optimal anti-inflammatory activity; more serious have DOI been widely reported. In 2 patients with salicyla1e in1ox- Effects on the kidneys. Although abuse ofcomhined analge-
ication asyslOle developed a!ler intravenous diaz.epam.1 II was sic preparntions conlaining aspirin has been implicated in the de-
adverse effects occur at concentrations above suggested lhat diazepam-induced respiratOI)' depression afl'ccted "elopmenl of analgesic nephtopathy, kidney damage associated
300 micrograms/mL. Symptoms of more severe intox- the acid-base balance so that the concentration of non-ionised with the lhcrapeutic use ofaspirin alone appears to be oompara-
ication or of acute poisoning following overdosage in- mcmbrane-pcnetraling fraction ofsalicylate was increased. Fatal tivcly rare. Many studies have fail<d to find an increased risk of
clude hyperventilation, fever, restlessness, ketosis, and aspirin intoxication in a 5-ycar-old child was marked by hypo· rCJial damage in patients taking aspirin.1·9
tension and rapidly progressive cardiac symptoms including l. New Zealand Rheumatism Auociation Study. Aspirin and the
respiratory alkalosis and metabolic acidosis. Depres- venlricular iachycardia and AV bloek.1 Extensive myocardial . kidney. BM! t974; I: S93-0.
sion of the CNS may lead to coma; cardiovascular col- nocrosis was found at aulOpsy. 2. W.lku BR, <I •I. A Spinn and renal funciion. N F.ngl J M<d 1971;
lapse and respiratory failure may also occur. In chil- For reference to the effects of aspirin on blood pressure com- 297: 140S.
3. Alcyol SM. <1 al. Renal function after prolonged consump(ion of
dren drowsiness and metabolic acidosis commonly pared with Olhe.rNSAIDs. sec p.tOO. aspirin. BJ.IJ 1982; 284: 631-2.
occur; hypoglycaemia may be severe. I. Berl< WA. AndCJSm JC. Salicyllt...ssoc:i11ed a1ys1ole: r<pon or • . Bonney SL, el al. Rcn1I sarcty or '"""O an:dgcsics used over IM
rwocases.AmJ M•d 1989: 86: so~. COWll<r. 1b•profen and aspirin.. Clin no"""""/ Th..- 1986; 40:
In acute oral sahcylate overdosage the UK National 2. PeA:t-Alomo YR. ct aL Aspirin in1oxiQ1ion in a chi kt assoc1at.cd 373,-7.
Poisons Information Service (NPJS) recommends that wiih myocardial necrosis: is this a drug-related le:sJon" Pttlidlr S. Sandlu OP. <1 "1. All'll~..ic use eJ>CI chr<>nic r.,..1 diseuc. N
DrvPmho/2003; 6: 342-7. E"tl J M«d 1989: 320: 1233--43. •
an oral dose ofactivated charcoal be given if the patient
is suspected of ingesting more than 125 mg/kg of sali- Effects on the gastrointestinal tract. Clinical end epidemi- *-'
6 . Pommer W, ol. Regular analgesic inlake and the risk of cnd-
ological evidence suggests that aspirin produces dosc>relatcd wcc renal failure. Am J N<p}orol 1989; 9: 403,-12.
cylate, or any amount of methyl salicylate, within I gastroinleSlinal toxiciryl.l lhat is some1imC$, but rattly, fataJ.2 7. Oul>Kh UC, tt ul. An cpidcmiologic Sllrdyofabusc ora..lgesic
hour of presentation. Activated charcoal not only pre- drup: e.ffecu or phenxetin a.nd .salicyl:ne on morc.iility and car·
Meta-ana!ysisl su&,oests that the risk of pstroinlcstinal bleeding dlOYIJ<•br mort>idily (1968 lo 1987).N bgl J Med 1991; Jl4:
ventS the abso1J>tion of any salicylate remaining in the is not significan1ly Jowen:d with the: use of oral low-dose aspirin I.SS-«>.
stomach but also aids the elimination of any that has (less lhan 300 mg daily). A systematic re~icw' of obsctvational I. Pcmcget TV. et of. Risk of kidney railure associated with lhc use:
epidemiologic studies also concwn:d with this lindini. ... nothcr o( acc.taminophm, aspirin, and nonstcroidal ant'iinflammatory
been absorbed. Gastric lavage should be considered in systematic review5 of randomised. controUcd studies found that dnJgs. N EnglJ Med 1994; JJ I: t67S-9.
patientS who have ingested more than 500 mg/kg of allhough low-<laseaspirin (up to 32S mg daily) increased the risk 9. Rexrode. K, ti ol. Analgesic use and renal function in men. JAMA
salicylate within 1 hour of presentation. 2001: 286: 31S-21.
ofmajor bleeding including gastroin1es1inal bleeding by twofold
Measurement of plasma-salicylate concentration when compared with placebo, the actual risk of bleeding was Effects on the liver. Aspirin-induced hepalic injury is general-
modest; for every 833 patients taking low-<lose aspirin for cardi- ly mild 11nd manifests as a mild IO moderalc elevation in ami-
should be carried out in patients who have ingested ova...:ular prophylaxis only l addilional major bleeding episode notransfetasc va.lues; howe"er, there isa risk of severe liver inju-
more than 125 mg/kg of aspirin, or any amount of me- will occur annually. In a population-based study.• the annual ex- ry.1 One reviewl reported an increase in aminolransferase values
thyl salicylate or salicylamidc, although the severity of cess risk of upper ga,'troin1es1inal complica1ions was about an in 59 of 439 palien1s given aspirin; lhe increase was considered
poisoning cannot be estimated from plasma concentra- exlra 5 cases per 1000 palients; however, the excess risk varied 10 be probably related IOaspirin in 23. Hcpaloloxiciry appears lo
tions alone. Absorption of aspirin can be delayed by wi1h underlying ga.~rroin1estinal risk factors such as old age and be corrclalcd with serum-salicylate concentrations greater than
might exceed an extra JO cases per 1000 patients in a higher-risk 150 micrograms/ml and with active rheumatoid disease. Aspi-
reduced gastric emptying, fonnation of concretions in group comprising ove.. I Olio of aspirin users. It has been suggest- rin-induced liver injury is usually reversible on slopping 1hc
the stomach, or as a result of ingestion of enteric-coat- ed that very small doses of aspirin can produce prophylactic ben- dJui.l
ed preparations. Jn consequence, plasma concentra- efits in cardiovascular disease witliout lhc ri!<k of gastroin1es1inal Sec also under Reye·s S)ndrome, below.
tions should be measured at least 2 hours(symptomatic toxiciry,7 allhough others have reported saslric injury even wilh I. Lewis JJI. Hepa.tic to1'tcity e>f rton.s-tcroid:il anti-inflemmatory
patientS) or 4 hours (asymptomatic patients) after in- doses of 10 mg d3ily.1 dnJgl. Clln Phorm l984; 3: 128-38.
There oppears to be no convincing evidence that the risk ofmajor 2. Freeland OR~ t~ o/. Hepatic s.afety oft"'() analgesics used over
gestion and repeated 2 hours later. A second dose of gastrointestinal bleeding associated \vilh • 75-mg dose is re- the counter: ibuprofen and aspirin. Clin Pltarmacol Ther 1988:
activated charooal may be given to those whose plas- duced by using cntcricxoa1ed or modified-release fonnulotions 43: 473-9.
ma-salicylate concentration continues to rise or those ralhcr than soluble aspirin,l~.9 although individual srudics have Effects on tfle mouth. Aspirin bum (ulocralion ofthe mucosa)
who have ingested enteric-<:Ollted preparations. If nec- reported a reduction in ac:ote mucosa! injury with cntcric coa1- layer of the lips) developed in o 26-ycar-old woman after laking
essary, measurementS should be repC3ted every 3 hours ing.10 an aspirin-containing powder for a migraine.1 The woman had
All known NSAIDs have the potential for causing aeu1e dam<lge swallowed the powder undissolved rather lh3n 3dding IO waler.
until the concentsations fall. to the gastric mucosa (see p.101). and comparative studies of l. Dclhnter TM. Livingsaon HM. Aspirin bum or the oral cavil)-.
Fluid and electrolyte management is essential to cor- acole aastric mucosal damage C:IUSed by such dru8$ consiStently A•m Pharm«XJf/~r 1998; 32: 1107.
rect acidosis, hypC!J>yrexia, hypokalaemia, and dehy- associate aspirin with the ~ SCVCJe lcsions.1Gastric mucosal Hypersensitivity. The main clinical features of patients who
dration. Intravenous sodium bicarbonate is given to en- injury can occur even with cuu1ncoos application-" have aspirin hypenensitivity include middle-age, female gender,
I. Graham DY. Smilh JL Aspirin and the stomach.. Ann Intern di:i11J10SCS of asthma or rhinitis, a personal or family history of
hance urinary salicylate excretion if plasrna-salicylate U.d t9S6; 104: 390-$.
concentrations exceed 500 micrograms/ml 2. Rod.crick PJ. 11 o/, The g.~ointcs.tinal toxicity of aspirin: tn
atopy, and 1 hislory ofn:isal potyps.•.2 Aspirin sensitivity occur-
ovuview of nndomisN controtltd trials. Br J Clin Pltnrttwco/ rin& with aslhma acd n&S.ll polyps bas been 1cfencd to in some
(350 micrograms/ml in children). Haemodialysis or 1993; 35: 219-26. n:ports as the •aspirin triad'. Other sensitivities oftm found con-
haemoperfusion are also effective methods of remov- l . Oury S. Loke YK. Risk of gastrointestinal hacmonhagc wilh comi1ontly include allergy 10 food dyes such~ wrUaZine and to
ing salicylate from the pla.~ma. The BNF 59 considel'S ~~~~t;~m use o( aspirin: me:l.3-analysis. BMJ 2000, 321: drugs such as olhl.1' NSAIDs.
haemodialysis the method of choice in severe poison- 4. G:t.rcia Rodriguez LA. rt al. Assc:-ci:nion betwe:ct1 aspirin and The prevalence of aspiri11-ind1JCCd asthma can vary according to
ing; it should be seriously considered when the- upper gaslrointe.s1inal complications: system;uic rf'Yicw of q:ii· lhe method used Ill mea.<ure iL A sys1ematic review' calculated
dcmiologic studies. g, J Cf;,, Pho,m•cof 2001; 52: S6J-71. the p<evalence of aspirin-induced asthma 10 be 21 % in the gen-
plasma-salicylate concentration is more than S. Mc:Quaid KR, La.inc L. Systctnati~ l"C'¥'icw and meu.·an:ilysil of eral odult asthma popula1ion and S% in children when deter-
700 microgramslmLor if there is severe metabolic ac- advcnc cvenls or low..cJosc ispirin and clopidogrel in r.ind·
omiied con1rolkd 1riols. An•J Med2006; 119: 624-38. mined by oral provocation tcSting. However, when based on
idosis. Vulnerable patients such as children (aged un- 6. Hc-mMdcz.-Diaz S, Garcia RodrigPez LA. Cordioprotcctive as· medical history alone it \V3S only 2.7% in adults and 2% in chil-
der JOyears) or the elderly (aged over 70 years) may pirin users and 1hc-ir excess risk of upper gas1rointiestinal com· dren. In another sludy4 using dala from palienl questionnaires the
pliea1ions. BMC Med2006: 4: 22. prevalence of aspirin-induced asthma wos 10 to l t% in pa1ienrs
require dialysis at an earlier stage. Available at: h11p://www.biomedcentrtl.com/contcn1/pdf/
with asthma and 2.5% in non-asthmatics.
1741-7015-4-22.pdf (accessed 11112106)
0 References 10 salicylalc loxiciry and its management 7. Lee M. e.1 al. Dose elTectS of aspirin on gastric proshri,i:;hmdins There is considerable cross-reacliviry between aspirin and other
J. Notarianni L. A reassessment of the treatment or salicylo1c poi· and stomach mucos:il injury. Ann Intern Med 1994; 120: I S.4- 9. NSAJDs and ii is generally recommended that patients who have
soning. Drug S•f•ry 1992; 7: 292-303. S.. C~r B, Feld.man M. Effects of very low dose d:tily, long-1cm1 had ii hyperscnsi1ivity rcaclion to aspirin or anr other NSAID
2. Woods D. ~I nl. Acute loxicity o( drug,s: i11hcylau:s. Pltorm J
::C!~~~e~~P~u;o;i~~1~~~~:~~k;~~m°::.~~'J:i:~!;~~i/~
0
1993; lSO: S7(;-8. should avoid all NSAIDs. Jn a syslcmalic review• cross-sensitiv-
3. Collec GG. Hinson GC. The: man1gtmen1of acute poisonins:. Br ogy 1999: 117: 17-25. ity 10 other non•scleclive NSAlDs (ibuprofen, diclofcnac, and
J An•Nlh 1993; 70: 562-73. 9. :-;:07~·rous. Whfoh prophylac1ic aspirin? Drug Th~r Bull 1997: naproxcn) occurred in over 90% of Uiosc patients with aspirin-
4. Wilson JE. Tagup<i ET. Suicide iHCmpt by means o( aspirin en· induced as1hma. A review oflhe litcra1urcf found little evidence
ema. Ann Phor••oc•lher 1994; 28: 467-9. lO. Cole AT, tt al. Protection of human ga.~tric muccsa againsr as-
of cross-reac1ivily with scleclive cyclo-oxygcnase-2 (COX-2)
5. Dargan Pl, ttl al. An evidence based llowchali to guidt chc ma~ ~:':J99~~'tJ:~;g~~13~r d0$C redur:tion? Alimt'nt Phomrurol inhibitors a.nd aspirin panicularly in patients with aspirin-
agcmenl of aoul¢ salit)'l&lc (aspirin) overdose. Emtrg Mtd J
2002; 19: 206-9. 11. Cryer 6, et nf. Effeotsof cutanoous a~plrin on the human stom· induced asthma; however, allhough there have been isolated re-
6. Ri\'era w. el al. Delayed salicy'late toxicity at)$ hours without ach and duodenum. Proc A.s.s-uc Am Ph)'1;cio1is l 999; JJ1 : ports ofasthma in such palienL< a ftcr taking cclecoxib or rofecox-
early manifes1ations foUowin& a .single salicylate i"&esti<m. Ann «S.·S6. ib. About 4% of patients with aspirin-induced skin rcac1ions may
Pharn1•co1her 2004; 38: 1186-8. Corre<lion. Ibid. 2006, 40: Effects on hearing. Studies h~ve shown lhal tinnitus develops develop a cutaneous rcac:Jion when challenged with a COX-2se-
999. at serum-salicylate concenuations above 200 micmgramslml..1 lcctive NSAID. l'arace1amol is usually safe in patien1s scnsi1ive
Effects on the blood. Although it has beneficial cfl'ccts on However. there appears 10 be considerable inle.subjcct varia1ion to aspirin and Cl'OSS-$CtlSlliviry 10 paracetamol has been calculat-
platelets, aspirin can cause adverse blood dfects. All indication in the response of the ear to salicylate;' tiMitus may occur at ed as abo1117%.' Based on 1hesc figures, ii is considered lhal less
of this toxicity is given by an early rcfcrenoe110 n:porU submit- lower concentrations, whereas patients with pre-cxisling hearing than 2".4 of asthmatic pal1cnts would be li~ely 10 react 10 both
ted to the UK CSM. There were 787 reports of adverse reactions loss may not have tinnitus despite serum-salicylale conccntra- porac:ctamol and aspirin.
All cross-references refer to entries in Volume A
 . Aspirin 23
The response 10 indi1·idual NSAJDs is believed 10 be closely also excend these recommendations to non-acelylated sali- Aspirin and orher saiicylates can interfere with thyroid
JinkeJ 10 the i:xlenl to whic-h tht:y inhibit prostaglandin synthe- cylaccs. In the UK, the MHRA•contra-indicates the u.'<C of topi- function tests.
sis.~' Tht:re may be a dose threshold below which no detectable cal oml pain relief preparations containing salicylates in children
symptorn~ occt;r and paLients who may be toleram of regulat' under 16 )'Cars of age due co the theoretical risk of Reyes syn- Breast feeding. The American Academy ofPediatrics' cons id·
low-dc>s< aspirin can develop symptoms when they take larger drome (for details. see Choline Salicylate, p.38). er.; that salicylales should be given wi01 caution to brcasl-feeding
d<>ses.' Some; use a fonnal challenge with a 300-mg oral dose of One group of workers 10 who re.examined some of the original moihcrs, since as~iri.11 has been associated with metabolic acido-
aspirin to confinn a diagnosis ofNSAID sensitivity but otl1er.;S studies susgested that there might also be a link bet\veen Reye's sis in the infant The BNF 59 also recommends !hat aspirin
consider tltis 10 be a dangerous technique and use inhalation of syndrome and d1e use of antiemetics, phenothiazine.s. and some sh(luld be avoided in breast-feeding mother.; because of the pos-
ly!\ine aspirin which they considCJ' lO be a safer and more predict- olher anlihistamincs, but their conclusions have been criticised. 11 sible risk ofReye's syndrome i11 nursi11g infa111s; che)' also advise
able alternative. Intranasal chollcngc with lysine aspirin has also More recently, others'~ have suggested Iha! Rcye's syndrome that infaulS with ncona1al vicamin I( deficiency may be at risk of
been used. 9·10 was caused by a viral mu1a1ion or the resull of misdiagnoses of hypoprotlirombinaemia after !he regular use of high doses of as-
I. Kwoh CK~ fei11stci11 AR. Rotes or sensilivity re<letions to lSpi- metabolic disorder.; but again these conclusions have been ques- pirin in breast-feeding mo1hers. However, a prospec1ive study'
rin: problems in interpreting the data. Clin Phurnuwol Thu tioned.&.IJ found no adverse effects in IS breast-fed infonlS whose mothers
1986; 40: 494-505.
I. ~J~~_M· Lynn R. Rcye's syndrome. N £n~I J Med 1999; l41:
were receiving aspirin.
2. Schia·1ino O. et al. The aspirin disease. Thora:r 2000; 55 (suppl
2): S66-S69. I. American Academy of Pediatrics. The lT'Mt~fer of JruPs and olh"'
3. Jenkins C, tH al. Systematic review of prevalence of aspirin in· 2. Waldman RJ. et nl. Aspirin as~ risk facto1· ill Reye·~ syndrome. a chemicals into human milk. Pediatric: 2001; 108: 776-.S9.
duced asthma and its implications ror clinical praccicc. 8.4/J JAMA 1982; 247: 3089-94. [Rctjrtd May 1010] Correction. ibid,; 1029. A lso available at:
2004; 328: 4)4-i. ' 3. M:ilpin TJ. et al. Re:yc's syndrome ;ind medic3!ion use. JAMA hll p ://a 3ppo lie y. a a p pub Ii cations .org:cg ii con 1en t lfu JI/
4. Vally H, ct ol. The prc\'~lcncc ofaspirin intolerant asthma (AIA) 1982: 248: 687- 91. pcdiJtrics~~b 108131776 (accessed 23/11/06)
in Au~trali:u\ as1hma1ic p31ients. 1'honu: 2002; S7: 569-74. 4. Hurwitz ES, et of. Public hea!lh service s'udy of Reye's syn- 2. Clark JH. WilM'ln WG. A J6..-day.old bre.ast·fcd intanl wi1h mcl-
5. Knowles SR, er ol. Manageinem options for palicn1s with aspi· drome and medic:nions: rep0n of the m3in study. JAMA 1987; ~bolic acidosis caused by S31icylatc. CJin PP.diotr (Philaj 1981;
rin and noosteroidal antiinflammatoTy d.rug sensitivity. Aim 257: 1905-11. 20: 53-4.
Phon11ocothl'r 2007: 41: 1191-1200. $.Hall SM, el ol. Prcadmissi0t\ antipy1etics in Rcyc's syndrome. 3. ho S. er al. Prospecthc follow·up ofadve:~e reactions in brt:ast·
6. Power 1. Aspirin-indua::d :is1hma. Br J Anuesth 1993; 7J : Arch D;.r Child 1988; 63: 857-66. fed infants exposed to tntltetnal ntcdit~li on. Am J Ob.1te1 Gwie·
619-21. 6. Glasgow J ,.(. Rcye:'s syndtome: lhe case for a causal link wirh col 1993; 168: 1393-9. ·
i. Frew .A... Selected ~ide -effttr $: 1;3, nqn-iterQidal !!IH i·inO;lrnn)~· aspirin. Drug So/eiy2006; 2?: 1111-21.
lOt')' drug_s and asthma. Pt\'scribers 'J 1994; 34: 74-7. 7. SchrOr K. Aspirin and Reye syndrome: o. review of the e"idcnce. Pregnancy. The potential adverse effects of aspirin when used
S. Davies SH. NSAIOs and asthma. P1~scr;bers· J 1994; 34: P•dla1r Drug• 2001; 9: .195 - 204. during pregnancy have been reviewcd. 1 Salicylates readily cross
163-4. S. MHRA. Aspirin and Re:yr:'s syndrome: quesliuns and an~wers the placenta and have been shown to be teratogenic in animals.
9. Ca$<ldcYall J ttt <11. Intranasal ch:sllcngc wi1h aspirin io lht dias· (issued 4lh April, 20-03). Av-Jilablc at; Allhough some irudies and anecdolal repons have implicated as-
nosis "'aspirin i111oletant as1hma: evaluation of na.s:il response htt p://www. in hra..go". ul:.lhomefidcplg'? I de$ crvi cc=G ET_
by acoustic rhinomcuy. Thoror 1000; SS: 921-4. Fl tE&dDocName;o::CONO I 95 I 2&RevisionSclectionMcthod• pirin in the fonnation of congenital abnonnalities. most large
SO. Alonso·Llamazarcs A. ~1 ol. Nasal provoc.:uion 1cst (NPT) with l..c:ites1Released (accessed 29/11/06) studies2... have failed to find any significan1 risk or evidence of
aspirin: a sensitive and safe mc1hod to diagnose aspirin-induced 9. MHRA. Press release: new ad\•ice on oral salicylate gels in un· ccratogeniciiy. Analysis of data collected by ~>e Slone Epidemi-
asoh1m (A IAl. A/1'"!:"2002; 57: 632-S, dcr 16s (issued 23rd April. 2009). A\'ailable ~t : hnp:// ology Unit Birth Defecls Study suggests thal use of aspirin dur·
www.mhra.gov.ukfl\1ewsCenlre/PrcssrcleascslCON0440 J4 (ac-
OESENSITISATION. Successful desensitisation has been <esscd 24104/09) ing !he early months of pregnancy, when the fetal heart is devel-
achieved using oral aspirin challenge pr·o tocols. 1·6 Incremen- 10. Castctls-Van Dade M, Eggcrmont E. Rcyc's syndrome. BMJ oping, is not associaled with an increased risk ofcardiac defects.s
tal doses of aspirin (traditionally slaning at 30 mg) are given 1994; 308: 919-20. The abiliiy of aspirin, however, to alter platelet function may be
until an allergic response occurs~ aspirin is rcadministered at 11. Holl SM. Rcyc's syndrome. BMJ 1994: 309: 411. a polen1ial risk. There have been a few reports of haemorrhagic
the dose that caused !he response and again incremental doses 12. Orlowski JP, cl ul. Is aspirin 3 cause of Re)'e's ~yndromc? A disorders in infants whose mothers had consumed aspirin during
c-ase againsl. Drug Sofqry 2002: 25: 225-3 C.
are given umil finally a 650·mg dose is toleratcd. 1 -~ After de- 13. Waller P. Su"'am:J R. Is aspirin a cause of Rcye's syndrome'? preg11ancy6 and of salicyla1e-associa1cd haemorrhagic complica-
scnsilisation, an intermption of conlinuous aspi1·in dosage re- Drug Safety 2004; 27: 7 1-3. tions in mot11ers.1 However. no clinically significant adven;e ef-
sults in the reappearance of sensitivity. Desensitisation has fects on macemal or neonatal bleeding or on fecal duct\JS flow
been maintained indefinilely wich as little as SI mg daily of Precautions were reponed in a meta-analysis3 of 6 controlled studies which
aspirin. 6 Aspirin has many properties in common with the evaluated low-dose aspirin (less than 325 mg daily) in pregnan-
I. Asad SI, l'I t1I. Effect of aspirin in •aspirin s,ensitivc" patients. cy-induced hypertension. Two more recent placcbo-coutrollcd
BM./ 1984; 288: 745-8. non-aspirin NSA!Ds, the precautions of which are de- sn.tdies9•10 have also found no clinica11y significant adverse ef-
2. Stcven.)on DD. Descnsi1ization of aspirin-sensitive asihmmics: a scribed on p. I02. fects on neonatal bleeding with low-dose aspirin. It apperued thot
1heraptutic aheroatjve'/ J Asthma 1983; 20: 31-8. the degree of cyclo-oxygenase inhibition produced by aspirin
3. Gol bpJdi RR, eJ ol. Aspirin sensiti,·ity; implic41tions for patieiltS Aspirin should be used cautiously, if at all, in patients
was unlikely to b! great enough to cause premal\lre closure ofOte
wilh coronary artery disease. JAMA 2004; 292: 3017- 23. prone to dyspepsia or known to have a lesion of the ducrus aneriosusorio affect the pulmonary blood vesscls.1 How-
4. Cotmi(:JJ\ U, "'of. l rnpr0\1ements in an oral aspirin chJllcngc
protocol for 1he diagnosis of aspirin hypcrsensilivity. CJ;,, &rp gastric mucosa. It should not be given to patiencs with ever, in some sntdies in patients considel'ed to have high·risk
All<rgr200S: JS: 717-22. haemophilia or other haemorrhagic disorders, nor to pregnancies the 1isk ofabruptio placentac11 or consequent peri-
S. Pr;i;:i.r 0, Klimek L. .~spiri n descnsi1i:wlion in aspirin intolcr· treat patients with gout (since low doses increase urate natal dcath 12 was increased by maternal dosage wi01 aspirin. For
an<e: 1pd3.tC on currenl s1andards 3nd recent improvcmc1ltS. reference to a possib le association between aspirin and other
Curr Opin Allergy Clio /rmmmol 2006: 6: 161-<l. concentrations).
6 . Knowlts SR, at al. Ma.\agtrnent options for palicnli wirh aspirin NSA!Ds and pe1listen1 puhnonary hype1tension ofOie newborn,
and nonstcroidal antiinOammalor)' drug sensitivi1y. An,, Phar--
Aspirin should be used with caution in patients with see under NSAIDs. p. 103.
mocml-.er 200?: 4J:1191-1200. asthma or allergic disorders. It should not be given to Allhough aspirin has the po1en1ial 10 inhibit uterine con1rac1ions
Hypoglycaemia. A re\ icw of Lhe literature' on drug-induced
1 patients with a history of sensitivity reactions to aspirin of 13bour i1 was considered 1hat intcn11inetu or low-dose aspirin
hypoglycaemia highlighled the fact lhal ovcrdosage wi01 sali- or other NSATDs, including those in whom attacks of was unlikely to inhibit cyclo-oxygenase for long enough to pro-
cylales could produce hypoglycaemia in children. Although long pregnancy or labour. 1
asthma, angioedema, urticaria, or rhinitis have been
lherapeutic dosesofsalicylates inaduhscan lowerbloud-glucose See olso Surgical Procedures, below.
conccn1r.11ions in diabetic and non-diabetic subjects alike, opin-
precipitated by such drugs (for further details of risk 1. de S'viel M. Fryers G. Th..: use of aspirin in pregmmcy. .I Obs.·e1
ion on th: clinical significance of this effect varies. Salicyla1es factors see Hypersensitivity under Adverse Effects, Gy11uecol 199C·; 10: 467-82.
above). 2. Slone 0, et nl. Aspi;in and cong.cnil~I malformations. lom:el
have oecn implicated in a few cases ofhypoglycaemia in adults' 1976; I: 1373-S.
and some' suggest that patients with renal impoirmcnc or those Caution is necessary when renal or hepatic function is 3. Shapiro S, er ot Perin111ul monality ~nd bir1h-weight in relation
receiving large doses, such as in the treatment of rheumatoid ar- to aspirin Lak~11 during pn:~nanc;y. Lancc.•t 1976; i: I 37S-6.
thritis, may beat 1isk. Hypoglycaemia has been reponed in a pa- impaired; aspirin should be avoided in severe renal or 4. Winship KA. ~1 al. M:nemal drug. hislories 3.nd central ntrvous
lient wtth renal failure afte.r excessive application of a topical hepatic impainnent. Aspirin shou ld be used cautiously $Y~le:m anomde.s. Arch Dis Ch;Jd 1984: 59: 1052-60.
S. \Verier MM. e.• ul. The relation of aspiri1l use du1ing. the first
prepaf'Ation co111aiuing salicylic acid.J in dehydrated patients and in the presence of uncon- lrimeslcr of pr>!gnancy 10 C<'ngcnil2I cardiac defecls. N Engl J
I. Sthzet HS. Oru~·induccd hypo,e-lyccmia: 3 review of 14 1S <:as· trolled hypertension. Mod 1989; 321: 1639-42.
cs. £ndocrinol Metob Clin Nonh Am 1989; IS: )63-83. 6. Ble:yet WA. Brccken.ric.Jge RT. S1udic.s on the detection or ad~
2, Pa.ndi1 MK, er ol. Dn1g-induced disordc:rs of glucose tolerance. High doses may precipitate acute haemolytic anaemia verse dn,1g reai:1ions in the newborn JI: the effects of prenatal
An1J lmern Med 1993~ 118: S29-39. in patiencs with G6PD deficiency. Aspirin may inter- ~spirin on ncwbom hcmo$t35is. JAM.A 1970; 213: 2049-~3.
3. Raschke R, et nl. Rcfroc1ory hyp<"glyce:mia seconclaf)' lO topical 7. Collins E~ Turner G. Maternal effects ofrcgulcr ~alicyJare ing.:s-
s.alii;yluc intoxicatioo. Arch lmtm Med 1991 ~ l SI: 591-3. fere wid1 insulin and glucagon control in diabetics (see tion in pregnancy. Lanai 1975; ii: 335-7.
Hypoglycaemia under Adverse Effeccs, above). S. !mperiale TF, Peuulis AS. A 1neta·an:i1ys;,_ orlow--dosc :ispirin
Reye's syndrome. Reye's syndrome is a disorder characterised for 1hc prcv~ncion of prcgnaney-induccd hypcrtcnsi.,.·c disco..<;c.
by acute encephalopathy and fatty degeneration of the liver. It The use of aspirin in children is extremely limited be- JAMA 1991: ?'6: 261-4.
occur.; aln1ost exclusivdy in young children although coses have 9. L(ludcn K.'\, ftol. NeonBtal pla1clet reacli\•il)' :ind serun1 1hrom·
cause of the risk of Reye's syndrome (see under Ad- box:int B: proCuclion in whole blood: the effect of m:ilern:il low
been S<.'Cn 1 in paticnL' over the age of 12. Many fae1ors may be verse Effects, above, and Uses and Administration, be- dose 3Spirin. Br J Obstt't Gy110,col 1994; TOt: 203-R.
involved in ils aetiology but it typically occurs after a viral infec- I 0. Dasari R, ct ol. Errect of matem~I low dose aspirin on nt>om1tal
ti(ln such as chickenpox or influenza and may be precipitated by low). pla1clet funetfrm. /ndio11 Pea'ia11· 1 998~ 3S: 507-11.
a chem icnl trigger. Sel'eral large studies, as well as individual Although low-dose aspirin might be used in some 11. Sibai BM. et nf. Prevention of preeclampsia with low-dose as.·
pirin in healthy. nullipar0us pregMnl women. N E11gl J Med
case reports, have found 3 link between Reye's syndr(lme and lhe pregnant patients, analgesic doses of aspirin should not 1993: 329: 1213-t8.
prio1· ingestion of aspirin~2· 1 the evidence for other salicylates be used at tenn as they may be associated with delayed 12. Hamid R. ttal. Low dose aspirin in women with raised m31crnal
could not be adequa1cly evaluated.' More recently, i11-vi11v stud- scrum afpha-foopro1cin and abnonnal Doppler wa,·erom1 pat·
ies have ~to""' biological plausibility for !he role of aspirin in the onset and prolongation oflabour and with maternal and ccm$ from the uteroplaeent:il circula1ion. Br J Obstcl Gynoecol
1994: 101: 4Sl-4.
development of Reye 's syndrome.6 neonatal bleeding. High doses may cause closure of fe-
Although a caus.11 relationship remains to·beestablishcd, the use tal ductus arteriosus in utero and possibly persistent Resistance. Some patienlS given aspirin for the management of
of aspirin and other acelylated salicyfales as analgcsios orantipy- pulmonary hY.Pertension in the newborn (but see Preg- cardiovascular disease do nol respond to treatment, a phenome-
relics is ~encrnlly considered contra-indicated in children under non that has been described as aspirin rcsislance. At prcscnl, as-
nancy, below); kemicterus may occur in jaundiced ne- pirin resistance is poorly undor.;tood and fun her smdies are need·
the oge of 12 years and, in some countries, in teenager.;. For ex-
ample, lhe UK MHRA has recommended that all children aged onates. ed to define it.
under 16 years should not take as.pirin.s (1bis advice superseded Continuous prolonged use of aspirin should be avoided References
lheir earlier recommendations to avoid aspirin during fover or in the elderly because of the risk of gastrointestinal I. Sanderson S. e1 ol l'arra1i,•e revie·w: tiSpir-in resis1ancc and ils
viral inl~lion in children under 16 y~ of age; Ihis advice was dinical imp1ica'. io11s. A1111 /n1trn Mecf 200~; 142: 370-80.
bleeding. 2. Hankey GJ. Eikelboom JW. Aspirin resistance. Umccr 2006~
considered too complex for products on general S3lc and given 1
367: (,O(i...17.
the wide 3vailabili1y of other analgesic preparations, 1here was Aspirin should be stopped several days before sched- 3. Michos ED. e1 cl. Aspiti·n and clopidogrel resistance. Ma.1•0 CUu
no need IO expose this age group to any risk.) Some counlrics uled surgical procedures (see below). Pr()c 2006; 8 1: 518-26.
24 Analgesics Anti-inflammatory Drugs and Antipyretics
4, Undas A, et al. Antithrombotic properties or aspirin and resist- plasma-salicylate concentrations. Metoprolol may also niere are limitations lo all these studies and further studies arc
ance lo aspirin: beyond strictly antiplatelet aclions. Blood 2007~
increase peak plasma-salicylate.concentrations. Sali- needed before any recommendations can bemade.7•11
109: 2285-92.
I. MacDonaJd TM, Wei L. Effeclofibuprofcn >n cardiopro1cc1ive
5. 031en JE. Aspirin resislance: is iL real? Is ii clinically sisnifi- cylate intoxication has occurred in patients on high- effect of aspirin. Lcncet 2003; 361: 5 i3-4.
canl? Am J M•d 2007; 120: 1-4.
6. Hovens MMC, e1 al. Prcv4tlcnce of pcrsis1cnt phucle1 reac1ivity
dose salicylate regimens and carbonic anhydrase inhib- 2. J( immel S~ et ol. The effects of nonselectiYe non-aspirin non·
s<croidal anti·inflammarory medications on the risk of nonfatal
de$pitc: use of aspirin: a syslcm:itic review. Am Hearr 1 200i; itors. myocardial infarction and their in1eraction with aspirin. J Am
153: 175-8) . Plasma-salicylate concentrations may be reduced by Coll Cordiol 2004; 43: 985-90.
7. Krasopoulos G. el al. Aspirin "resisunre" 3nd risk of cardiovas· 3. Kurth T. <t al. Jnhibi1icn of clinic:al benefiu of aspitin on first
cular morbidity: sys1cm:u ic review and meta-analysis. BMJ corticosteroids. This interaction is likely to be impor- myocardial infarction by nonsteroidal antiinflammatory drugs.
2008; 336: 195-8. tant in patients receiving high-dose long-tenn sali- Circulation 2003; 108: 1191-5.
S. Gasparyan AY, ct al. The role of aspirin in cardionscular pre- 4. P<itcl TN, Goldberg KC. Use of aspirin and ibuprofen compared
vention: imp)ica1ions of l\Spirin resis1.ance. J Am Coll Cordiol cylatc treatment. Conversely, salicylate toxicity may with aspirin alone and the r isk or myocard aJ infarction. Arch
2008; 51: 1829-4). occur if corticosteroids are withdrawn. Also the risk of Intern Med2004; 164: 852-6.
S. Curtis JP, et ul. Aspirin. Ibuprofen, and mortality after myocar-
Surgical procedures. Aspirin prolongs bleeding rime, mainly gastrointesti nal bleeding and ulceration associated dial inf'arcticm: retrospective cohorl stud)'. BMJ 2003; 327:
by inhibiting platelet aggregation. This elfect is irreversible and with aspirin is increased when used with corticoster- 1322-3.
new platelets musl be released into the circulation before bleed· oids. Antacids may increase the excretion of aspirin in 6. Catella·Lnwson F. et al. Cyclooxyg.enase inhibitors and the an-
ing time can ret\lrn to nonnal. Therefore aspirin therapy should tiplatelet effects cf ~spirin. N Engl J Mcd200 1; 34S: 1809-17.
be stopped several days before surgical procedures. In some clin· alkaline wine. 7. Etmina1' M, Samii A. Effect of' ibuprofen on cardioprolective
effect of aspirin. lon<et 2003; 361: I 558-9.
ical situations, aspirin may have been given shortly before a sur· Aspirin may increase the activity of coumarin antico- 8. Kimmel SE, Strom BL Giving aspirin and bupr<>fen after my·
gical procedure. When emergency ccronary bypass surgery is re· agulants, sulfonylurea hypoglycaemic drugs, zafirlu- ocardial infarction. B1\.IJ 2003; 327: 1298..9.
quired for myocardial infarction, most patients would have 9. Curtis JP, Krumholz HM. The case for an idverse interaction
received aspirin as part of the injtial trcatmenl for infarction.
kast, methotrexate, phenytoin, and valproate. Aspirin b<:twccn aspirin and non-steroidal anti·inflanmatory drugs: is it
Perioperative bleeding, transfusion requirements, and surgical diminishes the effects of uricosurics such as probene- time to believe lhe hype? J Am Coll Cartfio/2004; 43: 991-3.
cid and sulfinpyrazone. The manufacturer ofmifepris- 10. Chee.ma AA. Should people on aspirin avoid ibuprof'en"! A re·
re-exploration rates may be increased when aspirin is given.'
•iew of the literature. Cordiol Rf!ll 2004; 12: 174-<\.
However. some srudies2.J have shoY.n that the increase in bleed· tone advises of a theoretical risk that prostaglandin II. Corman SL. et ol. Impact of nons1croidal sntiinflammatory
ing is not significant; in addition, there have been repons that synthetase inhibition by aspirin or NSAIDs may alter drugs on the cardioprotective effects of aspirin. Ann Phm·nraco.
pre-operative aspirin may reduce the rate of periopcrative myo· ther 2005; 39: I 073- 9.
cardial infarction (with aprotinin).' improve oxygenation,s and the efficacy of mifepristone.
Spironolactone. For the effcet of aspirin in patients taking
even decrease mortality.3·6 Desmoprtssin may reduce the risk of Use of aspirin with other NSAIDs should be avoided spironolactonc, sec p.1537.
pcrioperative bleeding (see under Haemorrhagic Disorders, because of the increased risk ofadverseeffects; the car-
p.2389). dioprotective effects of aspirin may be abolished by Pharm acokinetics
Aspirin is sometimes given during the second and third trimester
for the prevention of pregnancy-induced hypertensive disease
ibuprofen and possibly other NSAlDS. Aspirin may Aspirin and other salicylates are absorbed rapidly from
(see under Hypertension, p.1290). Studies indicate that when decrease the plasma concentration of some other the gastrointestinal tract when taken orally but absorp-
given in a dose of325 mg daily or less, clinically si~ificant ef- NSAIDs, for example, fenbufen, indometacin, and tion after rectal doses is less reliable. Aspirin and other
fects on maternal or neonatal bleeding do not occur. Some have piroxicam. salicylates can also be absorbed through the skin.
suggested that aspirin therapy may ir.creasc the risk of formation
of extJadural haematoma thus making epidural anaesthesia 0 References. After oral doses, absorption of non-ionised aspirin oc-
inadvisable' but a subsequent study9 found that low-dose aspirin 1. Min~rs JO. Drug lnleractions 4nvol\'ing 3Spirin (acctylsalicylic curs in the stomach and intestine. Some aspirin is hy-
acid) Md salicylic acid. Clin PhcrmocokineJ 1989; J7: 327-44 .
during pregnancy did not increase the risk of bleeding complica-
2. Abc::bc W. Herbal medication: PQtemial for adverse in1cractions
drolysed to salicylate in the gut wall. Once absorbed,
tions during epidural anaesthesia. with analgesic drugs. J Clin Phorm Ther 2002~ 27: 39 1 ~01 . aspirin is rapidly converted to salicylate, but during the
Patients on low-dose aspirin, in whom roumiquels are used for 3. Glliano JM, Gibson CM. Po1en1ial for dru.g·drug interactions in first 20 minutes after an oral dose aspirin is the main
nerve blocks or other procedures, may be at increased risk ofde- patients taking analgesics for mifd·to-moderale pain and )ow·
veloping purpuric rash. 10 dose ispirin for C(1rdioprotec1ion. Am J Co1rliol 2006; 97: 23-9. fonn of the drug in the plasma. Aspirin is 80 to 900/o
It has been suggested thal in patients undergoing dennatologi- ACE inhibitors. For a discLLo;sion of aspirin and other NSAIDs
bound to plasma proteins and is widely distributed; its
cal, 11 or minordental 12 surgery, aspirin need only be stopped be- reducing the activity of ACE inhibitors, see p. 1318. volume of distribution is reported to be 170 ml.Jkg in
fore surgery in those patients with a prolonged bleeding time, adults. As plasma-drug concentfations increase, the
whereas patients with a normal bleeding time could continue Anagrelide. For the potential effect of aspirin in patients taking
anagrelide, see p.2468. binding sites on the proteins become saturated and the
therapy. volume of distribution increases. Both aspirin and sal-
I. Goldman S, et of. Improvement in cmly saphcnous vein graft Antiepileptics. Aspirin may inhibit the metabolism of va/-
patency after coronary ancry bypa.is surgery wi1h ao1iplatclct proote; for further details, see Analgesics. p.SSS.
icylate have phannacological activity although only
therapy: rcsuhs of a Veterans Adrninis1ra1ion Cooperative aspirin has an anti-platelet effect. Salicylate is exten-
Study. Circula1ion 1988; 77: 1324- 32. Antifungals. Plasma-salicylate concenrrations in an 8-year-old
2 . Reich DL, cl al. Asplrin docs not increase homologous blood child receiving long-term aspirin therapy for rhewnatic heart dis·
sively bound to plasma proteins and is rapidly distrib-
~~'~;-;~~~~~." cJcc1ivc coronary b~pass surgery. An~sth Analg ease were markedly reduced when treatment with griseofaM11 uted to all body parts. Salicylate appears in breast milk
3. Dacey Ll, et al. Effect of pieopcrative aspirin use on mo11alily was slarted.1 It was suggested lhal griseofulvin might interfere and crosses the placenta.
in coronary anery bypass gra:fting palients. Aim Thoroc Surg with absorption ofaspirin. Salicylate is mainly eliminated by hepatic metabolism;
2000; 70: 1986-90. I. Phillips KR, al of. Griseofulvin significantly decreases serum
4. Klein M, et al. Aprotinin counterbt:lances an increased risk of salicylate concenm!lions. Pedimr 111/ect Dis .1 1993 ; 12: 350-2.
the metabolites include salicyluric acid, salicyl phenol-
peri·operative hemonhage in CABG patients prc-..trcated with ic glucuronide, salicylic acyl glucuronide, gentisic ac-
aspirin. Eur J Cordiothoroc Srwg J998; 14: 360-6. CaJclum-c.hannel blockers. The antiplatelet effects of aspirin
5. Gerrah R. el al. Preop-er:uive aspirin adminisltation improves and calcium-channel blockers may be increased when they are id, and gentisuric acid. The fonnation of the major me-
o:tygenation in patients undergoing coron;try artery bypass used together; there have been isolated reports'.2 of disturbed tabolites, salicyluric acid and salicyl phenolic
grafting. Chw 2005; 127: 1622~.
6. Bybee KA, er al. Preoperative aspirin therapy is associated with haemostasis including abnonnal broising, prolonged bleeding glucuronide, is easily saturated and follows Michaelis-
improved postopera1.ive outcomes jn paticncs undergoing coro· times, and ecchymosis in patient~ taking aspirin and veropami/ Mentcn kinetics; the other metabolic routes are first-
nary anery bypass g:raf'ting. Circ111'orion 2005~ 112 (suppl J): concurrently.
1286-1292 . order processes. As a result, steady-state plasma-sali-
I. Ring M~. a1 al. Clinically $ignifieant aniipl:itelet effects or cat..
7. lmpcriale TF, Petrulis AS. A meta-analysis of low..:lose aspirin ciu in-channel blockers. .I Clin Phormocnl 1986; 26: 719- 20. cylate concentrations increase disproportionately with
for the prcven1ion of pregnancy· induced hypertensive disease.
JAMA 1991; 266: 26()-4. 2. Verzino E. et ol. Vcrapamil·aspirin interaction. Ann Phormoco· dose. After a 325-mg aspirin dose, elimination is a
tltu 1994; 28: 536-7.
S. Macdonald R. Aspirin and cxlradura1 b locks. Br J Anae.fth first-order process and the plasma-salicylate half-life is
1991; 66: 1-3. General anaesthetics. For the effect of aspiriJl on thiop!ntol
9. Sibai BM, e1 ol. Low·do~ aspirin in nulliparous wumcn: safety about 2 to 3 hours; at high aspirin doses, the half-life
anaesthesia, see p.1952.
of eontinuous epidural block :ind corrdation between bleeding increases to 15 to 30 hours. Salicylate is also excreted
time a.nd ma!cmal·nennatal bleedins complir::itio11s. Am J Ob- NSAIDs. It has been suggested that ibuprofen and possibly oth· unchanged iu the urine; the amount ex.creted by this
Slet Gynecol 1995; 172: 1553-7.
10. Runcic C J, t:I ol. Aspirin and intravenous regional blocl;.s. Br J
er NSAJD.i may reduce the cardioprotcctivc effect of aspirin. A route increases with increasing dose and also depends
Hosp Med t990; 43: 229-30. study' involving 7107 patients found that ~rdiov=ular monal-
11. Lawrence C, et al. Effect of aspirin and nons1eroidal amiinflam. it)• was increased in patients taking Jow..<fose aspirin for cardio- on urinary pH, about 300/o Qf a dose being excreted in
matory drug therapy on b leeding complications in dcrmato1ogic vascular disease when also Ullcing ibuprofen (adjusted h3.2ard ra- alkaline urine compared with 2% of a dose in acidic
5urgicaf patients. J Am Acod Dermctol 1994~ 3J: 988-92. tio I. 73 times that of patients not taking ibuprofen). Another urine. Renal excretion involves glornerular filtration,
12. Madan GA, et al. Minor or3l surgery without stopping d3ily
low-dose aspirin therapy: a study or 5 1 patients. J Oro/ /lfaxil· s.tudy2 found that although taking low-dose aspirin or NSAJDs active renal rubular secretion, and passive tubular rea-
lofoc S11rg 2005; 63: 1262-5. alone decreased the incidence of myocardial infarction, there
was a non·signifrcant increase in the risk of myocardial infarc-
bsorption.
Interactions tion when botit were taken. Another large sludy also found the Salicylate is removed by haemodialysis.
risk to be increased in those taking regular rather than intennit·
Aspirin has many properties in common with the tent NSAJD lreacmenl with aspirin. 3 However, a sludy4 involving
0 References.
non-aspirin NSA IDs, the interactions of which are de- I. Needs CJ, Brooks PM. CliniC31 pharmacokinetics of the s:a1i·
14 098 patients concluded that the risk of myocardial infarction cylah:S. Clin f>harmowkinttt 1985~ JO: J(j4-17.
scribed on p. l 03. was rcdUCl.-d in patients lllking ibuprofen and aspirin when com-
Some of the effects of aspi1fo on the gastrointestinal pared with those taking aspirin alone. Funbennore, a study' in
70 316 patients found that the risk of death in patients prescribed Uses and Administration
tract are enhanced by alcohol. Use of gold compounds aspirin and ibuprofen was comparable to that of.patients pre- Aspirin is a salicylate NSAID and has many properties
with aspirin may exacerbate aspirin-induced liver dam- scribed a<pirin alone or with another NSAID. in common with non-aspirin NSAJDs (p. l 03). Aspirin
age. TI1e timing of doses may be important; a study" has shown that and other salicylates have analgesic, anti-inflammato-
Use of aspirin with dipyridamole may result in an in- irreversible plolelet aggregation occurred when a single daily t)', and antipyretic properties; they act as inhibitors of
dose of ibuprofen was gjvCn 2 hours after aspirin; however, when
crease in plasma-salicylate concentrations. Drugs such ibuprofen was given before aspirin as a single daily dose or given
the enzyme cyclo-oxygenase, which results in the di-
as metoclopramide in patients with migraine headache three times daily, platelet aggregation was reversible which may rect inhibition of the biosynthesis of prostaglandins
result in earlier absorption of aspirin and higher peak limit the cardioprotcctive effects of aspirin. and thromboxanes from arachidonic acid (see p.2607).
All cross-references refer to entries in Volume A
 Aspirin 25
Aspirin also inhibits platelet aggregation; 11011-acetylat- veloped 10 limit C.\lnlplatek1 ctlects of aspirin. hlhibition is cu- Effects on the Gasirointestinal Tract, abo,-c). The meta-analysis
ed salicylatcs do not mulative on repealed dosage. and it has been cstunatcd that a dai- concluded that for the long-lenn prevention of serious v:tSCular
ly dose or 20 lo 50 mg will result in virtually complete events in high-risk patients, a daily dose of aspirin in the range of
Aspirin is used for the relief of mild to moderate pain suppression or platelet tlvornboxanc synthesis within a few days. 75 10 I SO mg should be cffecth-c; if :in immediate effect is re-
such as headache, dysmenonhoca, myalgias, and den- Large ~s of 150 to 300 mg can produce maxim1un suppres- quired as in the initial treatment of acuce myocardial infarct•on,
tal pain. It has also been used in lhc management of sion altn051 instantaneously. acute ischaemic stroke. or tJnSt8blc angina, a loading dose of I50
U•cs. Aspirin ·s antiplatelct activ11y has led to i1s use for the treat· 10 300 mg may be given. Other •11J11yscs15 have made similar
pain and inflammation in acute and chronic rheumatic dose recommendations. However, another review 19 has suggest-
disorders such as rheumatoid arthritis, juvenile idio- mcnt or prevention of a variety ofd1.sorders. 1• 1
ed that doses as low as 75 or 80 mg daily may be inadequate for
patl1ic arthritis, osteoanhritis, and ankylosing spond- • It is used as pan of lhe initial treatment of UllSUlblc angina the primary prevention of sirokc and myocardial infarction; it
(p.1273) and is siven in 1hc early treahncnt of m.\IOC(1rdial ;,,.
ylitis. In the treatment of minor febrile conditions, such farc1i<N1 (p.1294): it is also of benefit in the initial ltcatmcnt of
was considered that the mos1 appropriate dose of aspirin for pri-
as colds or influenza, aspirin can reduce tcmpcrarure mary prevention was l 60 mg daily. Aspirin should be chewed or
acute ischoemlC siroke (p. 1305). dispersed in water; chewing a tablet of aspirin ensures that some
and relieve headache and joint and muscle pains. • Aspirin is us..'d for its combination of anti-inflammatory, anti- buccal absorption occurs.
Aspirin is also used for its antiplatelct ·activity in the pyre1ic, and antiplatelcl activity in the treatment ofKawasalci The use of aspirin in dlildren is limited because of the risk of
initial treaunent of cardiovascular disorders such as an- discos• (see below). It is also used to treal thrombotic symp- Reyc's syndrome (see under Adverse Effects, above); however,
tonis associated with otllipllorpbolipid syndrome, such as oc- it may be specifically indicated in those at risk ofclot formation
gina pcctoris and myocardial infarction and for the pre- curs in patients with SLE(p.1652),ond has been recommend-
vention of cardiovascular events in patients at risk. after cardiac surgery or for the prophylaxis of stroke in high-risk
ed for prophylactic use in pregnant patients with children. The BNFC 2010//J has SUS8ested oral doses of I to
Other such uses include the treaunent and prevention antiphospholipid antibodies who •re at risk of fetal loss. The 5 mg/kg (up to a usual mllXimum of 75 mg) once d.1ily in ne-
of cerebrovascular disorders such as stroke. For further thrombolytic action of aspirin has also led to its use in throm- onates and children up 10 12 years of age: older children may be
details see Antiplatclet Therapy, below. botic thro111bocytope11ic purpura (sec llJrornbotic Microangi- gi\'Cll 75 mg daily.
opathies, p. I 185). Aspirin provides a modest reducrioo in risk
Aspirin is usually taken orally. Gastric irritation may be I. ~;~.~::;~Win H ~m ant•plalt-ktdn,,1. N £11gl J Med 199-4;
of pr~·ttlampsia and its complications (see Hypcncnsion,
reduced by taking doses after food. Various dosage p.1290) and is recommended in some women. 2. Lutonuki OM. n nL Pharmacokinebc optunisation or the trca1-
fonns are available including plain uncoated tablets. • 11 is of value for the pre••ntion or cardiovascular C\'C!lts in mcnt of einbolic disorders. Clfn Pharmott>ki~r 1 995~ 28:
67- 92.
buffered tablets, dispersible tablets, cnteric-coated tab- patients at high risk. including th06e with stable or lllSlable 3. Schr~r K. Anliplatele\ drug1: 1 compar.ath e r~view. Dr11$l
lets, and modified-release tablets. In some instances as- angina. current or prc'ious IR)'C>Cardial infarction, ischxmic 1995: 50: 7-28.
stroke, or transient ischacmic auacks.9 (soc Cardiov:iscular 4, Hung J. Aspirin for cardt0"-ucular disease prcven1ion. Mtd J
pirin may be given rectally by suppository. Risk Reduction, p.1281). It has also been used in 1he Joo&· ,fosr 2003: 179: 147-52.
The usual oral dose of aspirin as an analgesic and anti- term manag~mcn 1 of atrial libnllation (see Cardiac Arrhyth- S. Sasc.t'.n JJ. ASJ IP thcnrutic posit~n statement on 1hc cbi1y use

pyretic is 300 to 900 mg, repeated C\'elY 4 to 6 hours mios, p.1277) for the prevention ofstroke in patients wj1b con- 1~~$;,~~~2ors~v6e;:urf,:.1105~scular events. Ant J Health·
tra-indicotiOtlS to warfruin or if there aic no other risk factors
according to clinical needs, to a maximum of 4 g daily. for stroke.
6. Pauono C.111 al. l..ow·dast a-r,plrin ror tht preventi<'ln or athtm-
tlvomboois N !-,~/ J Med =oos; lSl: 2373-SJ.
The dose as suppositories is 450 to 900 mg every 4 7 5
hours to a maximum of3.6 g daily.
The "aluc of aspirin for primary pre,.enlion of cardiovascu-
lar events, particularly myocartliol i11/arclion and Slroke de-
· ~r ca';:i:\:=,~:~:~:;a0~l.~7cc~c~~;~~k:: f.!~kf~~~:
recommcnda1ion $lalcmenl . Amr " " " " M~d 2009; ISO:
Plasma-sali cylate concentra tions of 150 to pends upon the accurate estimation of 0'"'"'" cardiovascular 3%-104.
300 microgramsfmL are required for optimal anti-in- risk butroutine use isprob<lbly notjuslified in healthy indi,.id· 8. Antithrombotic Tri11ists 1 Collaboruion.. Colb.bor.ltin 1nct3·
....1s.1· 12 Published evidence of unequivocal benefit ,.;th Jow- analysis of ~ndomiud tri1ts or antipl11:telea therapy for prc"en-
flammatory activity (but sec also Adverse Effects, d- aspirin in such patients is lac.king; funhcrmorc, thefe is <ion of dcalh. nl)'Ot'udill infarction~ and $lrokc in hi&h risk pa·
above). Doses need to be adjusted individually to ticnts. DMJ 2002: 3~: 71-86. Correction. ibid; 141 .
an increased risk of gastrointestinal haemorrhage with long- 9. Baigenl C, c1 nl. An11thrombotic Trial isl$' (AlT) CoUobonnion.
achieve optimum concentrations. Generally doses of term 11eanncnt. Aspirin in the primory and Sttend.ary prevention of \'llJCUlardis-
about 4 to 8 g daily in divided doses arc used for acute AlthouiJJ aspirin may pre\'cnl l'DIOUS 1llmmboembolism casc~ COIJahor.. ti\•C mcta·anal)'Sis O( 1ndividUOI paflicip.1nt dala

rheumatic disorders such as rheumatoid anhritis or os- (p.1310) after surgery, other rre.tmet1ts have been preferred. rrorn nndon1i>«I trials. /.ant:er 2009, 373: tS4~60.
teoanhritis. Doses of up to 5.4 g daily in divided doses However, tt is recommended for use in preventing thrombotic IO. =~~~i~:s;; ~~~~r::::;~t:::b!~ht~i:.~d~:~~=
complicalions associated with procedures such as angioplasty nary risk derived ftom mcta-an1fys11 o( randomised !rials.
may be sufficient in chronic conditions. and coronary bypass gr.ifting (see Reperfusion and Rcvascu- /1'0r12001; SS: 26$-71.
Indications for aspirin therapy in children are extreme- larisa1ion Procedures, p.1301). Aspirin has been given as an 11. Anonymous. Aspirin for primary pre\•etll;oo of c.ardio\'asC:\Jfor
adjunct to patients with pn1plteral ar1e1·ial tliromi>Mmbolism disease? Dnts Th~r Dull 2009; 47: J22-S. Corrcct1on. lhld.
ly limited because of the risk of Reye's syndrome (sec 2010; 48: 24.
(p.1297) to prevent propagation of the clot and also to pmient 12. Barnett H,.rta/. 0on•1 bSta.spirin tbr primaryprevc:nltonorcar-
under Adverse Effects, above), but include Kawasaki postoperative comphcations. It may have some effect in de- diovucutar disc...,. BM.I 2010; 340: 920-2.
disease (see below), and juvenile idiopathic anhritis laying disease progrcs«ion and reducing vascular events in pa- 13. Berger JS, tr al. Aspirin for the prcvcruion of eordio,·oascut.tr
and Still's disease (see Rheumatic Disorders, below). tients witlt peripheral arterial cf11ease (see Peripheral Vascu- t"Venu in pjticnts with peripheral artrry disease: a met>analysis
lar Disease, p.1297); however, a meta-analysis 1l of Stll3ll and or randomized trials. JAMA 2009; 301: 190~t9.
Sodium aspirin has also been used for the treatment of 14. Patrianani P. t't al. Selective: cumulative. inhil,ition of pl:!ttfo.t
shorHcnn siudics did not find a statislieally significant benefit thromboXlne productio1t by IO'A •dost aspirin in he3lthy s:ub-
pain and fever. (i.e. I~~ relative risk reduction) of its use on cardiovascular J«1$. ./ C/;n fil>~sr 1981: 69: 1366· 72.
Homoeopathy. Aspirin has been used in homoeo- events when compared with plaeebo or dipyridamole. IS. Webler BB. <t al. Differential mhibmon by :titpitin of \oasGUlar
pathic medicines under the following names: Acetyl- The hcncfit ofaspirin for the primary prevention ofcarcliovas- in
~~~~~~~~~~J~·~~i;\is/O~~~sis 01hcrosclerottc p,utients.
salicylicum acidum; Acetylsal ac. cular events in patients with diabetes mellirus and who have
no other cardiovascular <Uk factors remains to be determined.
16. McLeod U, ~1 al The cfTccu
or different doses of somc.1cct,YI·
sa l ~cylic acid fMmulations on plotelct (Wtction and blccdmg
Administration in children. Indications for aspirin llicnpy in Use may be rccommcndt.-d in ll1ose at increased risk (sec Dia· limes in htahhy SUbJetlS. Sca,td J Hoe.ma1ol 1986; 36: 379-SA.
children arc extremely limited because of the risk ofRcyc's syn- betic Complications, p.~67 for fuither details). 17. B ir~h J. ~, ol Aspmn 1nd other platclc:I AC\IVC dNCJ! telatio ...
~~~:~;i";)~, d~gt[ectivencss, and side efl"ec1~. Clwst 1989; 95
2
drome (sec under Advet·sc Effects, above). For fw1hcr informa-
tion, including some doses, sec Antiplaldct Therapy, Kawasaki
The value of adding aspirin to anticoagulants tor the prophy-
Disease, and Rheumatic Disorders, below.
laxis of thromboembolism in patients with praslharic heart I8. Camp~ll CL, ~'al. Aspiri.D dose for tl1c pr-evention or cardio-
1ia/ws (i;ce Vulvular Hean Disease. p.1308) is also still to be \.Oscular discose: a systcmiliC- review. JAMA '.!OCH; 297:
Antiplate let therapy. Aspirin is an it~ublloroflhc eflZ)111c cy- finnly establish«!. II is usually recommended as an adjunct in 1011,..z•.
clo-oxygenasc, the action being coosidctcd to be due to an ine- patients ,.;th other risk factors. Aspirin alone may be consid- 19. Otten JE. Aspirin to prevent hc:an aruic:k ind stroke: what•5 tbe
riJhldo~?AmJ Med2006: It': t98-202.
versiblc acetylation procCS$. ered in patients with bioprosthetie valves who do not require
• In blood platelets sucl1 enzyme inhibition prevents the synthe· ruuicoagulation. Beh~et's syndromo. For reference to the use of aspirin in the
nia1ia~cmcm ofvasculilic symptoms ofBd~~Cs syndrome. see
sis of thromboxane A,. a compound which is a vasoconstric- Several phannacological studies have ancmpted to find a dose of
tor, causes platelet aggf~tion, and is thus potentially throm- p. 1637.
aspirin 1ha1 would inhibit syntltesis of platelet thrombounc A?
botic. while sparing the effCC1 on prostacyclin produclion'.."bu< it has Cataract. Evidence to suppon or disprove the hypothesis tha1
• Jn blood vessel walls the em:yu1e inhibition prevents the s}n- been pointed ou1l that in patients with vascular di~asc accocnpa- aspirin has a protective cffc<:t against cataract fonn3tion is con-
thcsis of prostacyclin, which is a '-asodilator, hus an1i-aggrc- nying or eouscd by endothelial dysfunction, such as in athero- sidered inconclusive. A SIUdy in the USA in over 22 000 males
~tin3 propenics, and is thus potentially anti-thrombotic. sclerosis, a selective sparing of vascular pros1acyclin produetioo concluded 1hat low-<loocaspirin (32S mg on al1ematc days) for S
Aspinn therefore appears to have opposing biological effects. in.'y not be obtained al any cffcaive antiplatclcl dose. However. years was unlikely to have a major effect on cataract formation
"fhc duration of these elfeels, however. may differ, with the lhe clmical relevance of inhibiting the synthesis of pros1acyclin but tba1 a slightly decrea.cd risk for cataract extraction could not
qffccl.< 011 1he "tCScvlor 1iss11e ge11e1•oll)' Ming thorler 10011 !he may have been exaggerated.11 E>.pcriinental evidence indicates be excluded.' In a later study2 in the UK <lflhlhalmic examination
effeCIS on lilt plo1elm (although lhe a11imal species studied, the lhal ai;pirin is thrombo¥cnic only at cxucmcly high doses ofo,..,.. 1800 patients who were receiving 300 mg_ to 1.2 &of as-
type of blood ,-cssc1 used, and the prevailing experiment31 con- (200 mg/kg), far exceeding the minimwn dose requited to inhibit pirin daily for transient ischacmic attacks failed to conftm1 any
ditions may alter the results). The difference may be explained pros1aeyclin production. Also aspirin is clinically cffecti\'C as an protective effect. Re.Malysis' of 1he rcsuhs of the originol US
by the facl that vascularceUs rcg;oin lhc ability to regcncntc pros- anti thrombotic~ at doses that inhibit the synthcsis of prosta- study idcnlified additional cases of cataract formalion or cx1rac-
tac)-clin in a few hOWi but platelets are unable lo re-synthesise cyclin. Further suppon for the lack of importance ofinhibition of tion although these cases did not affect the overall conclusions of
cydo-oxygeoase, which results in nonewthromboxanc A2 being prostacyclin synthesis comes from cpidcmioloa;ical srudies in lite original study. However. when the stut!l' patients were fol-
produced for about 24 hours unlil more platelets arc released by pr.uients with arthritis given large doses of aspirin and patients lowed up over IS years, observational data suggested that the
lhe ~ t1'131T"Ow; os platelet activity in bone morrow may also be with con1ieni1al cyclo-oxygcnase deficiency; neither of these use of low-dose aspirin may, in fac~ increase the risk ofcataract
aftectcd by o.spirin it is generally cons~ that aspirin only groups of patients have experienced an excess ofthrombotic ep- development It was considered that fut1hcr studies were needed
needs 10 be given once daily for inhibition ofplatelet aggregation isodes. IO establish the role of long-tcnn aspirin in cataract prevention.
10 occur. The inhibitory effect on thromboxane is rapid and unrc· In a meta-analysis conducted by the Anti1brombo1io Trialists' l. Seddon JM. et al. Low dose 11pirfn nnd risks of CIUH'X-t in I
lated to senim concentrations of aspirin, prohably because of the Collaboration' daily doses of7S 10325 mg appeared to be equal- nndomised trial or us phy51cianL A-cit Ophrhali>u>/ 199t; 10,:
ly effec°'"-c for their 1ntipla1clet effe...-i; doses greater ~tan SOO mg 2S2-5.
inactivation of cyclo-oxygenase in platelc1:1 in the prcsystcmic 2. UK·TIA Study Group. Docs aspirin affect 1hc rote orca11rac1
circulation. Since the cffOCI is unrelated to S)l$temic bioavailabil- did 1101 appear to be superior and caused m<Xc gastroinlcstinal fonn1tton? Cross-sccdonal resullS duritlg a rando1niscd doublc-
ity. modified-release and dennal delivery preparations whidl do adverse effects. Whether doses less than 7S mg offer the same blind pla«bo controlled 1rial 10 prevrnt smous va.tculal' cvc1lt$.
tlOI achieve high systemic conccn1rations ofaspirin are being de- enicacy with reduced ~trointcstinnl toxicity tS unknown (see 81· J Ophr/taltW>/ 1992: 76: 259-61.
26 Analgesics Anti-inOammatory Drugs and Antipyretics
3. Chdsten WG. ~' ol. L.ow-.dose n,min and risk of coanicl :md S. Tcrai M. Shulman ST. Prevalence of coronary ancry obnonm1.1i:-
subtypes in 1 rondomiud 1ri1I or L.S. phy.,ci1111. OpJ.tho/.,ic rics in Kawasaki di$Casc is highly dependent on g1mm1 globulin
Epithn1iol 199S; 5: 133-42. do.. bul indcpcndcnl or ..
1icyl•tt dose. J hdlorr 1997: 13 I:
4. Christen WO. ~' ol. A.1ririn use ind nsk or cataract m postuial 888-93.
rollow-up or Physicians· Ht1llh Sn.!y I. Arch Oph1holmol 200I : 6. Saulsbu.')' FT. Comparison of hig)l"'- ond low-<losc 11piri•
11 9: 40S- 12. plus intravenous immunoglobulin in the treatment or KawuaJci
syndrome. CJin /'edi<ur {/'Mio) 2002: •I : S97-«ll .
OysmenorT'hoea. Drugs such as aspinn and other NSAIDs 7. Durongpisitl..'UI K. t:tol. The prcventton ofcoronary antty anru-
lhar inhibit prostaglandin producrion lhrou&Ji inhibition of cyclo- rysm in Kawasaki discuc: a mct..analysi$ on lhc cffteac) of u-
oxygemse arc effccti\<e drugs iii the ltealment of dysmcnonhoea pirin and immunoglobulin trutmcnt. Ptdiorric:s 199S; 96:
(p.7). 1057~1 .
&. Hsieh K·S. et ol. TrutmeN of acute Ka"'-anld dilCaSC': aspirin"•
Fever. Methods for conrrolling fever {see pJO) include the use role in tht ftbriJc S12gc revisited AbStrKC PnliatriCJ 2004. 114:
of antipyreties and/or physical cooling methods (although the 689. full version: hup:J/pcdiatrics.aappublication1.0f;/Cgil
value of the lancr is qucsllOnable). Panic:ctamol, salicy13teS such n:prinlil 14!6i~ (•c:cessed 27111106)
as aspirin, and some other NSAIOs arc rhe main antipyretics 9. Baumer JH. a ol Salic:)1J.tc for the trcalmml uf Kawanki dit-
casc in chjldn:'n. Available in TheCochraneOatabuco(System-
used. However, salicylatcs :uc generally contra-indicated for the atic Re";cws; Juue ..i. Chichatct: John Wiley; 2006 (accessed
management of fever in children bcxause ofrhe possible link be- 27111106).
rwecn their use and the dcvclopme:it of Rcyc's syndrome (sec
under Adverse Effects, above). Leg ulcers. A 4-montb placebo-controlled study 1 in 20 patients
suggeSled that aspirin 300 mg daily aided healing of chronic ve-
Headache. Aspirin is often used for the symptomatic trcalmcnt nous leg ulcers; the mechanism ofa d ion was unclear.' However.
of various types of headache including migraine (see p.670) and the validity of lhe findings has been challenged. l The managc-
tension-rype headache (see p.671). Aspirin given at the onset of menl ofleg ulcers is discussed on p.1725.
symptoms can successfully treat a1 acuce attack of migraine. I. Layton AM. el al. Randomised 1rial of oral aspirin ror chronic
However, absorption may be poor cue lo ga.nric siasis which is venous leg ulccrs. l,oncel 1994; 344: 164--S.
commonly present in migraine. For !his reason dispersible and 2. Ibbotson SH, el oJ. The effect or Hpirin on haernostatic activily
effervescent preparations and compound prcpal'dlions containing i.n the lrea1men1of chronic venOtJs leg ulcenlion. Br J D1rmotol
1995; 132: 422-6. •
drugs such as metoclopramide which relieve gastric slasis have
l. Ruc::kleyCV. P rc~o11 RJ . Trea1ment ()(chronic leg ulcers. Lanell
been advocated. 1994; 344: 1512- 13.
References.
Malignant neoplasms. For references to scudies •uggesting
J. Trch-H•nien P, Oh:scn J. E IT~t\C$C!tl l mctoclopramidc and as-- that regular use of aspirin and other NSAlDs may reduce the risk
pirin (Migrovess) vcrsu1 errcrvuct 11l ts.pirin or placebo for mi-
graine attacks: a double-bHnd su:dy. C~pho la lg;o IY84; 4: of developing malignant neoplasms oflhe gaStrOincescinal cract.
107- 11. see under NSA!Ds, p. I04.
2. Burin& JE. ~I al. Lo"·-dose 1.spiri11 for migniine pruphylaxii. Myeloproliferative disorde rs. Aspirin in low doses may be
JAMA 1990: 264: 1711- 13.
3. MacGrcsor EA, e1 al Mouth~dispcn i blc upirin in 1ht treatment used to provide sympcomatic relief for crythromelalgia (burning
of mig111inc: l'I ph1ccbo-con1rolled s:1uc.1y. Htorlocht 2002: 42: pain and erythema of che hands and feet} in paticntS with poly·
249-55. cythaemia vera (p.711) and primary thrombocylhaemia (p.71 1).
4. Steiner TJ. ~I al. Aipirin jn cph.odic ICIUIOR·C)'pe headache: pl•· Pain. Aspirin, along with other NSAIDs and paracclJlmol, may
. cc~controlled dose-rengin1 comp:ruon wilh p:iraceumol. c~
phololgio 2003: 23: s~. be used for treating mild or moderate pain (see Choice ofAnalg-
S. Lipeon RB. d al Aspirin is cfficacion for the lttatmcnt of acute esic, p.2) and is also used in rnoderate or SC\= pain to potcntiace
mignino.. H•ndtx:h< 200S: 4S: 2!3-92. the effects of opioids. It is suitable for use in acute or chronic
6. Diener HC, ti ol. A)f)lrin in~ 1rcaiunc:nl uf lt.."Utc migraine at- pain. Aspirin should not be used for pain relief in cbiklrcn be·
1oc:lcs. &pm R,. Ncuro1hu 2006; {: S63-73 cause of its association with Rcyc's syndzomc (sec under Ad-
Kawasaki disease. Aspirin hu been given in regimens with vcne ElfedS. above).
nonnal immunoglobulins to cl111drcn with Kawasaki disease Dependence and tolerllllCC arc not a problem with nOD-q>ioid 3D-
(p.2435) because of itS an1i-innanllllleory, antipyretic, and an- algesics such as aspirin, bul there is a ccnms of efficacy, above
tiplatelet octh~cy. '"' which increasing lhc dose has no further therapeutic effect.
The usual pradice is to use an 3nli·in0ammatory regimen un1il References.
the fever has senlcd and then conven to an anuchrombotic rcgi· I. Rees J. etol. Single dose Ol'lf aspirin (or 1cu1c paiin. Available in
men. The BNFC 1010//I n:commcnds an oral dose of aspirin 30 The Cochrane OJ.ta.base of S)'1tematic Reviews; Issue 4. Chich-
" "'"John Wiley: 1999(accessed 27111/06).
Auranofin (BAN. USAN. rlNNJ
to 50 mg/llg daily in 4 divided doses in children aged I month
and over (neonates may be gh•en 32 mg/kg da.ily in 4 divided 2. Hersch Ev. ~t al. Over·thc-counrer analgesics and antipyrCIK:.S, a AuranofiW. Auranofna; AIJ<anoftne: Auranofirun: Oranofn;
critical assessme n1. C/in TMr 2000: l l : S00-48.
doses); d>is should be concinued until the pa1icn1is afcbrilc or for 3. ~rgnc P, Cl at. As.pirinc:, <loulcurs cl inO.:tmm;,lion. Rev M~ /,,. SKF-3'1162: SKF-0-39 161 (l-Thio-P-<>-tfucopyranosato)(tri-
the first 14 days after the onset of sympcoms. Once fever and 1<n1e 2000; 21 (suppl I): S9'-96s. ethylphosph111e)gold 2.3.'l.6-tetra·ace+.ate.
signs ofintbmma1ory disease rcsol\'c, the aspirin dose is reduced
co 2 co 5 mg/kg daily (neonaCC$ may be given 5 mg/kg daily) as Rheumatic disorders. Aspirin was once widely used m che AypaHO$-o1
a single dose for ics ancipla1elet effect. Aspirin may be stopped 6 trealmcnt of rheumaloid arthritis (p.12) buc has been supersedtd
by bener tolerated NSAJDs; however, juvenile idiopathic artM-
=
C10Hi.Av09PS 678.S.
co 8 weeks after che onset of illness but is u.~u~lly con1inued for CAS - 34031-32-8.
al least one yeor if coronary abnorm11i1ies ore prcscncand is con- tis (p.11) including Scill's disease arc among the limiced number
of indicalions for aspirin use in children. The Amarican Hospital ATC - 1-"0IC603.
tinued indetinilely if coronary aneurysms persist. Simi lar
regimens'" are used in the USA al!hough che inicial dose of aspi- Formula1y Service' suggests thacchildren weighing 25 kg or less ATC Vet - QMOICBOJ.
rin is more usually 80 co 100 mg/kg daily. may be given an inilial oral dose of 60 to 130 mg/kg daily in UNll - 3H0 4W281 0V.
divided doses; heavier children should be slarted on 2.4 to 3.6 g
Dcspile this widespread use che optimwn dose and dura1ion of daily. Altemacively, an initial oral dose of 1.5 g/rnl daily may be
trcalmcnt have not been clearly escablishcd, and the value of as.- given in divided doses. The usual maincenance dose is 80 co
pirin in Cho initial manaacmenl of Kawasaki disease has been I00 mg/kg daily although up co 130 mg/kg daily moy be required
questioned. In a mcla·analysis5 fever dwation was signilicancly . in some children; however, bc<:ause of the risk of toxicicy, ic is
shorter in those on high-dose aspirin; however, other studies• recommended that children weighing over 25 kg should not re-
have noc shown such a benefil. Me1a·analyses5" ha\'c also shown ceive doses of 100 mg/kg daily or above.
that the incidence ofcoronary ancry abnormalities is not signifi-
cantly ditfercnl for regimens using high (over 80 mg/kg daily) or I. Mcevoy GK (cd), AHFS Dru~ lnform•lion. (onllnc] 1lc1h..d1.
MD: American Society ofHcahh·Systcm Phann1ci11S. Av1ib1blc:
low doses of aspirin. Furthermore. a retrospective Study' sug- at: http:!/\1.-v.·w.medicinescomplete.com (accessed 13/01/10)
gested that aspirin use (irrcspedive ofdose) in dtc ac:ute phase of
the disease may be unnecessary as i•~ addi1ion 10 immunoglobu- Preparations
lin treatment had no effect on the rzte of coronary artery abnor- 8P 20 I Ck Aspirin ond ~ T.t>te<s: A5jlirin Tibiets: Co<odeprin Tat>
malities. A more rcccn1 review' fouid lhat evidence from com- leU: ~Aspirin T•!:ilcts; °"l>=tilo ~ Tatteu: E~..
parative scudies failed ro show thar aspirin reduced che rate of cent Soltble Aspim Tal:l<U: ~ A<pM 'r.bl<U;
VSP 33: Ac~andA.,,m lol:Jlets:Ac~,e.spn. and
coronary artery abnormal111es; a bet of good quality rnndomi.~ Cafi'eine Tablets; As;Wio or>:!~ l'hc!sphat< Tab'et~ " - " ~
concrolled studies prevenced any recommend:ltions on Che use of AipirW> ~· ~ Asf>rin ~- T-..: Aopm
aspirin in the treatrncncofKawasalo disease. Ellenoescent r-. for Or;! Soluc.on:AlptW> & < \ - Tabltu. M ·
I. Williams RV. ti al Pharmocoloe,ia l 1htrapy for patitnts with
K1wss1ki disco... Potdiow Drop lOOI; 3: 64~. ~~..:i~~~~~~=
~ and Aspri> T~ &lulbul. A5jlffl. rt! CaJeine Clp!ults:
Adverse Effects and Treatment
The mos I common adverse effects ofauranofin involve
2. Brogan PA, rt al K1 w.1SJt1 d'seau:an t"uk:ncc based ap~ch Bul.atit.t. A!pft\ and C.lfein<: ~ &r.-.i. Aspirn c.lltne. >net Co-
IG dia:nosis. lrealment, Ind propo.$11$ ror fulure rnearch. Art'h deine fllo<pha:e C.psUe.; ~ ¥>d A$pPY1 Tibiot.: Clr1'Cp'OClol the gastrointestinal tract and include nausea, abdomi-
Dis Child 1002; 86: 2!6-90. nal pain, lllld sometimes vomiting, but most often diar-
3. Newburger JW, ti ol Oia1noa1s, ucumcnt. W Jong-term man· ~~~~~T~~~~= rhoea, which can affecl up to 50"/o of patients and may
agemcnt of Kawasaki d1se.:ise: 1 s111tment for health profts.sion-- mc.rw..~.,. ~~t• ml\spm T.t>teu.
als from che C<l1nmi11ee on Rheum11ic Ftvtr. Endocardicis. and Proprietary Preparation! (decalls arc given in Volume 9) be severe enough 10 cause patients :o withdraw from
K1w1S1ki Disuu, Council on C.a•dtovasculu Dis.eat< in the
Youns, Americ1n Hun Associa1;on. PMiatrics 2004: 1H: AJr.: Aspimedf; "'""""°' A$pirineus; &lit;~ C.rc>oo,p.inc
0esenrnorno; E<otm Geniol FTtvencion: G<N:ll. SC "" c.r..na: L.actril!:
treatment. Other adverse effects are similar to those of
1703-33. Correccion. ibid. 200S; ll S: 11 18. Also aveilabl<: at: U fcasprina: N-.Jev~ Vip.irina Grdtx Corucn. Aurtrol. : Aspro: A$pro
sodium aurothiomalate (p.127), alth::mgh they appear
h1tp://ptdiatrics.1appublic11ion•.ori/cgilreprinli 114/611708.pdf Protect: Asttix Catd;ltY'c C.rtio; Oisprin; o;,.w. D.rtct: Solpnn: Sp-enf: to be less troublesome since fewer patients stop treat·
(occ<,.cd 12/04/07) Also published in C/rt:11/01ion 2004: II O: Vinc....-s Powdent: Aunrio: Acel<.apton: ~ Asp;rin Pl"ctect: 11£-
2741- 71. Also availahle 11: hup:llcirc.ah11journals.orgteai/ prcx ASS: Hen ASS: HerzKhvtz ASS: Soimontf: TIYombo ASS: Throm-
mcnt with auranofin than with injectable gold. As with
rcprin1/l IO/l712747. pdf(ace<sscd 12/(1<1107) bostad: Togal Mone: Belg.: Acenterir.e; A)Q.Setuer: Awllow: A!Pnnr. A•· other gold salts,-trealment ofadverseeffects is general-
4. Frecm•n AF, Shutmtm ST. K:.twasaki di:.easc: summary or the pmf; CvQoa"'"°ine: Cardiphar: D•pril; Sedcrgint: Thtr,..f, Brot.: N'S: ly symptomatic (see p.128). Modifying the diet to in-
American Hearl Assoeia1ion auidclincs. Am Fom Ph.\ •sicion A>scdatitt, AccticJf: Analgc<in: M:ilcb<int Al<cdorf: Asctisint. Aspirino:
2006: 74: 11 4 1 -~. llut!em: Ca-dio AAS: C.maas; Emit: H1pot.,mat Said: Silic1n: Slllllil: So- crease bulk. use of a bulking agent >uch as bran, or a
All cross-references refer co encries in Volume A
 Auranotin/,A.zapropazone 27
tempora1y reduction in auranofin dosage. may help the Uses and Administrration Pharmacopoeias. In US.
diaJThoea (but see Effects on the Gastrointestinal Tract, Auranofin is a gold compow1d with a gold content of USP 33 (Aurothioglvcose). A yellow odourless or praclically
below). odourless powd<r. An aqueQus solution is unstable on long
about 29%; it has similar actions and uses to those of standing. It is stabilised by the addition of a small amount of so-
0 RcviC\VS. sodium aurothiomalate (p.128). It is given orally in ac- dium acetate. pH of a 1% solution in water is about 6.3. Freely
I. Toi.man ECS. Gottlieb NL. Adverse reactions with o~I ;ind tive progressive rheumatoid arthritis (below); such oral soluble in water; practically insoluble in alcohol, in acetone, in
p3rent<:ral gold preparations. Med To:cicol I 987: 2: 177-89. lr"...atment is less toxic than intramuscular gold but is chloroform, and in e1hcr. Store in ai11ight containers. Protect
Effects on the gastrointestinal tract. Diarrhoea aod abdom· also much less effective. 111e usual initial dose of au- from light.
inal pain are common with aurdllofin. The mcchanjsm of gas- ranofm is 6 mg daily given in two divided doses at first, Profile
trointestinal toxicily has not been established bm may be associ· then, if tolerated, as a single dose. Treatment should be Aurothioglucose is a gold compound with a gold content of
ated witl1 a reversible defect in intestinal penneability. 1 Although about 50%; it has similar actions and uses lo lhnse of sodium
some have suggested that diarrhoea may occur in up to 50'A. of continued for at least 6 months to assess the response;
aurothiomalate (p.127). It has been used intramuscularly in the
patients taking auranofin, a srudy in 269 patients given the drug the dose may be increased after 6 months, if the re· treatment of ac1ive rheumatoid arthrilis and juvenile idiopathic
for rheun:atoid anhritis found thal only about 15% had loose and sponse is inadequate, to 3 mg three times daily. If the arthrilis.
watery stools over a 6-month period.1 Although bulking agents response is still inadequate after 3 months at this dos-
have been recommended in the management of auranolin· 0 for commeol on the relative efficacy and tolerability of au-
induced diarrhoea, no overall difference in incidence was seen
age, then treatment should be stopped. rothioglucose anC aurothiomalate, see Rheumatic Disorders~ un-
between patients given propliylactic psylliwn and those given Asthm a. A systematic review' found that oral or parenlcrJI der Sodium Aur()(hioroalate, p. l 28.
placebo; however, patients given psyllium had slightly fewer gold compounds reduced corticosteroid requirements in the Effects on the blood . "lbrombocytopenia developed in 2 pa-
days with loose and watery stools. management of asthma (p.1220); however, it was considered thal tients treated with inlramuscular aurothioglucosc. 1
Gold-induced colitis has also bceo reponed in patients taking au- the effect was probably oflimilL-d clinical significance and, given I. Levin M·D. ct of. Two paticn4 wi1h acute thrombocytopcnia fol-
ranofin.J.4 the adverse effects and monitoring requirements of gold com· lowing gold adininis1ration and five-year follow-up. Neth J Med
pounds, U1cir use in asthma could not be recommended. 2003; 61: 223-S.
I. Beh rcn~ R, el al. fnve~t i gat ic'm nf auranofin-induccd di 1urh<:1c~.
G111 1986: i1: 59-65. I. Evan• DJ. et al. Gold as an oral corticosteroid sparing agcm in Preparations
') \'an Bcusckom HJ. Cl al. The moderate inlC$lin31$idc effects or stable 3Slhma. Available in The Coehr~ne D:uab:iseofSyi.f.emat·
ic Reviews; Jssue 4. Chiches1er: John Wiley; 2000 (accessed USP 33: Al.f'Othi01glxose !flec:ta.~e S..JSPC~'!.ion.
auranofm do not require prophylactic chcrapy with a bulkfonn·
ing rigcnt. Outch Ridaura Stu!ly Group. Clin Rlt(f11nw10/ ) 997; 25/10/06). Proprietary Preparations (details are given in Volume 0)
16: 471-0.
Lupus. Since the introduclion of less toxic drugs gold com-
''"'°''
Solgonalt : Ntth., A<J'"°'""l"'•t: USA: So!z"1<11j".
3. Michel CJ, ~t al. Auranofin-.associated colitis and oosinophiJia.
M(()'O Cliu PrQe 19&7; 62: 142-4. powids are now rarely used in the treatment of SL£. however.
4. L3nger HE. cu ol. Gold colitis induced by auranotin treatment or there have been anecdotal repor1s suggesting tliat auranofin may
rheumatoid arthritis.; c.a~ report and rev i ~w of the liceraturc. A1111 be of use in patients with discoid lupus erylhematosus 1 or cuto- Aurotioprol
Rhi!11m Dis 1981; .j6: 787-92. neous lupus ezytheinalosus2 re(rnclory to conventional treat- Sod<urn 3-aurolhi:>-2·hydroxyp.-opar.e· 1-su!phonate.
Effects on t he kidneys. In a recrospective review' of 1283 pa- nlent.
Aypon<onpoA
1ie111S given. auranofin for treaunent of rheumatoid anhritis 41
(3.2%) were found lo have developed proteinuria. In most cases
I . D3Jziel K. ct fll, Trcaunent ofchronic discoid lupus erythcmaro-
sus wi1h :m oral gold compound (aur.tnofin). Br J Denuotol C 3H.AuNao,s, 390.2. =
1986; 115: 21 l-t6. CA5 - 27279-13-2.
proteinuria was lreated b)' stopping auranofin therapy. Long- 2. farrcll AM, Bunker CB. Or.:i.I gold 1hcrapy in cutaneous lupus ATC - MOIC605.
ienn follc·w-up of 36 patienlS indicaled dial proteiouria bad re- erythtmatosus (revisited). Br .I De.1•11u110! 1996; 135 (suppl 47): ATC Ver - Q/1>101 CB05.
solved in 31 within 2 years and in 29 wiUtin J year. Seven of 8 41.
palienlS later rechallenged ";1h auranofio had no relapses. In a
Pemphigus. A patiem -..itl1 long-standing pemphigus foliaceus
further rc-1iew of2 comparntive <loubl.,,blind srudies using gold
compounds in the treatmenl of rheumaloid anhritis, proteinuria being treated with prednisolone and hydroxychloroquine had 0
was found to have developed in 27% (23 of85) ofpa1ieo1S treal-
cd with sodium aurothiomalate, io 17% (42 of 247) of !hose
irea1ed wirh auranofin, and in 17% (36 of210) of those receiving
healing of his lesions within 6 monlhs of auranotin being substi-
ruted for the hydroxychloroquine. 1
1. Bagheri MM. ~t al. Pemphigus foliaceus presenting as eruptive
'':"r
HO"\\
0
S
OH
SH
Na•
seborrhcic kcralosis and responding to oral gold 1reatinent J
placebo. All patients were receiving NSAIDs. Drugs Dermotol 2002; 1:333-4.
I. Katz \VA., e1 ol. Proteinuria in go1d-tre-3ted rhnJmatoid :irthrilis.
.41111 lnltm Med 1984: 101: J76-9. Psoriasis. Al!hough topical auranofin has been shown io a pla· Au•
ccbo-contrclled srudy1 to be effeclive in the trcatmenl of plaque-
Precautions type psoriasis (p.J n3) the high incidence of adverse skio reac-
lions, such as contact derroatilis, was thought lo outweigh any P rofile
As for Sodium Aurothiomalate, p.128. Urine and benefit Aurotioprol is a gold compound with a gold content of about
blood tests should be carried out before starting au- I. Melm KF, et al. Topical auranotin ointment for rhe treatrne11l of 50%; it has similar actions and uses 10 those of sodium aurothi-
ranofin and monthly thereafter; licensed product infor- plaque psoria5is. J Am Aced Dermafo/ 1995; 33: 517-19. omalate (p.127). fl is given by intramuscular injection for the
treatmcnl ofrhcu111atoid anhritis (p.12). The initial dose is25 mg
mation advises tliat aw-anofin should be withdrawn if Rhe umatic disorders. Gold compounds are among the dis· weekly, increased to 50 to 100 mg weekly, until a total dose of"
the platelet count falls below I 00 000 cellslnm13 or if ease-modifying antirheumatic dmgs (DMARDs) that may be 1.2 to 1.S g has been given. rf improvement has occurred with no
signs and symptoms suggestive of thrombocytopenia, used in the trea~nem of rheumaloid arthritis (p. 12). Oral gold is signsoftoxicily. lhis may be followed bya dose of SO lo 100 mg
less toxic than inlramuscular gold but is also much less effective. intramuscularly e·,•el)· month.
leucopenia, or aplastic anaemia occur. US licensed Gold compounds may also be of benefit in psoriatic arthritis (see
product infonnation states that baseline renal and liver umlcr Spondyloarthropalhics, p.14) and have been used in juve- ~reparations
function levels should also be established before start- nile idiopathic anhritis (p.11). Proprietary Preparations (details are given in Volume B)
ing auranofin therapy. Auranofin should be used with References. Fr.: Alioc.h.")'Sinc.
caution in patients with inflammatory bowel disease. 1. Suarez-Alin:>wr ME. el ol. 1\ur.1nofin versu$ placebo in rhcuma-
loid :lrthrilis. Avail:>.ble in The Cochrnnc Dai.ab:ise of Systematic
Porphyria. Auranofin has been associated with acute anacks of Reviews; Issue 2. Chic:hcstcr: John Wi Icy: 20-00 (acce~~td
potphyria and is considered u~~~fe in porphyric patients. 09/0SIOS). Azapropazone (SAN. riNNJ
AHR· 3018; Apazone (USN~); AlSaproJl"tsoni: Azapropazoo; Az·
Preparatio ns apropa20na; Azapropazonum; MiSS: NSC-102824. S·Dimethyl-
Int eractions
Proprietary P reparatio ns (details arc given in Volume 8) amino-9-melh)i-2-propylpyrazolo( 1.2 ·O)( 1,2.4~zotriazine·
As for Sodium Aurothiomalate,p.128. Austral.: Ridaura; Austria: R.:caura; Belg.: Rid.aura.: Conod.: Ridaura: I .3(2H)-dione.
Oenm.: Ridaura; Fin.: Rid3ur-c:. Fr.: Ridan."lt: Ger.: R.icburat; Gr.: Rida...-a;
H ong l<ong: Rida1Ya:. India: Goldar: lrl.: Rid~ura: broel: Ridaura: I tal.: A3aripona30H
Pharmacokinetics
2 = 300.·1.
Rdaura; Neth.: R.idaur.o.t: Norw.: Ridwr& NZ: RidaUf"a: Port.: R.idaLW'a; C 16H20N1 0
Auranofin is incompletely absorbed from the gastroin· Rus.: Auropa.n (ArponaH); S.Afr.: Ridaur~t: Spoin: Rjda-oc:r. Switz.: Rklau.
CAS - I 3539-59-8.
testinal tract, only about 25% of the gold being ab- rai: UK.: Ridauraf: USA: R.id(IU(~
ATC -MO IAX04.
sorbed. Gold from auranofin is bound to plasma pro- ATC Vet - QMOIAXO~.
teins as well as to red blood cells. After 2 to 3 montlis UN!I - K2V01966Z!.
of treatment the steady-state concentration of gold in Aurrothioglucose
the blood is reported to be about 700 nanograms/mL. 1-Aurothio-o.giucopyranose: Aurotioglucosa: (o·GlucoS)1thio)
gold: Gold Thiog!ucose. ( 1-Thio·e>-glucopyranosato)gold.
The average tenninal plasma half-life of gold at steady
AypoTv.or1JQK03a
state is about 26 days while the biological half-life is 80
days. Tissue retention and total gold accumulation in c , H11Au05S ::: 392.2.
CAS - 12192-57-3.
the body are less than with intramuscular gold. Gold ATC - MOIC604.
from aur.inofin penetrate~:into synovial fluid. ATC Vet ·- QMOICB04.
Most of a dose of auranofin appears in the faeces due UN/I - 2P2V9QOE78.
to its poor absorption. About 60% of the absorbed gold
from auranofin is excreted in the urine and the remain-
der in the faeces. HO~ols'Au
0 Reviews. Pharmacopoeias. Br. includes the dihydrate.
I . Block.a KLN. ti al. Clinical pharn1acokinc1ic5 of oral and injccl· HOy··,,,OH BP 20 IO (Azapropazone). ·111e dihydrale is a white lo pale yel-
able gold compounds. Clin Phannaccl<i11c1 1986; l t: In-43. low crystalline powder. Very slightly soluble in war~r and in
'> Benn HP, ,., ol. Pharrnacokinctics of auranofin: a single dose OH chloroforro: soluble in alcohol: dissolve.< in solutions of alkali
Sludy in man. J Rhl!umarol t990; 17: 466-tt. hydroxides.
The symbol t denoles a prcpa.ra1ion no longer actively marketed
28 Analgesics Anti-inflammatory Drugs and Antipyretics
P rofile P reparations
A:>.apropa>.nne is an NSA ID (see p.100}, structurally related to BP 2010: Benor,.ate Or.I S..5P«•ior« Benorila"' l>blets.
phenylbut.azone (p.121). It also has uricosuric properties. Be-
P roprietary Preparations (de1.alls arc g,lvc11 in Volume B)
cause azapropawne appears lo be associated with a higher inci-
Belg.: Dwiumt: fr.: Sai;pr.,,t: Jr!.: Be...o'illt; Sw;n.: IJ\Mumj'.
dence of adverse effects than with some other NSAIDs, its use
was restricted to the treatment of rheumatoid arthritis, ankylos-
ing spondylitis, and acute gout in patients for whom other
NSAIDs have been ineffective. Be nzydamine Hyd roch loride (6ANM. !MN. llNl'lM)
Breast feeding. Small quantities of az.apropazone are excreted Af-864: Benzidamin Hidrokloriir; Benzindamine Hydrochloride:
into breast milk. 1 However, the American Academy of Benzydamine. Chlorllydrate de; Benzydamini Hydrochloridum:
Pcdiatrics2 states that there have been no reports of any clinical Benzydaminy chlorowodor!!k: Hidrocloruro de ben::idamina. 3-
effect on the infant associated with the use of azapropazone by ( 1-Benzyl-1 H-indazol-3-yloxy)-NN-dimethylpropylamine hydro-
breast-feeding mothers, and that thc1efore it may be considered chloride.
10 be usually compatible with breast feeding.
I. Bald R, ~'al. Excretion of azapropazone in hu.rnan breast milk.
r
6eH3"W!MHH2 'WJOXAOP11A
Eur JC/in Pharmocol 1990; 39: 271-3.
Be ndazac Lysine (6ANM '1NNM) C,9H23N;O.HCI 345.9. =
2. American Academy of Pediatrics. The transfer of dru§S and olh- CAS - 642-72-8 (benzydomine); 1 JZ-69-4 (benzydom-
er chemicals into human milk. Ptdfatrics 2001; 108: i16-89. Af- 1934: Bendzzac lisina: Bendazacum Lysinum. L-Lysine-{ l-ben- ine hydrochloride).
(Retired May 2010) Conection. ibid.; 1029. Also available at: 2yl-I H-indazol-3-yloxy)acetic acid. ATC - AOl.4DOZ; GOZCCOJ: MOIAXO?; M02AA05.
http ://a 8 ppo) icy . as pp u bl i Cali OAS . ors/cgi/content/f\J I JI
pediatriC$%3bl08131776 (acc!!s~cd 01/1 1/07) 6eH,Aa.3aK /\M3HH ATC Vet - QAOIADOZ; QG02CC03; QMOfAX07;
QM02AA05.
Effects on the blood. Aulo-immu.•e haemolytic anaemia, oc- CzzH 18 N,Os = 128.S.
UNll - KZG1407R4Q.
casionally fata~ often with pulmonruy infiltration, allergic alve- CAS - 81919-14-4.
olilis, pulmon31} fibrosis, or fibrosing alveolilis, has been report- Ai C - SO I BC0 7.
ed in patients receiving azapropazon!. 1•1 ATC Vet - QSOIBC07.
I. Chan-Lam D. ~1 al. Red cell antibodies and autoirnmtmt haerno-
lysis i.ftcr treatment w ith aupropazone. BMJ 1986; 293: 1474.
2. Albau.az MK, e1 of. Alveolitis and haemolytic anaemia induc~d
by >Ulpropazonc. BMJ 1986; 293: 1>37-8.
UNI/ - CUT957EGC.
Pharmacopoeias. In Chin.
Profile
r-0
N
3. Momsomcry Rn. Babb RG. Alvco1i·.is and hacmolyiic anaemia Bcndazac is an NSAID (p.100) structurally related to indomel-
induced by u..apropazonc. BMJ l 987; 294: 37S. acin (p.69). It has been used topically in preparations containing ~/CH3
I or 3% for the treatment of various inflammalory skin disorders. 0 N
Effects on the gastrointestinal tract- In a review' of the rel-
ative safety of 7 oral NSA!Ds, die UK CSM commented lhal Bendazac lysine has been used in the management of catarnct, I
CH3
azapropa:ione was associated with the highest risk ofgas1roimes- eye drops containing 0.5% being instilled three times daily.
1inal reactions in both epidemiological studies and an analysis of Hcpatoloxidry has been reponed. (benzydomine)
spontaneous reporting ofadverse reactions. Although it appeared
that some patients over 60 years of age had received doses ex· O References.
I. Oalfour JA, Clissold SJ>. Bcnda7,ac l15inc: a review of iL.i; phar- Pharmacopoeias_ In Br. and Pol.
ceeding tliose recommended for this age group, it was considered
that even when this was taken into account a marked difference macofoni031 properlics and therapeutic potential ;n the manage- BP 20 I0 (Benzydamine Hydrochloride}. A while crys1alline
ment ofcal3racts. Dr11gs 1990; 39: ~75-96. powder. Very soluble in water; freely solutle in alcohol and in
remained between gas1rointes1inal reactions for azapropazone
2. Prieto de Paula JM, el nl. Hcpitotoxicidad por bendaiaco: amlli- chlorofonn; practically insoluble in ether. A 10"/o solution in wa-
compared with other NSA!Ds. :ris <kl 16 casos. R<> Cltn EJp 1995; I 95: 387-9. ter has a pH of 4.0 to 5.5.
The CSM recommended that ozop1'(),?az<>ne should be resb'icted Preparations
to use in rheumatoid orthriti's, anf...ylosing spondylitis, and acute Adverse Effects
gout and 011/y when a1her NSAIDs have been i11ejfecti•"· Its use Proprietary P reparations (det.ruls arc givtcn in Volume B) After topical application 10 the skin local reactions such as ery-
in patients wi1lt a history ofpeptic ulceration was contra-indicat- Austria: Versust: Gr.: Ber.darina; Vcrsaba: Zcbi"lor; ltol.: Bendalina: VCf· thema or rash may occur and photosensitivity has been reported.
ed It was also recommended that v.11en used in patients over 60 sus: PhiJipp.: Bendlb"I~ Pott.: Sendabna: Venex..: Bendalina. After use as mouth and throat preparations, numbness or slinging
years of age for rheumatoid arthritis or 011kylasing spondy/itis sensations of the oral mucosa have been reported; hypersensitiv-
the dose should be reduced. ity reactions including unicaria, pho1osensi1ivity, and bronchos-
pasm may also occur rarely.
A>.apropazone has been "ilhdrawn in many countries including Be norilate (BAN. rlNNJ
lhe UK. Effects on the kidneys_ A 57-ycar-<:>ld wom311 v>'ho had used
Benorilaatti; Benorila;; Benorilate; Benorilato; Beoorilatum:
J. CSMIMCA. Relative safely of oral non--aspirin NSAIOs. Cur- 400 g of a topical cream containing benzydamine hydrochloride
Benorylate; FAW-76: Fenasprate: Win-11450. 4-Acetamidophe-
rent Problem:. 1994; 20: 9-11 . 3% over a period of 4 months W<IS found lo have raised plasma
nyl 0-acety!saicy'.ate. concentrations of crcatininc and urea consistent wilh a substan·
Effects on the skin. Of917 reportS of adverse reactions asso- 6eHOpwlaT tial reduction in glomerular fillralion rate. 1
ciated wilh azapropazone fo1warded lo the WHO Collaborating I. O'Callaghan CA, c1 of. Rcn~I dise3sc and use of topica1 non-
C 17H 1sNOs = 313.3.
Centre for International Drug Moniloring1 before Seplember stcroicfal anti-inflammatory drugs. BMJ 1994; 308: J 1n-11.
1984, 190(21%) wereofphotosensitiviiy. Ofl54 report.' of pho- CAS - 5003-48-5.
to.sensitivity evaluated. a causal rela'.ionship to use of azapropa- ATC - NOZBAIO. Effects on the skin. Photoallergic contact dermatitis devel-
zone was considered certain in 6, probable in 138, and possible ATC Vet - QNOJ.BAIO. oped on the hands of a 65-year-<>ld wom311 after the use of a gen-
in IO. In May 1994the UK CSM sta!cd2 thalsiace J976they had UNI/ - WIQX90V96G. ital wash containing benzydamine 0.1% for several years. 1The
received 464 report.' of pholosensitivity reactions associated lesions disappeared once the parient slopped using the solution.
wilh azapropaz.onc and commented that, when corrected for pre- L Loso Elgezun 0, ct al. Photo.ullergic h:md ccz.cm;i due lo bcnz.y-
scription volume, reporting of this reaction was 50 times greater d3mine. Ertr J Dermalol2004; 14: 69-10.
than with other commonly prescribed NSAIDs. They recom- Overdose. A 6-year old girl had hallucinalions 1 after receiving
mended that patients shoold be advised 10 avoid direct exposure 500 mg of benzydamine orally; it had been intended as a vaginal
10 sunlighl or to use sunblock preparations. douche for pruritus vulvae; recovery was spontaneous.
J. Olsson S, et al. Photoscnsiti\'ity duriig treatment "'ilh napropa· I. G0mcz-L6pcz. l , el al. Acute overdose due 10 benzydaminc.
zone. BMJ 1985; 291: 939. Hum Exp To:ritol 1999: 18: 471- 3.
2. CSM/MCA. Pt>orosensi1ivi1y asso:iatt:d "'1th aiaptopazone
(Rhcumox). Currer.t Problems t994, 20: 6. Uses an d Administration
Benzydamine hydrochloride is an NSAID (p. I03). 11 is used top-
Porphyria Azapropawne is considered to be unsafe in patients ically on tlie skin in concentrations of3 10 5% in painful muscu-
with polJlhyria because ii ba.• heen <hown to be pO!phyrinogenic Pharmacopoeias. In Bi: and Chin. loskeletal and soft-tissue disor~. Benzydamine hydrochloride
in animals. BP 2010 (Benorilate}. A white or almost white, odourless or al- is also used as a mouthwash or spray in oonrenlr'•lions of0.15%
most odowlcss. crystalline powder. Practically insoluble in wa- for the reliefof inOammatory condilions of the moulh :ind throat
P reparations ter; sparingly soluble in aloohol and in metl1yl alcohol; soluble in It bas been given orally or rectally for the relief of painful and
BP 2010: Auprnpazooe C>pwl.s: ~e Tablets. acetone and in chloroform. inflammatory conditions, and as a topical sclution for vaginal if..
Proprietary Preparations (details are given in Volume B) P rofile rigation.
Aurtrio: Prdoant: Gr.: PrQIOca.n: Hung.: Profocant; lrl.: Rheumoxt: Port.: Benorilatc is an aspirin·paracctamol ester with analgesic, anti~ Benzydamine salicylatc (bcnzasal) has been used topically on
Prolixant: S.Afr.: Rhe-.rr<>xt: Turi<.: Prod•>A inflammatory, and antipyre1ic properties. Afte,r abso!plion, it is the skin as a 6% cream or spray.
rapidly metabolised lo salicylate and par•cctamol. 11 has been
used orally in the treatment of mild 10 moderate pain and fever. Mouth disorders. Rcsulls ofa mndomisoo placebo-controlled
It has also been used in ostcoarthriiis, rheumatoid arthritis, and study in patients undergoing radiotlierapy for oropharyngeal can-
Bendazac (BAN. USAN. rlNN) soft-lissue rheumatism. cer indicated that benzydaminc as an oral rinse was effecrive in
reducing the area and severity of mucositis. 1 Bcnzydamine is
AF-983: Benda2.Jeo: Bendazacuni: Bindaz2c. (l-Benzyl- 11'1-inda- When an overdose ofbenorilate is suspected, it has been suggest- also used locally for the management o( mouth ulcers (p. l 849)
zol-3-yloxy)acetic acid. ed that plasma coocenaations ofbolh salicylate and parncetarnol ahhough an early study2 found it no more u;cful than placebo.
should be measured since a normal plasma-paracetamol eoncen-
6eHA333K I. Erstein JB. e1 ol. Bcnzydamine HCI for propl'iylaxis of radiition-
ua1ioo cannot necessarily be assumed from a normal plasma- induccd oral mucositis: rt..--sults from a muhi::entcr, r~ndomlz.ed,
C ,4H,.N; 0 1 = 282.3. salicylate measurement. double-blind, placebo-controlled clinical tri::I. Cancer 2001; 92:
CAS - 20187-55-7. 875-85.
0 References. 2. Matthews RW. et al. Clinical t\"aluation of benzyd3mine, chlo-
ATC - M02MI I; SOIBCOl.
I. Aylward M. Toxici1y ofbcnorylalc. 8,\,£/ 1973; i: I 18. rhe.'(idine, and placebo mouthwashes in the management of rc-
ATC Vet - Qfa102AAI 1; QSOIBCOl. 2. Symon ONK. et al, f'3U1I paracetamol poison ins from bcoorylatc currt:nt aphthous stomatitis. Oral Surg Orel )..fed Oral Poi/101
UNl1 - G4AG7 I 2040. the-rapy in c:hild \Vith cystic fibrosis. Lonee/ 1982; ii: 1 IS3- 4. 1987; 63: 189-91.

All cross-references refer to entries in Volume A

 Bendazac/Bumadizone Calcium 29
Preparation.s Profile . e•tract•on. When used pnst(lpcrati,·cly, it may he maned 24 hours
BP 2010: il~'l::yd<ln'"" c;..,_...,, 8'<:z)'damne Moot.,.....J'I Be<.i,.damr,. Beta-amine>Jlmpionitnle. a lysyl oxidase inhibitor, ~ an ami- afte1· sur;cry and contimoed for 1he nexl 14 da)'S
~'<o:.o!Sp17f inflammn1ory used as th~ fumarate in veterim1ry mcdiciM for the II was fomicrly given orally in the JJ13n3gcment of :>eutc ]>3in bul
Proprietary Preparations (details 3rc Q1VCfl in Volu1ne 8) 1reannc.nt or tendinitis. W'JS withdrown from the JJ13Jtet ofter repons ofS<\<ereandsome-
timcs fatal hepatic failure.
t;J~~=!:~~~~~~1~s:;~;f~~ Effects on the eyes. Sc-.'Ctt comeal melting (ulc:u.ition) "''IS
T°'""""1. 8nn.: BenfqWI: llenztrat: Ciflotex ~ Floio.Jlos• fl.
ogol•I>: Flogo<at fooe<goral: Nc:ollo111t Conod.: Sun-S...,z T•ntum: Cz.: Bicifadine Hydrochloride (IMN. r.NNN.) seen in 3 palicnts after 1op;cal use of bromfenac sodiurn. 1 All
RO<olgon; Tontum; ~nm.: A'ldoit>e Fr. :~. G.,.,
T...,,\JM Ros.a: 1an·
Biafacina. hicrodorvo de: Bicofod1ne l+jd"cchionoe de: Bi<ifado- J>3licnlS re<:overed 3fter bromfen:ic was wi1hdrawn. Siomlar cf-
tvm Verde: Gr.: Tiantutr\ Honi Kong: O.nturn: OiCirrc Ott!l.m N,i,i-in· fedS have been reponed with other ophu>almic NSAID prepua·
ni HydrochloricMn CL-220075; MCV-4147: NIH-9542. (±)-1·P·
~~~~~~:.~~E'!:,;~)r.}}=..~~~;, Tofyt-3-=t>icydo(3.1.0)hcxane h)<j1·omoridc.
tions; for further dcloils see un<kr Ad\'crse Effects of Diclofenoc,
p.47.
Muhvmt. Sanillor Coluloncx T..ium: 'le<>x: Xt:ro:.fid: Mofoysla: O.lbn1
Atr.Hollammi tOC')' Lo~ Oifft.am Forte Mti Jnfl.anvna10ty Throit r
6'11.1M~Al4"3 ~>CAOP"A I. Asai T. t:I ol. Thrtt cases o f comc::d mcluna after instillation or
Spcy. Oifllatn Solvtoon: M<x" .......oc.<t Ber>ilant Cilhor: Lcnot lt.rltat
N •th.: Tat>tvm: N Z: !>.fftom: Philipp, !>.6...-r( Pol" Hl>CO>epc $e!J<d...:
C 1 iH ,~N.HCI =
209 7. a n~w noMterC"lidal anti-infbmma:ory drug.. Cornea 2006: 2~:
T.antcm: Pore.: floaoral: ~ ~..igr. Tont"'1: T~otvm Ro..: Tonun
CAS - 71195-57-8 (/;1etfod•ne): 66504· 75.4 (birifadme 224-7.
Venl¢ Rus.: T•ntum Rose (T•"Tf"I Pe»): 1"nlim Verd< (Ta><"!)'M ~); hydrochroride). Preparations
~Afr.: Andolex; An-:k>sept; Sini,opore: Dl!&m; Spain: Agiion.at: f ~ UNI/ - 0£6G20P68T
Proprietary Preparations (detoils are i;iven in Volume 8)
~ Tn•.m T.,.,,.,, V..-do: s-d.: ~ Switz.: &.cco·Tontim;
Arg.: Nata><; Jpn: ~ USA: Xttl<oin.
Thol.: C>ill!<rc Turk.: Seniilex: 8en..o.n: hrerit't Ton/lex: Tant.int Temec
IJK: OillJm: y.,,.,._, Al.r.•n: 6<vi Olm; ~ ~ont Ginacclf: Tan·
H
" ""' T""un-Zydor\ N
Multi·ingredlcnt A'l·' llu<hc>< Emex D.r.>: E!pectoonf: Pcnlodtnlt:
Au<trol: (),flam .........,.,.m"'i:ory lo•~es
~~~o~=~"cit.;,,o~;'.';~~~
wO"Ccvj> ~<Sin!;

l""'1g<t: ¥;;fll•m MC>«h Gd; ~·C: Kloroben; lqpo.• ~pid Ref~

HsC-0{) Bufexamac (SAN. •INN)
Blf~: Bufc~rr.akas: S..1exzmaco: Bufoxamacum: Bu-
fexamjc: &.lexam•k. 2-(4-Butoxyphel)ll)Ke\ohydroxarnc acid.
Huni.: TlOrtum Rcr.rf; ttoL: Golt A<t.on. Lin••
F; MedplJSt, T>rll.rn 0-0. 6)-9c•ca..,<
UI'( Mofoyslo: Oofllom A..,.;<nilonvNtory lo...,_.., (wit.o A.'lt~'):
O.fbm Al>~·lnllammotory l~ {w.lh <<><•RI'> '"PP''-""'nl); DMlatn
(bm(odine) C 12H 17N01
CAS -
=223.3.
2438·72·4
Mou<ll Ge\ Diffi.lm·C. Mu" l<>nol S;>an; NZ: o.iTiarr. Anti·n1lorwrwtoty Profile ATC - MOIA817; M02AA09.
A....w.cte<Ql lozenge< Oim•m C~ Oi/llim Mo..1h Gel: 0.'lllom.C:
Pore.: 8enor.t Gu-tun: Ta<11un Verde: S.A(r" An<!oiex·C: AndOSOP«Co< Bicifadine hydrochloride is a novel analgesic that is rcponed to ATC Vet - QMO ll.817; QM02AA09.
Singof>O_l't: alrtam Antj...in<lamm1tory Ndi-&d~ loz~ngel: O.m,m inhibit serotonin and no~alinc rcuptake. lt is under in•esti-
l'\ovlh Get ~C: Spain: Bristocdr.. D<nvtt: Et..-mol Anlitus""" galioo for the treatment of painful conditions including postoper·
Meotimidic "'-""t T•nt""1: Voncisoptil Ofox Turlc.: Oodo' Av>: faf'-
he>:: Klodamn K<>'<Jben. Oroheks Plus: V•ne<-: llmau: GencM>I Com· alive dent:ll poirt.
puestot Sol...--.. Corrc>ue<to ORefcr~
l . Krictcr PA~ tt ol. Pharmacokinetics. dlspos,1.on.1nd mcu bol i~m
o(b1ci(adutc in humaJ\S.. Drug Metob 0;1po1l008~36: 252-9.
Benzyl Nicotinate
Sensytnikotinat; SentsY)1irol<otJNatt~ Senzil Nikotmat Benz,!• Pharmacopoeias. In £111: (seep.vii) and Jpn.
Nocottias: Nicotinato de ~ncilo. 8<nZ)'I P'lrid;ne.3..:arboxyt;,!c. Bornyl Salicylate Ph. Eur: 6.8 (Bu!examac). A white or almost \l.flitc, crystalline
6eK3HI\ HH•or~"ar Bomeol Salicylate: ~licibto ~ bornilo. 2-Hydroxybemooc acod powder. Practically 111SOluble in water, soluble in d1mtthylfor-
1.7.7·trimetl'lylbicydo{2.2. I J>ep<-2·yl ester. niamide; slightly soluble in <lhyl acetate and in mClhyl alcollOI.
C }H 11 N02 = 213 .2. Protect from li&ht.
CAS - 94 -44·0. 6ojlH>\ '1Cil11'1UW\aT

UNI/ - S4~7tCF9C9. =
c ,,HnO> 274.4. Profile
CAS - 560·88 3. Buf=unnc is M NSAID (p.100) th:il is applied 1opically in con-
ccntratioos of5% in various skio disordctS. Stinging and bwning
may C)Ct'ur after application; hypcrscnsith-ity reactions have boon

Oya"'°
reported.
Preparations
Proprietary Preparations (dc1ails are given in Volume 8)
Aurtrof.: P&"""'1'nj: Austria: S..(•xt S..fex>nf: ~j. Pnnoc:
0 Belg.: 0..0..rytt: Cz.: Cnl><rift: Fr.: Parlenac; G•r.: ~. <lndor-
malt; Haem<> E><!wud ~ Jomax Malip1¥1nt. Potfenx: WIOOol:
Pharmacopoeias. In Gei: ~!:-.'..~~.:.~. ~~r~ o.O><M)-tt: Menact: Pon.: l'riN<:
Profile Profile M<Jlri~n1,.,dlcnt: Au<troL: ~Pt.is; Rc.C>IYO; Aurtrlo: °""""'~
Benzyl nicotina1e is~ in topical prepartl10llS as a rubefacient. Bomyl s:slicylatc is a salicylic ocid Jc:rivali\'c ~»t has b<en used Cz.: Ma.tu S: Ger.: raktu •l:ul. H><nc>ntq>lll<m N: Hamo>gl pl.Js; Hox·
•l'IOf• &Jlexiiinac:. Mastu ~IC Honi Kone- f~ Soothi1~ Balmt MHtu
Preparations topically in rubefacient preparations similarl)' to methyl sali· S. Huni,: Mastu S. NZ: ,,.,..,....,, PUs. ~ Proctosan ("'°"TOllW~
Proprietary Preparations (dc1oils are given in Volume: 0) cylulc (p.89) for the n:lief of pai11 in musculoskclctal and joint Thai.: MasnJ Sc !Jiu-.: f'l'()Cl°"'n (~TO]OH~
Ger.: le.>kcru-~Jv-~ Perr>cNn Thenmo Tcii»d. Pb""'1n disorders.
Thermo llol'bod: Pykoryl Tt. ~ ll<itrimer.t-BN. Preparations
Muki·ingredicnt: Ari.: ~'f. Oxa Spc-rt; Pergaltn; Austrio: Alft. Proprietary Pre.parations (details are give1\ in Volume 8) " Bumadizone Calcium jr1NNMJ
C1uQt. Monthon<umt. 110~1-t;, '*"'
b<-»t: CJeri..c>n; Exp.ctal-SalAmt, lgib.w'Vltme.1tmtischet. Ii'('"'~
i'\hevTlex: RIJl>zon.l\neum~ Ru·
bm""'4: Thctmo·Rncvmoro: Thrombophc!>; Broz.: Etrllt. Trombofob:
Mufti-ingredient: Swfu.: Hyrgiodenntt. Bumadizona cilcica; Bu-nadizone Cakiquc: Calcio Bumadizonum.
Calcium 2-( I.2·d1phen)-fychzinocarbonyl)hexanoatc hemihy-
Cz.: ()olo.!W>Mie'1j~ Rh•""'-~ RbwntntNt: 'fhermo·Rhl'll·
nlO<'f; F'm: liCll'l'lx>«Jt Fr.; lumba!gOc: Got<.: NII:. W.orme·Salbtt: A.'T>- dratc.
t=• Nf: _ . . , Thonnot. ~COPQmOI Nt. C")'I! Rheum•· Bromfenac Sodium (VS>.N. :NM) K.-...'1 6y><i1A"30H
Bab•mt: l>.lloV.S- Salb•t: £maseic·N!: Hot th..Trot; t......ooon Thor· =699.8.
moj: mikaMf; ~ N: PhudcA w.,,.,..a.i..mt f'Nogont·Thtr· AHR. t0282; AHR· 10282B: llromfenac Sodique: Bromfenaco (C1,H!1N 203),Ca.'- "H10
m•lf: Pr•econ:fn St. Rtievm>-s.ibt Nt. Rhcvmo-S.'bef: Rheumos;ilbot: s6doco: Nari Bromfenacum. Sodi...,, [l·amino-3·(p-brorr.oben- CAS - 3583.64 ·0 (l>ummh~one); 3446/. 73.9 (bumc.d1·
Rubnmcnt Tach)<i<rg ~ Horwlbet: The~ Nt. Ther· zoyl)phenyl}acetrte sesqui.•ydrate. zone calcium).
rnosenext ziJc tO.rmot. Gr.: IVr S.lonpes: B~Un: Ehtbctc Sinor.....,, ATC - MOIA807.
ni..mo.l\o<pion: Honi "-F Salomethylt; Hung.: AT S.lorc*. ~ HaTp.,,;,6po+1.1• ATC Vet -·QMOIA807.
lni: Thenno-R'1tumont. Indio: Bq>oow: TI1ron~pl>Ob: lndo"" Stop C,sH 11 BrNNa01. I ''!H20 = 383.2. UNli - 7PSH384A}D (b"modizoM calcium htm•hydrote):
Xf: Thrombophob: ~rt /tof.; ~Sloan; Mu.: a.,..., Termo: CAS - 91714-94·2 (brom(enoc): 91714-93-1 (brom I 42R7TU2TN (onhydro~s oumadizone calcium)
Pol.: t..mioin: Tl-e-mo-~ Port.: ~· S.l,.mo
l"ltd.l"V"l'( Ru~: Clps;carn(~~~Oontmcr1(r~
""''="""' (eroc sod111m): 120638·55-3 (brom(enoc sodium)
Ma.t sw;1z.: Asson th<:nno: Domc'.ham - co1w·c le •'luna"" ATC - SOIBCI I.
met. ·Delo De<not"°"" Hi<talgano: M.....,.,.,.. N. T~u1'11f: Turk.: ATC Ve1 - QSO I BCl 1.
Tl.,..,,.,.Dc>tt: TJ.,.-mo·Rhevmon The<mollbc; IJK: S.lon.>r: Vcnez.:
f htkh ilot.-o.
UNI/ - 8ECV5 71 Y37. (')
Beta-aminopropionitrile
Amil'lOpropionitriie: p.,Aminopropionitrile: ll·Arninop<opoonitn .
HO~~
Br
Qy N
,.NH
0

o~
NH2
lo: SAPN: llc".a·a~le. 3·Aminopropionttrle.
6eTa->M~•Q(lp011M()t;MTpo<A 0 ~ ~ -
C1H• N2 = 70.09.
CAS - IS/ .18-8 (beto·cm•noprop•or.itrile): I I 19-28-4 - 0 CH3
(beto·aminopropionitri/e fumorote).
ATC Vet - QMOIAX91. (bromfena<)
UNI/ - 3SD5lj4KH2.
Profile Profile
Bromfenac: sodium, a phenylacetic :lcid dcri\'lllive related to di· Bulll3dnone calcium is an NSAID (p.100) that is metabolised to
clofenac (p.46). isan NSAID (p. 100). lt is insfilltd rwicodailyos phenylbutazune (p.12 1) and oxyphenbutazone (p. 112). Use has
0.1 % <)'C dtops foe ocular pain and inflamm1tio11 including post· t>ecn limited by lhc risk· of agranuloc11osis and 01her hocmato-
operative inOammaiion in peticnts who have undergone c.itaract logicol ad\Cl'S<' effects.
The symool t denotes a pref>3ration no longer actively marketed
30 Analgesics Anti-inflammatory Drugs and Antipyretics
Preparations Local reactions such as rash, erythema, and itching healthy subjects with buprenorphine-induced respiratory depres-
have been reported with the transdennal patches. In sion g iven large doses of naloxone 5 or I 0 mg, but not with I mg;
Proprietary Preparat:ions (details are given in \-blome 8)
Mex.: DesOam. reversal was gradual in onset and decreased the dw.ition of the
isolated cases delayed local allergic reactions with normally prolonged respiratory depression.• Other studies found
marked signs of inflammation have occurred; the that lower doses ofnaloxone 2 to 4 mg given over 30 minutes,'.6
patches should be withdrawn in such cases. US li- or bolus doses of2 to 3 mg followed by a oontinuous iofusill!l of
Buprenorphine (BAN. r.NN) 0 censed product information for Butrans (Purdue. USA) 4 mg/hour,• were effective in reversing buF cnorphine-induced
respiratory depression. The authors ofboth these S1Udies suggest-
Buprenorfonf. Buprenorlin; Bupren~rfoa; Buprenorfinas; Bu-
also warns that prolongation of the QT interval has oc-
ed that a longer duration of naloxone infusion may be needed for
prenorphine; Bup.'1!<1orphinum; l\X-E029-M. (6R,7R, I 4S)-17 -Cy- curred with transdennal buprenorphine when given at reversal of respiratory depression caused by high doses of bu·
dopropylmethyl·7,8-dihydro-7-[(IS)-! -hydroxy- I,2.2-trimeth)·l- a dose of 40 micrograms/hour. prenorpbine. The respiratory depressant and analgesic effects of
propyl]-6-0-methyl-6.14-ethano- 17-nonnorphine: (2S)-2-[(-)- Treatment of adverse effects is similar to that for other buprenoryhine were decreased by the concomitant use of
(5R.6R.7R.14S)-9a-Cyclopropylmeth>l-4,5-epoxy-3-hydroxy-6- naloxone. It should be noted that a combined sublingual prepa-
opioid analgesics (p. l 07). The effects of buprenor-
methoxy-6.14-ethanomorphinan-7-yl]-3.3-dimethylbutan-2-ol. ra!ion of buprenorphine hydrochloride and naloxone hydrochlo-
phine are only partially reversed by naloxone (see Ef- ride is available in some countries for the tte•tment of opioid de-
6ynpe><op$'1H fects on the Respiratoi:y System, below) but use of the pendence.
=
C 2,H,,N01 467.6. latter is still recommended. I. Dahan A. e1 al. Comparison of lhe respiratory effects of intrnc-
CAS - 52485-79-7. nous buprcnorphinc and fentany1 in human.$ and rats. Bt J
Incidence of adverse effects. Adverse effects reported' after Anoesrh 200S; 94: 82S-34.
ATC - N02AEOI; N07BCOI.
parenleral buprenorphine in 8187 patients were nausea (8.8%), 2. Schmidt JF, tu ol. Postoperath·e pain relief with naloxone: severe
ATC Vet - QN02AEOI; QN07BC01. vomiting (7.4%), drov;.siness (4.3%}, sleeping (1.9%), dizziness respirotory depression and pain after high dose buprenoq>hine.
UNI/ - 40DJSCR4GZ. (1.2%), sweating (0.98%), headache (0.55%), confusion Anoesthesio I 98S; 40: S83-6.
(0.53%), lighthcadedncss (0.38%1), blurred vision (0.28%}, eu- 3. Thom S-E. e1 al. Prolonged respiratory depression caused by
s-ublingual buprenorphinc. lonce1 1988; i: Ji9-80.
phoria (0.27%), dry mouth (0.11%), depression (0.09%), and 4. Gal TJ. Naloxone rever.:al ofbuprenorphine-indueed respiratory
hallucinations (0.09%). Some studies'" have reported nausea, depression. Clin Phormocol Thu 1989; 45: 66-71.
vomiting, and dizziness to be more ttoublesome 1>.ith buprenor· S. Dahan A. Opioid-indl)Ced respiratory cffccu: new data on bu·
phine than with morphine. prenorphine. Polliot Med2006; 20 (suppl I): s3-•8.
ln a study' of subli11gual buprenorphine, 50 of 141 cancer pa- 6. van Dorp E, ti al. Naloxonc reversal of buprcnorphinc-induced
respiratory depres5ion. Aneuhufology2006: 105: 51-7.
tients withdrew because of adverse effects, especially dizziness,
1. Lthmann KA.~/ ol. Influence of naloxone <.n 1he postoperative
nausea, vomiting, and drowsiness~ constiparion was not reported. analgesic and respiratory effects of buprcnc.rphinc. Eur J Clln
A woman developed' a painless ulcer on the upper surface ofhec Phormocol 1988; 34: 343-$2.
tongue after she bad put sublingual buprenorpbine tablets on
Overdosage. A 5mall case series reported' acute buprenor-
ralhcr than under her tongue.
phine intoxication in 5 children, aged from IS to 22 months, after
Shock occwred6 in 2 patients 2 hours afte< m:eiving epidural accidental ingestion of sublingual tablets; of these, 4 had inge.<;t-
buprenorphine 300 micrograms; rreabncnt with naloxonc was ed a combined preparation containing naloxone (Suboxone;
unsuccessful but symptoms disappeared spontaneously afte< 2 to Reckill Benckiser. USA). Symptoms included drowsiness and
3 houn;. mi<isis; decreased respiratory rates were reported in 4. All 5 chil-
In a multiccnttc study' of transdermal buprcnorphine, 252 of dren required hospital admission; 4 were treated with naloxone
Street names. The following terms have been used as 'street 1223 patients with moderate to severe cancer pain or non-cancer
names' (seep.vi) or slang names forvarious fonns ofbuprenor- and I needed mechanical ventilation. Accidental poisoning has
pain v.ilhdrew due to advcr.;c effects. The most commonly re- also been reported2 in a 9-month-<>ld infant who ingested Subox-
phine: ported were nausea (I I%), vomiting (9.2%). constipation
TEM;Tems. one; his symptoms were reversed by naloxone. A retrospective
(7.8%), dizziness (7.5%), drowsiness (4.0%), retching (3.7%), revie~ ofbuprenorphine overdoses in children under 6 years of
Pharmacopoeias. In Eu' (seep. vii). generalised pruritus (2.0%), and headache (1 .6%); local adverse age reported by US poison centres to a national surveillance sys-
Ph. Eur- 6.8 (Buprenorph'ne). A white or almost white crystal- effects included pruritus (1.4%), dennalitis (1.3%), and ery- tem from November 2002 10 Deceinber 2005 concluded that
line powder. Very slightly soluble in water; freely soluble in ace- thema (1.3%). Another studyl' reported oedema. headache, nau· overdooage is generally well tolerated. Out of86 reports, 54 chil-
tone; slightly soluble in cyclohexane; soluble in methyl alcohol. sea, palpitation, and d ifficulty concentrating as causes for tlicra- dren developed symptoms of toxicity. Such S)inptoms included:
It dissolves in dilute solutions of acids. Protect from light. py withdrawal in 4 out of90 patients. drowsiness or lethargy (55%), vomiting (21%), miosis (21%),
I. Hare.us A \V, et al. Methodology of monitored release of a new respiratory depression (7"A), agitation or irritability (5%). pallor
Buprenorphine Hydrochloride IBANM. USAN. rlNNM) preparation: b uprcnorphinc. 1JMJ 1979; 2: 163-S. (3%), and coma (2%). There were no fatalities, and significant
2. Sear JW. et of. Buprenorphine for postoperative analgesia. Br J
® Anoesrh 1979; 51: 71. CNS and respiratory depression occurred in 7%. Suboxone prep-
Buprenorfiinihydrnklo:id; Buprenorin-hidroklorid; Buprenorlin- 3. Kjaer M, el al. A eotnp3rative s1udy of intramuscular buprenor· arations were the most commonly ingested µ-od ucts. The aulho.s
hydrochlorid; Buprenorfa'lhydroklorid; Buprenorlino hidrochlori- phinc and morphine in the treatment of chronic pain of ma1ig.nan1 considered that any child who has ingested more than 2 mg and
origin. BrJ Clin Phc,mt:teol 1982; 13: 487-92. any aged under 2 years who has had more than a lick or taste
das: Buprcnorphine. chlomydrate de: Buprenorphini hydrochlo- 4. Robbie OS. A lria1 C'lf .sublingual buprenorphine in c;me:er paill. should be referred to the emergency department.
ridum: CL- I 12302; Hidrodoruro de buprenorfl'la; NIH-8805: BrJ CUn Pharmacol 1979; 7 (suppl 3): 31 SS-3 17S.
S. Lockhart SP. l)aron JH. Tongue ulceration after lingual bu· During the years 1980 to 2002, buprenorphi>e was mentioned in
UM-952.
prenorphinc. lJMJ 1984; 288: 1346. 43·cases of adult fatalities in the VK.' Of these, 27 deaths were
6ynpeHOpcl><t<a f HApDXllO;>l<A 6. Christensen FR. Andersen 1.W. Advc~ rcae:1ion to extr3dur31 conlinned to have involved buprenorphine including 7 cases
C29H.,NO.,HCI = 504.1. buprcnorphinc. BrJ A11oes1h 1982~ 54: 416. where it was taken alone. Jn those deaths where multiple drugs
CAS - 53152-21-9 7. Muriel C, el al. EITectiveness and tolerability of 1he buprenor- "<ere im10Jved seda1ives or benzodiazepines were detected in 23
UNI/ - 56W8MWJENI. phine transdermal system in paticnLS wilh moderate to severe cases and other opioids were found in 17 eases; alcohol had also
chronic pain: a multicentcr, opcn·labcl. uncontrolled. prospcc-
Pharmacopoeias. In Chin., Ew: (see p.vii),Jpn, and US. t~e. observalionaf clinical study. Clln Ther 2005; 27: 451-62. been taken in 10 cases. The authors also found an increase in
Ph. Eur. 6.8 (Buprenorphine H)'droch!oride). A while or almost &. Sorge J, Sittl R. Transdermal buprcnorphine in the trco1mcnt of buprenorphine-relaled fatalities since 1999 when the high-dose
white crystalline powder. SJ>3ringly soluble in waler; soluble in thronic pain: results of a phase Ill. mullicenter. randomized, fonnulation became available.
alcohol; practically insoluble in C)'Clohexane; freely soluble in double.·Mind, placc:bo·cOntrollcd study. C/in TJ1er 200~; 26: I. Geib A-J. e1 ol. Adverse effec~s in children oifter u nintention:tf
180&-20. buprenorphine exposure. Ptdiotrics 2006; ll8: 1746-SI.
methyl alcohol. Protect from light.
USP 33 (BuprellOl'phine Hydrochloide). pH ofa 1% solution in Effects on the heart. For a report of myocardial infarction as· 2. Cho CS, et ol. Explora1ory b1.1prenorphinc inAestion in an infant.
soeiated with abuse of buprenorphine, see Abuse under Precau- Ann EmcrK Metd 2006; 48: I09.
water is between 4.0 and 6.0. Store io airtight containers. Protect 3. Hayes BO, et al. Toxicity of buprcnorphinc overdoses in ehil..
from light. 1ionsl below. drcn. Abstract: Pedio1ric! 2008: 121: 807-8. Full version:
Effects on mental function. Psychotomimetic effects have http:!/pedi3trics.asppubliea1ions.org/cgj/reprint/121 /4!c782 (ac-
Dependence and Withdrawal been relatively uncommon with buprcnorphine. Hallucinations cessed 22/07/08)
4. Schifano F, el al. Buprcnorphine mortality, seizures and pre·
As for Opioid Analgesics, p.105. were reported' in only 7 of 8147 patients (0.09%) given bu- scrip1ion data in the UK. 1980-2002. Hum Psychophormacol
prenorphine by injection. There have been reports of hallucina- 2005; 20: 343-8.
Buprenorphine may have a lower potential for produc- tions after s11blingual2 or epidura\3 use.
ing dependence than pure agonists such as morphine. I. Harcus AW. c1 al. Methodology of monitortd rele3-se of a new Precautions
However, ii has been subject to abuse (see under Pre- preparation: buprcnorphinc. BMJ 1979; 2: 163-S.
2. Pal"3$kevaides EC. Near fa1al audi1ory hallucinations after bu~ As for Opioid Analgesics in general, p. l 07.
cautions, below). Abropt withdrawal ofbuprenorphine pr<norphinc. BMJ 1988; 296: 214.
is said to produce only a mild abstinence syndrome, 3. MacE,·illy M. O'Carro11 C. Hallucinations aflcr epiJural bu:·
Buprenorphine has opioid antagonist actions and may
which may be delayed in onse~ prcnorphine. BMJ 1989; 298: 928-9. precipitate withdrawal symptoms if given to patients
Effects on the respiratory system. There have been varying physically dependent on opioids.
Buprenorphine is used for substitution therapy in the
reports on the occurrence of respiratory depression with bu- Respiratoi:y depression, if it occurs, is relatively slow
management of opioid dependence (see under Uses prenorphine. It may be subject to a 'ceiling effect' in which res-
and Administration, below). in onset and of prolonged duration; it may be only par-
piratory depr<.'ssion does not increase further above doses of
about 3 micrograms/kg.' However. high doses of 30 or tially reversed by naloxone.
Adverse Effects and Treatment 40 micrograms/kg given as sole inrr3vcnous analgesic in bal- Licensed product information states that baseline liver
As for Opioid Analgesics in general, p. I 06. anced anaesthesia have been associated with severe respiratory function levels should be established before starting
depression.l
Acute hepatotoxicity, including elevated liver enzyme buprenorphine therapy, and periodic monitoring ofliv-
Respiratory depression may be delayed in onset and more pro-
values, hepatitis with jaundice, hepatic failure, necro- longed than with morphine and is only partially reversed by er function should be pcrfonned throughout therapy in
sis, and encephalopathy, and hepatorenal syndrome, naloxone, possibly because buprcnorphinc is very fomly bound patients being treated for opioid dependence. It should
has been reported in opioid-dependent addicts; these to opioid receptors. A study of sublingual buprcnorphinc for be used with caution in all patients with pre-existing
postoperative pain relief was abandoned when 3 of the first 16 hepatic impainnent.
reactions have also occurred after the misuse of bu- patients showed signs of late-onset respiratOJ)' depression after
prenorphine, particularly after high doses or intrave- the second dose ofbuprenorphine; the respiratory depression did Absorpt ion of buprenorphine from transdennal patch-
nous use. not respond to naloxonc.3 Successful reversal has been sho,vn in es may be increased as the temperarure rises and pa-
All cross-references reter to entries in Volume A
 Buprenorphine 31
lients should therefo~ avoid exposing the patch to ex- ., Fischer G. ~' ol. T~at1ncn1 or (lflioid·depcnden1 ptt1nant womc:n nide metabolites. Buprenorphine is subject to consider-
with buprenofl>liine Addi<'1lo11 2000; 95: :!39..44.
ternal heat; similarly, patients with fover may require .3. Johnson RE. 1111/. Usc- o( buprenorphine in pregnancy: p;Jli rnt able first-pass metabolism after oral doses. However,
monitoring because of im..Teased absorption. It may mam1geinenl and dfecu on die neonate. Dr11r. Alco/HI/~~ when given by the usual routes bup1-enol]lhine is ex-
2003: 70 (suppl~): SS7-S 101 .
take up to 30 hours for plasma concentrations of bu- Kahila H, <:t al. A prOSpcdiVC' study on bupcenorptnne use durin1 creted mainly unchanged in the faeces; there is some
prenorphine to decrease by 50% after removal of a ptt:nancy: dTccls on malcrr.al and Moorual o ulcomc. Acta Qb-- evidence for emerohcpatic recirculation. Plasma elim-
patch; patients who have had adverse effects should be 11<1 G1n«ol Scond 1007; 86: 115-90. ination half-lives have ranged from 1.2 to 7.2 hours af-
monitored during this period. US licensed product in- ter intravenous injection; elimination half-l ives after
Interactions
fom1ation for Butrans (Purdue. USA) recommends that sub lingual or transdermal use are longer and may range
transdennal buprenorphine should be avoided in pa- For interactions associated with opioid analgesics, see
p.107. from 20 to 36 hours or more. Metabolites arc excreted
tients with a personal or family history of QT interval in the urine, but VCJ)' little unchanged drug is excreted
prolongation and used with caution in those with hy- Buprenorphine is me1abolised by the cytochrome P450 in this way. Buprenorphine crosses the placenta and
pokalaemia or unstable cardiac disease such as atrial isoenzymc CYP3A4; consequently, use with other small amounts are distributed into breast milk
fibrillation, congestive heart failure; or myocardial is- drugs that induce or inhibit this isoenzymc may result
in changes in plasma concentrations of buprenorphine 0 References.
chaemia. I. E'lkader A. Sproule B. Buprcnorphinc: clinical ph:irmacokincdcs
and, possibly adverse effects. Some manufacturers in the trcatmcnc of op101d dependence. Clin Phonn«ok.ln~I
Abu~. A 22-year-old 111a11 had chest P"ins on each of two ooco-
sions after be had inhaled crushed buprtn<llphinc tablcts. An 1 state that dosage adjustment ofbuprenorphine may be 200S;44: 661-30.
ECG taken after the s=nd episode Sll",,gested that the patient necessary when used with such drugs. The UK li- Administration. auccAL ROUTE. Absorption of sublingual
had suffered a myocardial infarction. IntraYCllOOS injection of censed product infonnation for one sublingual folTilu- buprenorphine is relarively slow. In a IO·hour study' plasma
crushed sublingual tablets was associated with rbabdomyolysis lation (Subutex; Schering-Plough) recommends that concent.-.tions after 400 or 800 micrograms &iven sublingual-
and sciatic ncuropathy in 2 P"tients.' A case series> of4 P"tients the dose ofbuprenorph ine should be halved when start- ly peaked 11 about 200 minutes (range 90 to 360 minutes) and
reported severe limb and digit complications, such as ischaemia buprcnorphine was still detected 1n plisiM at the end of the
and gangrene, from parenter.tl nbusc of sublingual bup<a>or- ing treatment with the potent CYP3A4 inhibitor, keto- study. Systemic availability was about 55% (range 16 to 94%)
phine tablets; intra·anerial i1~cction in 2 cases resulted in ampu- conazole. and absorption was more or less complete 5 hours afier •
tation of the affected digits or limb. The use of adulterants in il- 11tere have been repons of respiratory and cardiovas- dose. However, the authors of a subseque.tt study considered
licit preparations may also cause adverse effects: 4 patients on that lhis was an overestimation, possibly due to mclhodolog-
cular collapse in patients given therapeutic doses of in- ical flaws. The later study results indicated that the bioavail-
substitution treatment dc-.clopcd candida endophthalmitis after
intra''CIOUS'r injecting sublingual buprenorphinc diluted wi~1 travenous buprenorphine and diazepam. ability of sublingual buprenorphine is about 3~'. and that
lemonjuice- Use with other potentially hepatOloxic drug,~ may in- sublingual holding times between 3 and 5 minutes arc
Hepalotoxicity has been seen in opioid-dependent addicL~ after crease the risk of liver damage. biocquivalcnl. Another single-<lose study' found that the bio-
buprcnorphinc abuse (see Adverse Effects and Treatment, availability of sublingual buprcnorphine was 50% less from a
above). Analgesics. lbctt is a risk that, with opioid -sonist-anragonisls tablet then from a liquid formulation. !..Ater studics..S noted
such u buprcnorphine, their antagonisric effects might impair that the bioavailability of buprenorph1oe from a sublingual
I. Cracowski J.t.. ti ol. Myocardial inCarctiOl'I associated wilh bu-
prcnorphinc. Ann,.,.,.,, M<d t999: 130: S37. more effective analgesic lherapy. This appeared to happen in 2 tablet relative to a sublingual liquid fonnulation was about
2 S«t RCS. Lim ECH. Jntn~ use or buprenorphine tabk:b cancer parients both of whom were given subling11al btipttnor- 70% after daily dosing for 7 days. One of these studies' also
associ:i1cd with rhabdomyolysu and comprosi"c 5Ci:uic ncurop- phinethat waslatcrsubstitllled by morphi11e.1Con,'Cntional dos- found that the bioavailabi lity of sublingual buprenorphinc
11hy. Am1 £m•rg M•d2006:47: 396-7. es of morphine were inadequate and in one patient raising the from a tablet fonnulation containing naloxone was higher
3. Loo HW. ~t of. Severe upper limb complications Crom ~rcntcrat dose of morphine ~'Od fatat than from a single-ingcdicnt tablet fonnulation and similar to
obusc ofSubulcx.n A1111Acod McdS;ngaP"'-. 200S; 34: S75-8.
4. Cassoux N. et al. Presumed ocul:IJ tmdidiuis in drus 1nisusttt
I. Ovcn,'Cg-von Kints J, StricL.-er BHC. Falendc pijnbatrijd1"S ti- that seen with liquid fom1ulations.
3ftcr in1ravmou.i use of oral high dose bu~norphinc (Subutcx).
jdcru wblingua:t.I acbru1k van buprcnorfinc. Ned Tijd,schr Ge· I. Bullin,iham RES ,~' ol. Sublingual t'luprtnorphine used poslop-
Br J Oplllhol~ :002; 86: 940-1.
n<otd 1981; 131: 1973-4. cntivt:ly: 1c:n lluur 1>!as.n:1 drug concc1llralKln unalysis. Br J Clin
Antivirals. Various HIV-protease inhibitoos and NNITTJs can Phar••ocol 1982; 13: 66>-73.
Breast feeding. From • study1 of a breast-feeding mother who
was receiving sublingual bupreoorphine 4 mg daily, it was esti- inhibit or induce cytochrome P450 isocnzym.es. and most = 2. Mtndclson J, ct ol. Bioav3ifab1lity of sublin:ual buprenorphir.c..
J Cll• Pharma<t>/ 1997; 37: 31-7.
mated that at lhe age of4 weeks the total amount ingested by lhe al;;o subslr•tes for CYP3A4; thus, they have the potential 10 in-
3. N1lh RP. "of. Buprcn0tphine pharmacokinedts: relative bioa·
infant during a 24-bour period was 3.28 micrograms for bu- teract with buprmorphinc. A pl1armacokinctie study' found I hat vo1libilil)' of sublingual l:iblcl and liquid fonnu1ations. J Clitt
prenorphine and 330 nanocrams for norbuprenorphinc. Another usual doses of11elfinavir, rirontwir. and lopi11avir-riro11tn:ir given Plw.-.1Q<O/ 1999: 39: 619-23.
study found that buprcnorphine, also taken sublingually. was to HIV-negative patients taking buprenorphinewith naloxone for 4, S1rain EC. et al. Rtlativt bio•vailability of dirfrnnc bupri'Cnor·
JY.CSCOt in the breast milk of a brcast·feeding, mo~1er with a ma-
opiate dependence did not produce any clinically significant in- phine fonnulations under chronic dosing conditions. Dn'I Alco-
teractions: ritona.vir i~ the area under the concentration- hol Dopc11d 2004; 7~ : 37-4).
rcroal milk-to·plasma ratio of about one. The au~1ors of bolh 5. Compton P1 t1 ttl Ph1rmxokinc:1ics. btoavailability and opioid
studies considered the aonow•t absorticd through breast reeding time curve (AUC) ofbupren<irphine by about 57%, allhouf' no
dTCCIS of liquid ''Cf1US tablet buprcnorphint:. OnJg Alt:ohol o~­
to below. ad-.-crsc effects were seen. Another pharmacokinctic study in a pcud 2006: 82: 2S-J I.
similar group of patients also fomd no clinically significant in-
The BNF 59 and some licensed product infonnetion stare that Children. The 1enninal elimination half-life of buprcnorphinc
teractions betwttn buprenorphine with naloxon• and de/cminiin•
buprcnorphinc, regardlc.ss of route, should not be given to moth- or efnwrrmr. dclavirdine increased the AOC of buprenorphine was only about I hour in small chilcnn aged 4 ro 7 years given
ers who are breast fcedins- fourfold, and efavirenz decreased it by about 50"!.i, but no ad- 3 mi<TOgramslkg intravenously u prcmedication, but could not
Studics in rols have shown that ii may inhibit lactarion. vel'$e effects,_,, seen. However, a small case seriesl of 3 opio- be estimated reliably because of the rapid decline in plasma-
l. Morquet P. ~ n/, Buprcnorphinc withdniwal syndtoolC in 1 nicw· id-dependent patients reported symptonu ofbuprenorphinc tox- buprcnorphinc concentrations.' Clearance values did, however.
born. C/hr Phormac<>l 71'u 1997: 62: ~6'>-71. icity, such as dimness, daytime somnolence, and decreased appear higher than in adults; steady-stare volume or dismbution
2. Johnson R£. ct al. Buprcnorphine creafmenl of pregnant op.aid· was similar. Premature neonates (gestational age 27 to 32 weeks)
dependent women: m:ncn\11 Ind neorunal oulcomcs. Drug Alco-- mental functioning. with concomitant atazanaw'r and riton~vir
I,,,/ D<p<1ul200 1: 6J: 97-103. therapy. given a similar dose followed by an iufusion of
Buprenorphinc does not appear to significantly affect the phat- 720 nonogr2mstk& per hour had 3 considerably lower clcaronce
Pregnancy. An infonr bom to a mother who was being treated rote and had a rnelln elimination half-life of20 hours.1 Although
macokinetic.s of an1irctrovirals. U
with sublingual buprenorphinc 4 mg daily for diamorphine Gd- this dD.'ling regimen appeared to be safe, sedation was judged to
diction suffered a minor withdrawal syndrome 2 days after I. McCancc-Kau EF. '1 al. lnlcractions between buprenorphinc
and antire-11ovirnls: J-lbe noonuckoli6c rcvcrse-mmscripta.sc be inadequate in 4 of the 12 neonates studied. It was suggested
birth.' The infant rapidly reco>ercd withow any tte:ltment. No in1ubi101s davircnz and delavirdiM Clltt hiftct Dis 2006; 43 that as bupreno1phine given by infusion might not produce con-
funher signs of withdrawal occurred when breast feeding was (suppl 4)" S224- S2l4. sistent sedation and onalgesia in pn:mature neonates. it could not
nbruptly stopped at the age of S weeks. In another report2 of I5 2. M1..-C.PCX-KalZ £f, ~I ol. Interactions tt.a...-een buprcoorphinc be recommended for use in neonatal care.
opioid-dc·pcndcnl mothers who hnd received buprcnorphine end antireuoviraJs: JI-The prolcHc inhibitors ntlfina\'ir. lopi·
I. Ollckob KT. ~' al. Phonnacokincttcs of intravenous buptcnor-
maintenance sublingually during their pregnancies, withdrawal navir/ritonavir. and riton:tvir. Clln Infect Dis 2006; 4-3 (suppl 4): phinoe in childrc:.. Br J C//11 Pl"10r·m,1col 19S9; 28: 202-4.
S23S-S246.
symptoms were either 1bsent or mild in 12'ofthc neonates- TIIC 2. Barrett OA. ~tol. The ph11nn:&cokine1ics and physiolosi~ I crrcc1
3. Bruce RD. Alliee FL. Three case rcpo11s ofa clinical ph&Macok·
n:maini11g 3 neonates n:quircd tn:atment 'vith morphine. lllcrc inctic interaction w11h tKipttnorphinc: and 11t3z,annir ptus rilo11a· or buprt1"t04'ph.ne inrusion in pr~macure nronatu. !r J CJ;,,
appeared to be no correlation ~eeo the buprcnorphinc dose vir. AJO:S 2006; 20: 783-4. Phu1·•10<ol 1993: 36: l1S-l9.
and rhe dci'CC of withdrawal symptoms. A literature re\'iewl Renal impairment. Buprenorphine cleurance appears to occur
found that of about 309 infants born to opioid-dependent moth- Pharmacokinet ics mainly by hepatic extraetion and inetobolism and would not bc
ers mau11&incd oo buprcnorphine (sublingual dose range: 0.4 to expected to be related to mul function, whereas mclabolites are
24 m& daily), 193 developed ncon•tal abstinence syndrome; of
After intramuscular injection, buprenorphine rapidly
excreted in urine. In a study, buprcnorphinc kinetics were similar
d1csc. 149 n:quir<d trealrnent. More than 40"1' of treated cases reaches peak plasma concentrations. Absorption also in anaesthetised hcalrhy patients to thooe in patients with n:nal
were confounded by misuse of other drugs. Onset of symptoms takes place through tl1e buccal mucosa after sublingual imP"irmcnt, with a mean elimination half-life of 398 ond 239
occu1Ted within the first 11 to 48 hours and peaked wilhin about doses and peak plasma concentrations occur after 90 minub:s, rcspccrivcly. 1 Plasma eonccntralioos ofthe metabolites
72 to96hours;dumionofsymptomswas about120to 16ghours minutes. Transdcnnal application results in absorption norl>upn:norphine and buprenorphine-3-glucuronide were in-
alth011gh in some infants, 11 was reported to la~tfor6to 10~1<$­ creased aboul 4 times and l 5 times, respectively in patients with
The 67 pregnancies of 66 women using sublingual bupmior-
through the skin; the minimum effective concentration renal impainnen~' but significant phannacol<>&ical acli,•ity was
phine have been followed in a prospecti\•c study.' The incidences is reached in 12 to 24 hours and peak plasma concen· unlikely since norbuprcno1phi ne has little analgesic activity
of premature binh, caesarean section, and low Apgar scores in trations occur after about 60 hours. However, there is a con1parcd with the parent compound and buprenorphinc-3-glu-
buprenorphin~poscdncona1cs"erenopcatcrthan those seen lack of correlation between plasma concentrations and curonide has none.
in the gcnenl populorion although the mean birth-weight of the analgesic activity. Buprenorphine is about 96% bound l . Uand CW.~r ol. BuprenorptHnt disposition in parientsW'lth rtnal
cxpo$ed nconaies was significantly lower. In the exposed group, impairmen1: ~ i nttle and con1.muous dosing. with .special refer-
91 % ofoconates needed intensive care trc:umcnt: 76% had nco-
to plasma proteins. ence 10 n1ctabo1itc.s. Br J Anon1h 1990; 64: 276-.8'2.
na<al abstinence syndrome and 57% needed opioid replacement Elimination of buprenol]lhine is bi- or triphasic; me-
therapy. TI1erc were also 2 cases of sudden inf.int de<lrbs in 1hc tabolism takes place in the liver by oxidation via the Uses and Administration
exposed group, wlti<:h wu considered to be higher than that gen- cytochrome P450 isoenzyme CYP3A4 to the pharma- Buprenorphine is an opioid analgesic(p. I 08) classified
erally CXJ>""'ed.
1. Marqucl P, w ul Ouprenorphin~ wilhdrotw111 S)'ndronM: in 1 Hew·
cologically active metabolite N-dealkylbuprenorphine as an opioid agonist.and antagonist It is used for the
born. ClfoPf,or11u1co/~r 1997;6.?: S69-7 1. (norbuprcnorphine), and by conjugation to glucuro- relief of moderate to severe pain and as an adjunct to
The symbol t denotes a prepar-dtion no longer actively marketed The symbol® denotes a substance whose use may be restricted in ccnain spons (seep.vii)
32 Analgesics Anti-inflammato1y Drugs and Antipyretics
anaesthesia. Buprenorphine is also used in the treat- lingually for premedication; 300 to 450 micrograms 4. Ficllin OA. e1 ol. Consensus $lalcmcn1 on office-b:lscd 1rc:a1-
men1 t'f opioid dependence using buprcnorphine. J SllbJf Almse
ment of opioid dependence. may be given intravenously as a perioperative analge- Trcol 2004; 27: 153-9.
Buprenorphinc has a relatively slow onset but pro- sic supplement. 5. Donaher PA. Welsh C. Menagine opioid 1ddic-1ion with bu·
prcnorphine, Ant Fom Physician 2006; 73: 1S73-8.
longed dur.ition of action. On intramuscular injection For the treaunent of opioid dependence in patients 6. Sung S, Conry JM. Role of buprenorphine in lhc m1n1gcment
analgesia is apparent within 15 minutes and lasts up to aged 16 years and over, the initial dose is 0.8 to 4 mg of heroin addie:1ion. Ann Phor111ocoth~r 2006; 40: 501-S.
'· Robin$01l SE. Bupttnorphine--con11;nin' trcatmcn1S: place in
6 hours. A slower, more prolonged response is sublingually once daily. The dose may be increased as the manasc:men1 of opioid addiction. CNS Drva1 2006; 20:
achieved after sublingual doses. The analgesic effects necessary but maintenance doses should not exceed 697-7 12.
I. NICE. Methadone and bupRnorphinc ror Ille manaacmenl of
of buprenorphine after transdennal application may 32 mg daily. Once the patient has been stabilised, the opoid dependence: Tcclinology APll"'illl Ouo.S.ncc 114 (is-
not be seen for at least 12 to 24 hours or up to n hours dosage should be reduced gradually to a lower mainte- sued January 2007). Av.ai11blc at: hnp:J/www.nicc.orc.ukl
ni«mcdia/pdl7TA I I 41\iccguidancc.pdf (acCCSJed 26/06l08)
in the case of the once-weekly patch. nance dose; treabnent may eventually be stopped ifap- 9. Boo1hby LA. ~ring PL Bupr<n0tp11;ne for 1hc tr..tm<nl of
propriate. For addictS who have not undergone opioid opioid dcp<r.<knce. AmJ HttJlth·Syst PAomo2001; 6-4: 266-72.
Buprenorphine is usually given by intramuscular or in- I 0. Mauick RP, et al. Ouprcnorphinc mainrenancc vcrsusplac.cboor
travenous injection or sublingually as the hydrochlcr withdrawal before staning buprenorphine, the first m~hadone maintenance for opioid dependence. Av1ilable in
dose of buprenorphine should not be given until the The Cochrane Database of Systematic Reviews: Issue 2. Chich·
ride or as transdermal patches as the base. For all routes cSlet: John Wiley; lOOS (accessed 26/06l08).
doses are expressed in terms of the base. Buprenor- first signs of craving appear or until at least 4 (USA) or 11 . Sullivan LE, f'iellin O.". Narrati\'c rtvicw: buprcnorphinc for
6 (UK) hours aJ\er the last opioid use. In those already opioid-dependent p;i1icn1s in orticc proc1icc. Ann Jn1e1·n Med
phine hydrochloride I 07 .8 micrograms is equivalentto 2008: 148: 662-70.
about I 00 micrograms of buprenorphine. receiving melhadone replacement, the dose of melha- 12. Schoncnfcld RS. et nl. Main1enancc trcttrricnt whh buprcnor·
done should be reduced to a ma.'timum of30 mg dai ly phine and naltrcxonc for heroin dependence in Malty$il! a ran·
Buprenorphine is given by all the above routes for opi- domised, dou'blc·blind, pl::icebo·controlle:d uial. J..aneet 2008;
oid analgesia in moderate to severe pain. before starting buprenorphi.t1e therapy. As a detemnt 371: 2 t92--2200.
to abuse, a combined sublingual preparation of bu- 13. Woody GE. et of. Exiendcd '" •hon-term buprcoorphinc-
• The dose by intramuscular or slow intravenous in- naloxonc for lrcnlmcnt of opioid-eddic.tcd youth: 1 randomized
prenorphinc hydrochloride and naloxonc hydrochlo- trial. JAMA 2008; 3-00: 200}-ll. CarrcetiOA. Ibid. 2009: 301:
jection is 300 to 600 micrograms repeated every 6 to ride is available in some countries for the treatment of 830.
8 hours as required opioid dependence.
14.. Onnan JS, Kea1in,g GM. Bupttn0tph1nclnato.onc: a review of
;'T,~;. lhc 1rca1mcn1 of op;o;d clcpmdc1'ce. Dntzs 2009; 69:
• By the sublingual route, doses of 200 to For details of doses in childr en, see below. t S. Gowing l., ., al.
Bupm1orphinc fe<r 111< .,,...,..,,.,. of opioid
400 micrograms may be repeated every 6 to 8 hours wuhdraw.al. Available in The Cochrane Dltahue of Syslcm.i.ic
as required Action. Bll)nnOIJ)hine is generally descn'bed as a mixed ago- Reviews; lnue 3. Chichester: John Wiley. 2009 (1cccss.cd
nist-antagonist acting mainly as a partial agonist at µopioid rc- 30/IMJ<J).
• For opioid treatment of chronic pain in patients aged c:q>1ors, with some antagonist acti•iry at < receptors. It has also
Pain. ACUTE ~AtH. The BNF 59 consider$ that buprenorphine
18 years and over transdermal patches delivering been shown to bind at Jl, 6, and <opioid binding sites aod to have
may antagonise the analgesic effect or other opioids and is
varying amounts of buprenorphine are available. high affinity for theµ and 6 receptors and lesser alliniry for the"
generally not recommended for the management ofposloper-
rcccptor. 1 Buprenorphine, like fentanyl, has high lipid solubility,
Doses should be individually titrated for each patient but has a lower intrinsic activity than fentanyl. Differences be-
olive pain. Nonerheless, it can be given intramuscularly, intra-
according to previous opioid usage. During transfer venously, or sublingually for this purpose, although the intra-
tween buprcnorphine and pure µ opioid agonists such as fenl.11·
to treatment with buprenorphine patches previous venous route may be preferred for acute pain relief. The ·
nyl, including relatively slow onset ofaction, prolonged duration epidural route• and continuous subcutaneous in~sion2 ha\'e
opioid analgesic therapy should be phased out grad- of action, resistance to antagonism by naloxonc, and lack ofcor-
also been used; an intranasal formulation of buprenorphine
ually in order to allow for the gradual increase in relation between plasma concentrations and analgesic eflCcls,
has been investigated for the management of postoperative
have been explained by differences in the way buprenorpbine
plasma-buprenorphine concentrations. Depending pain. 1 Patient·controlled analgesia with intravenous 3 and
binds to opioid receptors. In a study in >itro buprenorphine had
on dose required up to 2 patches may be applied, slow rates ofa.-sociation and dissociation from the opioid~ intramuscular' buprenorphinc is effective although its long
half-life may limit such use.
however, this should be done at the same time to tor when comiwed wilh fentanyl.'
Buprcnorphine bad no ad\'CfSC cardiovascular cft'cclS when gjv-
avoid confusion. Buprenorphine patches are not ap-
propriate for acute pain. In the UK and USA,
transdermal buprenorphine patches are available as
°""'
I. Bovill Ja Wluch po1ro1 opioid? lmponant cri1tri• ror sekcti<>n.
1911: 33: $20-30.
2. Boos RA. Vilhgc.r JW. Clinical ac1ionsofftn\.lt1yla.nd bvpc~nor·
en intnvenously after opcn·hcart surgery,' suggesting that it was
a suitable analgesic for patients with unstable circulation. Epi-
dural analgesia with buprcnorplrine has also bcera used af\cr car-
ph1ne~ rhe 1icn1fic~ of ttc~ptor bindjng, Br J A1taa1Jt 1985;
follows: 57: 192~. diac S\llEery.6 Buprenorphine was also considered suitable for
Administration in children. B\ljlfCllorpbine is used for the the relief of pain in myocorrliol it!forction.1
Transtec (Napp, UK) delivering buprcnorphine in a 1. Miwa Y, er nl. .E.pK!ur.il administered buprenorphlnc in lhc ptri·
range of 35 to 70 micrograms/hour. Initial dosages rtlicf of moderate 10 severe pain in children. In 01c UK, !hose opc:ralive period. Con J Anoeslh 1996i 43: 907-JJ.
aged from 6 months lo 12 years roay be given 3 to 2. Kawama1a T, et al. Pain manavcment lf1a lurnbir tpinaJ fusion
should not exceed 35 micrograms/hour in opioid- 6 micrOVdmsik(I by inrramuscularor slow intravenous iajcctiou surgery UJing con1in11ous sube11 1 1nC<"IU~ infusion Of buf)lCnOr·
naive patients. For patients who have been receiving every 6 to 8 hours; up to 9 micrognimslkg may be given if re- phinc. J Anusth 2005; 19: 199-203.
a strong opioid analgesic the initial dose should be quired in refractory cases. Jn the USA, parenteral bupr~'llorphinc 3. Dingus DJ. el al. Buprcnorphinc verJU5 morphine for palicnl·
is licensed in children aged 2 years and over; usual doses of2 10 con1rolled analgesia 3ftcr cholteyslcctomy. S11rg Gytttc0I ObSlet
based on the previous 24-hour opioid requirement. 199J; t77: 1-J;.
Use of a patch providing 35 micrograms/hour ofbu- 6 microgr.11nslkg may be given intramuscularly or intravenously 4, Harmer M. ~' al. lnlramuscular on d1:m1nd analgesia: double
every 4 to 6 hour.1 10 those up to 12 years old. blind e<>nlrollcd ui:Io(pethidine. buprcoorphinc, morphine, and
prenorphine is roughly equivalent lo 30 to 60 mg 'The subllng110/ route is licensed in Oic UK in children oged from m<pt. .inol. BMJ 19&3; 286: 680-2.
daily of oral morphine sulfate. Patches should be re- 6 to 12 ycors and the followinr, doses are given every 6 to 8 hoW11 S. Ro>enfek11 FL. t1 ol. Hocmodynomic effects or buprcnorphinc
placed every 96 hours at the latest with the new patch accon!ing to body.weight: •n•r hc.>n suf1!c.ry. BM.I 1978; 2: 1602-3.
being applied to a different site; use of the same area • t6 to 2Skg: 100 micrograms
6. Mehta Y, "al. Lumb>r versus 1horacic cpidurol bupr""°'l>hin<
for postopt1'1tivc analgesia following coronary •f\cr)' bypass
of the skin should be avoided for at least the next 2 • 25 to 37.Skg; 100 to 200 microgmns &nn swiery. Aero Anomhulol !kand 1999; O : 38$-9).
7. HaycsMJ, ct'11. Randomised tria1 comp1rina l>upcnarph.inc and
applications. • 37.S to SO kg; 200 to 300 microgra= diamorphinc foe chesl pain in s:uspec•e:d myoc1rchal infa.rction.
BuTrans (Napp, UK) and Butrans (Purdue, USA) Olda children requiring pain ~lief may be given the usual adult BUJ 1979: 2: 300-2.
de live ring buprenorphine in a range of 5 to dO<IC (sec above) for all the above rOtJtcs. CHA OH re PArH. Transdennal buprenorphine is used for chronic

20 micrograms/hour. UK licensed product informa- Buprenorphine is also used in the rrearment of opioid depend- i11troctable cancer pain.'·' h has also been used successf~ll~
ence; adolcS«'tltS aged 16 years and over may be given the u~a I in chronic non..c:mcer pain including ncuropalhic pain;•-,.s-
tion states 1hat initial dosages should not exceed adult dose (see above). howevcr, licensed p<oduct information states that this route is
5 micrograms/hour in all patients, whereas in the not suitable for the treatment or acute psin.
USA, this dose is licensed for the initial treatment of Opioid dC!pendence. 13uprenorphine is used in lhc lreatmcnt I. BOhlllC K. Buprenorphinc int rran.~cnnal thc1apcu1ic system-
of opioid dependence (p.105). I ts agonisl-antagooist properties 11 new Option. Clin Rheumulul 2002; 21 (suppl 1): Sl)-SIG.
opioid-naive patients or those who have been receiv- may mcon that it has a lower potential for dependence and a low- 2. E\•ons HC. Easlhopc SE. l'runidcrmal buprtnorphinc. Drugs
ing a strong opioid analgesic whose daily dose is less er risk of rcspiro1ory depression in overdose than pure agonists 2003; 63: 1999-2010.
than 30 mg of oral morphine or its equivalent. US such as methadone. Buprcnorphine can be used as substi1Urion 3. Siul R. Transdermal buprc11orphinc in 1he uc.auncnt of chronic
therapy in patierats with moderate opioid dependence for acute pain. E:xp<rl R...· Nt1<rotlwr 2005; 5: 31 S.-23.
licensed information recommends an initial dose of ... Siul R. Transdnm:;1J buprcnorphinc in c1ncc:r pain and palliative
management of withdrawal and in maintenance trea!ll!cnt as an care. Po/lint M«/ 2006: lO (•uppt I): S2S-S30.
IO micrograms/hour for opioid-tolerant patients alternative to or with methadone. Howe\•er, in paticncsdcpendcnl S. Kn:u llu Clinicol upd••< on lh< pharmaeolOI)'. clr-y and
whose daily dose is between 30 and 80 mg of oral on hig)l d<XeS of opioids buprcnorpbine may precipi~te with- .afcty or •~nsdcnnal buprcn0f1'hine. E•r J Poin 2009; 13:
morphine or its equivalent. In those requiring more drawal due IO ils p:utial antagonist propa1ics; the daily opioid 219-30.
than 80 mg daily oforal morphine or its equivalent dose should be mluccd gradually in such patienlS befon: begin- 6. JUJin1 Ci Ruprenorphinc treatment nf pthtnts with no~malig­
ning buprcrlOIJ)binc. Abuse of the preparation, os with Olhcr sut>- nan1 muse:uloskdctal di:sc&ses. Clm Rlt~"""°'ul 2002; 21 (s:uppl
the use of patches providing 20 microgramS1hour of I): 517-SIS.
sti1Ution therapies, may be a problem. A combined sublingual 7. Hans G. Buprcnorphine-a review ofi•s role in ncuropnhic pain.
buprenorpbine may not provide adequate analgesia; preparation of buprcnorphine hydrochloride nnd naloxone hy- J Opioid Mol!Dg 2007: 3: t 9S.-206.
however, application of multiple patches to provide drochloride is available in some countries as a deterrent to abuse.
Pre par ations
doses greater than 20 micrograms/hour is not li- References.
Proprietary Preparations (details arc given in Volume B)
censed in the USA (see Adverse Effects and Treat- 1. K3kkO J, ct ol. l·yc:i.r retention and soci31 func.tion after bo· Aurtl'Ol.: Nonpan; s.b.Aex: Temg01ic: Auwlo: S<Jbco<one: S..t>Jtex Tern·
ment, above). Patches should be replaced every 7 prcnorph1ne·11~~iMcd rc13p!lc pte'Veotion treatment for heroin de- gcsic: Tronsle<: Tridott : Belg. : S<Jboxone: S..butex: Ten'C"OC: Tr...nec:
pendence in Swtdc11: a randomi!cd, ptac:ebo-controtlcd oial. Brai.: Temgesic: Canad.: Subo><One: Chile: Tr.instec: Ci.: Norspan; S<J!).
days with the new patch being applied to a di fferent Lon«tl 2003: 361: 662-8. oxone: Svbute>e Temgesic: Tr>nstec: Otnm.: Anorlint: NOf'IP'ln: So.box·
site; use of the same area of the skin should be avoid- 2. Fudala PJ, ct ol. Officc·bued lrcatment of opiate 3ddiction "'ith one: Sulxitex: Tl!fnge<ic Transtec: Flo.: Nonpan: St.O.Mxt: Temg!1ic: Fr.:
ed for the next 3 to 4 weeks. //s~;/J~:;:f~ ~o79~1~~~if.buprenorphinc •nd n•loxone.
33 Suboxone: SIJ!>Jlex: Temgesic: Gcr.: Nol'spon: Subo>oono: s.butox: Temit·
tic Tror.stcc Gr.: Pr~ Subooone. s.bulex: Hong Koor: Subutex:
When used in balanced um1csthesia 300 micrograms 3. Mont0)'310, et ol. Randomi?.cd crial ofbuprenorphint for rrc11.~ T°""esic.: Hung" Buprenj: Svbo>cone: Tr>'lltee ln4io: ~ Pentoret
mcn1 nf concuncnl "J'iJilc and roc.aine deptndenee. CUn Pho,. T~ /ndon.: Siboxone: So.butt><: /rl.: BuTrans: SubcD<alO:: ~ox:
may be given intramuscularly or 400 micrograms sub- •nocol Thcr 2~; 75: 34-48. Ttmp; T~ /sroet BuT......., Noi>or"< s.bJle>c: Ito/.: Suboo<onr. S..O.
All cross-rtferences refer to cntrits in Volume A
 Buprenorphine/Capsaicin 33
vtex; Temgesic; lr&nSlt<; MGloyslo= Svboxone-; Subutc¢ Tem~t: iry and usage panerns ni.•y affect the likelihood ofabuse. Indeed, iranasal dose and may lost for 3 to 4 hOt.WS after porcn1cral doses
Mex.: B<o!jli1'" T~ T,..,,..... Noth.: S<boXO<le: Stb.r.ex T.,,.,,..ic US licensed product information sta1es that Uicro have been rnon: or for 4 10 S h(IUlS after intranasal doses.
Tr"""ec Norw.: l-.J0<-.poo. Stboxone: s.butox; Ttmgt>e: NZ: ~ reports of abuse wid1 intranasal preparalions than with injcclab!c
~'O'ic T~1;c; Pol.:~ ;...,,..ec Port.: Bvprex ~ for 1he relief of modcr.ue 10 scvcro pain, butorphan<ll 1anra1e is
~ WJUltx: Transtec Tnq..isc Rvs.: Nopon (Ho-); To·-.:; ones. given in doses of I to 4 mg (usually 2 mg) by intramuscular in·
(Tpo<'t<~ S.A(r.: S.bule>:: Tomgese S-mppo<e: Subutexj: Temzt<i<. Cases of butorphanol abuse have been published~) including a jection or in doses of0.5 to 2 mg (usually I mg) by inlravenous
Spoln: ~ S.~xt. Traosttc s-d.: Ncwi;>ot< Suboxooe: S-Jbvtex: fnjection evory 3 to 4 hours. It may also be gi\•en as a nasal spray.
Temtt" Swia.: Svbute.><. T..,,gesi:; Tr-.ec: Titol.: B.Jprlnet: Temgcs.ct; rcpon of fibrous myopotl1y associ~led with chronic intramuscu-
UK: S.ffrons; Stboxonc; S<AMc>: TCfTI&C'C T,..,,,,oc: USA: B.iprenw. lar abuse. in usual doses of I mg (I sptay in I nostril), repeated alter 60 to
Blf.rini.; St.boxone: St.b.c.c.<. I. WHO. WHO cJi:pcrt cc.unmiuct Uf1 drug dependence: thirty- 90 minutes, if necessary. llus sequenco may be repe.iled after 3
foonb tq>Orl. WHO T1"11 lltp Ser ?412006. Also l''>ilable at: to 4 hows as needed. An initial dosc of 2 mg ( I spray in each
hnp://libdoc.wlto.in1/ttS/WHO_TRS_94l_<np.pdf L•eccucd nosuil) may be given for severe pain. t.rt should not be repealed
26106/08) <Ultil 3 IO 4 hows later.
B utorphanol Tartrate (Bl.NM. U5AN. ~1i 2 . Wagner JM. Coh<n S. Fibrous ln )O~ll'I)' from butorph:mol in- In obsteJric a11olgesia I 10 2 mg may be &hen by intramuscular
k-o-BC-2627 (butorpnanol); Butafanol11.1rL'"3att1. Butorlanol-..ar- jcctious. J RMttt•alol 1991; 18: J934-5.
or in1ravenous injection during early labour in women at term.
=: Buto-phanol, Tar1nle de: Butorphanoli Ta'1ras: Tartnito de 3. l.mlcr E. P~t·m•rketing c"p:ri~ncc: with wn upioid nual spray
for nti&raine: liC'ssons for thr fulurc. c~pholol:io 2006: 16: This dose maybenepeatcd after4 hours ifneoessarybul analter-
~orfud (-)-17·(C~ytmelhyt)mo<phirlC!n·3.11-<Jiol hy· 89-97. 11alivc analgesic should be used if deli\'Cry is expected wiU1in 4
droget> iarua:e. hours.
Breast feeding. No adverte ctfec1s have been sttn in breast·
6yroJ>+aH01.a TaprpaT In anaesthesia, 2 mg may be given intramuscularly for prcmed-
fed infants whose mothers were given butorphanol, and the
ication 6-0 to 90 minutes before sursery. For use in balanced
C21H29N02.C.H 6 0 6 : 177.S. American Academy of Pediatrics considers' that it is thcrefone
anaesdlesia, a usu31 dose is 2 mg given intravenously shortly be·
CAS - 41•08·82·2 (butorphonol); 587136-99-5 (bvtorph· usually compatible wi~1 brc~st feeding,
fore induciion andlor 0.5 10 I mg given intravenously in incre-
onol coruate). In a studf of 12women,buoorphanol "'-asdetected in breast milk ments duting anacsLhesia. The 1otal close needed varies but most
ATC - N02AFOI after both intramuseular and oral doses. However. thc milk-to- patientsrcquire4 lo 12.S mg.
ATC Vet - Q.N02ArO: . plasma ni1io after a 2-mg intramuscular dose (0.7) was signifi- Dosa.ge adjustment may be needed in the elderly. When given
UNll - 2L7171RUHN. c•ntly less 1han tha1 afier an 8-mg oral dose (1.9) Although the by injection the initial doscofbu1orphanol for pain should behalf
mothers were no1 breast feeding at the lime of the study. the au- the usual initial adult dose. Subsequent doses should be deter-
thors concluded that the potential for any adverse effCCIS on nws- mined hy the patient's response; a dosage interval of a1 leaSI 6
ong infants •fu.r maiernal butorphanol use would be minimal hours has been recommended. For na.~I use the initial dose
I American Ac~demy of Pcdi~1cs. The transfer of drvgsand ~ should be limited to I ing follow~d by I mg alter 90 to 120 onin-
er d.cmicals into human 1l'lilk. P«lio1ri~s 2001; 108: 776-19 1~es if noocss.'ll)'; subsequent doses ifrequired should generally
(Retired May 20 IOJ C'Grrtctinn. ibid.; I029. At~o .ev1i1able a1;
hnp://1 a ppo Ii c y.o ap pub 1i c:at ions.org/c 1i/con cc nc/fu 111 be gi,·en at inlervals ofOOl less than 6 hours. Similar recommen-
pediauics,~b 108/Jn76 (•oc<>scd 2~) dations have also been made for patieolS with hepa1ic or renal
2. Pittman KA. ti ol. Hum on perinal.31 disaribu.lion or bulorphanol. impainneni, see below.
AmJObs1<1Gyn<eol l980; 138: 797-iOO. ORef~ees.
Pregnanc:y. Two instances of sinusoidal fccal heart rate pa1tem I. Atku'ISon 80, el ol. Double· blind comp»nson o( inlravcnous bu·
'vere noted out of 188 conseeulive cases ofbutorphanol use in torphanol (Stadol) and fcn1a nyl (Sublimate} for•natgcsia during
(butarphanol) active-phase labour. 1 Visual hall11cina1ions and paranoid dclu· labor. Ar.1J Obsret GJ.,«ol 1994: 171: 993-8.
sions developed in a woman.on receiving a 1-ong inuaveno~ 2. Oillis JC. e1 al Transnas.al bulorpllanol: a ~'·ie-w of i1.s phanna·
ccxtynamic and pharm1cokinc1ic properties.. and tbcnpcutic po·
Pharmacopoeias. In US. injection of butorphanol C3rly in labour; the psychosis had re, ttnti31 in acute: pain ma.ni$ement. Dnrg1199>; SO: IS7-7S.
USP 33 (Butorphanol Ta1-vate). A white powder. l1s solutions l!Olved 40 hours after the injecli<lft and was not noted on foUow· 3. Con1miskcy S. "ol. Butorphanol: e ffects of a protocyp;ctl 110-
are slightly acidic. Sparingly soluble in ,..-alcr; insoluble in aloo- up 2 weeks later.' nisMmtae,oniSl anal:es.ic on '(·opioid receptors. J Phan1HJCO/ Sci
hol. in chlorofonn, in ether, in ethyl at:eiate, and in hexBne; 1. Welt Sl. Sinusoidal fetal htatt rate and butorphanal ad1nininra- 200S: 98: I09-16.
slightly soluble in me1hyl alcohol; soluble in dilute acids. S1or¢ 1ion. A•1 J Otuttl G.wit·col 198S; JSl: ~62-3. Administration in hepatic or renal impair m ent. The~
in airtight containers et a temperature of25°, o.cursions pcnnit· 2. O."is A. •I ol Acule psycho~is associltnl wt1h bucorph::inof. J age ofbutorphanol may need to be adjUSled in pacicnts with he-
Nc"rop1ycbia:J-Cli11 Neuro.tci 199$: lO: 236-7.
ted between Is• and 300. patic or renal impairment. \'vlien given by injection the initial
Interactions ~ for pain should be half the usual initial dose (soc abo\•e}.
Dependence and Withdrawal Subsequent doses should be determined by the patient's re-
For inleractions associated with opioid analgesics. sec p.107.
As for Opioid Analgesics, p.IOS.
sponse; a dosage interval or at least 6 hours bas been recorn-
Butorphanol may have a lo..-cr potential for producing depend- Antimigraine drugs. No phannacokinctic interactions were mendcd. For nasal usc llic initial dose should be limiled to I mg
ence than pure agonists such as morphine. However, it has been reported wheu butorphanol nasal spray and subcutaneous Sii· followed by I mg after 90 to 120 minutes if nc:ccssary; subse-
subject to abuse (sec under Precautions. below). Abruptly stop- n10triptan were used within a minute of each olher in healthy quent doses if requited should generally be given at intervals of
pinJ chronic butorphanol has produced a less severe withdrawal subjeclli. 1 However, anotherstudi in healthy subjects found that not less than 6 hours.
syndro~ than with morphine. the AUC and peak plasma ooncentJation of intranasal bulorpha·
nol were reduced by about 29"1. and 38"o. tcspectively w~n giv- Headache. Butorphanol bas been advoca1ed for USC as a nasal
Adverse Effects and Treatment en l minute after intranasal sumatriptan. No such effect was not- spniy in the 1rea1ment of migraine. but there have been problems
As for Opioid An11tgesics in general. p.106, and for Pentazocine, ed when administration was separated by 30 minutes. h was •vilh abuse and dependence (sec above) and its place in Uitrapy.
p. 11 7. SU&itsted that sumatriptan inay rcduoe butorphanol abs01ption if 11/\y, still remains to be CSUtbhsho:d. Sec also An1imigrain.:
Headache. and feeling:s of floating m•y also occur. Hallucin3- b)' inducin_g tran.~ent nasal v3Soconstric11on. ~under Interactions. above.
1ions and other psycholomimetie effec1s arc rare and have been I. Srinivat: NR, ti ol. l.ac:k or plu1rm:tcoli.inctic il'l-teraction between References.
reported less frequenlly than with penlazocine. In add~ioo in· butorphanol 1artratc- nasal spray nod 'umalriptan sucdn11c. J 1. frei1ag FG. ~ IC"\llc trcatmc:nt of mit.l"line w-hb lransnuol bu·
somnia and nasal cong.:stion may occur frequently when bulor- CJ;,, Pharmacol l99S: 3S: 432-7. IOJph•nol (TNB). lltodo<he Q 1993; 4 (suppl 3): 22~.
ph:mol is given inlmnasally. 1. Vachharajani NN. n al. A ptu.m11cokine1ic interaction •udy ~­ 2. Hoffert MJ. "' ol Tnn.5nt~I butorphanol in the untm~t of
Because butorµbano l has opioid agonist and a111agonim acti\·ity, tween liu1ori>hanol and sumauipran nasal sprayJ ir'I healthy sub- ac ute miaraine. Htndocbc 1995: 35 : 6)-9.
jcc::u: impor1ancc or the liming of butorptuinlll administration. 3. Melanson SW,~'"'· Transnasal butorphanol 1n tM emergency
n)loxone is the recommended antagonist for the trentonent of Ctphololgin 2002; ll: 282-7. deparhncnl m1n1gcmcn1 or migraine hc-:idnchc. Atn J £,,1erg Med
ovcrOO...ge. 1997; 15: S7~l.
Pharmacokinetics
Elfccu on the respiratory system. Butorphanol 2 ms pro- Butorphanol is absorbed from the gas1ro1n1estinal 1ract but it un- Pruritus. Results from a small srudy' of 6 patients wilh sevtte
duces a similar dC8J"c of respiratory depression to morphine dergoes extensive first-pass metabolism. Peak plasma conccnlra· opioid-induced prwitus unrcsponsrve IO diphcnhydraminc, and
I0 ms, bul a ceiling effect is apparent wil11 higlier doses ofbucor- lions ocal< 0.5 to I hour a lier in1ramuscular and intranasal dosos &om a case series of 5 patients wilh intractable pruritus from Olh·
phnnol.1 It has been ~ed 10 be a less potent rcspiratocy de· Bnd I to 1.5 hours after oral doses. Butorphanol has a pla.~ma er causes,' suwst lhat intranasal butorphanol may be an effec·
prcssam than fentanyl; but more polent than nalbuphine.' elimination half-lift of about 4.S hours. About 80% is bound to live treatment. Doocs have ranged fi'om I mg every other day to
I. Nagashima H, e1 t1I, RtJ.r'ratory and c i rcula t~.ry crrccts of inlll· plasma proteins. 2 mg every 4 to 6 hows.
v~nuu:s butorph:mll1 :.nd morphine. Clin Phonuoro/ 1'11~ 1976~ I. Ountc-ma.n C~ rr ol. Tr..111sm1sail butorphlnol for th< 1rc1tmcot of
19: JJS-45. Butorphanol is extensively oictabolised in the li•er ~wougli hy-
opioid·induced pturitus unresponsive to a-ntilustannMs. J Pahr
l. Dr)·dm Ge.. Voloni:iry r1o.-spiratory effects o( bu10,phnnol •I'd dmxylarion. N·deal~-ylation, and conjugation; only S% l>eing ex- .~ymplom Moitng~ 1996~ 11: 2SS-60.
rcntanyl (otlowin.g barbitur.ue induction: a doublC'·blind study. J creted unehBnged. Exeretioo is mainly in the urine; about 15% of 2. Q3wn AG. Voe;ipo\itch Ci Butorphanol (or treatn)t'fll o(inttac1·a ·
C/;11 f'hormaco/ 1986; 26: 203-7. a parenteral dose is exacted in the bile It crosses \he placen1" blc prurilu$ J Am Aa;d O.n11010/ 2006; $.I: S27-3 l.
3. Zdckcr JR. ~1 al. Respinttory cfrccu ofnalttc,,phine und bu1orph· and is distribu1ed into breast milk.
t'uio-I in 1ncs1hetizC"d patients. Ant>srlt Anolg 1987: 66: 819-S l . P reparations
Administration.. INTRANASAL i.ourL References. USP n: &ncrphanot Tanritc ~ &norpl'anoi Tartra~ Na>~ Solu-
Precaut ions
t . O."'ii GA. ~1 ol. Pl'l:trm<11:oli.inetics of bulorphanol tartnnc ::1d·
As for Opioid AnalgesK:s in general, p. I07.
Allhoug)I cardiovasculareff«:IS moy be less than v.ith pmtazoc.
ininistc:rtd from single-dose intranasal sprayer-. AmJ Hr"ltlr-Syst
Plwrnr 2004; 61: ~61-6.
"""
Proprietary Preparations (de1oils.,., given in Volume B)
Canad.: 51ado1t. Ci.: ~foralt: Mcr•dc/t. India: Bw\m M••·' Sadot
inc, butorphanol should ecnerally be avoided an..- myocardial 2. Davis GA." al. Bioavail:ibility of imranasal butorphinol •d· PhWpp" SI06;JI; IWs.: Sl•dol (CT"'°'): USA: Sl>dol
infan:tion. mini~tcrcd (rom 1 sinste-dose sprayer..4m J Health·S,11 Phorm
200S; 62: 41H3.
Butorphanol may precipitate withdrawal symptoms if given to
3. Wcrmclina. OP, ~I of. Pharmat.-okinecic), blo~ui~alcnt.-e. and
paticnl$ physically de~ndent on opioids. Tiie d05Uge regimen of. spr1y weiaht reproducibility or intnui;astl butorphannl after ad- C apsalcin
butorphanol may need to be adjusxed in the elderly and in pa- miniscration wj1h 2 difTercnf. nasal spray p11mp». J Clin Pltarrno.
tients with hepatic or n:nal irnpainncnL col200S: 45: 969-73. Capsaicina; Capsaicirx.m; l(apsaoci1': l<all'<'icyna; Kapsaisiini (£)·8-
Mcthyl-N·vaoillyinon·6-eiamide.
Abuse. A WHO expert committee oonsidered in 2006 that 1he Uses and Administration
KancaHUHH
likelihood or butorphanol abuse was low and was not great Butoq>banol tartr.ue, a phenaothrenc derivative, is an opioid an-
enough co wamlnt international con1rol. 1 Abuse had been nepoi1· algesic (p.108) with opioid asonist and antagonist properties; it C 1aH11N03 " 305.4.
cd infrequently and only in a few eounu:ies. The commiaee al~ is phannacologically similar 10 penoazoeine (p.117). 'Rulorpha· CAS - 404-86· ~.
commented lhat, phannacologically, intranasal prqiaralions of nol is used for the reliefofmodorate to SC\'CTe pain, fncluding the ATC -M02A801 ; N018X04.
butorphanol do nol appear to differ in lheir abuse po1e111ial f'rom pain oflabour, and as an adj\11\Ct to anaesthesia. Onset of analge- ATC Ve1 - QM02ABOI: QNOIBX04
parenterol prepnratiani<; however. miler foclors such as 1vailabil- sia occurs within 1S minutes of intramuscular injcc1ion or an in~ UN:t- S07044RIZM

The symbol t denotes a preparation no longer actively marketed

34 Analgesics Anti-inflammatory Drugs and Antipyretics
other locations (e.g. in poSlhcrpetic neural&i•). Trntment may be Other lypt:$Ofpain syndrome for which capsaicin has been tried
repeated every 90 days if necessary. include reflex sympathetic dystrophy (sec Complex Regional
A long-acting topital .<olution is under investigation for painful Pain Syndrome. p.6), pcstmastectomy neuroma, amputalion
conditions such as postoperative, m\1$CUloskeletaL and trauma- slUmp pain, chronic neck pain, and the pain of oral mueo>itis.2
induced neuropathic pain includins interdigiuit ncurorna. See also Rheumatic Disorders. below, for use in musculoskeleta I
Action. The action of capsaicin and ielated compounds (vanil- pain.
loids) are complex and still being investigated. Capsaicin has I. Deny S, et al. Topical capsaicin for chronic. neuropathK: p:iin tn
aduhs. Available in The Cochrane Database of Sysremalic Re-
been found to produce burning pain 1.l by activatins specific va- views; Issue 4. Ch ichesler: John Wiley; 2009 (acttsscd
nitloid receptors such as TRPVI (transient receptor potential 29/01110).
channel, vanilloid subfamily member l) which are also $limulat- 2. 1-lou1kappe M, ct ol. Rc\'icw oflheeffecliveness of capsaicin for
NOTE. Do not confuse capsaicin with capsicin, which is capsicum ed by heat and acids. TRPV l is expressed by nerves and other p,ainful culancous di$01dcrs and ncurnl dysfunction. <.:!in J Poln
olooresin (see Capsicum, p.2492). tissues such as the kcratinocytcs of the epidermis, bladder 1998; 14: 97- 106.
Pharmacopoeias. In US. urotbeliwn and smooth muscle, and liver. Pruritus. Substance P is a possible mediator of i1ch sensations
USP 33 (Capsaici>). An off.white powder. M.p. 57° to 66°. The analgesic effect ofcapsaicin has been su&&csled 10 be due to and since capsaicin acts as a deplctorofsubslancc Pit has been
Practically insoluble in cold water; soluble in alcohol, in chloro- bolh ~e.pletion of subsWlcc P from local s~"nsory C-typc nme tried in the reliefofpruritus(p.1723) associated with various dis-
fonn, and in benzene; slighlly soluble in c111bon disulfide. Store fibres""' and to the desensitisation of vaniltoid rccep1ors. 1·?.8 eases and hacrnodialysis. '·'It
has also bern used to provide relief
in a cool place in airtight containers. Proted from ligllt. Since 1he effect ofcapsaicin docs not rely on vasodilatation in the from pruritus induced by hctaswch1 and for the itch and pain
skin it is lhcrefore not considettd to be a traditional counter-irri- associated with PUVA lhcrap)'.9,10
Adverse Effects tant. l. Orcncman DL. et al. Topjcat c:apsaicin fo:- 1rcatment o(hcmodi·
A warm, stinging. or burning sensation may occur at the site of 1ly1is·rel1te<I pnirirus. J Am Acod D.rmoto/ 1992; 26: 91-4.
I. Szallasi A, Blumberg PM. Vanilloid (c.apnicin) rrccpcort and
application; this usuaUy disappears at~ a few days of use but meclwlioms. PhartnaCCll Rrv 1999; SJ: tS9-2l I. 2. Leibsoh.n E. Trcatmcnl of nota1gi.a p:ucsthctica with capuicin.
may persist for longer ir applications are less frequent than rec- 2. Conrighl ON, Sz.>llosi A. Biochemical ph>nnocology of 1he va- Culls t992: 49: 33~.
ommended (sec Uses and AdmsniSbation, below). This sensa- ninoid receptor TRPVI : an upcbtr. Eur J Bloclrrm 2004; 271: 3. Heutmann G. ~t ol Aq1.t1genK: pruri1'us. PUVA and capsaic'n
tion may be pa11icularly painful in patienlS receiving 1he bigl>- 1814-19. Uutme:nts. 8rJ /)ermoJ()/ 1994; JJJ: 920-1.
4 . Febtu-Holsl R. Btud> J. EfTec:t of topically opplicd ap511icin
conccntralion transdermal patches; in some cases, the trealment- 3. Rumsfidd JA. West DP. Topie1l apsaicin 1n dtrmatoloaic •nd
poriph.,.1 pain disordOB. DICP Ann Plrormot0th<r 1991: JS: on pnmt\IS in patients with atopic dermatitis. J ~nnatol Trral
relatcd increase in pain has led to transient increases in blood 381-7. 1996; 7: 13-IS.
prcsswe. S. HautkappeM,1101. ke''liewoft.hccfrectiYCflC$$Ofcapsaicin for
4. Corlkn GA. Araujo OE. Capnicin: identaflCltion. nomentla· painful cut1ncous disordm and neural dysfunctjon. Cli11 J Pain
Coughing. sneezing. runny eyes, Cll' other signs of initalion may tur<. and plumra<OC!l<r>py.Am• P,,.,.,.ocOIMr t993; 17: 33o-6.
1998; "' 97-t06.
occur if vapows or dried residue frum lopical piqwa1ions ""' ~. Winter J, t:t of. CapsaK.in and pai11 mcch3nisms. Br J AftOath 6. StlnderS, 110L Trutmc1.11 ofprurigonodu1aris:withloptealcap-
inhaled 1bere ha""' been a few reportS of dyspnoea, wheezing, 1995; 75: 157~ •icin. JAM Acad !Hrma1012001: 414: -171-8..
and exacerbation of asthma. 6. Od Bianco E,., ol. Th< rffcc•• of rrpeate<I den1\1l "1'1'lica1i0'1 of 1. Ly~ J, ~r ol. Topical apsaici~a novel and effective treatment
cap.saicin 10 lhe human skin on pa;n and vasodilatalion induced (Of 1diopithK: •ntrsctaf.lc pruritus ani: a ri.ndCmised, placebo
Precautio ns by intradcnnal injection of acid and hypenonic solutions. Br J ccn1r0Ued. cr0$$0,·t:r study. Gut 2003~ Sl: 1323-6.
Capsaicin should be handled with care. Panictes should not be C/;n Phormacol 1996; 41: 1-6. &. Szeim>cs R·M, tr ol. SV«cssful cr-calmcnt of hydroxycthyl
inhaled nor come into coniact with any part of the body. 7. Fusco BM. Giacovauo M. Pep~rs and pain: I.he promise or cap. starch-induc~ pnaritus with topical capsaiein. Br J Der•otol
sakin.Dn(gs S997;SJ;909-14. 1994: 131: 380-2.
For topical application, contact with eyes and broken or irritated 8. Tominaga M, Julius 0. Capsai.c:iri re«ptor io die p1in p;uhway. 9. Burrows NP, Non-ii PG. Treatment of PUV.~·induced skin pain
skin should be avoided. Thick applications of the craom should Jpn J Pharmacol 2000; 83: 20-4. with capsaicin. BrJ Denna1011994; JJJ: s~s.
be avoided. 1l>e hands should be washed after application oftlie 10. Kirby B. Rogc~ S. Treatment of PUVA itch with apsaicin. 8r
Administration in children. ln the USA, capsaicin cream is J D.rmalul 1997; 137: lS2.
cream, unless the hands are the treated areas, in which case, they licensed in children, for details see above.
should be washed 30 minutes after application. lf bandages are Psoriasis. Since substance P has been implic.1ted in !he patho-
used to cover trellled areas they should not be wound too tightly. Headache. Prevention of a1tacks of cluster lteodache (p.670) physiology of several inOammatory dermatological processes,
Nitrile glo,·cs should be wom when handling the high-concen- by repealed application of capsaicin to the nasal mucosa has~ caps:iicin, a substance P depletor, has been tried with some ben-
tration transdermal patch and when cleansing 11'Catmcnt areas; reported.1The Z-isomer (zuca~aicin; civamide) has also been efit in some skin disorders including psoriasis.•·~
after careful removal of the pa1cb, the cleansing get supplied by found to be modestly effective. The usual mnnagemenl of psoriasis is discussed on p.1 723.
the manufacturer should be applied liberally to the trcatmcnl area Repeated nasal application of capsaicin has also been found to be I. »em~lein JI!, 11 of. Cffccls of 1opically applied caps.aicin on
and left for at leas! I minu1e before wiping off and the area elfeclive in chronic migraine' (p.670). moderate nnd SC\'trc psoriasis vulg11ris. J Am Ac:od Dumotol
washed with soap and waler. Mearing pads should not be used 1. Fusco BM, 111 ol. Prcven1a1ive cffecl o( rtpc:aled nas.al 1pplic.a· 1986: IS: S04-7.
with capsaicin, and paticn!S should avoid taking a hot bath or tions or capsaicin in c1uS1cr hc~dachc. Poin 1994: 59: 321-S. 2. Ell it CN, ti ol. A doubJe.blind evaluation of topic.al caps:aicin in
sltowcr immediately before 01 after application, a.~ the burning 2. Saper JR. Cf al. Intranasal civamide for lhe lt'Cltmcnt or episodic pNritlc psoriasis.. J Am Acod Dermato/ 1993; 29: 43842.
c1U$ter headaches.. Arch N~urol 2002; S9: 990-4 3. liautkappc M. ti ol. Revtcw oftht dftc1iwcncss of cap~icio fc;it
sensation may be exacerbated. p1inru1 cutancoos disorders and ncu~I dysfunction. Clin J fain
3. Fusco BM. t:t ol. Repeated in1n.n1.nl caps.aicin 1pplica1ions to
PatienlS who develop increased pain with the higll-concentcation lrtal chronic migraine. Br J Anoesth 2003: 90: 812. 1998; 14: 97-106.
tranSdermal patch should be given supportive treatment sucb as Rheumatic disorders. Topical C..psaicin is used for the tem-
local cooling or oral analgesics; howe,•er, those who""' already Micturition disorders. Intravcsicol capsaicin has been tried
for painful bladder disorders and to treat bl~dder dclrusor hyper- por1ry relief of the pain of arthritis. From the results ofa melll-
taking high-dose opioid arulgesies may not respond to oral opi· analysis1 ofrandomised, double-blind, placebo-controlled stud-
oids g;,oen for acute pain during and ofter the treatment procc· rcflexia.1·9 Rcsul!Shave been "ariable, and the characteristic sen-
sory cffccis of capsaicin make blinding of siudies difficult, but ies and later srudicsU it appears !hat capsaicin is effective in eas-
dure. Blood pressure should be monitored during the treatment ing the pain ofostcoarthri1is (p.11). Based on these resul!S, the
proocdw-e with transdcrmal patches. some paticn!S have reported benefit particularly those with neu-
rological bladder disorders. Instillation into the ureter has also Arthritis Research Campa.igrt in the UK' considered topical cap-
Minor and temporaiy changes in sensory function such as heat been tried in the management of the loin pain.'haema!Uria syo- saicin 10 be safe and can be effective in n:ducingF,in and tender-
detection have been reponed "i1h capsaicin; patients at risk from drome.10 ness in the afrected join!S. Published evidence for efficacy in
such effects should be cautious when using capsaocin. I. Lazun M. a ol. lntravcsicll cipsaicin for treatment ofsewere rheumatoid a.rthritis (p.12) appears to be limited. A review of use
Uses and Administration bbddcr pain; a ra.odomiicd placebo controlled sludy. J Urol in both neuropathic and musculoskeletal chronic pain concluded
Capsaicin is the active principle of the drio:d ripe fruits of Cups/- {Baltimore) t996; IS6: 947-S2. 01a1 i!S benefrts were at best modeDtc. but noted that in a minor-
2. de Size M. t:1 nl. CapiA:icin and newogcnic cktNJOt hyper· ity of patients wvesponsive to, or intolerant of, other treatments
cum spp. It is used as a lopical anllljlCSic (p.S) in penphenl neu- rcncxia: • doublc·blind placcbo<ontrolkd saudy in 20 p:a1ten1J
ropalhic pain including poslhcrpelic neuralgia after the lesions with spin:a1 cord IC'.sicns.. Nnroruol Urodyn 1998; 17: Sll-23. ii migbt b6 useful.' Capsaicin niay be a useful therapy for pain
have healed and diabetic neuropathy (S« Neuropathic Pain. be- 3. Petersen T, t:I of. lnuavesial capsaicin in patients with detrusor &$$0Ciatcd with primary fibromyalgia"' (sec Soft Tissue Rhcu-
low). and in osteoarthritis and rheumaloid 111hri1is <- Rheu. ~':;:.~~~~~{)~o:'.'l~lled oross·o\'Cr study. Sco•d J m11ism, p. l 3). which responds poorly IO conventional treatment
l. Zh••4 WY, Li Wan Po A. The cfTcctivencssofropirally applied
lll.ltic Disorder.;, below).
Capsaicin is usually applied sparingly 3 or 4 times daily (and not
4. de She M. et al. lntnvcsical instilla.lion or eap:saicin in urology: e>pmcin. £,,, J Clin Phormocol t994; 46: S17-22.
a rewiewor1he litu.turt.£urUro/ 1mJ6: 267-n. 2. Allman RD, ti ol. CapsaJCin creom 0.025% as monmhcra:py for
more often than every4 hours) as a 0.02S% or 0.07S% c,..,,m; in S. de SCu M~ cl al. Capsaicine in1rav8iC:3le d hypt~flexic du os1e:~r1hritls: a doublc·bhnd study. Stm;n Art/Jriti.s Rheunt
the UK these creams :tre not licensed for use in childttn, but in d~tru10r. e.'i~rienccdt 100 1ns:tillationss:ur une ~riodedecinq t994: 23 (suppl 3): 2S-)).
the USA they may be used in children over 2 years of age. A ans. A11n Reodapt Med Phys 2001~44: S14-24. ) . McCle:anc 0. The: 1nalgcsic efficacy of copic.:tl capsaicin is en·
6. Sullasi A, Fowler CJ. After 3 decade ofin1.ravcsical vonilloid hanccd by glyccryl triniu11e in painful osteoarthritis: a nmd·
more concentrated crewn containing 0.2S% capsaicin is availa- ~l~~~~l~ll mort. quctiions than answcrS. Lancet N~lfrol 2002:
ble in some countries. omite<I, double blind, ploorbo <'Olllrolled <tudy. Eur J Puin 2000:
7. Ef·MahrO\lky AS,~' al. The effect of inlr.a\"csic'11 C3ps.:sicin and 4: 3SS~O.
Capsaicin cream should be rubbed well into the skin until little or 4. Arthritis Research Camp:aign. C<>mp~menlary and altcm;itlve
no residue is left on lhe surface. Therapeutic response may not be rcsinifcraloxin in ocuroz.cnic bladder dysfonction. Adv Em Afe<I
Biul 2003: 539: 3S9-19. medicines for the trcatmtnt or rf'lcumatoid anhriti.s. osteoarthri1L$
evident for l to 2 weeks for arthrilic disorders, or 210 4 weeks for 8. de SCzc M. 11 ol. lntravcsical c:ips:iicin versus resinifer:itoxin ond lib<omyolgia (i1>ucd February 2009).
neuralgias (or e.....,n longer if the head or neck are involved). For for lhe tr~atmcn l of dctrusor hypc:rrcOcxia in spin:.il cord injured Avoilablt at : hup ://www.arthri tisre.searchuk.org/pdf/
p;tticrns: a Joublc·blind, r.mdQmited, controlled study. J Urol Comp lcmc n111 ry%20a nd!I. 20:\ Itern11 i ve%20 medic inc s_
the managemcnl of painful diabetic ncuropa1hy, UK licensed 110120101 $4331.pdf (acccsstd 28/07110)
product information recom10cnds !hat capsaicin should only be (Baltimore) 2004: 171: 2S l-S.
9. Laucri M, ti ol. ln1rovesical v;inilloids :md ncorogcnic inCOflti· 5. Deal CL. ct ol. ·rrealment of anhriti.S with topic.al capsaicin: a
used under specialist supervision and !hat trealmenl should be ncncc; H:n years experience. Urol Im 20CM; 72: 145-9. double-blind trial. Clin Thar 1991; 13: 383-95.
reviewed after !he first 8 weeks and regularly ro-cvatuated there- 10. Bultitudc MJ. Capsaicin in treatment of Join painlhacmaturia 6. Mason [.., et ol. S)'ttlcm11ic review of 10pical capsaicin for 1he
after. syndrome. Lancet J99S: 345: 92 J-2:. lrOtmcnl of chronic pain. 9,>.,LJ 2004: 328: 991-4.
Although not a countcr-initant itself, capsaicin has been included 7, McCar1y OJ, .rt ul. Truunen1 or pein due to fibromyalgia with
Neuropathic pain. Capsaicin bas been tried topically in vari- 1opinl cipsoicin: o pilot study. S.Cmin Ar1hri1U Rhei1m 1994; 23
in rubcfacicnt preparations for the relief of muscular and rhcu. ous ~ of pain including ncwopathic pain, which docs not (suppl 3): 41- 7.
malicpain. &cnerally respond to conventional systemic analgesics. Topical Preparations
A high-concentration transdermal patch conlJlinin& C<lpsaicin capsaicin cream (in a usual strength of 0,075%) is used in the
8'/o (equivalent to 119 mg in total) is available for the treatment management of diabetic ncuropathy (p.6) and postherpetk neu- Proprietary Preparations (de11ils ue i;i,'<n in Volume B)
Austral: ZosW< Austria: H~ Warme·Crome: Belg" Han;o.-nedic
of peripheral neuropa1hic pain in non-<liabcric patients. either as ralgia (p.9). A high-concentration transdermal capsaicin patch Wlm\\eplcister. llroz.: Moment Conod.: Ar.4>flloiinw>e Rub A·S35
monotherapy or as an adjuna. 1l>e treatment area and surround- 8% is also available for Uic treatment of peripheral neurOJl<llhic ~ Zoclem'c Zoitro¢ Chile: Presyc Fr" Qutenu: G<.: Arlnlgon;
ing I to 2 cm should be pretreated ";th a 1op~l anaesthclic I» pain in non-<:liabelic patients. A sysiematic r"'~ew 1 sugges1ed Gdceit ~ /ndon.: Clpu<tt lrt.: - Zacirt /<rat~ Zostri>c Mo-
fore applying the patch, for example, topical lidooine 4% left for !hat capsaicin, given as either a repeated dose of the cream or a loy1io: McNu Ni': M<r\ZZl Qt.: Mu.: C.plidcl: N orw" ~ NZ:
60 minutes. Up to a maximum of4 patches may be 1pplied to the single application of the patch. was of benefit in neuropathic Zonrnc Pon.: Honsoplast E"!l'la>llO Tem\iccx H"""'tenn; Qvtenu:
Spoin: /\lac.lpsin: ~flrmadot c.ap!ICirt CaP.si<um f Mma)'ll: Upsidot Gd-
most painful areas of the skin and left in place for 30 minutes on pain, although limited data and inconsistent definition of out- <e<t HlnSOlemc ~""°"""~Swed.: ~Swiu..: Em·
the f~ (e.g. in HIV-associated ncuropalhy) or for 60 minUles on comes meant that estimates ofbenefit and harm were not robust. platre Etokf: hcla C.0:-- N: Thol.: Upo.lco: UK: AxsUI: Qutenzo;

All cross-references refer to entries in Volume A

 Capsaicin/Celecoxib 35
~ USk A=I\ ~ Copuw>-1-1?. Ca;>zag,., P; Dolcn<t. OoUtlt· Adverse Effects, Treatment, and Precau-
up: No ~,;,,_1-f>: Q.r.cnta: f<.Gd R.cl-•·?.IO~ H?. 'lhe<'at": Zoo;ro<
tions
Multi-in&rtdienti Arc.: Atomo ~\le C: 11.iti S.111 Crenll: R.tJ
Soil Re>: Aurtrla: R•~-R.,.......gott, Conod.: Htttt. M.,,..h>O"I: R.b As for NSA IDs in generai, p.J 00.
AS3~...-Jnis:TcerB>lm Paich\l'lamt Cz.:Qp<<ollc: 0.. Theoss~
~ F•.: Up><: Cl'P(ol Spent: G....: "9»n"d Nt: Gr.: i'orostefX
Serious skin reactions such as exfoliative dennatitis,
Hon1 l<o"f: S.lome".hylt: Hung.: Imo~ Fone: Nkc'!e>< S•~ Stevens-Johnson syndrome, and toxic epidermal
Lini•'*'I. India: Nm.lid Nu~!: /ndon.: ~ No!lron. lrl.: /\liipznf:
Ira/.: 01..T!t: ~ Crcmtgel: Pol.: <:_,.; N: Nto-C.ps<de1·m: necrolysis have been reponed wiih celecoxib. Olher
Swlr..: ~ EtcJlle soloc)'ot; !10~ ClpS<UO N l"'5: UK; N>...Flo><: hypersensitiviiy reactions, including anaphylaxis and
Ukr.: Niu:r ~): USA: Arthriwe Od<r P.-eet: ~ Ma.:
Cap..,., Q\Jick ~ Oer>cnc"' Neu•'Odet1d'u-axcrc Golc Bond fool P11n angioedema, have also occu1Ted. Celecoxib should be
l\"""'1ng, Gold Bond P.> Rt!"""" Foot R<>l'On: Hert Icy HOI PM: M.. stopped at the first signs of hypersensitivity. Some of
c!rmc MentNt~ P•in Doctor; ~ these reactions have been seen in patients with a histo-
(carfenconil) ry of allergic reactions to sulfonamides and the use of
celecoxib is contra-indicated in such patients.
Carbasalate Calcium (BAN.IHI) Profile Celecoxib should not be used after coronary artery by-
Cale..., Acetylsalic)·late Carbamide: Qilciym Carbaspirin: Car- Carfcntanil citrate is on opioid analgesic rel•ted to fentanyl pas.~ surgery as there may be an increased risk of ad-
basalate Qlcqie: Carbas.1lato calcico: Carbasalatum calcicum; (p.SS). h is used in \oeterinary medicine.
verse effects such as myocardial infarction and stroke.
Caroastla'llJm Calcium: Caibaspirin Cakium !IJSANX Ka<tasalaat·
til<als1um: Karoasal;it vapena~ sCI: l<arbasalatlcaloum; Karbasalato
It should be used with caution, if at all, in patients with
kalcio drusb; Ka~t-lcAkium. Calcit.m 00(2-(acctO><)')ben· Carprofen (BAN. USAN. rlNNJ a history of ischaemic heart disease, peripheral anerial
ioate)-urea disease, or cerebrovascular disease; it should also be
C-5720: Carp<O(ene: Carpro'e,'>O: Carpro(~ Karprofecni:
Kap6ac;wir KW>t11<ii Karprofen: Ro-20-5720/000. (±)-2·(6.ChlorocOtf>alOl-2·yl)pro-
used with caution in patients with significant risk fac-
c.,H,,CaN209 458.~. = p:onic acid. tors for cardiovascular disease such as hypertension,
CAS - 5749.67-7. KapnJlO'l>eH hyperlipidaemia. and diabetes mellitus. For further de-
ATC- 801AC08: N028A IS. C1sH11CIN01 = 273.7. tails, see Effects on the Cardiovascular System, below.
ATC Vet - Q.BOIACOB; QN028A15. CAS - 537 r 6-49-7. ll1erapy is contra-indicated in patients with moderate
UNll-N607Fl7JPI. ATC Vet - QMOIAf.9 1. 10 severe heart failure (NYHA class II to IV), inflam-
UNI/ - Ffto0546HO.
matory bowel disease, and renal impainnent associated
with a creatin ine clearance ofless than 30 mUminute.
Celecoxib should also not be used in patients wi1h se-

~
C ~Cl vere hepatic impairmenl (Child-Pugh category C).
HO ~ # I Caution is recommended when using celecoxib in de-
N ,.9 hydrated patients; rehydration may be advisable before
0 H giving oelecoxib.
Celecoxib ~tment may need to be stopped if signs or
Pharmacopoeias. In eur. (seep.vii) and us for VC1erinary use symptoms of organ toxicity develop.
only.
Pharmacopoeias. In £111: (seep.vii). Ph. Eur. 6.8 (C•rprofen for Velemary Use). A white or ahnosr Poor metabolisers of celecoxib (see Phannacol<inerics,
Ph. Eur. 6.8 (Caibasalatc Cililm). A while or almost white, whi1e. aystalline powder. Practically insoluble in water; freely below) may have an increased risk of adverse reac-
crystalline powder. h contains not less than 99.0% and not more soluble in acetone; soluble in methyl alcohol; slightly soluble in tions.
than the equivalent of 10 l.O"Ai of an equi1nolocular compound of isopropyl alcohol. II c.xhibits polymorphism. l'<Otect from light.
calcium di[2-(occtyloxy)beru:oate] and urea, calculated with ref- USP 33 (Carprofen). A white crystalline powder. Practically lncidenc:t> of adverse effects. A prc:saiption-cvent monitor-
erence to !he anhydrous substance. Freely soluble in water and in insoluble in water, frttly soluble in ucctonc, in ether, in elhyl ing study' conducted after tl1e introduct.ion of celecoxib in Eng-
dimcthylfonnamide; practically insolubl~ in •cetooe and in an- acet•te, and in solutions of sodium carbonate and of sodium land in May 2000 fOWJd tliat the m0$t common adverse events
hydrous methyl alcohol. Store in airtight containers. hydroxide. Stoic in airtight conuiiners at a tempcralut'C of 25°, rcpo11ed were gastrointcstinal efTecls including dyspepsia (4.7%
excursions penni"ed between 15° and 30°. Protect from light. of all events). abdominal pain (1.8%), nausea or vomiting
Adverse Effects, Treatment, and Precautions Cl.6%). and dian!IOC3 (l.4%). Rash (J.2%) was also common.
A$ for Aspirin, p.21 . Profile Uncommon event• included anaemia. cougb. anxiely, hypettcn-
Carbasalatc calcium, like aspirin, should not generally be i;iven Ca;profen, a propionic ocidderivalivc, is an NSAID (p. IOO)used sioo, visual dist~nccs. and insomnia. Blood dyscrasias. gas-
to children because of the risk ofReyc's syndrome. in veterinary medicine. trointestinal bleeds, myocardial infarction. l~art failure. abnor-
Adverse effects. Pruritic, c:ythcm:uous, ecz.cmatous eruptions mal liver ftt11ction tests, nepluitis. confusion, hallucinations.
Effects on hearing. As of Jwie 2006 tlic Necherl•nds Pharma· sctious skin disorders. anaphylaxi~. and bronchospasm were
coviailance Cen~-c1 database contained~ repe>ns oftinnibt> and haYe bcense<n in workers after occupationll exposure to carpro-
fc:n. '~ Patch testing showed D strong posith-c photoallcrgjc rcac- rare.
I of otoloxicity associated with use of low oral doses of carba· I. Layton 0. er ul Safety Profile or ctltco.,-ib 3$ \ISed U1 ge1lmil
salatc calcium (38 or 100 mg usually once daily). The associ:t- 1io11 to carprofen.
pr:actict: in Engla1\d• tt'$11hs or a prt-scripc_ion-evenl monitorin1
tion between !ow-dosecasbasala1c calcium and rinniruswascon- 1. Welker SL. ~' nl. Occupa1ton1I pholo~ltergic conlact ck:1m1..1ti•bi study. En, JOin Phnrmo<'Ol 2004: 60: 489-SOI.
in ;:i ph:mu.lCcutic.aJ worker m:inufocturing coarprofen. a c-anine
sidcrcd to be dispropo11ion3I 0(1-11.Stcroid:i[ 3nli·in"3rmna1ory dru.g. 8r J D~iwnt~/ 1006: IS.: Breast feeding. No adve<$C effects were noted in 2 older in·
I. Ncderlilods Bijwcrkin,en Ccnlrum. Low dosage c::irl>ua.Jatc al· So9-70. fants (aged 17 and 22 months) whose mothers took ccleccxib
ctum and rinnilus. Available 1l: hHp:/Jwww.larcb.111fdocumen1.sl 2. Kerr AC. u1 of. OC'cu~tiONI c.arpcofcJl phv1oalleraie <on1xa
kv.1>_21KHi_3_c•rb3$.pdf(>e«...,., IVOC.'07) dcim;11itiJ, 81·.J Dtnm.uol :OOS~ 1$9: 1303- S.
while breast feeding. 1 The oulhors of this rcpo<t also measured
r:elccoxib plosmo conccmrations in 2 other women; from lhcsc
Interactions Preparations •11lues., the average milk-to-plasma ratio w~s calculated to Ile
For interactk>ns RSSOCiatcd w,ith aspirin, see p.~4. USP 33: c.rp..,rcn T•biel< 0.21 and infant exposure was es1imated ot about 0.3% of the
\\"eight-adjusted matcmal dose. Similar values have also been es-
Uses and Administration
timatcd from a study of blood and milk concentrations of
Catbasalole calcium is a I: I _complex ofcolcium acaylsalicylate
cclecoxib in 6 women.' Nonclhclcss. UK licensed producl infor-
nnd urea. II is metabolised to aspirin afterabsotption and thus h3S
the actions of aspirin (p.24). Cai·bnsalate calcium 100 mg is
Celecox.ib (BAN. USAN. rlNNJ mation contra-indicates the use of cclccoxib in l>reast-fccding
equivalent to about /8 mg ofaspirin. Carbasalatc calcium i£ giv- Cclecoxib: Ce'ecoxbJrr< CelekoX>b; SC-58635: Se!elcoksib: Sele-
wornen.
I. H31e TW. ct al. Trtnsftr or celecoxib into hurn,n milk. J Hum
en in oral doses equivalent to about 400 lo 800 mg ofaspirin C\'0- koksib< YM-177. p-{S·p-Tot/~ 3·(t•illvoroniclh)t)py!Ol.Ol- I • Laci :?004i 10: 391~ ).
r,· 4 to 8 hours 11p to a maximum of •boot 3 g dllily for pain or )'IJ;enzenesulfonamide. 2. Gardiner SJ.~' ol. Quantification of in font exposure to cd:coxib
fever. C:utas.1lotc c.1leium hos also been uS<.'tl in 1hc managema1t Ue.-eKOKCH6 through brl!asl mdk-. BrJ Clin Phormucuf 2006: 61: 101..,..
of thrombocmbolic disorders.
C,;H 1,F3N;01S = 381.4. Effecu on t he blood. Severe metliacmoalobinaelllia has been
Preparations CAS - 169590- 42-5. repo11ed in an cider!)• pa1icntallcr taking cclccoxib for I month. 1
Pr'Oprletary Preparations (deluils a1·c given in ~\JJnc Bl ATC - LO/ XXJJ: 1'101AHO I. I. tr\.aus.hik P• ._~, (If. Cc-lc-cox1t>--tndUC"cd mcthemoglobine1ni1. A»n
PIKW»noco1/l~r 2004: 38: 16lS-&.
Aunrio: h..,,.,... Vaiat I"-' Ilse•!: Neth.: Asal: Port.: A!at Spain: Ar ATC Vet - QLOiXX33: QMOIAHOI .
C.\lt; Switz.: Alc>C)l UNll -JCX84Qlj1L. Effects on the cardiovascul¥ system. Prelicensing studies
Multi·ingredient Auroio: ltoc:QSN• c C tfocop..,._i; lrO"rlir"-Qwl;.-c: did not repon any increased risk of serious catdiovasc11la.ce1Tcc1s
Cz.: Cephaloant: Fr" ~t: Switt.: Al<a·C: Tu•I<.: Alca-C. in patients given cdecoxib. 1.z Nonetheless, b)' February 200I the
UK CSM had m:eived a smnll number ofreports> of myocardial
iqfarr:tio,, ot 1sdtotn1ia associated wilh the selective cyck>-oxy-
genase-2 (COX-2) inhibitors. There were also 3 cases of tof3ade
Carfentanil Citrate (lMN rlNNM) ® tit p<)imrzs a~sociated with r:elccoxib use.• Subseq~tly, in Sep-
Carlen....i. Gtrate <!<!; Carlentar•i G!JOS; Citrato ~ caifentani- tcmbcl' 2004, the COX-2 inhibitor rofecoxih was generally wiU>-
lo; R-33m. Metil)4 1 -phenethyt-'l-(N·~ionamido)iso­ 00.wn worldwide by the manufacturer after fu11hcr rcpons of
n~cotat~ C"'tnte.
c::ird10\'ascular adverse cffeas (see p.125) and lhis has prompted
re-evaluation of the safety ofolher selective COX·2 inhibi1ors.
Kap<j>cHTaHw.a L!l<Tpar In De<:cmber 2004 a l•rs• study of celecoxib for picvention of
C11HioNiO;.C,1<,o, 586 6. = colon pol~ (lhe APC •tudy) W3S halted be<ause of 3n ioereascd
CAS - 59708-52--0 (cor(enwnil); 61380·27·6 (cor(en. risk ofcatdiovascular event$ (including death from e3J'diovascu-
:cnil (l{fOCC). lar causes, myoc3J'di•I infarction. strok~ :ind heart failure) in pa-
UNI/ - 7tG286j8GV. tients m:eiv111g the drug compared with those rcttiving place-
The symbol t dcnolcs a preparation no longer actively marketed Tile symbol ® dtnoles a substance whose use ma} be restricted in ccnain sports (seep.vii)
36 Analgesics Anti-inflammatory Drugs and Antipyretics
bo.s The resullS of this long-ienn study susgcs1ed lh81 lhcre was Effects o n the gastrointes tinal tnet. his generally accepl· spi1e the 1emro1111 relationship betweencclccoxib use and tl1e on-
a 2.8-fold increase in the risk of such e-•cnlS in pa1ients iaking ed thal the mhibi11on of cyclo--0xygcnasc-I (COX-I) plays a role se1 of hcpa101oxiciry, 1he manufacturers s1a1cd that evidence
either cclecoxib 400 or 800 mg daily and thai thc incre3SC was in the adverse ga.<trointcstinol efi'ecu of the NSA!Ds, and 1ha1 lhc available at that lime did nol support such a relaiionship. 2 How·
dose-related. 'The possibility of u dose.adv~effect relationship selccti•-e inhibition of 1he 0U1er isofonn, COX-2, by NSAIDs ever, other cases1·' have since been reported, ;ncludina a case
was supported by some aMhc·timc unpublished studies, the Prc- such as ccle<:oxib may cause less gastrotoxicity than the non-sc- rc:por1' ofla1e-onsc1 h<'patorenal toxici1y where symp1oms devel-
SAP and ADAPT studies. 1ha1 £howed no incr= in the risk of ltcti"" inhibition of the traditional NSA!Ds. oped IO monlhs after starti..i 1herapy. Licensed product infonna·
cardiovaswlar effects with oclcco•ib 400 mg daily when com- Results from controlled srudies suggested that NSAIOs selocrivc tion now states tbal cases of severe hepatic rcactiol'IS, including
pared with placcbo.6 These studies•> ha\'C since been published for COX-2 were a.•sociatcd with a lower incidence of serious f\Jlminanl hepatitis (some fatal), liver necrosis, and hepatic fail-
and their finished rcpons were less reassuring than ini1ially gas1roin1cs1inol effccis. In a ploccbo-conlrollcd study' the inci- ure (son1c fa1al or requiring transplant), have been reported. Of
thought. The risk of serious cardiovascular events was found to dence ofcndoscopically detcnnined gastroduodenal ulcers in pa- the cases thal rc:poned 1ime 10 onse~ most of these reactions had
be increased in the cclecoxib group when compared "ith the pla- tients takin& celeooxib for rhcwnatoid arthritis (do5c range 200 developed within I monlh ofslarting cclecoxib therapy. PaticnlS
cebo group ald1ough die difference was nol significant In addi- to 800 mg daily) was not significanlly d1ffcrcn1 lO that seen with wilh signs andfor sympioms suggesting hepa1ic dysfunction, or
tion, an update• of the original APC study confirmed that the risk lhc placebo group. Anothcrs!udy2 in patients 1:1king c<:lccoxib al in whom an abnonnal liver test has occurred, should be mooi-
of adverse cardiovascular evenls W'J S significanlly increased for suprathcrapeutic doses (800 mg dail)') concluded tha! thcrc 1v-.is torecl closely; celccoxib therapy should be stopped if clinical
both high-dose (800 mg daily) and low-dose (400 mg daily) a lower combined incidence of symp!Omatic ~1roin 1cs1inal ul- signs and/or symptoms consislent "ilh liver disease de..,lop, or
cclccoxib when compared wi1h placebo treatment; however, cers and ulccrcomplica1ions (bleeding. perfi>ration, and obstnJC- if systemic manifostations occur.
high-dose treatment was associated wid1 the greatest risk. In. tion) afler6 monthsoftrcaunen1 "1lencon1parcd with non-selcc;.. For a case of acute hepatitis with pancrea1i1is, sec Pancrcatitis,
creases in blood pressure were also more likely wi1h both tiveNSAIOS (ibuprofen 2.4 gc!Jlilyordiclofenac 150 mg daily). below.
ccleooxib groups than with placebo. An analysis 10 using pooled Howe,-er, the incidenccofulccrcomplications alone was DOI sig· I. O'Beimc JP. Cairns SR. Choles1a1ic hcpatitb in associ11ion wich
data &om 6 randomised placcbo<0ntrolled studies, including the nifu:anilydi fi'ercnl to that seen with otherNSAlDs. A re-;inalysis cclccoxib. BW2001; 323: 23.
APC, PrcSap, aod ADAPT studies, found the following relation- of the study by !he FDA. including bolh 1he 6·month and full- 2. Arellano FM.~ ol. Case of cholcstetic hcpt1i1i1 'Aith cel«oxib
ship hetv.-een dose and adverse cardiO\'l!Scular clfect, in descend- term da1a, •lw found that there was no signif>cant reduction in did not fulfil in1cma1ional criteria. BMJ 2002: 32.C: 789-90.
ing order of risk: 400 mg twit<: daily (adjusted haz:l1d rauo 3.1 the rate ofulcer comphcations with celecoxib compared wilh the 3. Grieco A. ~' nl. Acute cho1estatic hcpa1iti1 associared with
ccltt0x-ib. Ann PharmtJ(<t1llwr 2002; 36: 1887-9.
times 1ha1ofplacebo), 200 ma !Wice daily (hazard ratio 1.8), and non-selective NSAIDs ollhough, in subjects not taki"g aspirin, 4. Chamouard P, et al. Protonsed choJcs:ussis 8.$$0Ciotcd wi1h shon·
400 mg one<: daily (bawd ratio I. I). (The result for 400 ma !here was a soong trend in favour of cclecoxib compared with Jenn uscofcclc<:oxib. Gostr0<nrero/CliRBiol200S; 19: 1286-8.
once daily was not statistically significant) There was also evi- ibuprofcn.lThe ri.slc ofulccrcomplications was also signiliCMJly S. Tabibian JH. et ol. l..11c-onS('l cclecoxil>-i.nduccd combined
dence to suggest that the adverse efi'CC1 of dose is more pro· increased in celecoxib usc11> taking concomiiarn low-dose aspi- h<paio-ncph<o1oxici1y. BrJ Clm Pltormocol 2008; 66: ISO-I.
nounced in paticnlS with higher baseline cardiovascular risk. rin. 2 A later systerDiltic review' of Stlld~ of patienlS receiving E1fects on the lungs. Rcpon of a case of pulmonuy oedema
In 200S, based on the findings of slUdics available at the lime, EU eelecoxib or NSAIDs for al least 12 weeks claimed lo show im- and possible pneumonitis in• patient taking cclecoxib.1
regulatory au1hori1ies11 •13 recommended tMl: proved ga.!lrointcstinal safety and tolerabilily in !hose receiving I. Olin JJ.... 41 ol. Putmoury edema and possible pneumonitis as50-
• selcaive COX-2 inhibitors should not be used in patients with cclecoxib (including in palienlS also laking low-dose aspirin) but ciatcd wi1h cclcco,ib. Ann Phormutoflier 200•: JI: 1086.
established ischaemic heart disease or cercbrovascular dis- Ibis has been criticised on grounds of data scleclion.!.6
Effects o n the nervous system. Acute neuropsychiatric re-
~; Ibey arc also contra-indicated in those wilh peripheral II has been nolcd that the use of aspirin appears 10 nullify any actions such as confusion, somool~ and insomnia, have oc..
arterial disease potential prOlcctive clfcct ofCOX-2 selectivity by cclccoxib.7·f curred after cclecoxib use. 1 There has also been 1 case report of
• paticnlS wilh risk factOB for heart disease such as hyperten- There have been individu31 ca..<e reportS of gasirotoxicity with aseptic meningitis.. l
sion, hypcrlipidaania. diabclcs, and smoking should be care· celccoxib...11 I. Adverse Drug RcatioM Ad"jsory Committee (AOR.AC). Acute
fully monitored if given selective COX-2 inhibitors I. Simon LS, ct al. Anti·inflammalory and upper gaStrointestinal ncuropSyc.hiJtrie evcn11 ''-ith cclecoxib and rofcco:xib. A1111 Ad·
cffedS of ceJecoxib in rhcumilOid anhr11is: a randomized con· ''"'~ Dmg React Bull 2003: 22: J. Also available a1: ht1p://
• oil patiems should be assessed individually on the risks and ironed \rial. JA.~~ 1999; 282: 1921_.. www.tga.hcahh.gov.au/adtl&1drb/aadr0302.pdf (accused
benefits of selective COX-2 inhibitor trca~ncnt, particularly 2. Sih·crstein FE. c1 nl. Gastrointcstin111oxicit)' with celecoxib vs 01111/07)
cardiovascular and gastrointestinal risk factors, and allema-
ti\'e treatments considered :t:e":.!:~~a!;1~r\i;i~~~~~ ~:J;: ~o~:~,~i~~r~~~i:.~ 2. Papeioannides DH, e1 al. Ascrtic mcninai1is possjbfy as:socia1cd
with cclccoxib. AM Pltanm>e0tlt.r 2004; 38: 172.
led trial.JAMA 2000: 2$4: 1247-55.
Similar advice has also been issued by the FDA;1' however, the 3. FDA. Cclcbrcx copsulcs (""lccoxib) NOA 20·998/S009-Mcd- Hypersensitivity. A S2-ycar-old man developed allagic vas-
only absolute conlnl·indication is in lbe immcdiale postopcralh'C ical Ofticcr Review. 2000. /\vailablt-. ai: h llp:J/www.fd~.govl culilis afier 8 days of 11ea1ment with cclecoxib. 1 Despite inten-
period after coronary artery bypass sutgery. (In d1e USA cclecox- ohrmsld0<kctsl•c/O Ilbricr.ng/36 77b 1_0>_med.pd( (1ce<.,cd
OllW07) sive treatmeol die policnl died from multiple organ failure and
ib is currently the only a\'3ilablc selcc1ivc COX-2 inhibitor.) 4. Deeks JJ. e1 al. £fT'IClcy, tolctabilily, and upper psa:rointcstinal diffuse cuiancous nccrolysis. The aulbors noted tha1 po1cntially
COX-2 inhibi1ors such as c<:lccoxib do not possess the intrinsic safety or cclccoxib for lrt:ttmcnt of os1eoar!hri1ts 1nd rhe:u1n1· falal skin reactions hav• oe<:u<Nd wilh other sulfa-containing
anliplatelet activity associated with aspirin and possibly other or
tOid on.hri1is: sys1em.1ic r..:vicw randomiJC-d controlled trials. drugs, although !here is wme cvidcncc suggesting 1ha1 the poten-
non-selective NSAIDs and consequenO~ do not provide protec- BM./2002; 325: 61~23. 1i1I for cross-rcac1ivity in patients sensitive lO sulfonan1idc$ is
S. Joni P, "o/. Svs.tcmlltic review of ctlt"Cax1h for o!tte<>arthri1is
tion against iscbacmic cardiac events.l. 1 and rhcvma1oid anhritis: problems com~omisc: re\ icw's valid· relalivcly low;2 none1helcss, licensed product infonnalion con-
1. Silverstein FE. a"'· G111rojn1cstinal toxicity" 1th cele<:oxib vs i1y. BM./2003; 326: 334. tra·indicincs the use ofcclecoxib in such patients.
non~teioid11 1nt..,inrlammatory drugs for ott«Olr11\rhis and 6. Metcalf( S. «I al. Srste.ma1;c rC\· ~ of cefccnxib for osteoar- I. Schneider f , ~' al. faaa.J allcrgie vuculitls r.~M)ciated with
rhcumalotd arthritis. The CLASS s1udy: 1 randomized control· thritis and rheumatoid arthritis:: cclec.oxib'.s relative gutroin1es- e<lccoxib. /A~ct 2002; 359: 852-3.
led \rial. JAMA 2000; l84: 1247-55. 1in:il S3rt1y is ovcrstalcd. BAIJ200J; Jl6: 334--S. 2. Shapiro LE. C' al. Safety or cielccoxib in individuals allergic 10
2. White wa. tf of. Cot11pAri.son of lhrombocmbolic CVtlllS in pa- 7. Lichtenstei1l DR, Wolrc MM. COX-2-~lecti ve N!;AIDs: new sulfonomidc: 1 pilo1 s11>dy. Drug Saf~t)' 2003: 16: IS1-9S.
•nd improved? JAMA ?000; 284; 1297-9.
:::s~~::~:di;~~~:;cl~t:;i~k,fc~X~~:~c~~Jro~c~~t,;~~;~ S. Batc-s DE, Lemaire JB. Possible cdccoxib-induc.cd gastroduo- Pancreatitis. Acllle hepatitis and pancrc:atilis de""loped in M
•lS-30. dcnal ulceration. Anu Pl'lon;oco1l1er 2001; 35: 782-3. elderly patient with a reported hislory ofhyperscnsilivity 10 sul-
3. CSMIMCA. COX-2 selcctiveNSAIO< l><k M<ipla1dttaaivi1y. 9. Mohammed s. Croom OW. G11>Uopa1hy tJue 10 celceo:.:ib, a ~y­ fonamides who was given celccoxib. 1 Symptoms resolved on
Current Problttms 1001: 27: 7. clooxygcnasc·2 inh;bi1or. N Engl J Mrd 1999: 3•0: 200S~.
10. Advc:rsc Drug Reactions Advisory Commiucc (ADRAC). stopping thedrug.Pancrcatitis has also been reported in a sulfon-
4. Pa1hak A. ef al. CclcccxiHssocia1cd tor~dt' de poinh:s. Ann
P/,onnu<Oihtr W02: 36: 12!XH. Cclccoxib; e.arfy Australian reporting CApc:rien«. Au.:st Adverse amidc-1olcrant patient.~
S. Solomon SD. d al. Adtnoma Prcvel'ltion with Celtc0xib (APC) Drui Reoct Bu/12000; 19: 6·-1. Also anilablc al: bllp:// Cclccoxib was one oflhe more commonly implicated dnlgscited
Study ln\'t..1lig1tors. Cardiovascular risk associated with www iga.go• 1u/adr/3adm/aadr0006.)'df (aa:used 29/08108) in ca.c reports of drug-inducm pancrcatitis received by the Ad-
II Advmc Dru& Rc•c1ions Ad\'isoryCommillc<(AORAC). Seri-
cclecoxib in a clinteal trial for colorcctal adcnoma pre'-lcnlion.
ous g:as1rointcstin11I dY'cclS with celecoxib and rofcco:<ib. Aust ~ Drug Reac1ionsAd,isory Corrunittce in Australia.3
N Eilg/J Af<'d2COS: 352: 1071-80.
Adwn~ Dmg RMot:I Hul/2003; 22: IS. Al.!'O l\'lilablc at: hup:I/ I. Carrillo·Jimcnei R, Numbc-rger M. Cclccoxib-induccd acute
6. FOA. Cdccoxib (marketed as Cdcbr~~) (is~d 7th April.
2005} Avail•blc ai: h11p:l1www.fd1.go•/cdcr/drug/infop1gc/ www.1ia.health.gov.1ul1dr/udrblaadr0308.htin (1cccucd pancf't'a1i1is and hep.a.libs. 1 ca.sc: report. Arch lntti'lt Jkt/2000;
cclcbrcx/cel<brcx·htp.pdr(1cceu<d 01111/07) 01/l t/07) 160; 553-4.
7. Atbcr N. ~' al. C'clecoxib (04' 1M prcw:ntion of coto.i·ectal aOellO-- E1fects o n the kidneys. Increasing evidence suggests Iha! se- 2. BaciewiczAM,,tn/. Aai1e~ncrcati1i~ 3~S()Ciated •11hcclccox·
ma1ous polyps. N Engl J Mod 2006: 355: 88S-95. ib. Ann lnrem Aird 2000: 132: 6SO.
lective cyclo-oxygenase-2 (COX-2) inhibitors such as cclecoxib 3. Australian Adw:TK ONg Reoc1ions Advisory Committee
8. ADAPT Rcsc:atch Gl"O\lp. Cardtovucular and ccrcbrovascular appear 10 have adverse effects on re Ml (unction similar 10 those
cvent.s in the randomizrd, con1rolled A l ihc i mcr~s di5Casc anti- (AOR.AC). Drug inductd poncrcalilis. Autl A"-'• Drug React
inRamm:uory prc\·cntion trial (AOAP1'), Available at: hnp:i/ oflhe non-selective NSAIDs (see p.102). 81.t/ 2006: lS: 22. Al<o >vailaMc 11: hUp:l~"'·.1ga.gov,,ufadr/
c l inic.-a I1ria Is.plosjoumals.orgtarchi ve/ ISSS·588711 t7/pd (I Some rcfeiences 10 the advcrsc renal elfocu of cclecoxib. ..11rbludr0612.pdf (•«<s.<cd 01/ 11/07)
I 0. 137 ljoumal.pc1t.OOI0033·L.pdf (•cc«•td 011111'07) 1. 8o)'d IW, a ol COX-2 inhibitors •nd ttn1I (aih.m:: the Lriplc
9. Ben3g,nolli MM. ~111/ Celccoxib IOr the prevc.n1ion of ~die ....-t.ainrny revisited. Mtd J Aust 2000; 17l: 274. Interactions
col°'«tol adcnomu. N £f1¥.I J Med 2006; 355: 813-8~. 2. Pnau111 ~A. Tray K. Sclcclivc cyc:looxyeenuc-2 inhibitors: a
JO. Soloinon SD. ti ol. Cros.41 Trial Safety As.sessmcnt Group. C:tr· pattern of ncphro10.\icity $imHarto traditional noos1eroid1l 1nti- The metabolism of cclecoxib is mcdiat.ed mainly by
dio~.scvbr risk of celcco>-ib in 6 randomi~d placcbo·con1rctl· inflamma1ory drugJ. Am J Akd 2001; 111: 64- 7. the cytochrome P450 isoenzyme CYP2<.'9. Use with
Jed trials; d~ cros.s trial s.arc1y 1n11)·"Sjs.. Circulolion 2008: 111: 3. Graham MG. Acute ren1l f1ihn related 10 high-dose celeco.-ib
2104-13. Ann Intern Mcd2001; 135: 69-70. other drugs that inhibit or induce or are metabolised by
l I. MHRA. Updated ad\'icc on the sa(tty or sclcctivt:: COX-2 iohib- 4. Alkhuja S. et al. Celu.ox1b-induccd nonoligu.ric acuJC rmal fail~ this isoenzyme may result in changes in plasma con-
uors. Message from Profcssnr G Duff. Chainnan or CSM {is.. ure. Ar111J>hnnnacorher2002: 36: S2-4. centration of celecoxib; fluconazole has increased
su-.:d 17th Fcbn.iary. 2005). A'"1iJ1blc 11: S. Ahrnad SR, e1 ol. Renal failure as~ia 1cd with Lhc use- of
hUp://ww w . mhra . gov.ulc/home:Jidcpl~? l dcScrviu·""-GET _ e<lccoxib ond rofcCO><ib. O..•g S<J/'1)' 2002: 25: 537-44. plasma concentrations of celecoxib aod UK licensed
FILE&:dOocNamc•CONOl9<lS8&:Revisio11Sclcc1ionM<1bod• 6. Alper AB, c.r ol. Ncphrot.ic s:yndrornc and in1crsti1~l r.q>hri1is product infonnation recommends that the dose of
Laic$1Rclcosed (IC«Sled 01111/07) usoci1ucd "ith cc.kcoxib. Am J Kld1JtJ' Di1 2002; 40: 1086-90.
celecoxib should be halved when given with flucona-
12. ~~~·&;:!li:.,~~~i(~~~~c~~ a;:r:c;~ 2~s~·~~=:
7. Akhund L, et al. Cclecoxib·rclatcd renal papillary r:ccmsis.
Arch /nttrn Med 2003: 163 : 11 4-IS. zole,
ble a1: ht1p:llw""'" .c n1e1 . ~uro pi1.cu/pdfslhumanlprc11/pr/ 8. Markowitz CS, ti al. Mco1brAAO\IS ,&lomcrulopa1hy and acute
627S70~n.pdf (oettsscd 29/08/08) lntct$titi1I nephritis following trea11nc.n1 with ccfccoxib. Cli" Celecoxib is an inhibitor of the isoenzyme CYP206
13. EMEA. European Medici1lCS Agency conclurk$ action on f>l•pltml 2003: 59: 137-42.
COX-2 inhibi1ors (issued 271h June. 200S). Available at: hup:il 9. BrCW$lcr UC. Pc:l'aLtUa MA. Acute rubuiointersti1ial ncphrilis and the potenlial therefore exists for no effect on drugs
www.cmca.curopa.culpdfslhuintinlprcs.slpr/20716605en.pdf usoet:.led with celecox1b. Nrphrol Dial Transplant 2004; l': metabolised by this enzyme.
(ac.._...d 0111 1107) 1017-18.
14 FOA. FDA i.$.~ucs poblic health ach-ilory •tcommendino limited 10. CtiITord TM, el fJI. Cdeeoxib-indu«d ncphrotoxicity in a renal For interactions associated with N SA!Ds in general,
use of cox·2 inhibitors: agency ~uircs evaluation ofprcven· tNllnspl:int recipient. PhormM011Nrcpy 2005; 2 S ~ n3- 1. sec p.103.
tion stuchu involving cox-2 ~lcct1vc 1g«11S. (issued 23rd C>c- JI . T1bibh1n JH, t!f ol. l..ate-onset celccoxib-indueed combined
hcpato·nephroto..:icily. Br J Gitt Pltormocol 2008; 66; IS0-1.
~~;~Jg~Jo..~~~~8:~;~'.h:'.:i~t.~:S7~~dg.1~?~~~ropi<$/ Effects on the liver. Cbolestalic hcpalitis developed in a 54-
Pharm ac o kinetics
15. Bing RJ, Lomnicli.I M. Ylhy do cyclo-oxygenue-2 inbibttors Celecoxib is absorbed from the gastrointeslinal tract
cause crudiovoscular n~nrs7 J Am Coll Ct1rtliol 2002: 39: year-old woman laking c<:lecoxib;' her liver function teslS im-
521-2. proved 3.nd her S}'lnploms resolved after drug withdrawal. De- and peak plasma concentrations occur after about 3
All cross-references refer to entries in Volume A
 Celecox1b/Choline Salicylate 37
hours. Protein bindine. is about 97%. Celecoxib is me- Licensed prod<"-~ inform..tion recommends Oiat lhc contents ofa <•. Sc.hnitZ.tt TJ. "' ul, VACT-1 ::md \'ACT-~ (Pro4oculs I06 ond
I50) Scud)' GroUJ'd F.flicacy uf rofeco,.ib. ttl«GXib, :ind ace ta·
tabolised in 1he liver~nainly by lhc cytochrome P450 cclccoxib c~sule '"'> be sprinkled ont<> apple s:iuce if a poticnl
minorhcn 1n paticn4s with osteoarthr-iti,: of lhc knee· 1 combined
h.1s difficulty swallowing th< capsules. The spnnklcd capsule an=l)lsis or 1hc VACT studies. J Rh~mntnt>l 200~~ 32:
!soenzyme CY P'.!C'9, which shows genetic polymor- should be t.al<en iminC"di:ncly; however1 i< remains stable at a 10113-llO~.
phism; the three identified metabolites are inaclive as
inhibitors of eyclo-oxygenase-1 (COX- I) or COX-2
tcmpcn11ure <>fhetwrcn 2° to S" for up 10 (• hotn·s.
Administration in hepatic impairment. Licensed product
'·lSS-<56.
~:~,:~~1i; ~ri~~~~cu~.r'ti~~~~~1~,·~d~,~~r=~;r
enzymes. It is eliminated mainly as metabolites in the inform.11ion recommends lh3l doi;es of cclecoxib sbould be re- a B:nkhuizen A. Cl"'· Ccl«oxib IJ cfficaciou~ :ind weU t<'llttatcd
faeces and urine; less than 3% is recovered as unchan- duced by 50"/o in pa1ien1s wi1h modcr.1tc hepa1ic impairment in tr~1ing sig:ns and S)·mp1on'll of 1nkylosing spondylitis. J
(Child·l'ugh category B); iis use is contra· indicated in those with l!Mvn101ol!OOG: 33: ISOS-12.
ged drug. The effective tcm1inal half-life is about 11 9. Luyten FP. e1 nl. A prospccthoe randomistd muhiccntr~ s1udy
hours. Celeco:-cib is dimibuted into breast milk. The severe impairment (Child·J>ugh catcgol)' C or a score of I0 or comparing con1inuou1 ::ind intcrmittcr.t treatmc:nt with cclccoxib
more). in patientS with ostt0:tnhri1i.s c>fthe knccoch1p. An11 R/Jt111t1 Dt:~
phannacokinctics of celecoxib may vary in different ~OOi: 6': !>9-106
ethnic groups; it has been stated that the area under the Familial adcnomatous polyposis. Cclccoxob is used in 1he 10. Focldvari l,tt ol A prospective study comperina c~lecoxib with
trcatmenl of fomilial adrnomatous polyposis, o.n inherited syn- n:aproxcn in children wi1h juvenile rhcum11oid arthri1is. J Rheu-
concentration-time curve is elevated in patients of drome known 10 prcdispooe sufferers 10 the development of co· mntol 200~ 36: 174-82.
Afro-Caribbean origin, although any clinical signifi- Ionic cancer . A randomised study 1.l found thal 1rea1n>00t with Palmllt'plantar erythrodysesthesla syndrome.. Cclccoxib
cance 1s unclear. ccleeoxib reduced lhc nw11bcr or colonic polyps; the aulhors has b<.-en investigated in the 1rcannent of capeeilabine-induc:ed
0 Reference$.
considc~ cclccoxib 10 be • uscNI adjunct to lhe slandard thcr• hand-foot (palmar-plantarerylhrodyses1hcsia) syndrome; ref: ror
apy of colectCMny. cr<nC<S, see under Adverse Effects 3nd Precautions ofCapocil·
Da\~S NM. #I ol. CliniQI pl1nrm~cokincttcs and pMrm3cad)•· I. Str1nb-•ch G. cl ul. Tiu: cO(ct of «lttoxib. a cycJooxygc:nuc·2 abine. p. 7;>7.
n3mie:s of ttlccoxib: a :.cltc (l\•C cyclo--oi")'~nue-2 inhibitor. inhibilOr. in ramili:>I atlcnon11tous polypos.is. N E11gl J Med
CJ;,, PhaMntKC>kind 2000~ 38: 22S-42. 2000; H2: l946-S2. Preparations
2. $h.~mp:i:k D. n nl. SU~-<tosc al\d .sie:idy-sunc phannxokinctic$ 2. Phillips RKS. " al A randomis,cd, double blind. pltccbo tort·
· or ceh::coxib in children. C/l1, Phormacol n,,r 2002: 71: ~9Q.-7. Proprietary Preparations (d•11il• an:°given in Volume 8)
trolled nud) of CC"lceoxib. 3 stScc1ivc cyclookYlenast 2 inhibi· A~:~ Celebrex: Ceiemoxt: Oc><bt: U>octtn!o: Rltd:Cacine; Aus.-
Corre<lion. Ibid 2006: SO: 667. lOr. on duod'11al polyposis in fami lial :idcnomatoos polyposh.
J. Kifcl1hcin~I' J. ttt nl tnOuente of CYP2C9 a,enttic polymor- WI.: (A:ebrcl<; Austrio: C.,I~ Sok:xot; Bello' Cclct><e>c: Bra~: Cele·
Cui 2002: SO: S.<7-<IO. bra: Conod.: Celetl'e< CM/o: Colelira: Cl.! ~ Onson<I; Oenm.:
phi.sms (In phormnC'n~inetics or cel~coxib nnd its 1nc1~boli1es.
Phunru.t<1CJg(1iletiC's 2003; 13: .. 73--80. Malisnant neoplasms. Celccoxih is under investigation as ad· Cclcbr1. Ons....t Rn.: Celeb<._ Fr.: Celeb<e><: 0.-..~ Ger" Cetdlrex:
juvan1 rherapy in 1he trcaimen1 of cancer;•·• preliminary results Olisen•I: Gr.: .Adarto< Celebro>< Hong Konr- Ce:ctrcx: Hung.: G:lc:lrc>c
• l..undbl1d MS. ,,, ti/. Accumutaoon of cclccoxib wiLh a 7-fold lndla: Ceiedol: Celbt C.0C.C O'\hocet UIV.ccl!j: Zyc:tl; ln<l<>n.: Cele·
hicher drui exposur~ in indiYidu:als hon101.yg.nus for have been variable. It has also b«l'I investisated for chemopte· brex: lrl,:O:lebrc><:O-.- •-~ Cetcox: Cololn: ltol" Ar!Jort.Cei.·
CYJ>~9•.l. Oi" f>hruwm:ul ntn· 2006; 79: 287-S. vc:ntion of tn31ignanC)' 1o.11 (see also Familial Adenoma1ous trex; Solexot: Malaysia: Cdtbrt>c Mex.: Ce~...., Neth.: ~
Polyposis. above), b111 a large slUdy fort~ prevention of colon Onsenat Solexat: Norw.: Co!tb<a Onsenalt NZ: Ccldnit Pllffipp"
Uses and Administration cancer was tcnnin31ed ca1·ly because ofinercascd C3rdiovascular O:lte>o<: Cetebre>e Cele>cit> E..-clbm; Aom.r. lexlb: Pol" C~tbre><: """-:
Ce'et>re><: On•cnal:Sole>&: Rus.: C.-.X {lleM6pH(); S.Afr.: Cu!>n:x:
Celecoxib is an NSAID (p.103) reported to be a selec- risk.U· 1 ~ Sln,opott: C.lebrelc Spoln: Aniol: Celett-...: On!cnal: Swed.: Cdtln:
I. O~ng CT.~: ul. Ph.asc II Sllld)' ot"ce:lce:o.1ub and tr:istuzumab in o-..n.t: Switz.: <M:brcx Thal.: Ce!ebtex T..-k: Ctltbrex: UK, Cele-
tive inhibitor ofcyclo-oxygenase-2 (COX-2). It is used m~llstt.Uc bceast nuctr poticn1.s who ha\'C PNV<S.SA:d :.fi<r pd· brcx: On>enll; Uhr.: Celebl'C?< (Uer.~); fleio>cib (<l>AOf'O<m6):
in the o·eatment of rheumatoid a1thritis includingjuve- ot 11otSlutum:tb-based Lrtutmen1s. Clin Cmtttt Rfs 2004; 10: ,.,.,_. ~k l\eumoxi> (Pu.'°"M6)c USA: O:lcbi't>e Vcne;z.:
4062-7. Coleln>¢ Ce><b. ·
nile idiopathic arthritis, osteoarthrilis, and ankylosing 2. Renr<loo DA." al. PhaM" II 1rial of irinoteran plus eclccoxib in
spondylitis, and in the adjunctive treatment ofadenom- aduhs with f\.~urnn1 malianam 9liom111. Ct11K'~r 200S: 10.l:
J~O -JS.
atous eolorectal polyps. In the USA, celecoxib is also ; Nuzc1ll FW, "' ol. Oocclaul and cycloo:<ygt1\:>sc-2 inhil»tion Choline Magnesium Trisalicylate
licensed for use in the management of acute pain and with cdcco~ali for adv1nctd non-small cell lung canctt pto-
grusing 3rtcr 1>kHinu1n·bAKd chemotherapy: a muhkcnlu TrisaJicilato de coir\3 y mopsio.
dysmenorrhoea. phase II tri;.11. l1111g CmH..vrr 2005: 48: :!:6/-73. XON<H MarHe3HYM T~AaThl
For osteoarthritis the recommended oral dose is 4. (jasparini G. fl td. The combination or the SClc(tivc C)l<:1oo;.y.
s.ct\Ho,."'2 inhibilor c~tceo"<ib with 'Nettkty pic::lilaxcl is a 111fc ::md Ci,H19010NMg 539.8.=
200 mg daily given as a single dose or in 2 divided dos- CAS - 64415-90·7.
;h~: .~~~ ~~,.~ht~~~~:~j::r ::~~.~, c:!c!:~."' 200~~··; 1~
1
es. If necessary a dose of 200 mg twice daily may be
209- 16.
used. For rheumatoid arthritis the dose is I 00 to 5. l>rince HM."' ol. A muhic.:nlcr phase 11 lrial of 1halidomidc and
200 mg given twice daily. Celecoxib is also used for
ankylosing spondylitis in an initial oral dose of
cdccox1b (orpatitn1s with relaps.C'd o.nd rcfrac1ory multiple my·
(:IOm:1. Cliu Conctr Ra 200S; J1: 5504-14.
6. Pa:n ex, Cl"'·
A pha$t' ti lrial of irinotcci.n. 5-0uorotttaeil and
OXO',OH H,C-ri;:1y-011 02YOH
?' OH
200 mg daily, as a single dose or in 2 divided doses. In
the USA, the dose may be increased to 400 mg daily
after 6 weeks, although if no response is seen at this
lcuco,·orin combined wilh cdcco~ib and ;Jut.amine as first-lnlC:
~t~g~ for ad\•anccd color<e'titl c3nccr. 011(0/ogr 2005: 69:

I . Csiki 1. e1 al. TarJClina. cydooxygcnoise·· 2 i11 recurrent nOftoo

small ccll lunac3ncc-r: a phase 11 •ri~I ofcclccoxib 11111d doccl1.:<·
CT CH3
""'" I
dose after a further 6 weeks, alternative treatments d . Clin Con<'4'' Rt» :!005: t I: 6634-40. Profile
should be considered; a similar increase is also pcnnit- 8. C~ LWC. rt til, S(rum lipid profiks in p:uienu rttciving c:o· Choline tfl0$J>C.1ium 1risalicylate is a combinalion uf 1he salic)1ic
ted in the UK. However, for all lhe above indications, docri•c UC'almcnr for brc3s1 canccr-lhc ruults from the acid <kriva1iv•s choline salicylatc (j).37) and magnesium sali-
Celtc0Jib Anli·Aroma1i1se Nccadjuvant (CAAN) Trial. Biomed C)13te (p.83).11 has •nalgcsic. anti·inOam1natory, and antipyrttic
UK licensed product information recommends that if Pl1tm•oeo1""· ~oo;: 59 <suppl 2): s;o2-s;o5. ac1iuns similar lo those of aspirin (p.24~ Aller oral administra·
ineffective, the higher dose should only be continued 9. i:cmri V. '1 ol. Gcmci1abinc plus ttlccoxib (GECO) in ad-
v1111ccd p;iner<atic canc~r:. :i pl'l:iise JI trial . Clmcrr Chc111oth<!r tion, cl1olioc magnesium trisalicylate dissociates' and the sali·
for 2 weeks before considering al1emative treatments. PlwnnbCOf2006; 57: IU- 90. cylate mo~ry is rapidly absorbed. Each unit dose of 500 ms of
I 0. Limburg PJ, ct al. Random•7Cd. placcbo-.con1rollcd. csoph<ilv~ul salicylate is provided by about 293 mg of choline salicylale wilh
For doses in children with juvenile idiopathic arthri- squ:Jm(IUS cell CIJ\Cff chtmoprevtnfiQn trial of StleftOMdhtO- 362 mg of magnesium salicyla1e (anhydrous). Choline maSJlCSi·
tis. see below. ninc 3nd cclttoxib. GMtr«nierologi· 2005~ 129: 86)-73. um 1risalicylatc h3s hocn u.<ed in osleoarthritis, mcumotoid ar-
11 . Solomon SD. r-1 ol. Adtnom1 Prcveotion w;1h Cel"'-"COkib (APC}
In the treatment of pain and dysmenorrhoca, an initial Study ln"cs1i;aLor1. Cardiova$Cular risk associ31ed wi1h rhritis. and other arthnud~ it has also bttn ~ in lhe setieral
oral dose of 400 mg followed by an additional dose of «ln.'Oxib in :i. cllntcal tnal for colorc:cu1t :idcnom1 preve.ntion. managcmc11t of 01hcr fonns of pain and for fever.
N Eng/J Mtd 2005; 3Sl: 1071-80.
200 mg. if necessary, is recommended on the first day; 12. Bcruplli MM. fH al. Cclcroxib for the prevention Ofi:qlOradic
thereaf\er the dose is 200 mg twice daily. colorccal od<nomas. N Engl J .lf<d 2006: 355: 873-84.
13. Atbrt N, 4:111L Ctlcco.xib ror the pr~\'-cnlion ofcolortcl31adcno· Choline Salicylate {/JAN. USAN. rlNN)
Celecoxib is also used as an adjunct to standard therapy 1n3lous polyps. N Engl J Mod 2006: JSS: S&S-95.
Ololrie. Salicylate de: Cholini Sall()las: KoliO>isalisylaani; Koinsal·
10 reduce the number of adenomatous colorectal pol· Mu•culoskeletal and joint disorders. Cclecoxib is IJSCd in
icyla~ ~llato de colina. (2-Hydro><)1!~.timethylammonium
yps in patients with familial adenomatous polyposis. th~ 1re•11ncn1 of ostcoarthriris (p.11) and rheumaroid ar1hri1is
(J>.12) includingjm•enile idiop•thic anhritis (p.11). However, in salicy!atc.
For this purpose it may be given in oral doses of XoAMMa CaN<W.llolT
lhe UK i1 is re«>mmendcd that lhe use of cclccoxib and other
400 mg twice daily with food. sclcc1ive cyclo-oxygrnase-2 (COX-2) inhibitor.. be limited to =
C 12H 19 NO, 241.3.
Reduced doses are recommended in patients with he- t~ patic111s considerod to be at high risk of developing serious CAS -1016-36-6.
patic impai1ment (see below) and in those also taking gaslroinicstinal pt'Oblems if given a non-sclcc1ive NSAlD and ATC - N028AOJ.
who donor ha'~ pre-ex isling cardiov.>Sculor risk facrors(see Ad· ATC '/er - QN0]8A03
nuconazole, a poten1inhibitor of the cytochrome P450 v~ Effccts. above). UNI/- KD510KllQ'll~
isoenzyme CYP2C9 (see Interactions, above). The Ccleco:.ib is also used in the Jrc•lmcni of ank1losing spondyli1is
dose of cclecoxib should be reduced to half the lowest (see Spondyloanhropathics. p.14).
recommended dose in patients who are deficient in Rcrcrtnces.
CYP2C9 and hence poor metabolisers of celecoxib. I. Be1\sen we. ·~'"' Ttf"4ln\Cl\C or ostcoanhri1is with e.cteco>.ib, :ill H3C, PH3
cycloo.~ygcnasc·! uthibilor: a randomized controlk:d tri:tl.
'.>Reviews. Mo1'0Cli11Proc1999;14: 109~ 1 105.
2. Sin.lC'>11 LS, ti ol. Anli·innmmatory ;ind uprcr gutrointestinaJ
HO~t:J'CH3
I. Ocmcu O,Cio:• KL. Cclcco.•ub: a rc"~worils u.c:c ino1tcoanhn·
1is.. rhcum~toid 11rd1rilis and acu1e~in. Dmg,r 2000; 59: 957~QO. or
effects celcco'<1b io rhcwnouoid anhri Li~ : ;i randnmiud con·
2. F~mpeoo JE, Kcutios GM. Celecoxib: a rt'View or its use in the 1tolkd trio!. .l.4MA 1999: 28?: t921-l8.
; E1MT)' I,, e1 n!, Cdccoxib \"CtSuS diclo(cnac in long·lcnn man·
man11cmcnt ot" arthri1is and z:C'ute pa1n. Dr11g.t 2007; 67: <1rc1ncm of rht.:umatoid anhritis: rlndnmi"td double·bllnd com· Pharmacopoeias. Br. includes a solution.
2433-71. par>son. Loner! 1999: 3S4: 2106-11. BP 20 I0 (Choline Salicylaie Sol.Jtion). An aqueous solution con·
Administration in children. In 1he USA, cclccoxib is Ii· 4. Ooupdos M. t!, t1J. Eflicac.·y of cc1«u'Cib. a cyclooxygena.sc 2· 1aining47.510 51.5% ofchohnesalicyla1e. l1 isa clear colourless
ccnsc:d for ~ie ueatmcnt of juvenile idiopalhic artbri1is in chil· sptt1f.c inhibitor. in the 1rc111ncn1 of a.nkyk>sing spond)lli1is: I' liquid. II may coni.in a sui11blc antimicrobial preseov.uive.
s1:c·w«k con1rollcd s:tud)' wi1h co1n~risoo ag,~insl pla1.:cb¢ and
drcn •gcd 2 years and o"er. TI1e recommended oral doses, based againsa :a COO\-entional nonst<roid:::il :mtiinflammatory dl'ua. A,... Profil~
011 body-weigh1, arc: 1/Jri1is /Ck1UH 2001 : 44: ISO-S.
Choline salicylale is a salicylic acid dcriva1ivc (sec Aspirin, p.21)
• 10 to lfkg: 50 ms !\\ice daily ~. S1c1lgaarO..Pf"dcncn K. 111 al. Cckcoxib 200 mg qd i$ cOklici<'us
in the m~n1anncn1 of ost.:oarthri1is of the kn«« hip rt,prdleu: used io rhe treatment of pain and fever, and in lhc management
• OVCf 25 kg: I00 mg l\\'i<e daily of th-: lime o( dosi"J. R~t1motolo~' (Oxford) 2004; 4J: 592-S. ofrheuniatic disorder... In 1cnns ofsalicylatecontclll, choline s.'1-
The symbol t denotes a prepar.ation no longer aclively marketed
 38 Analgesics Anti-inflammatory Drugs and Antlpyretics
icy late 435 mg is tqul\'8len1 to about 325 mg of aspirin. Choline Profile
salicylale is given orally in doses of 435 10 870 mg evay four Clofexamide has been used topically u lhc hydrochloride in

H3CO~
hours as necessary for,,ain and fever, and in dosesof4.810 7.2 8 prcparalioos for musculoskelctal.join~ and soft-tis.<ue disorders.
daily in di,·ided doses for rhcuma1ic disorders.
Cl1olinesalicyla1c is also used as a local analgesic. Solutions con- lu
taining up to about 20% choline salicylale ott used in ear disor·
dcrs such as the relief of pain in otitis media Qlld cx1ema but ore Clofe2on e (<INN) 0. H
consldcted to be of doubtful value; 1hcy arc also used 10 soften ANP-3260: Clolezona: Clofezone: Clofeionum. AA eqJimolar \ NCH3
car wax as an aid to rcmo,..,I (sec p.1876). AJJ 8.7% gel is used
combrli!tion of dofexa:nide a"ld phcnytbuti1%one.
for lesions of1he mouth (p.1849). Choline salicylatc has also
been applied topically in a rubefacicn1 prepara1ion for lhc relief l<Aoci>e•o~ Ho·· u
of muscular and rheumatic pain.
Choline salicylatc is also given in the fonn of choline magnesi-
C11H2,CIN202.C19Hl()N202.2H20 629.2. =
CAS - 60104-29 2. Street names. The following terms rove been used .., 'street
um trisalicylatc (see above). ATC - MOIAA05. M02AA03. names' (see p.vi) or slong names for various forms of codeine:
Adverse effects and prec,a utions. A 21-monlh-<>ld boy de- ATC Vtt - QA~OIAA05, QM02AA03. ACJDC: Barr; Capiain Cody; Cody; Cotics; Cough Syrup;
veloped salicytatc poisoning al\cr his mOlber bad rubbed lhe con- Down; Karo; Lean; Nods; Scl>ool boy; Schoolboy; TJ.
UNI/ - TPT3MH65LO.
tents of3 tubes of Bonjcla 1celhing oinlmelll (containing a total Pharmacopoeias. In £11r. (sec p.vii), In/., US. and "kl.
of2.61 g ofcholine salicylalc) oo his gums over 48 hours.1 Pro fi le Ph. Eur. 6.8 (Codeine). Wllitt or alniost white, Cl)'Slalline pow-
In anolhcr case, an 8-ycar-old boy wilh G6PD deficiency devel- Clofcz.ooc, a combination molecule containing clofexamide der or colourless aystals. S<>luble in boiling water, freely soluble
oped an oral mucosa I bum a few hours after application of aboul (ahovc) and phcnylbutazone (p.121), has been gi\•ci orally and in alcohol. l'rolcct from fighl
half a rube of Tcejel oral gcl.1 He developed n1001h ulcers and by rccwl suppositO<)' and applied topically in pn:pazations for USP 33 (Coden?). Colourless or white crystals or white crys·
displayed signs of apathy, lethargy. and nasal congestion 3 days musculoskelctal,joint, and soft-tissue disorders. talline powder. II effion:sces slowly in dry air. Soluble I in 120
af\erexposure. 1Jisconcl11ion improved after a week. The authors of water, I in 2 of alcohol, I in 0.5 ofchlorofonn, and I in SO of
fell 1ha1 G6PD defJcienc:y may have been a contnbu1ing faclO< in ether. Its saturated solution in water is alkaline to litmus. Store in
the occurrence of adverse effcclS. airtight eoniainers. Protect from light.
Clo nixin (IJWJ. ....iN)
In the UK, the MHRA contra-indie:11es the use of topical oral
pain relief prq>ar.itions containing salicylatcs in children under CBA-93626; Clonixiie: OoM<incx Cloni>cinum: Sch· I 0304. 2-(3- Codeine Hydrochlo ride (l!llNM)
16 yea!$ of age (for details, see Reye's Syndtome, below). 0>loro-o-toluidino)nicotinic acid. Codelna. hiaodoruro de; Codc!ine (chlorhydra1e de) ~rate:
I. Payn1er AS, Atexander fW. Salicylatr into~ication caused by IW>HMK<>1H Codeini hydrochlori<i.rn dihydrict.rn: Kodei;nihydrol<lorididohy·
teething ointment. Lum:c1 1979; ii: 1132.
2. Sapir S. Binlllcin E. ChoHns;alicylatc gel induced orel luion: K'-
pM of <.'>SC. J Clf• Pcdiorr /Nnl 2000; 24: I03-6.
C13H11CIN102 262.7. = d~tti: KodeirW'idroldorid.O;hidrat Koden-l'o)'drochlorid dihy-
drat Kodei~rat Kodeino hidrochlotidas dihidro-
CAS - I 7737-65-4.
tas.
~EYE'S .SYNDROME. The link between aspirin use in children UNI/ - V70XNOM42R.
and the development of Reye's syndrome is well recognised KoA..... rY.Aj>OXAOPMA
3lthough a causal relationship remains to be established and C 11t-i,.N03.HCl.2Hi0 371.9. =
ohe evidence for olhcr salicylates could not be adequately CAS - 1422-07-7 (anhydrous ce<kine f:ydrocliloride).
evaluated (see p.23,). However, a 20-monlh-old boy who had
received a lcething gel containing choline salicylate (applied N ~-XCI UNI/ - NTZ53GG7XN.
Pharmacopoeias. In Ew: (sec p. vii).
in doses of 1.31 g daily, equivalent 10 acetylsa licy late
100 mg/kg daily, which exceeds the recoinmcnded dose) de-
veloped Reye's syndrome following a viral illness.' The ou-
lhon noted that lhe Ml IRA in the UK were aware of two ear·
lier reports suggesting an association between choline
CX J~) COOH
Ph. Eur. 6.8 (Codeine Hycrochlonde Oihydrate: Codeine Hy-
drochloride BP 20 I0). Small colourless crystals or a while or al-
most white, crystalline powder. Soluble in water; slightly soluble
in alcohol; pnctically insoluble in cyclohcxanc. Protect from
light
salicylatc and Rcye's syndrome. As of April 2009, the
Clonixin Lysine (~)
Ml-IRA 2 had received 3 such reports in which all 3 children
wen: hospitalised but Rcye's syndrome was not conftnncd in Clonixi'l Lysin;rte: Ooni>cine L~nc: Ooroixino isina: Clonxinum C odeine Phos phate (BANM)
any of them; in addition, 4 reports of vomiting or diarrhoea l ys1run; L-104: Lysine Clon1xinate; R· 173. Codeina. fosfato de; Codeine. phosphate de; Codeine Phos-
afier the use of choline salicylate oral gel had bcal received. phr.t Hemihydrate: Codeini phosphas: Codc"1i Fhospha.s Hemi·
IW>H""CMHl l\'1)'AH
Consequently. lhe MHRA contra· indicated lhe use of topical hydricus Codcinii Pl>osphas: Kodciinifosfaatti: Kodein·fosfat
oral pain relief preparations containing salieyla1cs in children CllH 11 CIN202. C6H 14 N201 = 408.9.
~t Kodeinfosfathemi: Kodcin·foszf~t-hemiiidr.it Kodci-
under I6 years of age due 10 the theoretical risk of Reye 's CAS - 55837-30·4. no fosfaw hcm1hodratas; Kodeiny fosforan: Kodeiny fosforan
syndrome.
P rofile p61wodny. Me\hylmorphine Phosphate.
I. Om.an TK. ~'al. Topl c~ I c,hl)fjnc salicylates implicated in Rtyc's
syndrome. 8.W 2008; 336: 1376. Clonixin is an NSAID (p.100). It has been used as lhc lysine salt KoAe~Ha <Doc~•
1. MH.R.A. Press release: new1'dv1oc on cmd salicylatc: g.ds in undu in oral doses or up to 2$0 '"' four limes daily for the n:lief of C1eH2 1N03,H3P0., 11,H20 = 406.4.
161 (issued 23rd Apri l, 200~) . Availobk 01: hnp:!/ pain. Clonixin lysine has also been given by intramuscular or in· CAS - 52-28-8 (anhydrous codtine phosphate); 41114 -
www.mhra.&ov.uk/NtwsCtntrdPttnnle:ncslCON044014 (•c· IJ'8\'Cnous injcction and as a reetal suppository. 62-6 (code1.•e phosphate hemihydrate); 5913-76 ·8 (co-
eesStd 24/04/09)
O References. deine phosphate sesquihydrote).
Preparations UN/I - GSL05 YI MN6 (codeine phospllote hemihydrotc):
I. Eberh1rdl R. ct ol. Analgesic efficacy and tokrabili•y of lysine-
BP 20/0:0d..,. ~hr Drop~ o.or.... S.lic)iattOrcmucosalG.t cloni.xinitc vets.us ibuprofen in patients •1th aon1rthro1is. C11rr 2XS85M IM3T (anhydrous codeine phosphate).
Proprietary Preparations (details are given in ~lumc 8) Tl><r Rtt 199S; 56: S?;-80. i..'QT'£. Compounded prcparatious or codeine phosphate may be
Arg.: Oen:ol'na;Aomrol.: Apptka;net. Hem:n e.by T....,,,,,, Gd, 0fa·Sed represented by the following names:
Jel: Get" Audo><1: Hone Kong: Or.i·Sed: India: Golan; Zyte« lrl.: A.idil><: Preparations
Mo/ayJio: Ora-~ NZ: O<a·Sed: Po/, Odnex
•
°"""m:
Pon.: Bu-
Rus.: Olrun (0..HH)'M); Siniopo'"-' Or.i·Sed. UK: Auda><t, Ukr.:
Proprietary Preparations (details are siven in Volume B) • Co-codarnol xly (~where x and y are the s1rengths in
milligrams of codeine phosphate and pararelamol respective-
F......., (a>.>P"-"™"): Otitium (°"'">'M~ USA: Art/Yq>ant. Ari.: Ooni><i: Diclcn: Dole><: eor_,., Broz.: Oobn;n: Chile: 8lonalc
c.lc><: Oonalg;n: CMna><: ~ Oiminon; O~t; LAltesic Me6- ly
Muftj..lnzre.dient Arg.: Panscnl, Auftl'DI.: Bonjeb. Seda-Get Austrio;
~...ti 81fr.: GN>ie>: Teejet Cz.: 1'11.rdu~ Fr.: GMltx: nnsorot w'"
aosoc: Nelersil; li<ur.ioct Mu.: °''°'•t
Oonodoi: Dor.>cna; t'ir>c l0<illl\
lOt'O>tcr: Prestodol: ~ Port, AJtimato: ClooOc: Spain: Oolatglit
• Co-codAPAP (PEN)-<odeine phospha1c and paracetaonol
'"'-"<lltolf: G": MuoCl..t Hone Kon1: Bonjel•f: Demiojelot Ori!-ict V•nn..: D0tixN. • Co-<:odaprin (BAN)-<odeine phosphate I part and aspirin SO
Hung" Mund.sot. In" BorjEli: Tetjct lsro• I: 8oby Gum: Bor,e!a: Teejet, parts(wlw)
Molo yslo: e o r , . = NZ: 8onjeb: Po/.: S.C.l>o!MlSlcmot~
Rus.: CholiSll ~ Po,,,.,,.i (floHCopM); S.A(r.: ~ $/nrci- ~=riatr.~~=~~':r!'!'t::=~~ • Co.:odaprin (P£i\~cine pho<!phate and aspirin.
Oori>rino; t1loNr< Nov> P~·.wopna (OCT.pcMllllT'( ~: Ser\al Com-
re~~~n;,::~=n~~~~~~~te~~~Pt~ ~~.~i puesto. Broz.: Oolri> fle>: Chile: Oonal1W> ~O:Ergonef: M;ara·
Nefenit ~sll 8' Nwro<am: M •x.: Oollri>c bonodooCompvestcx
Pharmacopoeias. In Chi11., Eur. (sec p.vii), /111., Jp11, US. and
(X°"""111): GN*'< (!"....-<]. Jliet.
Dcri>iN Rel>lC Espacil C<>mpuesto: fira: """" Klc>nua: 0pt;um; """"
~~t!~~~ind<t Venez.: Ooiogme><: °""'°"' Pharmacopoeias may specify the hemihydrate, sesquihydratc, or
b!>lh, either under one monogniph or as separate monogrnphs.
Ph. Eur. 6.8 (Codeine Phosphate Hemihydrate; ~ Phos-
C lofexa mide (rlNN)
phate BP 2010). A white or almost white. crystalline powder or
ANP-246; Oofexamida: Oofexamid.rr.. 2-(4.Chlorophe'l()l()')· small, colourless aystllls. Freely soluble in water; slightly solu-
N·(2-diethylaminoethyf)acetamide. ble or very sliglltlysoluble in alcohol. A 4Yo solutiOll in water has
Codeine (BANJ a pH of4.0 to 5.0. Pro1ec1 frnm light.
~•ca ...1A
=
C 14 H2 1CIN201 281.8. Codena: Cod6ne: Codcinum; Codeirum Monohydria.Jm: Ko·
deioni; Kodetrc Kodeill monohydr.!t Kodefla; Kodeinas: Melhyl-
Ph. Eur. 6.8 (Codeine Phosphate Sesquflydrate: Codeini Phos-
phas ~h)<k'i<\Js) . A white or al~ white, crystalline pow-
CAS - 1223·36-5.
morpline: Mctilmonlna: MO<phine Methyl Ether: 7,8·Dideh}'dro- der or small, colourless ct)'$lals. Freely soluble in wa1cr; slightly
· UNll - 07 I P4J77HF.
~.S-epoxy-3-metho><y- I 7-methyl~6-ol monollydrate.
soluble in alcohol. A 4% solidion in water has a pli of4.0 to 5.0.
Prolect froni light.
KOA!t<H USP 33 (Code'"'e ~e). The hemihydrate OCCW$ as tine,
C11H21N03,H20 = 317.4. white, needle-sll.'lped crys1als or white crystalline powder;
odourless. Soluble I in 2.S of water, l io 0.5 of water al 80", I in
CAS - 76-57-3 (anhydrous codeine): 6059-47-8 (codeine 325 of alcohol, and I in 125 of boiling alcohol. Its solutions are
monohydrate).
acid lo litmus. Slore in airtight containers at o temperc!llre up to
ATC - ROSDA04. 40° as pcnnirtcd by the manufacrurc{Pro<cct from light.
ATC Vet - QR050A04. lnGom patibility. Acetylation of codeine phosphate by aspirin
UN/I - Q830PW7520. has oceumd in sulid dOS8ge forms containing the two drugs,
All cross-refcrenecs refer lo entries in Volume A
 Clofexamide/Codeine 39
even :ll a Im'· JllC"listurc level.• Au/nm/ '''Ork suggested 1hat the Ove..dosage. Aculc c;odcin: in10,ica1ion in 430 children. due 4' , Heulth C;anac3tJ.an.s.sc.t1~0ttho. hn~on~'' satct)' tnror1natioll
analsesic acuvi1y of codeine wa.• not ottec1ed by aceryls1ion.: •~ accidental ingestion of antitussivc prcpara1ions, "'"15 re· 3bout usie of'ffylf'J\Ot• '"'ith codeine NO 2.3.4 and elixir in nurt:-
J Ci.tlant( R~. t!t rd. Solid·:natf accl)lllion of codci1ll! phc>J~uuc vicwed. 1 Tite children were nearly all between I and 6 }'Cal'S old. i:'I: mod:>ers and ullni-r.apid rnet:ibolizt-rs or codeine (issued 6th
b)'Hp.tri~.J pJ,um1Sc:l 1979i 6R: 14~-8.
Oc1ober. 2008). A' aibble a::
Sympt<>ms in decreasing order or frequency included somno- hup://www.hC'·sc.:c.c..a/dhp-mps/alt_formntslhpfb-dgpWpdf'
Huel:.t-11 V.R. n of The nn:ilaesk properties of SOtinc 14~~ub~li· laice. msh. miosis, vomiling, ilching, aia.xia. and swelling of the mcdeft71ylenol_codeinc_ hpc-c?>-<nJ.pdl (occcss<d 0 I /0211 OJ
lut«I dcri,-.:li'"CS or codeine :ind cod<:inonc. J Phclm: Pllormncol skill. Rcspira1ory failure occurred in 8 children and 2 died; all S 5. MHRA/CHM. Codeine: Wery .or< nslt ofside-efTe<ls in b<castfCd
19~: 16: 17442
hod leken 5 mg/kg or more. lnfancs arc at special risk and Chere bobiu. Dmg Safety Upda1c 2007; 1 (4). 3. A"ailablc 01:
have been fa1alitier-' and severe ad,·ersc effecu"'1 af\cr inappro- http://www. m hrs.gov.uk/hornclidcpls,? IdcSt.rvict•G ET_
Codeine Sulfate priale lreatment in infanlS ond young children ajven producis FILE&d0o<Na:ne=CON20.12917&RevisionSele<1io11Method•
L•1cstRelcowl (oceesscd 26/06/0Si
Codtt-.a. sulf.rto de; CodeW>e Sukih.te (8m.v.;. containing code.iDc. 6. Ani<rican Aaidemy of Pc<lia1rtcs. 11,c traMfcr of ctrup and oth·
KOAC!I- Cy,.t><l>ar Opioid toxicity, in addition to severe salicyla1c 1oxici1y, has oc- er chcmi~ls "110 human milk. Pediatrics 2001; IOI: 776-89.
curred in adulls after overdoses ofaspirio and codeine tablets.' [Retired M•y 2010) Conenio.•. ibid.; 1029. Also available 11:
(C1aH1 N03)i.HiS0• .3HiO ~ 7S0.9. hl lp :/laappol icy. u ppubl ica lions .o r&lc gi I co 111e ntlru 11/
CAS - 1420-53-1 (onhydro"s code'ne sulfo1e): 6854-40- I. \-On MOh1end.ahl KE. ct al. Codeine hno>.ic:ation in childhood. p<diou icso/•3bl08/3n76 {•e<:ased 26/06/081
6 (codeJOe sll1(01e uihydro<e). Lona1 1976: ii: 303-S.
7. Ba1cman ON. 01 '''· Codeine and breutreeding. lo11c~1 2008:
1. Jvey HH. Kanwinkcl J. O:tnf.cr of Acuf~d-C. PeJiafrifs 1976: 372: 625.
UN/I - I /QV98SOC8 57: 164-S.
Pharmacopoeias. Jn US. 3. Maanani 8. Evan$ R. Codeine intoxication in tM nt0n1,c. Ab· Children. See Overdosage, above, and Ad1nini31ration in chil-
USP 33 (Codeine Su.ate). White crystals, usually nccdlc· like. MrAct: Pedio,rics 1999: 104: 1379. dren, below.
or white cryslollinc powder. Soluble I in 30 of waler, I in 6.5 of Full version: htlp:/iped1a\rics. a>apPublicaticms.orc,/cci/contcn\/
Mlll04/6/e7S (ac:ecssed 26/06l08) Driving. Codeine phospllJl1c SO mg alone and v.ith alcohol had
water ai 80°, and I in 1300 of •lc<>hol; inwlublein chlorufonn a delclcrious effccl on driving skills in a simula1ed driving icst. 1
codci~ intoxication in 3-
4, FureirOs N, tJt ol. F111I and sc'\"Crt'
and in ether. Stori: in airtight containers. Pio1cci froin light. yar-<>id lwins-intcrprcunion ofdrug and metabolite conccr.tra- I. Linnoila M, H5kkinen S. Effecu of diaicpam and codetnc. alone
Stability. Codeine >'Ulfote solu1ions appear to be inlrinsically lions. Int J Lego/ Mt'd 2009; 123: 387-9•. and in combina1ion wi1h alcohol, eon simulated drivirt,g. Clin
Pharmocol Ther 1974: IS: ;68- 73.
niore s11blt 1han codeine phosphaie solu1ions.1 · 5. \\filkes TC'R, et ol. Apnoen in a l-month-old beby p~scribcd
compound hnc.tusconlainingcodcine. ~~, 198 1; i: 1166-7. Genetic polymorphism. Life-lhrealening IOxicily in a patient
I. l'owell MF. Enhanc~ M.ability of codeint $ulf.uc: cfl"t:el of pH. 6. I.« AC. et ol A case or probable codeine poisoning in a young
bu rfcr. and tcmpc:r.nure on the d:and;nion 6f codeine '" aqueous given moderate doses of codeine was lhoughl 10 be due lo a gen-
solution. J />harm Sd 1986: 75~ 901-3. infon1 1ncr 1he U$IC of a propricrnry coua,h :ind cokl medicine.
Ho11g Ko11g M<JJ2004; JO: 285·7. otype predisposing him 10 uhrarapid metabolism of lhc drng into
1. Hcmumns.-.Clausm M, n of. Drug dosing error wilh d«>p:s~ SC· morphine by lhc cytochrome P4SO isoenzyme C'vP2D6, cou-
Dependence and Withdrawal \'t1'c clinical coul'$c of codt111e irnoxica1ion in IWins. t.ir J PM· pled wi1h drug-incb:ed inhibition of 1he usual major metabolic
As for Opioid Analgesics, p. I 05. Cir 2009; 168: 819-24. palhway medialed by CYP3A4, and lransient reduction in ienal
I l.cslit- PJ. n ol. Opilue 1oxici1y after selrpoisonina with aspirin function.' Genetic polymorphism was also considered lO con-
Codeine is subject lo abuse (see under Precautions, be- and codcille.B~I/ 1986; 292: 96. tribule lo Ille dealh of a 2-year-old boy given codeine after an
low), but produces less euphoria and sedation than adenolonsilleclomy had been performed to resolve sleep apnoeo
morphine. Precautions and snoring problems.1 Olher contn'bulory faccors include.evi-
As for Opioid Analgesics in general, p.107. dence ofbronchopneumonia at post-monein. For 3 report of the
Neonatal abstinern:e syndrome. Some of~"' S)11lptoms ctlect of lhis genotype in breast-feeding mothers, see Breast
characteristic of lbe neonacal ab$rinence syndrome were seen in Abuse. Allhougll the risk of dependence on codeine is low" ilh Feeding, above.
a nccna1e whose mother h3d 1aken about 90 mg of codeine daily normal use, 1 ii is the subject of dclibera1e abuse. Jn France: and I. Gosche V. ct"'· Codeine into:\ica1ion ossoci:.tcd ";th ull'ra.npid
during the last 2 months of pregnancy.' in the UK linciUSeS containing codeine have been particululy li- CYP206 me•obolism. N Engl J M#d 2004; 351: 2827-31. C0<·
I. Khan t<. China J. Nconn1al abstinence syndrome due to codeinc. able to abuse. Repon.~ in 1he hterarure n1Clude lhc use in New m:iion. Ibid. ZOOS; 351: 638. •
Ar<h Dis Ch,/J 1997: 76: FS9-F60. Zeal3nd of codeine-oon1aining Jll"parations 10 produce demeth- 2. Cistkuwski C, er al. Codctne, uhDrapid-mctabolism aenot)'Pt',
ylated producis known as "Homebake" conlaining variable ond postopcn11ivc dcalh. .'I £nil J M<d2009 ; 361: 827-8.
Adverse Effects and Treatment amounls of morphine1and abuse ofco~aprin labl•IS for tlteir Pregnancy. See Neonatal Abstinence Syndrome under De-
As for Opioid A.11algesics in general, p. I 06. codeine coo1ent.+. pendence and Withdrawal. above.
I. Rowden AM. LopnJR. Cadcioc flddic1ion. DICP Ami Pharmd• Renal impainnent. The renal clearance ofcodeine and ilS me-
Jn 1herapeutic doses codeine is much less liable than coiher 1989: 13: 47S-7.
lsboliles is signilicandy reduced in parienlS \\ilh end-stage renal
morphine to produce adverse effects, although consti- 2. Armand C. "' <rl. 10 ens de d.!1oumemein d'usagc du Niocodton•
disease on regular hacmodialysis therapy. Ooe such elderly pa-
~lrt 1992 ct2002: Ncocodton6 misuse: evolution bCT\\'t'CR 1992
pation may be troublesome with long-tenn use. After Md 2002. Tlte1·opie 2004; 59: S4i-j3. tienl dc\'elopcd tonic-clooicseizures 7 days after s1:>rungoral co-
large doses of codeine, excitement and convulsions 3. Shaw JP. 0.ugmisusc in New Zc1land.PharmJ 1987; 2~8: 607. deine phosphAIC 30 mg 4 times daily; no further seizures OC>
may occur. 4. Sokol MS. S1ark CR. Codeine obuse. Lonc<t 1989; II: 1282. curred after codeioe was stopped and naloxooe sianed. 1 The
S. P31erson JR. .:1 "'· Codeine nbu.st: (ror.i co·codaprin. L<mat dosasc ofcodeine should be reduced according lo renal ruoccion
Codeine, like morphine, has a dose-related histamine- 1990; 335: 224. in p11ients wilh renal impainnent but no specific rccommcnda-
releasing effocl Anapbylactic reactions after intrave- 6. Saknl MS. S&.art tR. Coclciqc abuse fion, co-cocbprin. Ltmcet Lions ~ppear to be given in 1he 1i1erarure.
nous use have been reported rarely. c990; ns: 22.. I. Kuo S-C. et ol. Probabfc codeine phnsphato-induced $c-izUres.
Breast feeding. Breast-fed infanlS of mod1ers Inking codeine Ann Pltfmnoc()I/~,. :?004; 38: IS4S-St .
Effects on mental function. Cen1ral effocis ofcodeine phos-
may be al on inc1cascd risk of10J<icity !Tom i1s metabolile, mor·
pha1e ~ppcarcd IO be limi1cd, bul dose-related, in subjeccs given Interactions
phinc, if Ille mo1he1 is an ullrarupid mctaboliser of codeine. In
30, 60, or90 ing: visuo-niocor coordina1ion was allt:rcd wich dos-
one rcport.1 a 13-day-old infanl died from opioid 1oxicity after For interactions associated wilh opioid analgesics, see
es of 60 and 90 mg and dynamic visual acu11y wi1h 90 mg.1
being e.>.poo;ed lo morphine in his inolhcr's breast tnilk: lhe molh- ?.107.
Drowsiness ieponcd by subjecis !1.i"en 90 mg or codeine phos-
er had bt<:n taking oral codeine 30 mg lwice daily as pan of a
phale could nol be lrnked wilh impaired pcrfoni~ whece<is Quinidine. For n:ference 10 a SUiS"'tion thal quinidinc can in-
combinaliOP ircparation with parncelamol for about 2 weeks.
nausea could. hibit lhe Malgcsic eITw ofcodeine, s.:e Mdaboli:1m under Phar-
Assayed morphine eoncen1ra1ions in lhc brca~ milk 'vuc found
I. Bradley CM. Nicholson AN. Eff«:ls of 1 p-opioid receptor a.;o- mncokin..:tics. below.
10 be 87 nonograms/mL: 1he usual range is 1.9 10
nist (codcint pho~ph11e) on vis.uo-motor coordination <ind dy·
namk visual ncuil)' in man. Br J Cf;,, Pltarmocol 1986; 22: 20.S nanogra.mslmL after repeated doses of codeine 60 mg four
S07-12. times daily. Laler inves1igations found 1ho1 lhc mother's gcn<r Pharmacokinetics
type for 1he cytochrome P450 isocmyrnc CYP2D6 (the enzyme Codeine and its salts are absorbed from the gastrointes-
Effects on the pancreas. A 26-year-old woman developed
invoh'Cd in the conversion ofcodeine to morphine) classified her
acute 1ianercati1is on 2 sepam1e occasions a few hours afkr lak- as on uhrarapid meloboliscr of codeine. Olhers1 have subse-
tinal tract Rectal absorption of codeine phosphate has
ing a single, 40-mg do5c of codeine.' There was no hislory of been reported. Ingestion of codeine phosphate produc-
que111ly reported severe neonolal 1oxici1y in bn:as1-fed infanls
alcohol consumplion •net her recove.ry was uneventful. Other whose mothers were CYP2D6 ullrarapid me1abolisers. es peak plasma-codeine concentrations in abouc one
cases ha"e been reported.""
I. H3Slier P. ct ttl. Pt1Mrt:Mil.is induced by codeine: a cast repor·t
The l'DA has advised' 1hal nursing mothers taking codeioe ho111: Codeine is metabolised by 0- and N-<lemcthyla-
with p0si1lvc tcc:hallt:ng_e. Grit 1997: 41: 70$":'6. should be infonned of the potential-risk of morphine OYerd= tion in the liver to morphine, norcodeine,andotherme-
2. Locher C. ti al. PrmcrCalite alsl>C aprCs ''prised 'unc nssociation and 1he need to moni1or hreast·fed infanlS for signs of toxicily tabolitcs including nonnorphine and hydrocodone.
paractA1nu1-..,ldtinc. Gosn'Ocmrrol C/111Blol2003~ 27: 124-5. sucb as increased sleepiness.. dilf"'"lly fccdinj! or breathing. or
3. Kohlcn K.. rt al. Codc-in-induzicne Pankreati1is. Dtsc/r Mtd Wo - limpness. NutSing mothers, Lhemseh'CS. may also develop over·
Metabolism to morphine is mediated by the cyto-
c/,,1uchr 200S; DO: SiS-9. dose symp1oms including ex1re1nc sleepiness, confusion. shal- chrome P450 isoenzyme cvno6, which shows ge-
4. Moreno Est~ MC. et t1l. Prmcn:atitis due to codeine. ~w~,~- low brcathini. and severe cons1ipa1ion. Similar advice has also netic polymorphism. Codeine and its metabolites are
1ol /111n1111wp01hal (.\fotk) 200$: 33: 175-7. been isSU<.-d by hcallh au1hori1ics in Canoda4 and lhe UK.1 Nonc-
S. Belhll$Stn Garcia M. ~I of. Poncrcatitis s«undQril o y.anccta· excreted almost entirely by the kidney, mainly as con-
moJ.codcin~ . Au Al~ /mf!mQ 2006: 23: 400-40 I.
lhcless, codeine appears IO h3ve been used safely for many years jugates with glucuronic acid.
in breas1-feeding moibers and several aulhoritit." including lhe
Effects on the skin. Pruritus and burning erythemnlo-vcsicular American Academy of Pedi11rics' and the BNF' .S9eonsider Chai The plasma half-life has been reported to be between 3
plaques lhat developed in a pa1icri1 in response 10 oral codeine it is usually compa1ible wi1h hn:ast feeding. Moreover, some of and 4 hours after an oral or intramuscular dose.
were atuibuted lo• fixed drug eruption.' A similar reaclion oc· 1he findings oflhc original case repon have been qucstion.e<l; in
curred in ano1hcr pa1ient after !:>king various analgesics includ· Codeine crosses the placenta and is distributed into
particular, the amounl of paraoctamol fouod in 1he infan1's blood
ing a conibincd preparnlion of p3nlccc..mol and codeine;: pa1ch al (>0<1·nt0nem was considered 100 high to be derived from breast milk.
1es1ing showed a positi"" response for codeine only. Moculopa· brca.<t milk.' 0 Rcfacnces.
pular rush hes been seen as part of a hypcrsensitivil)' syndrome I. Kortn Ci et ol rhann~ogenclics of morphine p0isoning in I I. Guay OR; ct ol. Ph.armacokinctics or codeine after si1,gle. and
associulcd wilh oral codeine phospha1c;3 fever, splcnomcgaly, breaslltd neonate of a co&inc•pttscribed mother. Lllntrl 2006; multiple"°ral-do.K adminisaration 10 l'IOtmal volunteers. J Cli11
and lymphadenopalhy also occurred. 368: 7()4. Pharmucol 1911: 27: 983-7.
I Cionzafo-Garijo MA. Re~a-Amnz F. fixed drug eruption 2. M11dadi P. ~' cl. PhannacotC'f'littics of neona1al opioid tOXkity 2. J>CB.llM K,no/, Thc-pos:opcr:11ivcphum•cokinc:licsofcodcinc.
due lo codeine. BrJ D~nnato/ 1996: Jl.S; -198-9. following nrntcrMl use of cackine dunn! brl!astfccding: • cuc- EurJ C/111Phormocal1992: 4l: 663-6.
2. G:i.-s1aminza G. ;:1 et! Erythrodermr., caused by allergy to codeine. t'ontrol siudy. Cli11 P/,01·,.10("0/ 1'1tc-r 2009; 85: 31-S. 3. La(olic P, tt al. Urine and pluma phsnnac:okinctic:1 of codtmc
Co111oct !Hrrnatiflf :?OOS: 52: 227- .6. FD.4. Information for hulthcnrc pro(cssio.n1I: use: of codeir.e .,, h.c:ilthy volunteers.: imphcattol1s for drugs-of-:ibu.sc lt:5'l'lg. J
3. EnC'lmotG M. ~10( C..~oclcine phosphate-1ndu«d hypttKnsitivity produc1s in nut1ina mothcri (issued 1711\ Auausl, 2007). Ano/ Tuxicol 1996: 20: 5<1-6. .,,,.
syndrome.""" Pharlfrncothtr 2004: 38: 799-30?. A\ ·ailable at: hup://www.fda.gov/Otu11iOrugSaft:1y/ 4. Kim I, ~1 al. Plasma and oral nuld pharmacokinttics ind phar-
Pos1fnarkctDru1S1(cty lnformationforPalftntsandProvidcrs/ mrttodvnamics after orlll codeine adn1iniJtralion. Cl/u Chem
Hypel"Scnsitivity. Sec Effects on the Skin, above. ucm l24889 (l«nl<'d 02:081 10) 2002; 48: .. ~96.
Th< symbol t denotes a preparation no longer actively markcled
40 Analgesics Anti-inflammatory Drugs and Antipyretics
Administration. Jn a compararivc study' codeine had an deine phosphete I mJl.'kg given orally or by 1ntnmuscular Croto n Oil
oraVincraonuscular analgesic relative po1ency ratio of 6: 10. This injection lhcrc was a relatively small risk of n:sp1ratory depres- Acerte de cro100: Atc~e de crot6n; Oeum Crotoois; Oleum
was high compattd with that of morphine and was anributcd to sion in neonates, but significant respiratory dep<ession has oc-
Tigli.
prmocrion from r.ipid fll'Sl·pa.% 1nc1abolism rather than more ef- curred with multiple doses and patients should bc ubserYed
ficieot ab$crption after oral doses. Jn a comparative srudy in closely.' Ca5" reports ofadverse reactions such as vasodilatalion. KpoTC1Moaoe MaCAO
children2 the absorption r• lc of codeine from a suppository was severe hypotension, and apooea in infants and children after in- CAS - 800 1.28-3.
found to be similar to that from an intramuscular injection; how- travenous doses of codeine have procloded its use by this route UNll - W K97£QGS 7S
e•·er. peak plasma conccnttations were nO( as high when given in chiklrcn of all agcs.3 • Pharmacopoeias. Chin. includes fruits of Cro10111ig/i1un.
rectally. Antimotility drugs such as codeine should not be used in infants Profile
I. ~aver WT, ,,, of. Anlgc.s.ic studies or C6dcinc ond oxycodone and young children wi1b acute diarrh1>ea."' Croton oil is an oil expressed from the seeds of Croion 1igli11m
in patients whh c1nttt I: comparisons o f oral with inlr&musculu
c.odeinc and of <>Dl wuh intramusc:ular oJtycodone. J l'ltonuocol The BNFC 2009 advise. that cough supprcssanlS con1'1ining (Eupholbiaceae). Externally, il is a po"'~ul counter-irritant and
Exp Thcr 197S; 207: 92-100. pholcodine or similaropioids (such as codeine) arc gencnilly n0< vesicant. QO(on oil is also used with pl1enol in cosmetic chemi-
2. McEwan A. et al, A eompa.rison of rcclal and inlrlmuscvbr co. recommended for children and should be avoided in those under cal peeling of the skin.
deine phosphate in chikltcf'l rollowing nrurowrgtry. Pa#dlan· 6 years of age. However, codeine phosphate is licensed to allay Crolon oil has such a violent purgative acrion thai it should not
AllDesth 2000; IO: I 89-93. non-productive cough; the BNF S9 recommends that children be used as a 13J(ative. Croton oil contains phorbol es1ers, which
Metabolism. The analgesic e!Tecl ofcodeine may be partly due aged 2 IO S years may be given 3 mg three or four times daily and are carcinogenic.
to iLS mellbolite morphine and it has been suggested that ils effi- those aged S 10 12 yea~ 7.S 10 IS mg three or four times daily. Homoeopathy. Ooton has been used in homoeopathic incdi-
cacy ma~ be impaired in patienLS who arc poor mctaboliscrs of Otildren and adolescents aged I2 years and over may be given eines under ~1e following names: Croton tiglium; Crol tig.
oocleinc .. or in those who are also receiving drugs, such as qui- the usual adult doses of codeine ~hate for all these indica-
nidinc, that impair ils mctabolism. 1 However, palicnts unable to tioos (sec above).
0 References.
I. 8cnsimon RH. Croton oil peels. Aeslltet SuriJ2008: 18: J;-45.
dcrnetllylate codeine 10 produce detectable plasma concentta- I. lk>yd·Thomas AR. Pain management in pacdiauic pa1imts. Br Corrcc1ion. i6KI: 221.
tions of morphine oblllined a similar analgesic effect to patients J Anawh 1990; 64: IS-104.
with deteciable plasma morphine concentrations.s A snidy' in- 2. The College of Emcrsency Medicine. Clinicel Effec1i ....cnu.s Preparations
volving infants aged 6 10 I0 months ha.< indicated th•t children Comminee guideline (or the management of pain in chi1dren Proprict:ary Prep!\l'atlons (details arc @ivcn in Volume B)
were capable of demethylaling codeine 10 morphine at !he age of (May 2010). A'"311ablt 11: hllp~/sccurc.colkme:rgicncymed.1c,uk/
1sp'documcnL"'9?1D"46B2 (""ccucd 3M>6/10) H omoeopu hlc Conod.: 1-tomto.fo:m CO; Hyial1ds Formula Pl
6 months allhougli glucuronidalion of the morphine appeared to 3. Marsh OF, e1 ol Opiokl systems a.nd I.he M:wbom. Br J Anoe11h
be impaired when oompared with older children. 1997; 7,, 787-95.
For reports of sevete toxicity thought lO be due to altered me1'1b- or
4. Anonymous. Drugs in the m1nasemcn1 tcutc diarThoca in in·
Devil's Claw Root
olism of codeine see Genetic Polymorphism, above. f:on1s end young children. Bull WHO 19~; 67: 9~ .
S. C;molal N, C3rtcr JE. Aotimotilily agents for pacdia1.r.tc use. Djavulsklol'ot HarplgofytO\lj kolen: Harpagor>juuri: Harpago-
J. Ocs-meu.Ju J. t!I al. Impact of e:nvironment1l and gcnc:-1ic factors
on codeine analacsia. Enr JCUn Pha.rmocol J991: 4 1: 23...6. Lane•/ 1990; 336: 874. phyti radix: Harpagophy\on: Harpagoph)'IOn, raCl!le d; Harpago-
2. Chen ZR. ~1 ol. Disposition and metabolism or codeine tfttr 'in- Administration in renal impairment. See under Precau- phytum: lnbrudilj Saknys; OrdOgcsaklya C)"Oll.Cr. Raiz de harp-
glt and chronic doSC"s in one poor ::snd seven cxu~n11i"c mc:tabcr _tions. above. agofrto: Teu'elslcrallenwurzel
li>Crs.Br JC/111PhormocoJ1991: 31: 381- 90.
3. Slndrup SH, et of Codeine: i~rc.ascs p.ain thresholds to copper Cough. A systanatic review' of over-the-c:ounter preperations f apnarocjiMryM; At>ooOl\li(K>IM KoroT•
V3p0T IHCT stimuli in 0.ltRSiVC bul nOI poor rntl3boll2ert Of for acute cough concluded thal codeine appeared no more efl'oc- CAS - 19210-12-9 (horpogos1de).
SJ"'nt inc. Clinl'hanoocoJTlitr 1991; 49: 6S6-9l. tivc than placebo in reducing cough symptoms in adults or chil- ATC Htrb - HMO,AWS009 (Horpogophytum pro(um·
4, Wllli11ms l>Ci. £t al. Pbannxogcnc1ic1 or codeine mciaboJism in dren, tllhough the number of patients in the studies considered bens: root).
an 1.1rN.n populllion ofchildren and its implicaliOA! for an.algc.sic UNI/ - IOYM338E89.
rcli1bility. Br J A110<Slh 2002; 89: 839-45. wassmall ·
S. Quwting H. ~al. Analgesic c flcct and plasm1 cioncencrationl' of See also Administrdtion in Children, above.
codtine and morphine after twodoit levell ofcodeine fol lowing I. sm;th SM. Cl al. Over-the.counter m.edicllions for 3C-ute cough

Ho~ l0
or.II scug<ry. EurJ Clln 1'/1Urm1J<:ul 1993; 44: 3 19-23. 0
in children and adults in .ambulalory senina.1. Available in The
6. Q\,Jiding H, el al. lnf1n1s and youn.c children mc11bolise codeine Cochrane Oatubuc ofS)'llcmatic Reviews~ Issue 1. Ch1e.hc:11cr.
to morphine: a Study a0cr 5in,tc and repealed rcctal adminillr&· John Wiley; 2008 (ICCUS<d 2Ml6108).
ti0<1. Br J Clin PhormnN>l 1992; 33: 4S-9.

CH3~0
Pain. Systematic rcviewsl.l comparing parautamol-codeine
combinations versus parace1amol alone concluded that in single·
Uses and Administratio n dose studies addition ofcodeine 10 parace1'1mol produced a com-
Codeine, a phenanthrcne derivative, is an opioid analg- ~otively small but s1'1tistically sig11i!icant increase in analgc•ic
esic (p.108) obiained from opium or made by methyl- effect; howe\'cr, there was an increased incidence of ad..crse ef-
HO
HO :V
0 .Hw 0
ating morphine. It is much less potent as an analgesic fects with the combination. Ano~1cr systetnatic review3 of anolg- 0 =-
than morphine and has relatively mild sedative effects. esie use in moderate to severe postoperative pain found that sin- ~ ~
gle oral d0$CS of codeine alone pw.idcd low levels of clinieally
Codeine or its salts, especially the phosphate, are given
orally in the fonn of linctuscs for the relief of cough,
useful pain relief when compared .,;th placebo; better p3in relief OH OH ~ fl
was noted with other commonly used analgesics such as
and as iablets for 1he relief of mild to moderate pain, NSAlDs and paracctar11ol, given alone and in combination prep-
(horpogoside)
often with a non-opioid analgesic such as aspirin, ibu- arations wilh codeine.
I. de Cracn AJM. et ol. Analecsit efficacy ftnd S3fet)• of panceta·
profen, or paraceiamol. The phosphate is also given by mol-codcinc combinations versus parecc11mol Jitonc: a S)stcm· Pharmacopoeias. In Eur. (sec p.vii). which also includes the
intramuscular injection, in doses similar to those used otic r<\'iew. BMJ 1996; 313: 32 1-S. dryexllaCt
orally, for the relief of pain; the intravenous, subcula- 2. Toms L. f1 al. Single dose or:1I puraccumof (xctaminophen) Ph. Eur. 6 .8 (Devirs Claw Root DeWs Claw BP 20 10). 1lle cut
with codeine for postoperative. pain in adulta.. Available in The and dried tuberous. secondary roots of Horpagophy1um ptr1<.Vm·
neous, and rcclal routes have also been used. Cochrane Oa1abuc of Systematic R.cvicWSi Issue I. Chichester: bms andfor If. zeyheri. Greyish-brown 10 dark brown with a bit-
For the relief ofp3ln codeine phosphate may be given Jolln Wiley; 2009 (oce<sscd 02111109).
ter taste. Contains not less than 1.2% harpe.goside
3. Derry S, 1.1 al. Sinatc dose oral codrinc. as • dnsle •atnt. for
in doses of30 to 60 mg every 4 hours to a usual maxi- xute postopcn1ivc pain in adulU. AvaiJablc in The Cochrane (C;ooH300 11 • 494.5), calculated with reference 10 lhe dried drug.
mum of240 mg daily. Datatr.lsc of Systc:matic .Reviews; Issue 4, Chichcslcr; John Wt- Protect from light
ley; 2010 (occcsscd 30/06/10).
To allay non-productive cough codeine phosphate may Profile
Preparations Devil's claw root is used in herbal remedios for muswloskelctal
be given in doses of 15 to 30 mg three or four times and joint disonlets. Its activity is attributed in part rn the plant's
daily. BP 20 10: Co<od=cl ~ C0<odamol Tobl<"ts: Co<odo"'1<1 Tat>
leu; Codcon< LincU; Codeine Phos!lllate In~ ~ Phosphate content ofiridoid glycosidcs, notably harpagosidc.
Codeine phosphate is also used as tablets or in mixtures o...I Scll/tiOI'( Codctt Phosphlte Tablets; O:spcnillo Co-codoprin Toi> Pain. Preparations con1'1ining devirs claw root have been tried
lets: EWer.-c:<11 Co<odMTIOI Tablets; Paedotrit Co:le..,. Uictus: Par."
for the symptomatiereliefofacute diarrhoea in doses cetamol. Codtne Phosphate and Cafl'ci..., Qpwtes: P.,.e,...,.,.. Cod<W>e with some suettss in the treatment ofnlU5Culoskeletal disorders
of 15 to 60 mg given 3 or 4 times daily. Phosphatc . i ~ Talllot.; such as low back pain and osteoarthritis. There is oome evidence
USP 33: AcetMTWl<lplien and Code<le ~· c.,,...i..:
/\ctt>mi- of efficacy for daily oral doses stand.11dised lo 50 tn 100 mg
for delails of doses in children, see below. oophal ...i Codere F'hosphate Oral Solubot\ Ac~n ..,d Co- ~side but the quality of reporting in studies i~ generally
deine Phosph.ne 0..1 Su!pe"'oon: Ac.,..'Tir.cp.en and Codeine J>no..
Other codeine salts used include the hydroch loride, poor and itsy tacc in U1erapy is not establishcd. "2 An e>-idence·
sulfate, camsilate, and hydrobromide. Codeine G,~~;J~.~: ~,~0.!:;C~:~s~~tcT~t~ based report' by the Althritis Research Campaign in the UK coo-
U - &it>lbital. Aspim. ~ . i C:OO.... Phosphate Capwtes; C.... cluded that although devil's claw root may be c1Tcc1i'"' for os1e-
polistirex (a codeine and sulfonated dicthenylbenzene- ICpl'C<lol Aspirin. •rd Codeine ""°"""'e Tabl<"ts: Codei'>• f'nosl>hlte Ill. oartluitis, advcrne effects remain a concern. Serious, but uncom-
ethenylbenzcne copol)'1ner complex) is used in modi- i«'JOrC Codeine PhospNte Tlllleu; Codein<t SUlrte Table1S: ~ mon, adverse effects such as abnormal heart rhythm and
.,,d Codtinc l'hosphote S,.,.x Te<pn Hydriltc •rd Codeine &r.
fied-release preparations. Proprie tary Pr""aradons (details ore given in Volume B)
bleeding have been reported.
1. GaJnier JI~ tr ol. H·arpg.ophytum [sic} procumbcns for ostc:oar·
Administration in children. Licensed produe1 information Aurtrol.: Act.ICOde: Aunrl<t: Codipertus,;,,: Codoptont Mono: Cod11rdt;
Makltus,;,,.~"""""""1: Triced... Selr.: 8romopNr. hlcto·pe<:tcr
thmis and k>w back pain: a sys1cma1ic rc~1cw. BMC Compl~ment
for codeine in the treatment ofpain often restriclS iLS use to those Alt<m M<t/2004: 4: 13.
ralis Codtine: ~ llronchosedat ~Wit Glcxe<Jat. Glott)t
ovu I year ofage, buuome authorities consider codeine lO be an Toux·Son Codeine Conod.: Code;ne C""'"' Fr.: Cod<dn11: Codenfart 2. Gagnicr J.J, rt ul. Hetblll n'l<'dicirac: for low back pain. Available
clTeetivc analgesic in neonates and children. ' In the UK; the Neo-Co6on: Padt-y~ Gor.: MlhusSM.m ~ &or~h>c:um Mono Co- in ne Cochronc Database of Sy$tcmatic Reviews: luuc 2.
BNFC Z009 suggests that neonates :1lld children aged UJl 10 12 d.rt ccdi OPT: Co6c1ps 1rono; Co<Sclps Neo; Co&ompren: CoclipOf'- Chicllester: John Wiley; 2006 (1ccc<s<d 05110f06).
years may be given codeine phosphate 0.510 I mg/kg every 4 to lu,,... Codipnlnt Monot; Maki\"""' Coder<~ Kodein: Tryasoll; 3. Anhritis R~c21.f('h Campai&J'). Complementotcy and ahcmative
medicines for 1h" trntmc.nt of rheumatoid arthritis.. osteoan.tuiti$
6 hows for mild to moderalc pain up to the usual adult maximum
dose of240 mg daily; tl1esc doses can be liven omlly, rooally, or
=~~~~f..Z:{N~s,,;~~~;,,~ and ribromyalgia (issuN February 2009).
Pl'tilip p.: Cod jpro:it N; Port..: Tos.eiN. Rus.: Neo-CodlOtl (Heo- Ava ilable a l ~ h1tp://\\~w. a rthri1 i .srcsearchu k.or1/pdfl
by the subeutMcous or intramuscular routes. Guidelinesl for an- ~)t. Spoin: Bisoltus; Coclctsit> Co<Uinf: llJctan C.00.--z ~ Complc mc:nta ry%2 Oand%2 0 a It c r na t i"c%20mcd ic inc s _
algesia in chi ldren in Accident and Emergency departments in r. Notuson: f'erduretas Codeino: TO<eino: Swlu.: lropea nou.e1e 1om1u1e: l 1012010154Hl.pdf(m:mcd 28/07110)
the UK recommend the use oforal codeine a.~ an alternative. or M.i<aluSSin """"''" (gm'-"': Tricodenf; UK; Bepro: G>lcoc)ne; v.,,.L: Preparat ions
Cod'opror.t Mono.
in addition, to diclofenac, for moderalc pain such as that ass.;.,;. Proprieu ry Prep•rations (details •re gl\en in Volume B)
Multi·ln g~dlent: ~ p-epantions al"t lis1cd f\ \ldui'ne 8.
ated with small bums or scalds, linger tip injuries, rorcann, el- Oiabo: 'ICritr.lt Fr.: ~ El...-., Haipagesoc;
Broz.: Glln do
bow, or ankle fiaclUrc, or appendicitis. With a single dose of co- Ha/'p>dot~ Gtt" A;ruit All)Qt,An!volett..-.l-lf':Arthroli!bs:

All cross-references refer to entries in Volume A

 Croton O iVDextrop:"Opoxyphene 4!
SC•ect o~mes. The following 101ms have heal used as 'strecl
names' (seep.vi)°' sl:ing names for rnrious fonns of dcxtropto-
po,yphenc:
Dummies ..

Dextromoramide (BAN.J>l'IN) ® Dextropropoxyphene Hydrochloride

Dekstromonimidi; DextrodiphenopyrTie: Deiaromoramid; (SAto/1111.;1'1'1/Aj
Oextromorarr>dc: Oextromonm~rn; d-Moramc!: ~lami ­ Deks:ropropol<.~en"1ydi·ol<lc,rodr; Dei<s~feno t>dro-
dol. (+)-f-(3-Methyt+morpholino-2,2-dphenylbutyryt)wrofi- chforidas. Oext1qiropoxifen-hidroklorid; Dextropropoxifenhy·
dine. droklotid: Dextropropoxyfen-hydrochlorid; OelrtJWtlpOxy-
AeKCTpoMopaMMI\ pnene. chlorhydnite de; DextropropoX)pheno hydrochloridU1'1;
Hidrodoruro de dcxtropro;x>Xifeno; Propoxyphcne H)'d-och!o-
C2sHnN10 2 = 392.S.
nde (<J5AN).
CAS - 357-56·2
ATC - NO'lACOI. AeKCTpo:ipono•c"4>e><a r -~P<A
ATC Vec - QN02ACOI. C21HnN02,HCl = 375.9.
UN/I ·- 9S4 S6CIY83. CAS - 16J9-60-7.
UNI/ - C8Z1L9PSOT.
Dexibuprofen (IWI. UW( tfflJ >:OTI'- Compounded prcpamtions of dexrropropoxypltene hydro-
DeksixJpro{~o; Oexibuprofene;
Oeiabuprofeoo; Oexibuprofe. chloride may be represented by the following names:
num S{+)-lbupro{en. • Co-proxamol (8A.V)-dcl<tropropoxY1>he11e hydrochloride I
Ae•o16~
pan and pa1~cc1amol I0 pans (w/w).
CAS - 51 r 46-56-6. Pharmacopoeias. tn £11r. (seep.vii) and US.
ATC - MOIAE/4. Ph. Eur. 6.8 (Oextropropoxyphene ~e). A white or
ATC Ve1 -- Q!.tOll'.E I ~. almost white crystartine powder. \.l:ry soluble in water; freely
UN// - 671DKG7P5S soluble in alcohol. Pro1cct from lighL
USP 33 ~ Hydroct*mde). A white odOW'less
crystalline powder. Freely soluble in waler; soluble in alc:obo~ in
Street names. Tiic following terms have been used as 'screet acetone, and in dilorofonn; pructically insoluble in ether end in
names' (see p.vi) or slons names for various fom1s of dcxtromo- benzene. Score in ainight con1aincrs.
ramide:
Palf. Oextropropoxyphene Napsilate (SANM.f.INIW-V
D~ne. Napsilate de: Dextropropoxyphene Na-
Dextromoramide Tarttate (SANN, pJNNM) © ps)'late; Dex-.ropropoX)'phelli N•ps)as: Napsilalo de dextropro·
Bitartratc de Dextro.-noramide, DekstromoramidlurVaani; poxrfeno; Propoxyphene Naps)'la1e (lMN). 0extropropoxy.
Profil e Dd<stromoramido wvaw. Oextromoramidc kid Tati.rate; phene 1>aphthatene-2-sulphonate monohyefrate.
Del.ibuprofen is lhc S(+)-enan1iome. ofibuprofen (p.66) and is OeXll'OmOl'amiGe Hydrogen Tannte; Dextremoram~. v.r- AeKCTponpono•c..... HancwaT
11scd similarly in the management of mild lo moderate pain and trate de: Dexl/'omoramidi Wtras: Dextromoramid-lllrtarat:
inOaorunation in condi1ions such as d)'Slnenorrhoca, headache, CnH19N02.C1~HiO?S.H20 = 565.7.
Oextromoramrdartrat Tartr.rto ee dextromoramoda. CAS - 17140-78-2 (on/oydrovs de;ctropropoxyphene nop-
postoperative pain. dental pain, sprains, end soft-tissue rheum•·
Ae•CTJX>Mopaw·.AA,a Taprp•.r s1lote); 16570-10.5 (doxtropropo•yphene nopsilotc mono-
tism. lt is also used in musculoskelelol ond joint disordcts such
as ankylosing spondylitis.. ost«J.'lrthrilis, and rheumatoid anhri· C2~H;1N102.C,H,06 = 542.6.
l>ydrotej.
UNll - 3BM1 I 9LI OJ.
tis.. II may be used as an an1ipyre1ic lo reduce fever. CAS - 2922-H-3.
The usual oral dose is 600 to 900 mg daily in up 10 3 divided UNll - j778U505W5. NOTE. Compounded pn:pDralions of dcxtr0propoxyphcne napsi·
late may be repttSenled by lhe following Mon«:
doses, odjUSted according to mporu.c. to a usual maximum of Pharmacopoeias. [n£11r. (seep.,ii).
1.2 adaily. Elderly pa1ion1s ~hoold be started at 1he lower end of Ph. Eur. 6.8 (Oextrornoramidc Tanr.ne). A white or almost • Co-proxAPAP (P~xtropropox)'f'hene napsilaic and
the dose: l'lllgc: rJo>aie may chcn be increased according to loler- white. Cl)'$Ulline or amorphous powder. Soluble in water; spar- para~etamol.
ancc. Dose reduciions are also recommended on paticncs wich he- in&)y soluble in alcohol. A Wo solution ia water has a pli of3.0 Pharmacopoeias. In Br. and US.
patic or rcnal irnpaonncm. see below. to4.0. S P 20 I 0 (Dexti'Opropoxyphenc ~t~). An odourless or al-
For doocs in ehildttn. see below. onost odourless while powder. h exhibits polymorphism. Practi-
Profite cally insoluble in water; soluble in alcohol; freely soluble in chlo-
0 References. Dexlromommide isan opioid analgesic (p.108) sll\IClllrallyrclat·
I. Phkrs W. Ovcn•itw on dimcol d;t.ta of c!exihopiOfon. Clin RJ~u­
rofonn.
ed to melhodon< (p.86). II bas been used in 1hc trcalrnenl of se- USP 33 (Pr~ NapS'1late). A while powder having es-
""''ol 2001: 20 (>oppl It. SIS-Sll. vere pain ulchough ii was not m:ommcnded for use in obstetric
1. Ma}rhofcr r-. Effi,acy and fona·tcrm safc1y of dcxibuprofcn sentially 1>0 odo1U'. Very slightly solubk in water; soluble I in 15
(S(,.)-·ibuproref'I): a shott•tcm1 tffic:.cy study in paticu1s with OS· analgesia because of an incrc:ascd risk of neonatal depression. of alcohol •nd 1 in I0 of chlo:ofonn; soluble in acetone and in
h:oardvili$ of rhe hifl ::uld 11 I-year 1olcrabil:1y study in p:iticnts Dcx1ro111ornmide is subject 10 abuse. n!Clliyt alcohol. Stllf< in •irtigbt container.;.
"'llh rheumal~ disurJt"rs. C//11 Rlir11mn1012001 i 10 (suppl I); Dcxtron1ornmide has been given onlly as lhc urtracc. fl has also
S22- S19. been gil'cn rectally as suppositories and by subcutaneous or in·
3. Ma\"·eJ R. d ol. Compari<c0n of lhe cnicac}' and 101mbitil)' of Dependence and Withdrawal
du Ibuprofen and cel«<"'X•b in the uea1men1 or osttt1anhritis of ti·arnuscullt injection.
the hip. /111 J Clin Phnnoacol TMr 2003; 41: I53-«.
As for Opioid Analgesics, p. J05.
Preparations
4, Moor<: RA,otol. Sin;ledoscoral d<•ibuprofen [$(+)-ibuprofen) Dextropropoxyphene has been subject ro abuse {see
for acute posto~rativc pain in .Wulls. Available in The Cochr.inc: BP 2010: Dcxtromor&modo Tabieu.
Oat.bQ.sc or Sy~cm:tlic RtvK!w1: bsuc 3. Chichester: John w;.
under Precautions, below).
Proprietary Preparations (details arc &iven in Volume B)
Icy: :!OO'J (K«SS<d 08/09/09). lrl.: Pilll'ur.t. Ncrh.: Pa~..:e; Pi'l'oum. 0 Rcpor1S of dex1ropropo.•yphrne dependence and its treatment
Administration in children. Allhougb dexibuprofen is nol Ii· I. Wall R. t:t al. Addic1ion to Oiua1Ecsic: (dc>.1ropropo.xyphent).
ctnsed for use in children under 18 years ofage in the UK, some BW t9SO: 280: 1213-14.
coun1ries permit such use. f'or example, in Swiizrrland. dexibu·
2. o·Abidic NO, Ltnlon JO. PropoxyphC'oe dcpcodi::m:~: prQblcms
in rnan3Gtmcnl. Sou1/1 Mc:dJ 198-4: 17: 299-30 I.
profen h•s been given to children aged 6 years and over; usual !Oextropropoxyphene \BAN. {)INN)
oml doses are 10 lo 1S ms/ks daily in 2 10 4 divided doses. Li·
ccnsed producl info11na1ion for one prcpar.uion recommends • Oekstropropol<sfeeno: Oextropropoxifen; Dcxttopropc:»cifeno; Adverse Effects
onaximum dose of 300 mg daily for 1hose weighing less than Oextropropoxyphene; Oexttoprvpoxyphenum; Propo><yphene. As for Opioid Analgesics in general,p.106.
30kg. (+){ IS,2R)· f-llerlzyl·3-dmetly.amino-2-methyt-I-phe")ofpro- In the recommended dosage the adverse effect~ of dex-
A mullicentrc mndomised srudy1in children aged 6 months 10 14 P'tl propionate. tropropoxyphenc are less marked than those of mor-
years found single doses of dc•ibuproftn 5 or 7 mg/kg 10 be •S AeKCTpor11>0noKC'°4ie>< phine. Gastrointestinal cfiects, dizziness, and drowsi-
e1Tcc1iv• as ibuprofen 10 msJkg in reducing fe\'tt
I. Yuon JS. c1 ol. The c1TttlS und sarcty of dcxibuprofen compered
=
C12H:,N02 339.S. ness are the most common. Liver impainncnt, manifest
with ibvprofcn in fcbri1t chiklrc11 c.auscd by upper rupir.11ory CAS - 469-62-5. as abnom1al liver fi.mction tests and, more rarely, as re-
tnct in(cction. Dr J Clm Pltano1ocoJ 2008: 66: 854-60. ATC - N02AC04. versible jaundice, has been reported.
Adminirtration in hepatic and nmal impairment. UK li- ATC Vet - QN0]AC04 There have been a large number of fa1alities from ei-
censed product infonnalion ~pecifiC$ lhll lhe ini1i3f dose of dcx- UNI/ - S2f8JW9'lTK
ibuprofen should be reduced in patients wicll mild to moderate
ther accidental or intentional overdosage with dcxtro-
hepatic or renal impairmenc: ii should not be used in 1hose wich propoxyphene. Many reports emphasise the rapidity
severe impA1nncnl. with which death ensues; death within an hour ofover-
H3C'- _,....CH3 dosage is not uncommon, and it can occur within 15
Pharmac:.okinetics. For mencion ofihe meubolism of R·(-)-
ibupoofcn iodexibuprofen,seep.67. HC N minutes. Overdosage is often complicated by patients
f'unher references. also taking other CNS depressants such as alcohol and
I. Eller~ . r1 al. Phannacok1ndies of deJubuprofcn adminisltred u using mixed preparations such as dextropropoxyphene
200 mz and 400 mg film..c.031ed tablds i.n lw:11hhy \'OlurHeers. /m
JC/;nPho•.,JO<:O/Tlicr 1998:36: ~14-17 . ~CH3 with paracetamol or aspirin.
Preparations 0 Symptoms of overdoS3ge ore similar to those of opioid
Proprietary Preparations (dc1aits arc &ivcn in Volwne B) poisoning in general, but in addition patients may have
Arg.: CeW.X \l. ~ Austria: Actrfent: fo·Med Ne\.( Monac\rlt. -psychotic reactions. T!1ere may be cardiac conduction
M"""'1ef; Sotr.tt Ch8e: 0......: Cz.: Senci~: 0-m.: S<nttiv: Fin.: ~
De>itt: Gor.: DolWM: Dolooup>: Gr.: S<nctil; Hunr-: S...C-;t Indio: abnormalities and an·hythmias.
T~ symbol t denotes a preparation no longer actively marketed The symbol® denotes a subsinnce whose use may be rcs1ric1ed in cenain spons (seep.vii)
42 Analgesics Anti-innammatory Drugs and Antipyretics
Dextropropoxyphene injections are painful and have a deaths reached a peak in 1977 and then fell at a rate thal was not dextropropoxyphene can be exacerbaled (see also In-
very destructive effecl on soft tissues and veins when matched by a decline in prescribing. teractions, below). Stimulants should 1101 be used be-
It is not clear whether the metabolite, nordextrorropoxyphenc, cause of the risk of inducing convulsions.
abused in this way. plays an importan1 role in fatalitics. 12 However. nordcx1ropro·
Anorectal reactions have followed the prolonged use poxyphenc, like dcxtropropoxyphcne, is considered to have local Patients takiug overdoses of dextropropoxyphene with
of suppositories containing dextropropoxyphene; the anaesthetic activity and the membrane Slabilising activity ofdcx- paracetamol will also require treatment for paraceta-
reactions appear to be dose dependenL 11opropoxypllene has been implicated as a major factor responsi- mol poisoning (p.112). Mixtures of dcxtropropoxy-
ble for i1S severe cardiac depressant cffect. ' 3
Effects on the blood. A 12-year hisiory of haemolysis and phene and aspirin may be involved; the treatment of
In Janunry 2005, the UK CSM found the risk of toxicity of*
subscquentsignificantbacmol)1icanacm.a inanelderlywoman1 proxamol in O\~rdose to be unacceptable;" consequently, aspirin poisoning is described on p.21.
was associated with chronic. periodic, and occasionally exces- co-proxamol has been gradually withdrawn from the UK market
sive intake of co-proxamol. Around that ume. frxed-do$c combinations of dcxtroprop0xy- Precautions
I. Fulton JO. ~cGomgal G Stcrotd rt:t:pansivt hanrlolytic anaemia phene and paracetamol "-ere also witfldrawn in several other
due 10 dexlrop'oroxyphenc par1ttt11nol combination. JR Soc As for Opioid Analgesics in general, p.107.
Med 1989; 8?: 228.
countries including Sweden and Switzerland. More recently, in
June 2009. the EMEA" recommended that oil dcxtropropoxy· Abuse. There have been reportS 1 of the abuse of dci.iropropox-
Effects on the ears. A report of complete nerve deafness asso- phene-cooi.aining preparations, bolh single- and rnulti-consiiN· yphene. and some? considcml that the ready availability of dex·
ciated with chronic obuse of co-prox3mol was made to the UX ent, be withdra"11 lhrou10hout the EU; ii was considered thal the tropropoxypbenc made it liable 10 abllSe althou~h it was a rela-
CSM.' TheCSM h•d received 2 other repo11sofpennancn1 hear- benefits of dextropropoxyphene did nol outweigh its risks, pat· 1ivcly weak opioid analgesic. However, others thought there
ing loss attributed to co-proxumol abuse; transient hearing Joss ticularly the risk of fotal overdose. In October 2009 a re-analysis was no evidence that dextropropox)'J)hcnc was frequently asso-
had also been reported in 2 paticn1S taking usual doses; 7 further requested by 1hc produc1 licence holders upheld the EMEA's ciated with abuse, or concluded 1hat, although there was abuse
reports described tinnitus. original recommendation for non·parenteral preparations of dcx- potenrial, it was of relatively low irnponance in terms ofthe com-
1. R;Jmsay BC. Complcti: 11c1vc: dc:afhns ane:1· abust' of C:().ptoxam· tropropoxyphenc.16 For parentcr.<I preparations, it was consid· munity as a whole.'
ol. l.m>W 1991; 338: 446-7. ered that, although lheir safety in overdosage may be less of a A seven: withdrawal syndrome has been rcponcds in an elderly
Effects on the liver. There have been occasional reports of conccm given 1heir supervised use in hospitals, d11a on efficacy patient who covertly con.wmcd a daily dose of dextropropoxy-
jaundice in patients taking dcx1ropropoxyphene alone but many "'ere lacking. Consequently, tl1e EMEA rccormnendcd that prod- phcnc of I to 3 g for at least 12 months. The patient was treated
of the 49 suspected hep<1tic reactions with dcxttopropo.•ypllcne uct licences for parcntenil prcpararions be suspended until fur- by a graduaUy dec.reasing dosage schedule of dcxtropropoxy-
n:ported to the UK CSM by 198S 1 had in"ol"ed use with pant- ther data on their efficacy aic provided. In the USA, dcx11opro- phenc over 9 weeks.
cetamo~ clinical features including 1nala1sc,jaundice, raised sc- poxyphcne-con1aming p~parations remain available although I. T<nnant FS. Complications of propoxyphenc 1buse. Ard> lm"d
rum trans3mirl3ses. and sometimes f~r. were"°"'~ general- steps such as improvingprcscnl>cr awareness have been 1aken 10 Med 1973; 132: t91-'I.
ly characteristic of dextropropoxyphene alone. Relapsing reduce lhe risk of overdose. 11 2 . l..lde< M. A.,.,seof\\'eak opioid analresics. H•m To.ria>l t984;
jaundice mi.nicking biliary disease was attribu:iiblc to the dcx- An analysis" of pn:scriplion data in England and Wales from 3 (S\Jppl): 229S-l6S.
tropropoxyphcne component of CO·proxamol in 3 palients, 1 1998 to 2007 found that although lbc withdnlwal ofco-proxomol ). F>nkl• BS. Self-poisoning wi"1 du1ropropoxyphrnc anddcxtro-
propox>'Ph~nt comp0unds: lhe USA txptrienec 1111111 Toxicol
whereas lbere was no abnormality ofliver function in 11 paticn1S resulted in a siillificant increase of prescriptions for analgesics 1984; 3 (suppl): 1ISS-34S.
on long-tem1 co-proxamol analgesia.l Another repon of9 cases such as co-codan1ol, CO·dydramol, codeine, and paraceuimol, · 4. Tum<r P. Final r<mark.<.H11m Toxl<0/ 19&4; 3 (suppl): 237S-8S.
found lha11he hepatotoxicity or dextropropoxyphcnc mimicked there wus no staliSlical evidence for an increase in dcalhs by poi- S. Htdenmalm K. A case of SC\'C'rC whhdrawal syndrome due: 10
symptoms of large bile duel obstruction, and suggested that such soning due to substitution wilh these analgesics or olher druas. Jex1ropropoxyphene. Ann /utcm M~d 1995; 123: 47).
toxicity might be misdiagnosed.' A more recent reviews also
I. :!~,';~~lio~~~~J?:i~~j~ha~a~~;~~~~~~:~s~h~g·~~cil~8~.
0 1
concluded that hcpatotoxicity with dcxtropropoxyphene might Br east feeding. No adverse effects ha"e bcco seen in breast-
mimic a biliary tract disease, sometimes with few or no •)'Jllp- 2. Madsen PS, It ol. Acute propoxyphcne sclf-paiumi1\g in 222 fed infants whose mothers were receiving dextropropoxyphcne,
toms. constcutivc pa1itnl$. AC'fu Anoesthesiol Scund J984: 28: 661 -.S. and the American Academy of Pediatrics considers' that it is
3. ~~~~'}n.;;:,0;9~7i:"f: ;J;1: ~~troprop6xyphene in Denmark.
I. CSM. Hep2101oxitily with dc<i:1rop1~ypht'ne. C11r"n1 Prob- 7 therefore usually compatible with brca~1 feeding.
1. Ameri<'an Academy of Pediatrics. The 1ran.sfe.r ot drues and 01h·
lems 17 I9S6. 4. Jonauon u. rt al. Corre:luioo betwettt prescription or \'lriO\iS
2. 8aucndinc M F.~' of. Da-tropropoxyphc~ induced hepaw1ox- <k>ilfOJ?fOPOX)'phenc prcpar;i1ion.s and lMir involvcmenl in facal c:r chcnttcab into human milk. P~tlialrkl 2001: 108: 776-89.
ici1y mimicking biliary lrect disease. c"'
19&6: 17: 444-9. pOi$0mnas Fof'f'NkSci /n1 f999; IOJ: J2S-32. IRctittd May 20101 Correction. ibid; 1029. Aloo &Ylolabk ar:
htt p:J/11 ppo lie y.aa ppu hIica t io ns.oratc aIfcon lent I fu1l!
), HUlchlnson DR~ rl ol Lh'U function an pa1ie.nts on long-1cnn
puacct.3mol (C"o-pronmol) Jnalacsia. J p1;or., Phormocnl
s.e.,...,, D.<1 al. (ed~ Outalgcsic; Afdyand •ffiuc:y. H... Tox-
ptdiattia%3b10S:-.>1776 (acusscd 26/06/l)S)
ico/ t984; 3 (su!'l'1): IS-238$.
1986: 38: 242-3. 6. Proudfoot AT. Clm.cal featuru 3nd m:snagement of OiS1.al1c.sic Porphyria. Dcxtropropoxyphcne has been associated with
4. R-.berg WMC, n al. Dottoptopo.xyphcne induced hq»ro- o-.rclose. H•lfl Toskol t984; 3 (suppl): 8SS-94S.
toxKit)': a report of nine cnscs. J Htpotol 1991; 19: 4i0-4. 7. Whillinston RM. Dexiropropoxyphcn~ deaths:C()f()net'srcport. acute attacks of porpbyria and is considered unsafe in porphyrie
S. Bergeron L... ti ol. Dexlropropo_-<yphfnc el JllC'intu h~tiqun: j H•n1 To.•lcol 1984; 3 (•uppl): 17SS-185S. petients.
propos de 4 cu ct rc,•uc de hulraturc. Thtropir 2002; 57; 8. Youna RJ. Llwsun AAH. Oistalgestc poi~omng-c:ausc for
464-72. c:oncem. BM.I 1980; 180: 10.tS-7.
9. H3"'1on K. "fJI. Co-proxam0J alld suicide: a srudy of national Interactions
Effects on the lungs. Hypcrscnsitivi1y pneumonitis and skin moniilily 111ti11tic1 u11d local non·f-au•I ~lf·poisonings.. JJMJ For interactions associated with opioid analgesics, see
rash have been reponcd in u P3tien1 1:1kins *proxamol. 1 No 2003; 326: 1006-8.
p.107.
such reaction occutTed when the patient was subsequently given
paracclamol alone.
10
~i~i~~ ~~~~a~~ ~:O~~!~~~~~:.:~usdi~ rfn~~:~~~0~~ &~!.~J.!:'r~
1
Plasma concentrations of dextropropoxyphene arc in-
mocol 200S; 59: 207- 12.
J. Matusiewicz. SP. f!I ul. Hypcrscn#ilh•ify p11cu1noni1is :associ:ttcd 11. AC$hari R, tu u/. Co-proxamol overdose is associated wi1h a 10· creased by ritonavir, with a resultant risk of toxicity;
with co·proxam<1I (~racc1amol .. dcx1ropmpo.'<)phrot) 1hcf3py. fold excess monaliry compared with 01her p:aracc1amol tombi·
PoSlgrod M•d J I 999; 7S: 47S-6. n.~tton analgesics. Br J Clin Phormoco/ 200S: ctO: 444-7,
they should not be given together.
Hypoglycaemia. Hypo;lycaernia 113s occasionally been re- 12 Finkle BS. Sclf·poisoning with dcx1ropropoxyphenc and d<X· CNS depressants, including alcohol, may contribute Lo
1ropropoxyphc1"1c compounds; the USA experience. Hum Toxl~
ported with the use of dexlropropoxyphene. 1-4 col 1984; 3 ("'PP.I): llSS-34S. the hazards of dextropropoxyphene, see also Overdos-
I. \Vi~crholl IC. ~' al. R«urrcn1 epilOde:s of hypogtye<mta in· 13. Hcruy JA. Cassidy SL Membrane sta~li.sing activhy: a major age, above. The convulsant action of high doses of
duc:.:d by propoxyphcn<. N<11rolo11 I96i; 17: 703-4. ca\.1$t of fa1al pooonlng. Utnco 1986~ i: 1414-17.
2. Alm~IJ J, cl ul. Propoxyptiene.,nduced h)'pOllycc:mia in a pa· 14. ~1HRA . Withdra"'·al of co-prox-:unol products lnd interim u1[ dextropropoxypbene may be enhanced by CNS stimu-
t~nt with chronic renal failure ,l\'tpltron 1939; SJ: 273-~.
l. L3uttn1 M. ., DI. HypogJ)cimo< S«JS dc>troptopoxypl!!n< chez
dessrandsvicillard.: 7ca.PruJrl<ktl1991; 20: t628.
~i:!':n":'c't!in~~:;oi;i~ ~~~~~r~s:r,~b~
1

h11p://www.mhr-a .gov.uk/homelgroups/pl·a/documen11/
..; lants.
Dextropropoxyphene interacts with several other drugs
4. Lowm:saein W, t:I al. Hyposlyc;Cm~ tu ck:ttropr0p0xyphCn~ w<t>sitcmourccslconOl946t .pdf (ace~ 28108/08) through inhibition ofliver metabolism. Drugs reported
unc urgenc;e dw:7 le ln\icntnane. Prru.: .'1t01993; 21: 1ll. IS. EMEA. Press rclcuc: Ewopcon Mcdic-inc-s Agency r«om·
S. ~ntos Gjl I. ~' al. Hipoalucemiit sccundAria :a ingcstiOO de dcx· mends wi1hdraw1I of dcxtropropoxyphct1c·CC1nt:iining mf'di. 10 be affected include antidepressants (see p.410). ben-
tropropo.xifcno en un p21cicntc •dicto a drops. J.ltcl Clin (Bore') <IOC$ (issued 2Srb Jun<, 2009). Av-•ilablc 11: 1.odiazcpines (see p.1093), beta blockers (see p.1353),
1998; 1tO: 47S-6. hnp:/lwww.en10.curopa.cu/docs/en_GB/document library/
6. Sh.ah P. et al, ProPoX)'phene·.)nd\ICcd hypoclycemia in renal fail- Pr<ss.rclcosci2009/l l•'WC50001036S.pdf(occcmd 0°2!08110) carbamazcpine (see p.516), phenobarbital (see p537),
ure. £11doc:r Pmt·f 2006: 12: 170-3. 16. EMEA. Quesiions and answtts oo lln: wil11tl111w;tl of1hc 1narkcl· phcn:r1oin (see p.542), and warfarin (sec p.1565).
in' emhorisations for medicines conh1ining dcxtropropo~y·
O verdosage. There have been several reviews or retrospective phtnt (i u ucd 22nd October. 2009) . Av•i lablc ot: Antimuscarinks. A suggestc<.I inleraction belwccn orphcn-
srudics of acule self.poisoning with dextropropoxyphene. 1... At a hllp://www.i:m11.curopa.cu/doc:s!cn_GB/doc:umcn1 library/
Referrals .d0<:umco>tldcxtropropoxyphtn<_31 IWCSOOO r4076.pdr ndrine and dextropropoxyphene has been questioned (see
syrnposium on the safely and efficacy of dextropropoxypbcncS (aC<C$'1td 02/QS/I 0) p.896).
many of the panicipants dc•lt with the problems of dextropro- 17. FDA. t\cw1 release: FDA takes x1ions on Darvon, other pain
poxyphcne O\'erdosage, o0cn in conjunction witl1 paracet3mol m<:dic11ion1 con1>inin& propoxyphenc (issued 71h July, 2009).
and sometime> with alcohol. Profound and e"tn fatal CNS de- Avoilabtc al: hnp;l/www.rda.gov/NcwsEvcrits/'Newsroom/ Pharmacokinetics
pression can develop rapidly as a result of the dc.'tropropoxy- l'r<osAnnounc<m<nu/2009/ucml70769.htm(a<c:<SSC<i01/02110) Dextropropoxyphene is readily absorbed from the gas-
18.. Howton K, tt ol. Effe-cc ofwithdraw31 of co-.pmxamol on pre·
phenc content and in many uses death has occwred within an scribina and &:a1hs from drug poisonins in En:,t30d and Waln: trointestinal tract, the napsilate tending to be more
hour;6 it was suggested that as few as 15 to 20tabletsof co-prox- lllM Kllf'I analysis. Abrid~cd vcrsioo.: BJ.IJ 2009; 339: .ilS-8. slowly absorbed than the hydrochloride, but both are
amol may be fatal. 1.1 Analysis of suicides in\'olving drugS in Foll •<ft•ioo; h11p:Hwww.bmj.c0mlcgi/Tqrint/3lllljunll_2ib2270
subject to considerable first-pass metabolism. Peak
England and Wales bc1ween 1997 and 1999 revealed that the (ICCUStd 02/11/09)
odds of dying after overdose with co-pro.umol were 2.3 times plasma concentrations occur about 2 10 2.5 hours after
that for lricycfic antidepressant ovctdosc, and 28.1 times greater Treatment of Ad ve rse Effects ingestion. It is rapidly distributed and concentrated in
than for pataoetamol. 9 Another analysis of suicides due to poi- As for Opioid Analgesics in general, p. I07. the liver, lungs, and brain. About 80% of dcxtropro-
soning in 3 areas of the UK between 2000 and 2001 identified Rapid treatment of overdosage \\~lh naloxone and as- poxyphene and its metabolites are reported lo be bound
123 casc:s of fatal overdose with co-proxamol; 10 those who also
sisted respiration is essential. Cardiac effects may not 10 plasma proteins. Oextropropoxyphene crosses the
ronsumed alcohol haJ generally lakcn fewer co-proxamol tab·
leis than those who had not, emphasising the increased toxicity be reversed by naloxone. Although the benefit of gas- placenta. ll has been detected in breast milk.
of the combination. tric decontamination is uncertain, activated charcoal Dextropropoxyphene is N-demethylatcd to nordex-
An analysis of overdo.,age involvins combination analgesic may be of value within I hour ofingesling a potenti~lly tropropoxyphene (norpropoxyphene) in the liver. It is
prepar•tions prescribed in Scotland between 2000 and 2002 also toxic amount; dialysis is oflittle use.
found that overdoses with co-proxamol were l 0 times more like-
excreted in the urine mainly as metabolites. It is now
ly to be fatal when compared wilh co-dydramol or co-C-Odamol." Convulsions may require control wid1 an anticonvul- recognised that dextropropoxy.phene and nordextro-
In the USA 11 the incidence of dcxtropropoxyphcnc-associatcd sant, bearing in mind that the CNS depressant effects of propoxyphene have prolonged elimination half-lives;
All cross-referenc-cs refer to entries rn Volume A
 Dextropropoxyphene/Diarnorphine 1-!ydrochloride 43
valuesof6 lo 12 hours and 30 lo 36 hours. respectively, on the market in other countries. including the USA. For furlher 3. Rlntclen B. ._.,of A l'llct3·ou:ilysis of C'{'mlrolh.'CI e:llnicol .nudics
details see Ove;closa!!•· ab<wc. w11h diatcr~in in 1ht tl'C:>tmcnt ofo.stet"larthri1i1. A't'lt Int~• J.Jed
have been reported. Accumul:1tion of dextropropoxy· 2006: 166: 1899-1906.
I, Seavc-r WT. Am1lgc:sic cffi~f ol' ck>.Croptopoxyphenc a1~d dcx ..
phene and its metabolites may occur with repeated dos· Lropropo>.yphcnc·concaining combmo:.tOnS: a review. Hum To.d· . a. Oancls EM. <·I 11/. SymptOStt¥tic efficacy ;ind 14fc1y of diaccttin
ln the lralnit'nl <'rosteo.'Uthriti.s::, 111et3·~n1ly•i' orrnndomi.zcd
cs and nordextropropoxyphene may contribulc 10 the col 19!14: J oupplJ: t91S-220S. plaCC'bo-cCMUrulh:d tri::al'I. O:f;mor1l11·i11J Cttrl/lage ~010; IS:
1oxicily seen with overdosage. 2. Muurc RA. « of. Single dost dexiroproroxyphcnc. alone 1.md 289-96.
wi1h pau«l~mol (acttominophc:n), for postoperative pain.
0 Reviews. ,.\nil1'blc- in Tiit Codv1nc OaHtbHc ofSysce-mahc Aevicws: Is· Pharmacokine.tics. References.
sue J. Chichester: Jolin Wiley: 1999(oeces"'d16!06/08) I. Debord r. Nol. Jnnue.nct o( n:1'8l functiotl on 1hc pha.nnacoki-
I. Pe:ar:i;on RM. Pharm)colinrtics ofptopos~1,hcnc-. HHm Tos.1eol J. fJoigh S. Jl Years on· co-proxomol rt"visi1e:d. loJ'ICf'I 1996~ 347:
198-l: 3 (s 11 1~> l 1 : 37S-•os. ne1ics of diaoerein :after • single or:JI dose. Enr J Drug Mc1ob
)840-1. Corredion ilnc/.: 348: 346. PJ:ormocokinel 1994; 19: 13-19.
The elderly. The elimination holf-lh-cs of dcxtropropoxyphcne 4. Syk~ JV. el (If, Corro.umot rc,·isiced. luMut 1996: 34S: 40S. 2 Nicolai> P. el al. ClintcaJ ptiarmacokineiic$ of d11«rf·i n. Clin
S. Li Wan Po A, Zh:.na WY. Sys1ematic O\'C'l"Yitw of co-proxamol Pliorm(J(Oki11d 1998: JS: 341-S9.
and ilS mcuibolitc nordcxlropropo><yphenc were prolonged in lO A.SSCU ant'l)~Hit effects o( addition o( dc>.ltOprOpo:xyphcnc IO
healthy elderly subjecis when compared wilh young conlrols.1 parac<1'1mol BMJ 1997; J tS: IS6S-71 C0«ee1ion ;b;d. 1998: Preparations
A ftcr mul11ple dosing median hulf·livcs ofdcxtropropoxyphene 316: !!6 .,,., 656. Proprietary Preparations (detail$ arc s,ivcn in Volume B)
and 1101-dcxtropropoxyphcnc were 36.8 and 41.8 hours, respec- 6. Anon)'1tt0'4 C<>-proxamol nr parac.°'uunoJ fut ac•lc- pain'? Dm: Arg, A."ltOCbr. Auwla: Artrolylj: Vert>ont &.o.... Ao1roda•~ Chile: Ann·
tively ill the elderly comptred widi 22.0 and n.1 houts in !he Thor 811111993. 36: SO. zona: C>.: An.'Odot: Fr.: Ht: Zcndar: G1.: kWriJr: Ar1hror<irc Qe.
young subjects. In this study' there was a Siron& corTClation be· ...-erc O.at.... Daceti: ldeot1e: lnllat>on: t1)otlloc o...m: Pentacrin: Rt-
PN!parations umane.t - ~ Hong Konr: Ar\IOdr. lndon., Mrodar:
tween half-life of no1'dcx1ropropoxyphenc and .s1ima100 Loeitli-
BP 20 10: Co-proxamol lablels. OticlroprclllOX)l'llene c.p......, /,..oel: Art: Oiltm'C /tol.; rl90daf; Moloy1io: Ant-. Pon.: AIVoi)'t:
mnc clearance. USP 33: l'ropox)JX>eoe 11,.0-« and Ace1<1minophen ~:>lets;""'­ Cartivi><: Au1" ~ tA.>•po...,p•.,): Spoin,Galaxda<. ~Thal.:
t. Flanagan RJ. nl. l>tlMrml\cokinehcs
ttf or
dt:<tropropoxyphtne ~ Hydrodllo- Czp!Ues: Propooc)llllene Hydroclioride. Asp.. Antod:ar: Turk.: Ar.rodor, lloxeN: VeMz.: Arttodil<
and nurdatroprOC)oxyphcne in younc and ddctly voluntects af.. M. and Ca~..,. Capsultt l'l opoo<)pl>o11e i'olop<yl<IC W
Aceta~ Muld·ln&rcdient Mex.: Ooocariip
ler sinitc and 1nuhipk dc.\tropn>pOX-yphtne dosage. Br J Clln Tabra P~ne Nopsylat• !.-.I.....,..., T.olcts: Prop°")'phme Nop-
Phn"'t<IC<>I I QS9: 28: ~63-9. •,C..te On! Su<;>••,.1on ~ N'P')llte Tabltt>
Hepatic impairment. Plasma concentrations of dcxlropro· Proprie!ttry Preparations (de1ails are given in Volume B)
A.g.: Gobl:ogtslcf. Awtrol~ Dol°""roe: Self•' [)eptonot CoMd.: M2.
poxyphcnc were higher in paucn1s with cirthosis ghoen die drug Oarvon-N: Otnm.: ~ Doloxcnt: Fin.: ~ G-.: Romid<><l: Zi· Diamo rphine Hydrochloride (BANM)
than in healthy subjCCIS whctw concenlr.uions ofnordexcropro- d"""'' Hone Ko~~ Dop00<y: l r>dlo: Parvodox 11aL: U>ei:nt.
po~yphene were lowcr. 1 M elt.: Darvon Simplet: S.lude.x: Neth,: 0e,?rom¢ NZ: Oolo>Ct"4tf; ®
S.Aft" Ooloxene: Spo;n; Dtp<onccl. Sw«I.: Dexor..,. Ooboenc USA: Diacetilmorfina, t>drock>rJto de; Oiacttylmorphine H)<lrochlo·
I. GiDComini KM. rt ul. Propoxyphcnc .and narp.:opoxyphenc pbs.- °"-" Dor""'1·N.
ln3 conctntrations after or~I propoxyphenc in cirthotic p3tients nde. Heroi" Hydrochloride:: Hidroclon.iro de diarnorlila: H.dro-
with md w1tbool surgicalty constrUtted port.~aval Muna. Clin HultNJllre<U"1t: A11.: Arl;le:,._ C¥nopirint. Q.P~: Ocxprofcro: Dex·
\IO + DlpO-ona: Dmtoclp1: Doti,.,.. Farte: Gott>oulm: l<losidot Klosidol dor..-o de herofna. 1,5-Epoxy-17.methyfmorphinan-3.6·dlyt c»-
P/hJrmo<ol Th" 1980: 28: 417-H.
81 S6 Bl~ P'Oium P\i1, Sup·~sic; V~AunroL: Ciplde>e c;.c;,. cet.-ie hydrochloride mo~.
Renal impainnent. Higher and more persisl<nt plasma con· ""' P.,-.de>C AuJcrio: N>1>< Si~•Gn 8., lortef: s.1.1>'.A!Jophene; Brat.:
O~-A; Fr~ Dt>orctt( Di Do!<o: Di·Arluk !Mlgnoc; Dio•lgo: p,..,. f epoMH• r ><ApoXllOP"'A; ~ f HAPO><J\OPMA
cenlrations of de•lropropoxyphenc nnd nordex!ropropoxy~ne
pofan: HOt>f Kone: COY•lcsic Doloci« Ooipcntmot Medonol Prccetal· C 21 HnNOs.HCl.H 20 "' ~23.9.
in an~phric patients when compared wilh healt~y subjects were ette: Procetomol ~ Uro-Proo<.vno•: Hunt' No.q>y.i,,t. lndlo:
anribu1cd to decreased lirst-pass metabolism of dexaopropoxy-
phcne and decreased renal t.•tttlion of nordc•tropr0poxyphtnc
SutaprO><)'V0111 !bu.~ P.n.on: Par"°n Foru: Panon Spas;
N: Proxyub: PrOIC)\<ln; Spwno.P""'l"Cl\ Spasmocip: ~PM: s,,.
"""°"" CAS - 561 -27-3 (diomorphine): r 502-95-0 (diomorphine
hydrochlo1ide).

~~~~~~t~~~~~~~~
in the anephric patients. ATC - N02AA09
1. Gibson TP. c-1 tr/. Propox)'phcnc :and nntpr0poX)'l>hcne pl3sn1a ..O.TC Vet - QN02AA09.
•OJ<: N Z:Apc·Pandexf: Capade>c: Pamux: Port.: Al&Jfone: S.Af1.:
c:(mcrncn:1ions in the l!IH.:j)hric patient. Cfin l'l;.armocol Ther DllUl:?aic Doloxe:ie Co: Do.-,lcno: lf«020<ic Syoapc Swed..: D.Sl>'ge· l/NI/ - 8H672SHT8£.
1980: 27: 66S-70. >ict. Coluo.•t: P<r•llex compf. Ulu.: S°pi..,o-l'tox)"On (Cna>MO-
~~~A.;=•tD•1v;xet D..-....,:~1Mt_,Ulmj)our.dt.
Uses and Adm inistration
Dextropropoxyphene is an opioid analgesic (p. I 08)
structurally related to methadone (p.86). It has mild an-
H3c[(o~
o I .o
Diacerein (rlNN)
algesic activity and is given ornlly as the hydroch loride
or napsilate to alleviate mild lo moderate pain. Unlike Diace.-eina: Diacereine; Diacere.-...:n: Diacerhein: Diacetylrheiii: 0. H
2.1.0ckilo.-obenzylique. alcoot Rl>ev> Diace".ate: SF-2n: SF-277. 0 ·. NCH3
1he laevo-isomer (levopropoxyphene), dextropropoxy- 9.10.Dol')'dro-4.S-dihydroxy-9, 10-dooxo-2"'-'lthroic acid diace-
phene bas little antitussive activity. tate.
Dcxtropropoxyphene is mainly used wilh olher analge- A1..auepe1-1H
H3CA O.. b
sics that have anti-inflammatory and antipyretic ef. C,,H 120a = 368 3
(d>omorphine)
fects, such as aspirin or paracetamol. In the USA the CAS - I 37 39-02-1
ATC - MOIAX21
usual licensed dose is 65 mg of the hydrochloride or ATC 1/et - QNIOIAX/I Street names. "Ille followin.. 1enns have been used as 'street
! 00 mg of the napsilat~ given every 4 hours up to a UNI/ - 4HU6)11£L5. nomes· (seep.vi) or slang nnn'les for va1ious fonns of diainor·
maximum total daily dose of 390 mg or 600 mg, re- phine:
sp.'Ctively. ln the UK sim ilar doses were given three or 51 Chevy: A Sidani; AIP; Al Capone; Amelia; Antifrecz.c; Aries;
Aun! Ha21:I; Aunlie Hazel; Aunty Hazel; Bacalhau; Bad bwidle;
four rimes daily. Bod ~; Ball: Ballot; Ban Simpson; Batman; Beast; Bi$ Dad
TI1e EMEA has recommended that all clextropropoxy- Boy; Big bag: Big doodig; Big 11; Big Hany; Bin laden; Bondie;
phene-containing preparations be no longer available Birdie powder, Black; Black Dragon: Black eaJ!le; Black Girl:
Block pearl; Black sruff; Bl•ck tor; Black lOOISic roll; Bl3nchc;
in the EU (see also Overdosage, above) although such Blanco; Blast: Bleuc: Block buslers: Blow; Blows; Blue bag;
preparations remain on the market in other countries Blue hero; Blue sl.'.lr; Bobby Brown; Bomb; B<lmba: Bon1bc;
including the USA. Bombido; Bombila; Bombiras; Bombs away; Bone; Bonita;
Boy; Bozo: Brad; B1ain damage; Brea; Brick .:wn; Broja; Broth-
Pein. A detailed review' of lhc tmal8Cl'ic efficacy of de,lropro- er. Brown; Brown crystal~ Brov:n rhinc:~ Brown sugar; Brown
poxyphcne suggested 1ha1 with respect to sioglo cnl doses.=· tape; Bugger: Bull dog; Bundle; Burra; Buru; Coballo; Caco;
ommended doses of dextropropuxyphene were no more (and Calbo; Capital H; Caps: Coplain Jack; Carga; Came; Cavalo;
probably less) efleaive 1hm °""'I doses of paracetaniol. aspirin. Chang; Oiapopol~; Charley: Chawra; Cheese; Cheevnh;
or other NS/I.IDs. Howcvtr, the c:otnparalive efficacy may vary Clieva; Chcv:il; Chi: Chitia: Oiick; Chicken: Chicle; Chieva:
Profile China cal; China "ilite; Chinche: Chinese H: Chinese red; Clli·
substantially depending on !he cause oflhe pain. Oiaccrein is an anthraquinonc derivative that is used in oslcoar- ncsc Rocks: Chinoise; Chip; Chiva; Chocoran; Choco-fan;
\\-"hen it comes to comparativt studies in\'olving combinations of thritis Cp. l I) in oml dnscs of 50 mg ll•ice daily. D=s should be Chueva: Chunks; Climax: Cocofan: Co(Jec; Catie~; Cotton Can-
dextropropo•1phen< with other onol&esics, lindingi; are even halv~d in patients with crcatininc clearance less than dy: Courag~ pills: Crank; Crap: Crop; Crown crnp; Cura; Dead
less clcar-cuv 1l!e efficacy ofco·pro,ernol has loug been• nial· 30 ml..hninu1e. Diarrhoea is a common adVC1SC effect with di•c· on arrival; Dcl!d p1~siden1: Deuce; Diesel: Diagidy; Dir!; DOA;
tcr of conuoversy )'Cl dcs1~1e 1his • survey' conduc!ed in 30 UK crein. Tis :»ictivc metabolite, rhcin, a constituent of rhubarb Dog food; Dogce: Dogie; Doogic; Doojec; Dookcy Rocks; Doo-
teaching hospilals found ll"'t co-proxomol was the most widely (p.1923). is reponed toacl as an imerleul:.in-1 inhibitor. ley: Dooscy; Dope: Downlown; Dr. Fcelgood; Dragon; Dreck;
used ~racctamo}oQ)flta:init~ analgt:sic al the Hme. fr was sug- OT; Du~; Dua••: Duji; Dujra; Dujre: Oust; Oyno; Dyno-purt;
acs1ed !hat !he popularity or ro-proxamol was pw-cly do"11 10 Administration in renal impairment. See abo\"e and l'hor-
mAColcinclics. lielow. Eggs; E1gh1; Eighth; Elephant; Estuffa; fechiva; Fcrrydusl; Fix;
pn.'SCribing habits passed on 10 new medical Slaff, rather lhan Flea powder; Foil: Foo foo slull; Foolish powd~r; Fwni; Gallo1>-
hard evidence reg•rding efficacy. This view hls been refuted by Muscutoskeletal and joint disorders. Diaccrein is thought ing horse; Gallup: Gainot; Garbage; GAio; Gear; G~; George
others• who say 1ha1 a large nwnber of srudics have shown cle11r lo act via inhibition ofin1erle111dn-IP.,1 which plays a role in in- smack; Ghost: Girl: Glac1ncs; Glass; Goat; Gold; Golden
analgesic effec1s for dcxtropropoxyphene. However, any as· nalllmatory processes. Sys1cma1ic rcyjewr~ on 1hc osc of diac- BtoM1; Golden girl; Golpe; Goma; Good; Good H; Good Horse;
sumplion 11..,t the combination was widely used because ii was ercin in the 1rca1111cn1 of osteoarthritis have indicated thal di· Good and ple11ty; Goods; Goop; Grape Jolly Rancher; Gravy;
more effec1i"c 1han paracclamol alone was n<ll _S!Jpponed by a ~cerein p<oduccs a small, hut consistent, unprow:mcnl in pain. Grey sbields; H; H22: li-bonib; H Caps: Hadle; Hair; Hairpiece;
systematic overview o(singlc-do~c siudics.5 This concluded thal f urther research is necessary to confinn ilS short· and long-term H•iiy; Hammer; Hud candy; Hard sauff; Haniet Tubman; fur·
while co-proxamol was inttecd an effective analgesic ii was no efficacy and s,afcty bot there is some evidence ofresidual bene1i1 ry; Hany Jones: Hayron; Hazel; Hea\'cn; Heaven dust; Heavy
hencr than para<:elamol aloM. Although the e'idencc from !his on stopping 1rcatmcnt,1 which bas been postulated to represent stuff; llelen; llell dusl; Henry; Hera: Hero; llcro of die under·
world; Hcroa; Hcroina; Heron; Herone; I Jessie; Him; Holy lcr·
•nd Olher systcm•tic rc"ie"s indicate Iba! co-proxaniol should an improvcmenl in the disease process. The increased risk of di·
rm; Hombn:; Homebake; Homicide; Hong-yen; Hood; Hop;
bt replaced by paracet•niol alone for acute pain, the posh ion for o.nhoea was a noted effccl with diaccrein.4 Horning; Ho1-se; Horsebilr; Hot dope; Hot heroin; HRN; lsda;
chronic use is coosidcre<t 10 be noi so clear (but see bclow).6 I. Y.t1t den Berg WB. Lu inkanismes d'aclion 6e l:i dioccrh~inc. Jock; Jee gee; Jcny Springer; Jesus; Jive; Jive doo jee; Jolwilo;
Concerns about !he safety and eflicacy ofdexuoproxyphcnc, in pttmicr inhibiteur de l'i111crJCt1ldnt l dans l'1rthrosc. Prt'su
Med2004: 33: 10- 12.
Jojcc; Jones; Joy; Joy dust; Joy R•kes; Joy powder; Judos; Junco;
particular its safety in overdose. have led ~1e EMEA lo rc«>m· 2. Fidclix TSA. ~I al. Oiacerein for osteoa.rthrills. Av1ih1blc in Tl•e Junk; Kab:Jyo: Kaka Water; Karachi; Kermit !he Frog; la Buena;
mend that all dc•tropropoxyphenc·containing preparations be Cochrane Dae.abase of Sy11erna1ic Rt?v1ews: Issue: I. Chichestct: t.a Chiva; Lady H: l•ynci LBJ: lemonade: Ufc saver; little
no longor avail•ble in !he EU although such preparations remain John Wiley: 2006 (ae<e»«I06110/06J. bomb: Man: Manteca; Mou:akow: Mayo: Meleican Black Tar;
Th( symbol t denotes a preparauon no longer actively marke1ed The symbol @denotes o substance whose use may be restricted in cenain sports (seep.vii)
44 Analgesics Anti-inflammatory Drugs and Antipyretics
Mexican brown; Mexican Din; Mexican horse; Mexican mud; In another stability study* diamorphine hydrochloride in concen· IS. Kric:g:stcin AR., et al. Heroin inhml3tion ind progrc.nive. spongi-
Mister Brownstone; Mojo; Money talks; Monkey; Montego; !rations of both 1 and 20 mg/mL in sod ium chloride 0.9% was fom lcukornccphaloparhy. N E"gl J Med 1997: 336: SS9-90.
Morse Code Features; Morotgan; Mona! combat; Mother pearl; stable fora minirnurn oflS days at room temperature (23° to 25°) A fora I case of sporrgiform lcukocncephal0pa1hy
16. Lon& Ii. al al.
linked 10 ..chasing !he dragon". J TQ).'lcol Cli" T~icol 2003; 4 t:
Mr. Brownstone; Mud; Murotugoni; Muule; Nonoo; Nice and and4° when stored in a PVC container. In one type of disposable 887-91.
easy; Nickel bag; Nickel deck; Nixon; Noddy Brown; Noise; infusion device (lnfusor) similar solutions were stable for IS 11. Dabby R. tt ol. .4.cute heroin-related ncuropathy. J Pcripher
Nose: Nose drops; Number 3; Number 4; Number 8; Nurse; days even at 31°. In another infusion device (lntermate 200) Nuv S;•si 2006; II : 304-9.
Qddy Noddy; Ofcourse my horse; Oi;oy; Oil; Old garl>agc; Old diamorphine was stable for a minimum of 1S days at both con- JS. Kinri P. et of. Toxicological d1;11 af1cr heroin overdose. Hr11n
navy; Old Steve; One way; ~ngc line; Outfit; Pack: Pakisrao- ccnrntions and all 1em~tures C.'<cept for the 1 mglmL solution Toxlcol 1989; 8: 487-9.
aisc; Palco; Pangonadalol; Parachute; P-dopc; Peg; Pepper; Per- kepi 1131°when stability was only maintained fora minimum of 19. ~c,.·an A.a ol.. Bcw:ty pac.ki.ns,-a c.ag rtpon and review of the
fect higb; P-funk; Pluto; Po; rocira; Poison; Polvo; Poppy: 2 days. When SIOTCd in glass syringes both strengths of dialOOf- l11eratur<:. Postgrod .\led J 1990: 66: 6S9-61.
Poudse; Powder; Prtdator; Primo; Prodlllo; Pulbom; Pure; Quill; 20. Tritib SJ. e1 ol. Pediatric ~)' peck1na·. A1d1 Pedtotr Atlol~sc
phine hydrochloride were stable for IS days at 4° and et room Med2003: t57: 17•-7.
Rxc ham Olarlie; Racehorse Olarlte; Ragweed; Rain; Rambo; tcmpcnturc the 1 m1tmL solution was stable fOf a minimum of
Rane; Raw; Raw fusion; Raw hide; Raw OppoltlUlities; Ready 7 da)'S and !he 20 mglmL solution was stable fOf a minimum of Adm inistr;otion. Although generally free from complicarions,
rock; Red chicken; Red devil; Red eagle; Red rock; Red rum; 12 days. There were no substantial changes in phys~al appear- sterile abscess formation was reported io 2 peticnrs with ad-
Reindeer dust; Rhine; RingofTurd; Robflahei1y;Rock; Rocks; ance or pH. vanced cancer receiving diamorphine by continuous subcuto11e·
Rush hour; Sack; Sall; SC11g; Scat; Seate; Schmack; Schmeck; ous infusions.' Acute dysphoric reactions have been "'ported af-
I . D>Vey EA. Mumy JB. Hydrolysis of diumorphine in >queou1
Scluncek; Scott; Scramble; Second 10 none; Shit; Shmcck; solutions. Phorm J 1969; 203: 737.
ter the use ofepidural diamorphinc.2
Shmeek; Shmck; Shoot; Silk; Skag; Skid; Skunk; Slack-dad-eal- 2. Davey EA, Murray 18. Determination of di:amorphine In the I. Ho:skin PJ, 1:1 cl. Sterile abscess rormation by continuous subcu-
your-heart-ou~ Slam; Sleeper; Sleepers; Slime; Slow; Sludge; presence orl1s dtgr&dalion produclS using gas liquid chrOm8tO&· llllleous infusion of diamorphint. BMJ I988t :Z96: 1605.
Smack; Snotty; Snow; Spider; Spider blue; Stuff; Stunna; Sugar; rophy. P/1on• J 1971; 207: 167. 2. Holder KJ, Morgan BM. Dysphoria .-Oer cxtrndur31 diamor·
Suicide; Swc:cl dreams; Sweet Jesus; Sweet stuff; Syntbe; Tang; 3. Cooper H, Cl nl. S111bilhy or diamorphine in chloroform water phinc. 81' J Anoeslh 1994: 72: 728.
Tar; T351e; Tecata; Tecarc; Th1ilandaisc; Thanic; The beast; The mixture. P/1om1J 1981 : 226: 682-3.
fake throwdo,.11; The Jack 3aucr; The Loud·HOll<e Pemiadillo; Breast feeding. The American Academy of Pediatrics has
4. Tu:ycron .RG. Slability of diamorphinc in chloroform w11er. stated 1 that, when used as a drug of abuse by breast-feeding
The Nax; The wireh; Thing; Thunder; Tiger; Tig,e: ligre Blan- Pharm.11981: 227: 2 18.
co; ligre del Norte; Tits; TN"r, T.N.T.; Tongs; Tootsie roll; Top S. Beaumont JM. SLlbility or dtamorphillf! in c.hloiofom1 w.ier. mothers, diamorphine has caused adverse effects in the infan~
drool; Train; Tra.~; Twin IOWCIS; TWists; Vidrio; Wllack; PoormJ 1981 : 227: 41. notably tremors, restles:sncss. vomiting. and poor feeding. How-
Whicked; White; White Bilch; White boy; White dra.,o0n; While 6. JOMS VA, ~t ol. Oiamorptune sc.ability in aqueous soluttoft r°' ever, the BNF 59oonsiders that dillTlOfJ-.11inc when given in ther·
dynamite; White girl; Wl1i1c hone.; White junk: White lady; .ubcul.m<OUJ inflmon. Br JC/in Plrarmo<o/ 1987: 2J: 6.5JP. apcutic doses to a brcaSl·fccding mother is unlikely to alfect the
White nwse; White Pony; While stulT; White Tiger; Wicked; 1. Omar OA. '' ol Diamotphuie stability in aqueous solution (Of breast-fed infanL
Wings; Witch; Wilch hazel; WTC: Zoqude. •ubc1111neou1 mfusM>n.J pftar., Phonnaco/ 1989; 41: 27S-7 Sec also Opioid Dependence under Uses and Administration, be-
¥. Kleinberg ML. <I oL Stability of h<roin hydn)chloride ;,, U.fu·
Pharmacopoeias. In Br. and Swiss. Swiss also includes the an- sion dev1QCS »nd conteincrs (or inlnvcn0\l$1dmfn\srn1ion. ,,,,,, J
low.
hydrous fonn. HospPho•m 1990; 47: J17-81. l . AfM'rican A.cackmy of Pediatrics. The tran.sftr of dN&S and o<h·
er chemicals in<o hum~m milk. PcJ101rlc1 2001; 108: 7i6-89.
BP 20 IO (Diamorpl-inc Hydrochloride). A white or almost [Retired May 20101 Correction . ibid; 1029. Also available 11:
white crystalline powder, odourless when freshly prepared but De pende nce and W ithdrawal hllp: IIaa ppo Iicy.aappu b 1ic aIions. orgfc gi/con le nt/fu11/
develops an odour characteristic ofacetic acid on storage. Freely As for Opioid Analgesics, p.105. pcdiatrics%3bt0813n76 (acc<ssed 26/06/0S) •
soluble in water and in chloroform; soluble in alcohol; practical- Hypersensitivity. Anaphyloxis occurred in a patieat given
ly insoluble in ether. Protect from light. Diamorphine is subject to abuse (see under Adverse
EffccL5, Treatment, and Precautions, below). i11trotheco/ diamorphine and bupivacaine for surgical anaesthe-
lncompatibilit:y. Diamorphinc hydrochloride is incompatible sia; 1 the authors noted that the paticnl received paticnt-co111rollcd
with mineral acids and alkalis and with chlorocresol.1 Diamorphine is used for substitution therapy in the analgesia with morphine shonly after the reaction withoul prob-
management of opioid dependence (see under Uses lem. Subsequent skin prick tests identifred diamorphine as the
The BNF 59notes that cyclizine may precipitate from mixrures likely causative agent.
with diamorphine hydrochloride It concentrations of cyclizine and Administration, below).
J. Gooch I. GwinnuH C. A"aphyla::icis 10 intra1hec1l di1morphint.
greater than 10 mglmL, Of in the presence of so<lium chloride Resv1citotitm 2006: 70: 470.-3.
0.9%, Of as the concentration ofdiamorphinc relative to cyclizine Adverse Effe cts, Treatment, and Precau-
increases; mixtures of diamorphinc and cycli2.inc arc also liable Phaeochro mocytom;o. Diamorphine can liberate endog-
tions enous histamine which may in tum stimulate release of eatecbo-
IO precipitate after 24 hours. As for Opioid Analgesics in general, p. I06. lamiocs. Its u;c provoked hypertension and tachycardia in a pa-
h also con.•iders that mixrures of diamorphinc and haloperidol Pulmonary oedema after overdosage is a common tient with phaeocluomocyt(lma.1
are liable 10 p<CCipitale after 24 hows iftbe halopcridol conccD- J, ~turv~di NC~ ef al. Di.amOIJlhine·induced tU.ack o( p;itOJCys--
tration is above 2 mghnL. Under some condition' mixtures of cause of fatalities among diamorphine addiets. Nausea mat hyf)C'rttnsiott in ph:aeochromnc)'1oma. BMJ 1974; ?: $38.
meroclopramide and diamorphinc may become discoloured and and hypotension are claimed to be less common than
should be discarded. wilh morphine. Pregna ncy and t he neonate. Some rcfercnces 1•1 10 diamor-
phine dependence in pregnant women and lhe effects on the feltlS
I. McEwin JS, Macmorran GH. The compa1ibility of some baclC· There are many reports of adverse effects associated and neonale.
ricides. Phnrm J 1947: 158: 260-2.
with the abuse of diamorphine, usually obtained illicit- I. Fricker HS, Seg_:JI S. N:Jrcotic :Jddiction, pretnancy, •nd the new-
Stability. Diamorphinc is relatively unstable in aqueous solu· ly in an adulterated fom1. born. Am J Dis Child 1978: IJl: 360-6.
rion and i< hydr<>lyscd 10 6-0·monoacctyhnorphine and then 2. Osuea EM. Cha,,ei CL Perin:i1al prohlcms (excluding neonatal
Abuse. Mos! of the reports of adverse effects with diam0tphinc withdrawal) in mattrnal dru¥ addiction: u ilul.ly or 830 eases. J
morphine to a significant extent at room 1cmpera1ure; 3-0- P•dio1' 1979; 94: 292-5.
monoocctylmorphinc is only occasionally detected. The rate of involve its abuse. In addition to the ccnlrol effects, there arc ef-
fects caused by the odrninistration methods and by the 1duhcr- 3. Lifschitz MH. et al. Fel:JI and pOStnot~I s,rowth o( ch1fdrt-n bom
decomposition is at a minimum at aboul pH 4.'-' to narco&ic-clependcnt women. J Pcdln1r 1983~ JOl: 6R6-9J.
ants.1.l Thus in many in$1onces it is difficult to identify the factor 4. Klenka HM. Babies bOl"'I) il't a dis:tric.1 general hospit.11 10 mothers
In a study of the st1bili1y of aqueous solutions ofdiamorphine in causing rhc roxiciry. MOS! body systems arc involved includinn
clilorofomi water it was concluded that such soluiions should be t•kin' heroin. BMJ 1986; 2'J: 74S-6.
the immune system,> kidneys.O liver,' respiratory system,1·• S. Greg JEM. n ol lnhaJing heroin durinJ plt&Aatq. effects on
used within 3 weeks ofp<eparation when stcnd at room temper- and the nervous system.•!·•• lhc boby. BMJ 198': l96: 754.
ature.' AnOlher study• noced !hit the degiadation products of 6. Link BB.. ~t al. Ma1c:rnaJ and fetal effects or heroin addiction
dia01orphine were not ck."VOid ofanalgesic acti,ity. Using a more Other as~rs of the illicit use of diamorphine include fatal
overdose 1 and smuggling by swallowing paclca.ges of drug l9JO during prqi1ancy. J Rrpn>d Mrd 1990: JS: IS9-62.
sensiti•-e analytical method ii was ttported lhat although the pH Of other methods of internal bodily concealment. 7. Mur s~ A,~' of. Asociac:iOn ennc el cnnsumo d~ heroina. du·
r:inge of ma.<imum Slllbility of di3morphine in iqieous solution nntc la ges1.aci6n y anom1lia.s tS.lrueturalcs de los c1hos rrspir.\-
I. lltndricl<Je RO.., ol. Aflatox;ns and hefoin. B~U 19&9: 299: torios en el pcrio<!o neonatal. An tip P<dio" 200 I: SS: HS-8.
was 3.8 to 4 .4, rhe addition ofboffc!l reduced stability.' Simple 492-3.
unbuffered chloroform water gave maximwn stability, the shclf- 2. COC. A1yptcal re~ecions H!r.OCiatcd wl1h heroin use: five states.
life of such a solution being 4 weeks at room tempcranuc. January-April 200S. MMWR 2005: 54: 793- 6. Corrcciion. Inte ractions
Ibid.; 8S2. For interactions associated with opioid analgesics, see
The BP 2010 recommends that soluiions for injection be pre- 3. lfu~by a et ul. Smooth muscle antibody in heroin addkls. Amr
pared immediately before use by dissolving Diamorphine Hy- llll•m Mtd 197S: 83: 801-S. p. 107.
drochloride for lnjeclion in Water for Injections. This may pose 4. f;;f:ir~~~1~ ~~:6: of. Hcroin-associalcd nc:phropulhy. JAMA
a problem wiUi solutions for subcutaneous infusion when co11- 9 Pha rmacokinet ics
ccntratc<I solutions 1riay remain in infusion pump reservoirs for S. do S:Jmtiro Faria M, '11 al. Nephrop.Mhy associated with heroin
abuse in Caucasian pat~nlS. Nephrol Dial Tronsplout 2003: t 8: Diamorphine hydrochloride is well absorbed from the
some time.6 Investigation of9 concenirations of diamorphine
stored at 4·diffcrcnt temperatures for 8 woeks7 revcalccl ins1abil-
2308-13. gastrointestinal tract, although this may be erratic, and
6. Wcll~r IVD. ti al. Clinical, bioche:mK:al. scrolo$-1cal, histoloci-
ity undez conditions of conccntralion, time, and tcmperarure c1il and uhrast.l'Vetural r~alurcs of liver dl$casc 1n dru& abusus after subc:uta~us or intramuscular injection. On in-
prevalent duringsubwrancoo.~ infusion. Degradation ofdiarnor- Gut 198-4: lS: •17-23. jection ii is rapidly hydrolysed to the active mctabol_ite
phine OCCWTcd at all conccnlntions (0.9810 2.SO rnglmL}at tern· 1. Antkrtun K. 9rundlospum and intravenous strc:ct Mroin I.a~ 6-0-monoacetylmorphine (6-ace1ybnorphine) in the
peratweS of 4° and above; the cffca ofrcmpenirwe was signifi- e<I 1986: I: 1208.
a. Cypn J. ti ol. fnhated heroin-induced status aslhmattcus: (hoe blood and then to morphine (p.92). Ora.I doses are sub-
cant at 21° and 37°. The percentage fall in diamorphine c~Ks and a revi~· of Lhc litcra1we. Ches1 2000; 1J7: 2n-5.
cooccntration was directly related to initial concentration and ject to extensive first-pass metabolism to morphine;
9. Boco dt los Buc1s A.'' al. Bronchial hyPCTTnetivity in piiOcn" neither diamorphine nor 6-acetylmorphinc has been
wos aecomp3nied by a corresponding increase in 6-0- who inhale hc:toin mixed with coc3ine "·apori:tcd on 2luminium
monoacctybnorphine and, to a lesser cxient, morphine; other foil. Chm 2002: Ill: 122l-JO. detected in the blood after giving diamorphine by this
possible brcakdowo products such IS 3·0-monoocerylmorphinc 10. Spottr KA. Dom E.. Httoin-n::latcd noncardioaenic pulrnooary route. Both diamorphine and 6-acetylmorphine readily
ed~m• : a cue series. ChtJI 2001~ JlO: 1628-32.
were not present in detectable quantities. Diamorphinc degrada- cross the blood-brain barrier. Morphine glucuronides
IJ. While CJ, •r al. lnh.3k<I heroin c.ausing e life.threatening Hth·
tion was associated with a fall in pH and the development ofa ma exacerbation and mal'i<ed peripheral cos:inophilia. Br.l llosp are the main excretion producL5 in the urine. A small
strong acetic acid-like odour. Precipitation and a white turbidity Med 2007; 63: 332-3.
was seen in solutions of I5.6 111glmL and above aOer incubalion 12. Seinpt:re AP, at al. SPongiform leucoc.nccphalopathy aOer in- amount is excreted in the faeces.
for 2 weeks at 21° and 37°. Jl has been noted that solutions for holins heroin. Lc11u1 1991: 338: 320. 0 References.
infusion are generally freshly prepared and used within 24 hours, I;. Roulcl Perez. E~ '1f of. Toxic lwc:oencephalopathy after heroin
inies1ion in a 2~~-year-oJd child. Lance1 1992; 340: 729. I. Boerner U. et al. The n1ctabolism of morphine and heroin ln
bur that signs of precipitation should be watched fOf, especially 14. Z.uckerm1n GB. Ncuroloi:ic complications fo11owing intranual m•n. Dnig Mttob Re- 1975; 4: .l9-73.
when using longer-term infusions and high concentrations of administration of heroin in an ado t~c:t:nL Ann Pl'lllnnoco1hcr 2. lnn.nisi CE. tt ol. The pharmacokincticJ of heroin in palicnls
diamorphine. 7 t 996: JO: 778-S I. wilh chro.,;c p>in. N Engl J Med 1984; JtO: 1213-17.
All cross-references refer to entries in Volume A
 Di~morphine Hydrochlo1ide 45
;. >.1oor.t R/\, c·t fll. Opi:Jlc meubolu•n ond curction. Boi//~~l phine by lirst-pass metabolism (see Pharmacokinetics, or sickle-cell crisis . ... suagcs1cd do."' 10 he ac~iscd into ooe
Clm Antte1thC'1iQJ 198-:; 1: S?9-$8. nostril is I00 micrognurulkg given in 0.2 mL of sterile water.
'4. 8ur~u DA. el al. Morphine kinetics :ntr diamorphinc il'lfU$ion above). Dia morphine hydrochloride may also be given
I Elias-Jonrs AC. ct nl. Oianl«Phinc inrusion in 1he prct::rm n:-
in prcm1curc ncom11c~. lJrJ Clm PltOKUNJ<YJI 1991~ Jl: 3 1-7. by continuous subcutaneous or intravenous infusion or ooate. Ar<lo Di• Ch/Id 1991: 66: 1135-7.
s. G1r:ud1n F. el nl. Ph:mntw:okincliC-l of high doses or intr:m1u~CU• intraspinally. 2. Ga..-tcl' or.~' tJI. Randorni$C'd. double blind triill of1w0Joadio1
fir :rnd {'llr:i) heroin in narcotic oddicu. Chn PllOf"llHICOI Th(!r
dos.c rcgimcms or diamorphinc in vcntil:.ted newborn inran1s.
2003: 74: ~41-~2. For details of doses in children, see below. Ardo 0(< Ch/Id 1995; 73: F22-F26
6. Il:tlbsg:u1h U• .:.t al Orat di;acclylmorphinc (hctoin) yickti grcatec ;, Wood CM. ~101. Randomised double blind uQl of morphine ''CT·
morphine bio.1va1bb1lit) th:m OC31 morphine: bioaviaib.bilily r~ A«ion. Beca= of i<S abuse po1emial. supply of diamorpbui< is S\ll d1atnorphinc for scdarion of pretcnn 111eona1cs. Arc.fr Dis
l1t~d to do$.1gc :.nd prior CipKMd r:'(posurc. Br J Clfo PIKN"rRxol carefully controlled and in many cow11ries il is no1 available for . Child F.,nl Ntonora/ Ed 1998; 79: F3~39.
2003: 66: 78 1- 91.
clinical use; morphine can provide equivalent wialgcsia by dose 4. Semple D. e1 al. Comparison of iv nnd sc diamorphinc inrusions
Administration. INHALATIONAl ROUTE. A Jiterature review' adjuSIIllelll. Tioc:rc has been much deb•t• regarding the relaU\'C for 1he trc111mclll of acute pain in d1ildren. Br J A1>0atb 1996:
found lhal intranasal diamorphinc had a similar pharrnacoki· merils of analgesia with diamorphine or morphine. Many now 76: 3 10-!2.
nctic profile 10 lhal of intramuscular diamorphine. his rapidly reg.ard oral morphine to Ix the opioid analgesic of choice al- S. Kendall JM, Ls111cr VS. lnuanual diamoq>hinc as an a1termliw
lO in1ramuseular morphine:: phJrmacokinetic and pharmaoody-
absorbed, as a dry powder, via 1hc nasal mucosa although this 01ough di:lmorphine hydrochloride may be pl'eferred for injec- n.:unic upccts. Cli1t PhnnnoroAiMt200l•"42: 501-13.
is nol as complete as by inlrnmuscular injection: intranasa l tion because 11 is more soluble in water thus allowing the use of 6. The CoUegc of En1crgcncy Medicine. Clinicol Effeelivencss
absorption appeared IO be dose dependent smaller dose YOlumcs. Diamorphine hydrocllloridc may also be Commiue.e CUldelinc for 1hc manaacmttit of pa.in in children
The pllamiacokinetjcs of inholed diamorphinc fumes ("chasing preferred 10 morphine sails for intra~pinal use because it is more (Moy 2010). Available o<: http;l/securt.coll<mergcncymed.ac.uk/
•sp/d0Cllm<nl.'-'P?I0=4682 (accused J0.'06/10)
lhc dragon") have been studied2 in diamorphinc addicts receiv- lipid-soluble.
ing subslitution therapy with diamorphine and methadone. Ab- As a guide 10 relati\'c potency: Opioid dependence. The 1reatmcn1 of opioid dependence is
sorption d1tOugh lhe lungs occurred \'Cry rapidly and was vinu- discussed on p.105. Many opiate misusers have expressed a pcef.
• diamorpbine hydrochloride S mg given intt11muscularly is
ally complete immediately after inhalalion; bioavailabilily was equivalent to about I 0 mg given orally, .-itich in ti.om is equiv- erencc for wilhdraWlll U$ing diamorphinc rather lhan rnclhadone.
es1ima1ed to be about 53%. In a comparative study stabilisation was achieved using either
. alcnt ro about IS mg of oral morphine S\llratt
I. Kendall PA. Ytltr VS. lntranaS.11 diomorphine as an i.llcrna,ivc diamorphinc or methadone I mg/mL oral solutions; 1 paticnls
10 in1mmuKulw m.oq>hine· ph1rmncoki1u:tic and phann1cody· when either drug is given by subcutaneous infusion, diamor- could nol identify which tile)• had been given. Whenever signs of
namic a5pec1s. Oin P/1t1rmatokinl't 1003: 41: SOl-13. phine hydrochloride I 0 mg every 24 hours is cquivalcul lo physioal wilhdrawal were seen 10 niL ofeither solution wnsgiv-
l. R.ook E-J. ti ol. Population ph.armocok.ineries or heroin and its about IS mg every 24 hours of morphine sulfate en and lhe t0tal amount over the first 24 hours taken as the pa·
nnjor met~bolites. C/m pJta,,>1ocolti11t11006; 45: ~01 - 17.
Administration in children. In the treatment of 1tul• or tient's daily ~uiremen t. The mean dose of diamorphinc re-
INT1t•sm<AL ROUTE. Diamorphine is much more lipid-soluble chro11ic pain in childrC'l, lhC BNFC 1010/1/ suggc•IS !he follow- quired for stabilisation v.-.s SS mg compared with 36 mg for
•nd has a more rapid on sci and shorter duration of action than ing doses of diamorphinc hydrochloride according to age or methadone. Somccentn:s have given diamorpbinc in lhc fonn of
morphine. Ailhough deacetylation to morphine occurs rapidly body-weigh!: reefers. Diainorphine bas also been prescribed wilh methadone
in the blood ii occurs only slowly in the CSF after intraspinal in the m:inllgcmcrit of addicts.2 A syslcmatic revicw1 lhat includ-
~,contiml0l1$ in1rtwcno11s infusion:
injection ofdiamorphinc.' Aller intrathecal injection diamor- ed lhis sllldy. failed to produce conclusive results about the effi-
phine was remo.cd from 1he CSF much more rapidly than - neonates "ith spontanc'Ous respiration may be given 2.5 lo cacy of diamorphinc (alone or wilh mclhadonc) in maintenance
morphine.: Peak plasma concen1ro1ions of morphine after 7 onicrogiamsl!<g per hour lreabncnt: however, since the studies were nol directly compara·
cpidur•I diainorphine injection were significantly higher and • \'Cntilolcd ncon:iles may be given 50 micrograms/kg initinl· ble, continued evalualion in clinical studies is required: Oral
were achieved significanlly fas1cr lhan aOer epidural injection ly by intravenous injection over 30 minulcs followed by tablets• and intravei1ous injection 5·• of diamorphine have also
ofmorphine. 3 IS 1nicrograons/kg per hour by continuous i11travcnous in- been tried in severely dependent, treatmenl·rt:Sistant patients.
J. M<KJ;ln M. The ratioo1l 1.1sc ofintratbcul and .:;...uDdu1aJ opio- ti.1~ion . Breast feeding has bc:eri used 10 1rca1 diamorphinc dependence in
id<. BrJAnaath 1989; 63: 165-&&. 1 monlh 10 12 years: 12.S to 25 micrograms/kg per hour the offspring of dependent mothers bul this is no longer consid-
l. Moore: A. ~t ul Spinal lluid kinetiQ of morpnirw: and heroin. ered lo be the best method and some authorities recommend tbal
Cli11 Pharniucul Thor 1984: 35: 40-5. ~'' iurrot'Cn()US injeciion:
;. \Vuson J. cl ol Plasmtt morphine conccn1ra1ions and analg_uic • 1to3months:20 niic.rogramslkgevel)6holll'$ifnecessary
b<east fttdiog should be stopped.
clTect.s or lumb:»r CltrJd\lf'31 morphine tlld heroin. An~lh AnMg I. Qhodx AH,e1a/. Comparison oforal pttpanlions orhcroina.nd
1984; 63: 629-34. • 3 to61nonlhs:25 to SO microgramS!kgcvcry6hoursifnec- mtlh.ador.e 10 ~u1bilisc opialt n1isusel'3 as inpatients. BMJ 1990;
essal)' 31)(1: 719-20.
Children. Loading doses of ci1hcr 50 micro11rams/lcg or 2. van den Brink W, e1 al. Medical prcscnp1ion or heroin to treal·
• 6 to 12 monrhs: 75 micrograms/kg every 4 hours if ncces-
200 micrograms/kg of diamorphine were given as an intrave. menl rcsisrani hc:roin addicts: two randomised conlr'Olled tcials.
nous infusion over 30 111imitcs lo 19 vcntilaled neonates followed sruy Ab1idged \'trsioo; 8.W 2003: 327: J 10-12. Cometioa ibid.;
by a continuous infusion of 15 miaog"unslkg per hour, and the • I to 12 yC<Jrs; 75 to 100 micrograms/kg every 4 hours if 724. Full version: hu;p;//www.bmj.com/c1i/reprinll327n41()1) 10
n=ary (l<<e!IStd 26/06l08)
pluvmacokinclics of the pl'oducls of diarnorphine metabolism ). Ferri M, 11 ttl. HcToin m1lnttt1a.ncc foe chronic heroin depend.
(morphine, morphine-6-glucuronidc, and rnorphinc-3-glucuro- oro/(1: u"s. Anilable in The Cochrane Database of Sys1cmalic Re·
nidc) ~•udied. 1 Al1hough the overall elimina1ion of morphine was • I month lo 12ycars: l00to200miaogiamslkg(maximum vie:"·s: lnue 2. Chichester John Wiley; 200S (acceucd
reduced compared with adults, ~1e relative contn'butions of the ol'lO 01g:)C\'CI')' 4 hours if necessary 26/06!08).
\'llrioos metabolic routes of morphine remained similar between '4. Frick U. el al. A pro:spccti\'e col\On SLudy on orally 1clminis:tered
neonates and adullS. Data mm lhis s!udy did no1 indicate any
i11tl'011asally (for aculc pain in emergency scning or shc>rt painful heroin 5Ubstilultori ror $CVCftl)' :iiddicted opioid ustrS. Addiction
procedures only): 2006; IOI: 1631-9.
advantage for th• higher loodin& dose (see also under Uses and S. March JC. et ol. Controlled uial of pre~cribcd heroin in lhe tr'ea1·
Administration, below). • childn:n weighing over 10 kg; I00 micrograms/kg (ma.,i-
mentor opioid 1ddiction. J S.bst Abuse 1i·u1 l006; JI: 20.>-l t.
I. 8ane1t DA.,._, nl. Morrhinc.. n'l(M'J>hine--6-g.hicuronidc and mor. mum of 10 mg) 6. Ovicdo·Jod:cs E. e1 cd Oiac:ecyiinorphinc 'cuus: mclhadone- (or
phtnc-)-glucurooidc pharmo~kinclic~ in nc~"btw'n infan11 rt.- In a study' of the effects ofdiamorphinc in 34 pren;iaturc infants 1hc treatment of opioid ~ddic1ton. N Engl J Mtd 2009; 36J:
cei"ing d&amorphinc infUsions. 9.,. .I Clin Pbof11K1t'0/ 1996~ 41: (gestational oge 26 to 40 weeks). a loading dose of 7i7-416.
,;Jl-7. 50 microgr.11nslkg gi\'Cn as an intrt1•-enc11s infusion over 30 min- Pain.ACUTf PAIN. Rapid pain relief may be obtained wiUt the
utes followed by a continuous infusion at a rate of intNtvcnous injection of diamorphinc_ Other routes include
Uses and Administration IS micrograms/kg per hour was considered to be s:ifc and resull- the intraspinal route for which diamorphinc is well suited be-
Diamorphine hydrochloride is an acetylated mozphinc ed in plasma concentt:llions of moophjne 00t11po.rable wilh !hose cause of its lipid solubility and pharmacokinet«:s. Epidural
derivative and is a more po1ent opioid analgesic that usually po'Oduce adequate analgesia ill children and adults; doses of diamorphinc have ranged from O.S to l 0 mg. 1Analg·
(p.108) than morphine (p.93). Diamorphine is used for the duration of the infusion ranged fr0<n 14 lo 149 hours. Small csia was significantly inorc prolonged ond more intense after
but significani reductions in heart rate and mean blood prcs.<ure epidural ralhcr than inlntmuscular injection of diamorphine
lhe relief of severe pain especially in palllative care. It "ere noled bul 1hese we1'C no1 asiocia1cd "ith any clinical dclc· S mg in women who had h.ad caesarean scction;1 itching w.,s
is also used similarly to morphine for lhe.reliefofdys- oioratooo. TIIC fall in respiration rate rcRected lhc desired inten- reported by SO% of patients under&oing epidural analgesia.
pnoea due to pulmonary oedema resulting from left tion to cnc:ouragc synchronisation of the infants' brealhing with Epidural diamorphinc alone' or "ith bupivacaine4 has been
vcn11icular failure. Diamorphine has a powerfol cough the ventilator. The authors concluded !hat intravenous diamor- used for a1U1lgcsia during labour; addilion of adrenaline ap·
phinc could be given safely 10 neonates and would provide ade- peared lo improve the quality and duration of an.algesio with
suppressant effect and has been given as Oiamorphine qualc nnalgcsia. A later sludyl indicated 1hat 1he use of a diamorphinc.l In another study ~ddition of di11norphinc lo
Linctus (BPC 1973) to control cough associated with 200 micrograms/kg loading dose conferred no benefit over a bupivacainc produced a high incidence of prurilUS and drow-
tenninal lung cancer although morphine is now pre- SO micrograms/kg dose and mighl produce undesirable physio- siness.~ A study6 of paticn1-con1rollcd analgesia for pOSIOper-
ferred. · logical effects. In a comparative studyl wi th morphine ative pain found thal although epidural diamorphine, used
(200 mitrog1'ams/kg loading dose over 2 hours, followed by alone or with bupivacainc, reduced lhe analgesic dose re-
In the uuunent of acute pain usual doses of diamor- maintena.noc infusion of25 microiJ'!rns.'kg per hour) in venulat· quirc:men1, there was Jiu le cllnical advantage over the subcu·
phine hydrochloride by subcutaneous or intramuscu lar ed prctcrm neonales requiring scdaiion, diamorphine laneous route.
injection are 5 to I 0 mg every 4 hours. Doses cquiva- (120 micro,nnisikg over 2 hours and then IS micrograms/kg Continuous epid ural infusion of diamorphinc
lem to one-quaner to ono-half of the corresponding in- pc:r hour) was as effective as morphine in producing sed:ition and SOO microv,nrnslhour in 0.!25% bupivacainc provided poslop·
tramuscular dose may be given by slow intravenous abo hlld a faster oll$Ct ofacrion. The small but significant drop in cr.11ivc analgesia superior lo 1ha1 with either drug •lone in~­
blood pressure noted during morphine infusions WllS no1 seen tien<S undergoing major abdominal gynaecological 5U1&"ry. A
injection. wirh diamorphine infusions. similDJ' infusion p1oduccd analgc$ia >upc:rior to thal wilh eitli<r
For the pain of myocardial infarction doses of 5 mg arc The subcu1011e;)11.f roulc a~red lo be as effective and safe as epidural bolus injection or palicn1-conlrollcd intravenous
given by slow intravenous injeclion at a rate of I lo the intra""11ous route for infusions in children for postoperative diamorphinc in pa1i.. us undergoing lotal abdominal hys«:recto-
2 mg/minute with a further dose of2.5 to 5 mg if re- p:iin reliefafter cl«Cive abdominal sur&Cl'Y·• The do<;e ofdiamor- iny.1 Howcvor, more patients recci\'ing lhe continuous epidural
phinc used in bolh groups of children was I mglllggi,..,n at a raie infusion"'"'" hypoxaemic than in lhc other 2 groups.
quired; doses may be reduced by one-half for eldcl'ly or of20 micrograms/kg per hour. Diamorplti.ne has also been given inlrathccally for poslopa-ative
frail patients. Doses of2.5 to 5 mg may be given intra- lntro110.1ol diamorphinc has been investigated in adults 111d chil- analgesia and should be effective al lower doses than wilh lhe
venously al the same rate for acute pulmonary oede- dren, and appears 10 be clfectivc and well tolerated; because it epid11111l route because of greate1· CSF concentrations. Diamor·
ma. does noi require a needle it may offer particular advantages in phinc 250 or 500 microgams given intrathccally wilh bupi·
For chronic pain 5 to I 0 mg may be given by subcu- childten.5 Guidelincs6 for analgesia in childll:n hi Accident and vacaine spinal anaesthesia both provided greater post0pa2tivc
Emergency deparuncn<S in the UK R<Xllllmcnd U1c use of intra- analacsia lhan bupivacainc alone.• but the incidence of odverse
taneous or intramuscular injection every 4 hours; the nasal diamorphinc as an alternative to, or before 1reannent with, effects. especially nausea, vomiting, and urinary relcnlion, was
dose may be increased according 10 needs. Similar dos- intravenous morphine for severe pain such as that associated still high witll eilber dose· and routine use oflhis technique was
es may be given orally, although it is converted to mor- with large bums. long bone fracrun: or dislocation, appendicilis, nol rccomrncndcd. lntrathcC3l diamorphinc wilh bupivacaine
46 Analgesics Anti-inflammatory Drugs and Ant1pyretics
hasalso been used founalgesi3 during labour''" and - J. Boltt L. <1 Ill Evol..11 'fl'n&l onalaHia pracuec ., polliatiY< Oidofenac Sodium {6.W\\ USM(""""")
ICCUon.1:1." In 1 SNdy'l 1n patients uodetgoio& caesanen sec· taR. l'ollJOt Mfit/2004. 11: SOi- IS.
~ sodique: OiclokNc:o s6dic« Dclofenatun Nlneurrc
lion, inll'llbecal d....orpllme 250 microgr.ims sbowcd compat1· 4. R....e llo'I;. Todd JG 1ru,.vtn111cular d~>< •.a an Om·
Odophenac Sodium; Oil:lorenaaldan.run: 0.ldofenlk ~
blc pos1opcn1ivc .,.lgesia with a 5-mg epoclural dose and "'*' ""'Y' sbmt for "'traetablc c:anttr pom BP J A-11h 199ll: 65:
S44-7. slA: Odcior-k Sod)\m: ~ltlium: DiklofcNk-nWiun.
apocalCd with IC$$ postoperative naiua and vomiting. Other
studies',·" found that intrathccal di11norphinc reduced supplc-
Flock P. Pilot study to dc:tcrmtM &he: c:ffc:c1inn~u of di1mor·
plunc ~I to control pressure ulcer pein.J Poltt Sympte>m Mo,..
C»doktlako natrio dt\111«< GP 45810: Nattii Diclo~ »
mcnuil .,.lgcsic n:quircmcn1sdWVl8 and after ca<:$1lrean section 6um [2·(2.6·ckhloroa'*>o)pl".eny1acetate.
2003; 25: S-'17-54.
when compared wilh intra1hccal fcnlllnyl. b11ruthccal diamor· Abbas SQ. Oiamo:phine·lntranic drcllmK• (or p1infu t pcssw-c HIT!"'~ A ..~~
phine 400 microgroms was considered by some" 10 he the lo\<·- ulccn J Puin S)'nptom Mont1g1 200•; l8: SJ2_., C,.H,~CltNN10i
CAS - I~307-7Y-6.
= 318.1.
csl dose required 10 reduce inrraopcrative nnalgc.•ic $Upplemcn·
cation 10 below 5%; however. lower doses of 300 m.crosrims Pre parations ATC - 01 I AX I B
have been used in ptlctice." BPJOIO: ~~ ATC V•t - QDI IAXl8.
Oiamorpbioe has beUl extCllSlvcly used by cardiolo&ISU in the B/'C 1913' 0--pt.,M lr.aUL UNll - QTGl 26297Q.
UK for lhe tnanlgemt:nl of pain in acute left vencriculat failute, Proprietary Preparadons (dccails 11'< IP>en in \\Jlume BJ >:On. OICL isa code ~pprovcdby the BP'.1010 for weonsi"'lll•
unslable angina, end myocardial infarction II his been theomed Swrt&.: 04>'1h um1 doses of <)'C drops coaita1ru111 diclofen:lc sodium wbo-c the
that d1amorphinc 1112)' offer bencfics over morphine because ils 1nclividl.9I container may be IOO sm1U to bear all lhe 1ppropril1e
shmulatory dfeas 11 opioid 6 rccq>IOr1 on the myocardium may lobdhn& mfonnauoo.
reduce the extml of myocardial cbmagc." E~ to support PharmKo~ In Clim , £.,, (see p.~ii),Jpn, US. and Vin
this theory 11, however, laclcing. Diclofenac (BAN. "'./NJ Ph. Eur. 6.8 (Odofenac SodUn). A whiie 10 sbiblJY yellowuh,
I. Morp> M The mional use otinlmh<al and e>1111d11111l oplC>- slightly h)'llOICIOPit:, Cl)"S!alhne powder. Sparingly soluble in
ids. 1J,J AMUI~ 1989: 6J: lf>S-U. Didofenac: Odo~cx Otcb<enacurrc O.~ Oik- water; soluble in 11cohol; slightly soluble in ICCIOne, 6ttly solu·
2 Ma<nt OJ. n ol Double-blind comi-nson or tho ell"tc:ac:y ot '<>fenak. [2-{2.~)plieny1)ace1ic aocl. ble in melhyl •loohol Store in oinighl containets. Pro4cc1 fi'om
extradural d11morph1ne. u.lndural phcnoptndinc aM am.
d11morphine f0Ucw-.1n;1 caesarean sec·1jon, Hr J AnoM-1• 1917, Al-<""*"!J< light
59: JS4·9. C,.H 11 0;N0 2 = 296 I. USP 3l (Ddo<o-tlc Sodium). A white to off-white, hygroscopte,
3. Keenan GMA. ei tt/_£x1radur1I diamorphinc wi1h adrcnahnc 1n Cl)'Slalline powder. S)18rinaly soluble in waler; soluble in alcO·
l1bour. comparison wi1h diamorphinc and bup1uCca1nc R,. .I CAS - 15307-86-5. ho!; pntCtic:llly insoluble Jn chloroform and in ether; freely solu-
Anomh 1991: 66: 242~. ATC- D I IAXl8; MO I A60S, M01M l 5: SOIBCOJ.
4, McOrady EM. <1 al. Epidu,.1 diamorph1ne and bupi\'•Cain• in ble in melhyl olcohol. pH ofa 1% solution in water is be•~
l•bowr Anonth'1io 1989; 44: 400-J ATC Vet - QDI IAX/8; QMOIABOS: QM02AAl5: 7.Oand 8.S. ~ore in aini;ht oont1ine1s. Protecl from light
S. Bailey CR. "ol Oia.morphine-buph'llc:aine mia.t\lrc compared QSO l8C03.
"'•lh ofain bupivac.ainc:: for analgesia. Br J Aff«llh 1994; 71:
S*-'I UN/I - I HOBQLOLI Adverse Effects and Treatment
6. Goplnalhotl C, 11 al. A c~.n.. JhMly or petlent•conuolled As for NSA IDs in general, p. I00.
epid\nl diamorphinc, so.beulueous chamorphlne and •• .,...
lunl dJamorphiMl'bupi'l'&Cl.tDt <Ombin.ation rc.w postopctal1¥C There may be p1un and, occasionally, tissue damage al
peU. E11TJA•om/waiol?Of»'. l1: 189-96. the site of in,Jedion when diclofcnac is given intramus-
7. Lee A, tt al. PoAopcnli-e .,,.lpia bJ .-inuous oll9d1nl
1nrus,.., ofbur>"'-"'" and d..-rpl11n• Br J ,,_,,. 1911, cularly. Diclofenac suppositories can cause local mita-
60: go.so. tion. Transient bu ming and stinging may occur wilh di-
8 MackJTll,•ol H_.,,iaal>dpeinmi<fallulow<r-.
11\ll IWIUY; compuison of exrrldura1 and pMtt11t-concrolW clofenac ophthalmic solurion; more serious corneal
an1IJ«it.. Br J A-.th 1992: 69: SSC- 7. adverse effects have also ooeurrcd (see Effects on the
9 Ra)' BA, 11 ol Low-dose intrathcail dia.morphlftC: 1n1tccii1
roll°"''"' major onhopardic surgtty. Br J Aooath 1919; 62: Eyes, below). Topical preparations of diclofenae. such
241-Sl as plasters and gel, may cause application site reac-
10. Kcsu.n Kl «t al An1l.ac1i1 for bbou.r .ld ckhvcry ualna incrc· tions.
mct'llll d11morphi~ and Mlpi\.'IC&ine vii a ll·l•uJe in1r11hc:c.al Oiclofenac Oiethylamine (8ANM)
catlletcr Br J AnoOllh 1992: 68: 244-7. Oidofenac Di~ Oiclofcnaco d1etrlan"ana, Dik· Incidence ohd•erse •ffects. /\ rcviewof\\orldwideclinical
11. Vaughan OJA, ttl ul. Cl'oicc o1' opioid for ini1iatk>n of 'ombtncd studies "'ilh diclofcn:>e 1 ho,, reponed thcindd<ncc: ofdrug-asso·
1pinal epidural al\llgcsia ift labour-fcnl~nyl or dia~inc. Jofenak Oielilamooyum.
Br J /IOIO<Jlh 2001: 86: 567-9 cialed advenc: elTccts 10 be about 12%; about 16% orpo1ients
12. lloll"onh SP, <1 ol. C00>pa1ison or inu11hcxal and epidu111I AM""*""• Atonw- who had ad'-a11C cl!'ccts stopped trcatmon1 (•figure correspond·
d11morphinc for <liccu"-e C1csart:1n settion t,aSjna a combtntd C 11HnCl?N202 = 369 3. ma 101bout 2"-' of the cn1irc patient sample). The m05t frequen<·
splnal·tpklural tedwtique. BrJ Anawh 1999: 12: 2U- J2. CAS - 78213- 16·8. ly ~adverse effects v.-ae gastroinlcstinal and were rcporl·
di:a.mc:wphiM • addition 10 bupivacaint (« c..,,.,.
13 Cow11" ~ tt fl/ Comparison of im.r1thcc.al (cncainyl and
unda' ~l .,....IM.U. Br J ANJath 2002, It: 02- 1
1«tion ATC - D I I AX18.
ATC Ver- QO l I AXIB
ed in 7.6% of potients. CNS-rclltcd adverse e1Tcc1s were
reported in 0.7% or J19ticM and 1Jle111 or local reactions in
IC. $.ara~mn S, «Ill _Minimum dose of iiutathtcal d,~1.nc UN/I - 6TGQ3SZ7 I K. 0.4%. This and other reviews' hive shown 1hat advme clfccts
==.r:c::::::::::....w;,~~~;~~~6~;'t Phannacopoeias. In Br
associated with d1clofc:nac we US11ally mild and transient aad "f>"
pear to be unrelated IO 1bc do5c givm.
I~ - Lane~. n of A compoti- or m<ralhocal renW>yl and dlall'lOI'· BPlOIO (Oic~~). A."tutc1olightbeige,CJ}'$"
phwae n tdjuncll in lplntl anec:slbu• (Of Cacurcan MCttOn The incidence o( ad~ clftlds m children is similar to thlt '"
A-.t~la 200S; 61: 4S3-7 caUinc powder. Sponngly IOl\Jble 1n water and in l<:ICIOM; &ee.Jy adults.;
16 W,..,,.h JJ. <to/ Dose . _ 10 inltalll<. .1 diamorph1 .. rot soluble in alcohol and 111 methyl aleohol; pnctic:ally msoluble 1n I WHtltem RF WottdW1dt dinical Afc.y c:xpaj.mcll' •rth d1·
tlcct1\t caes1rc1n sc.:t.ion and comphan« wilh a n•1.oe1l 1ud" JM sodium hydroxide. The pH of'a 1%solutton 1nalcchol(IO'/o) dorcnac. ~·· Arthrotrr Rllfllm 191S, 15 (suppl l); 10$- 10.
11and1rO. /n1JObs1.,A-.•2001; 16: 17- 21. is between 6.4 and 8.4. Store in ainiaht concaincn. ProteCI from 2. Small RE. o..1orcnac liOdiuin. Cl.n l'I'°"" <989; 8: 545-8.
17. Poultls M. Oiamorpbineand British cardiolo11y M> ....,. tiiJ>t! light. l . SlttMhn1 JF, ti al. Prospc:c.lht o~"al1onal s-.udy of advcr.,e
lltart 1999: 11: 64S-<i. dnat rc1c:hons to diclofcnAC 1n chitdttn. Br J Clin Phormncol
CNAONrC " ' "· P11ien1s with chronic opio1d-sens11ivc pein ere 2009. 68: 243-51.
oflcn l/Cated with dtamorphinc given b)' COOlmUOllS SUbc\JtO· Dlclofenac Epolamine
Effects on th• blood. Results of a large survey undoukcn to
neous infusion usina a small battery~rated syringe driver. DHE?: 01clofenac Hydroxyethylpyrroidine &SSC$$ the relation between agranulocytosis, nplastic anaemia,
The following 1echnique has been described.' Oiamorphine ~K3nOA3MMI< and drug cxp<»ure indicated that diclofenac was sianilicantly U ·
hydrochloride I g could be dissolved m 1.6 ml of waler 10 sociatcd with aplastic inacmi>, pro,idins an cstimalcd !enfold
i''e a solution with a volume of2.4 ml (4 I 5 mg/nil). bu1 the C,.H 1,CJ2N02. C.H 11NO : 4 I 1.3.
CAS - 119623-66-4 incrc.'lse in risk.' lbere arc rcpons of o<hcr hacm•toloaical ab-
ma>.1mum susgcs«d c:oncen1r1tion was 250 mg/ml. If the normali1ics iocludina haemolytic anaemia,u tlvombocytopc·
analaesic requirement was onlcnown lhe follow1n11 protocol ATC - DI IAXI 8 nil.'.$ neulToptllia..s and agnu1uloc)'IOSis' oc:currins in pelients
wos recommended· ATC Vet -QO I IAX / 8.
Sw1 irucellOUS every 4 hours ofl.S or S mg dolmotpbine, or, UNll - XSF8EKL9ZG ·"~ dtclofcnac.
Loah.cd 1p9<11111COUS bl~lltg,' bru1smc.'inhibction ofrta1clet
i( tho pe1jcn1 has aln:ady ~ taking O!Hoods. • dOfe WI is •Jlllrtpllon,7and prolonged bleeding tinic' ba•e been rcponed.
cquivtl"'1 IO the lasa dose Diclofenac Potassium ~ WN '**"'~ l , T1t< lnieroa!Jonal Agranuloeylosis MCI Apl..ht Anemia Study.
• If 1his i$ UOAUSflCIOI)' increase this dose 111 ~ incremenlS R..u or •.,.,,.,1ncy1<•<1• and aplHlic anemoa· a litt1 rq>an of
wittl the pa~ rq>MS even a little pain rd1cf CGP-'l!>S«la Oitlo"'1« poWSique; DicldenlCo po1asico; Ot- lhcir rela1ion 10 dn.ta 1.ttt 'Wtth special reference 10 1nal,a.t<1.
dofenaosn kalia.on; O.'<lofenNWcaisrc Oiklofcnak dras811 sajf; JAMA 1986; 15': 1749- S7.
• Calcuble the 24-hour requ.ircroent by multiplyina by six, ind ~ Potasyum: O&Jolc~ OiklofeNk·kahum: 0.1c· 2. L.Opc-z A. " hi. Auto t~ hemolytic anemia 1ndu«d by dt-
swt the infusion at !his level cJorcnac. A11n P/tom1Ut;011- J99S: 29: i87.
lolenako kalio dru>k.i: Kalii O.C~utn Potass.um [o-{2.6·
• Increase lhe 24-hour dosage in the pump by SO"/ci increments dochloroanaino)phen)'l)acetate.
3 Ahrens N. ti ul. M1td•inosi1 in pgricnl) with diclofcni.c·tn·
wiul lhe poin is controUcd. Nole that requirements may VMY duccd hcn'IOlysia: new CIMS 11nd ia concise r"icw. AMJ Htu1ntol
finm le$S thAn 20 mg to more than Si per 24 hours ~A~ 2000: 81: 121-ll
4, Ocorv• S. Rahl AHS. Thromboc)'lopenla a<SO<i>ttd with di·
When swting an infllSion ii is important not to ollow any break· C,.H,~CJ 1 KN0 2 = 331.2. clorci>ae: lhenpy A•• J l/1a/1/i.Sy.1 /'h•n• 199S; 51: 42()-1 .
lhrough pain. This may be achieved ei1hcr by stat1ina the infu- CAS - 15307-8 1-0. S. Kim HL. Koncs MJ. Oiclofcn»C.4110e•tcd lhto1nboc-)1opcn11
sion more lhan 2 hotn before lhe previous oral dose weats off or ATC - DI IAX/ 8 and •<ul,.ni1 Anrt PhnrnOOC<>IMr 199S: 29: 71l-IS.
by giving a lo>dina dose injcclion of the 4-hourly requirement 6. ColomiN P, 011cl• S. Acr.1Aulocy1osis c..xd by diclof<nac.
ATC Vet - QDI /AXIS DICP Ann Pl•on.,,rot1- 1989; 2.J: 507.
Allhou;h generally liec Jiorn coniplications.-* 1bs«ss for· UNI/ - HOSUA6C8~ 7. Price AJ, Obeid 0. S~ "°"""S1JOin1ts1inal bkcd1oi
mahon was Jq>Oflcd in 2 palicnts with a<haiccd Cll1Uf rccciv· asso<iat<d "llh d1tlof<MC /.6Mtt 1989: ii: l S20.
1na dwnorphine by continuous subculaneous infusions 2 Pharmacopoeias. In E11r (seep.vii) llld US. a. KNun V. tt ol Oiclorcaac: toJiuni aod bruisins. A.,. 1......
Ph. Eur. 6.8 (Dido'enK Poussun). A white or slightly yellow- Md 1990; 112: 472- J .
The llllnqJUlll' and intraventriculll' - have also been UJed ish, slightly bygroscopic:. aystalhne powder. Sparingly soluble
succaminy m patients wilh inlntclable J191n. Topical appbca1ion
in waler; soluble in a~ sl111nly soluble in aoctcne; freely Effects on che c:an:tiovascu~r system. For a clisamion of
of dilmcrplnne has also been ~ for the control of pressure 1hc cardiovucular dfecls of NSA lDs. including diclofemc, sec
soluble in methyl akobol Store in 1i111(1h1 oontaioeis. Protecl
ulcer pain '" • small numbcJ or palliative ure pauenu. "fiolnlighl p.100.
I. Dover SB $)·1inge clriYa';,, 1emtinol <or<. BAU 1917; 2'4: USP 3l {OidoloNc fb'~sun). pH of1 "~ tolutlOl'l in water is EfTe~t• on •lectrolytes. /1. syndrome resembling 1hc S)'ll·
SSJ..5
2 Hoskin IJJ, 111 ol. SCer11t: 1bsctss forma tion by con.tin'*- wbc:u- bct\veen 7.0 and U. S101e at a te111pcn11ure of20" to 25°. Protect dronie of 1nappropri.ic antidiurc1ic hormone sc:crrtion bas been
11neous infusi"" of dwnu<pl1in•. BAU 19BB: 29': 1605 from light. reported 1n rldcrly women given diclofcnoc.'·' Also lhe UK
All cross-references refer lo enlries in Volume A
 Diclofenac 47
('SM h3d received a report offotal h)'ponatraemia in anolhct cld· and <1)1hem:1 muhoformc.:J Local irritation and necrosis ha'c Gastrointestinal drugs- A dccn:ase in the plasm. concenu-a-
erly woman.= occurred on intramuscular injtetion of diclofenac.""' tion ofdiclofcnac has been r<poned1when given after sucra/fate.
i. Pc1er.1son I. el <11. Water intoxicatioo 2ssociatcd with f\('ln-s.ttnM- t. Cial:iric!$tn T0. c1 ol. Orvg,-indueed bulll'lus dtmia1osis w11h Im· J. Pt:dniuuli J. r.1 al ShorMerm ~ucralrott administration ahers
dal anu·infl~m m :ttory dnig !htt2p)'. Ac-'o Mftl Scmuf t9S7; ?21: car lsA d~f)(Jsiu ak>ng the basement mcmbrn11e. A(.'fo °"'1• fir"· polauium dictofcnac ntisorption in h~ilthy male: voluntecn. Br
~21 -3. "'"to/ (S1nckt.J IQSI: 61: ~3~1. J Clln Ph<rrn"1<Qf 1997: ..e3: 10-f-8.
l. Chcun' NT. 1u (I/. Syndrome of inappropriate secretion of anti~ l. Motri1 BAP, llcultulla SS. ElytMm:i mulliforme m:>jor follow.
diur<1i< llonnoo• induced by dicloronac BW 1993: 306: 186. Lipid regulating drugs. Colntyrt1mfne "Prie•rs suhslantially
1n1 U:St ofdicloren:ic. Ctm Mt'cf AuocJ J9SS: 133: 665. to redoc:e 1he bioavailabilityofdiclorenacwhen the twodrugure
3. Youni J. E1y1hcm:; multifom1t·ht..~ (f'Uf>l.ion as a resuh -0( ·so.
Effects on d'le eyes. A pa1ici1t who had been taking oml di·
l1riu· ueauncnt. J Dt1wo1nl Tl'eoi 2003: 14.: 189.
gi''en togcd>er; 1 co/e.<tip<>I )l!Oduce.< a similar but sm•ller elTecl
clofcnac for se...eral years and had increasingly complained of I. al-Balla SR. ,, al. The cffttts or chof$)-r:tmine and colcs.ii~ .
dry, sriny eyes noticed thal eye irritalion disappeaed within 3 4. Stricker BHC. van Kastcren OJ. Oiclofmac-iOOuecd isolu1cd on the absorption or diclol"eruc in man. "11 J CUn P/lornU1CUI
myonccros.is and the Nicalau $)'ndrome. Ann /111~~11 >.(,od 1992:
days when diclofenac had to be stopped because or g;istrointesli· Jl7: 1058. r-1994: Jl: ~•t-5.
nal effects. 1 S. Pillans Pl. O'Connor N. Tis~ut 1lccrosis and nttroc.isin1 rueiitis Misoprostol. T1lC plasma conccniration of diclofenoc was re·
Ocular diclofcoac and related drugs have been implicated in re- af1er Jntn1muKUtaradminisl:ation of diclofcn1e Ann Plwnnoco- duced wl~n it was given as a I 00-mg dose daily in the f00n of a
pol1S orcorneal toxicity. Ulceration of lhe conjunctiva orcomea. th•r t99S; )9: Z64. modified-release preparation to subjects receiving misoproslol
corneal or scleral melts. and perforations hbve ~n reported in 6. Wcdinc K, et ol. 'Nicolau syndrome following dielorcnac ad· 800 microgramsdaily.1 Usetoged1er was also associated with an
palicnrs using diclofeoac eye drops, panicularly after cataract ministra1lon. Dr J Dt-nnoto/200..; ISO ~ 38S-7. increase in the incidence and sevcri1y <>f gaslrointestinal effects.
SWllCry.l-l Keratilis and perforations \Yen: also reported with 1. Mvt11lili: S, Bclg..aumkar V. NK:olauf;)'tldromc:;, rcpon of2 c:lSC'S Srudics by the manufaci.uml hod failed to find any significant
J Drog1Dc.n11orol2006; S: ln-8.
kctorolac eye drops,' although less f'rcqucnlly. For mention of phannacokinetic intcnelions bclwccn diclofenac and miscpros·
corneal melting with bromfonac. sec p.29. Hypenensitivicy. Aspirin-scnsith"' asthmatic paticnls h3ve tot when given in a fonnulation containing dictofenac 50 m: and
I. Reid AL"'. Htnd<rson R. Oiclofe:n11e :md dry.jrritablt t)'\'S.. Med developed reactions (rhinorrhoea, tighln= of chest, wheezing. misoprostol 200 micrograms.
J A'"r 1994: 160: JOS. dyspnoea) when challcnscd with diclofcnac in doses of I 0 to I. Dammann HO. ct ttl. l)ifftr(nlial etrcns of mi50pros1ol 1nd nn-
2. Lin JC, ctul. Comal 1ncltingassociatcd "'<ithuse ofl0pic1I non· 25 mg' and the UK CSM has recei,·ed • report of an aspirin-, itidint on lhc pham1:1cokinciics of dtdoknac and aastrointesti-
s1eroidal onti-ennamm;nory drugs nfLtr ocul•r suric1y. Arch nat symptoms. Br J C/i11 Pl1arnHNol 1993: :16: 345-9. .
Ophtlwlmol 2000; Ill: 1129-32.
sensi1ivc pa1ient who died from <Icutc asthma 4 bows after a sin·
gle 25-ing dose of dklofenac. 2 2. Kanm /\. Ph~nnAcotifltt K:s of diclofenK and misoprostol whrn
l. Co~don NO, tf al. Come.al ccmplication~ aAAOCialcd wi1h 10pi- ad1n11\iMcred '~or as a co1nbin*1iou product. Drugs 1993; 4S
cat 01,h1hotmic u.M' of non~taoidal a111ii11n~u111m11ory druo~ J Anaphylac1ic shock has bttn reported.' (suppl t): 7-14.
Cawoct Refi·11<t Surg !001; 27: 622- 31.
~ Quidcra AC. rl al. Kcr.ui1is. ulcmtion, ond pcrfora1ion :associ-
1. Szcicklik A,~' al. AsthmaJic attacks induced in aspirin-$Cn$itin Parasympathomimetics. Licensed )l!Oduct infonnation for
1tcd with topical nonsteroidal a01i-1n01mma1ory drug$. Oph-
patients b)' diclofcnac and napr0>.en. BMJ 1917; 2: 2:>1-2. acciylcholine chloride ophlhahnic prepara1ions bas stated that
1/mfmo/a1y 200 1: 108: 936-44. l. CSf\VMC,\ . Avoid all NSAIDs i" :i.spirin-sensiti"c p~licnlS 1here have lx.-cn rcportS that acel)~choline and carbacho/ have
S. f'lach AJ. Ct.vneal mchs ouoci;itcd wtth lopicaUy applied noos· C#l'tc11t Pnibhmu 1993; 19: 8.
Ileen inel\ective wl~n used m patients treated with topical (oph-
teroidal :anci-inflamm~tory drup. Trnm .<fm Oplulrnlmol S« '*'
3. Dux S, ol. Am1phyl1c1ic .shock induced by diclofena<'., 8.MJ
thalmic) NSAIDs.
2001; ,,, 20)-10. t9S3; 286: 1861.
Effects on the ,ascrolntestinal tract. Tl.e most frequenl ad- Pharmacoklnetics
vc"c effects rcponed in pllicnts given diclofenac systemically Precautions
arc gastrointestinal in narure. Typical reactions include epigasnic As for NSAIDs in general, p. I02. Systemic diclofenac Diclofenac is rapidly absorbed when given as an oral
pain, nausea, vomiting. and diarrhoea. Rarely pcptie ulctt and is contra-indicated in patients with severe hepatic or re- solution, sugar-coated tablets, rectal suppository, or by
pst1·oi11tes1inal bleeding have occurred. Diclofenac has also na l impairment intramuscular injection. It is absorbed more slowly
~n i1nplicated as the <:aus:llive agent in colonic ulceration.' when given as enteric-coated tablets, _especially when
~11all tx1wel perfora1ioo,1 and pseudomembranous colitis.; Di· In addition, use of intravenous diclofenac is contra-in- this dosage fonn is given with food. Although di-
dofcnac suppositories may c:ouse local reactions such as itching. dicated in patients with moderate or severe renal im-
burning. or exacerbation of haemontooids. clofenac given orally is almost completely absorbed, it
pairment, hypovolaemia, or dehydration; it should also is subject to first-pass metabolism so that about SO"~ of
L Carson J. ,.., nl. Colonk ulcera1ion and blitcdjng during di-
elofenac lhtrapy. N ~II J Utd 1990; 32.3: 135. not be given intravenously to patients with a history of the drug reaches the systemic circulation in the un-
2. Dc:ikin M. ''al Sm:.11 bowel pcr(oration 4SSOl.;ialcd with un ex· haemorrhagic diathesis, cerebrovascular bleeding (in- changed form. Diclofeuac is also absorbed percutane-
<.-c:~i '<t: d(d(' of slow retCl.Sc diclofcn:tc sodium. BAU 198&: 297:
4R8-9.
cluding suspected), or astluna nor in patients undergo- ously. At therapeutic concentrations ii is more than
J. Gcntrlc A. Ptnncc YL Diclofenac-indu~ pscudomrmbf11'1C'ltJ~ ing surgery wid1 a high risk of haemorrhage. 99% bound to plasma proteins. Diclofenac penetrates
colitis. Lui~r 1992: 340: 12~7.
Ophthalmic preparations containing diclofenac shou ld synovial fluid where concentrations may persist even
Effects on the kidners- Reru:I papillary nL'<:rOsis 1and nc:phrot- not be used by patients who wear soft contact lenses. when plasma concentrations fall; small amounts are
JC syndrome?" have been rcponcd in patients taking diclofcnac_
See also Effects on Electrolyta, above. Breast feeding. Oiclofcnac is distributed into breast milk al- distributed into breast milk. The terminal plasma halt:
1. =:~·s!ti:~~. 1i~;1 1 gg~~1~97: ~~~is assocfoted "'ith di· though lhe BNF 59 considers the amount to be too small to be life is about I to 2 hours. Diclofenac is metabolised to
harmful lo breas1-fcd infallts. 4'-bydroxydiclofenac, 5-hydroxydiclolenac, 3'-hy-
2. Brun GDM~ '' uJ lsol:ited 1ninimal ct.an:c- ncph1~~:11hy 1asoci·
31c:d wioh di<lotrnoc. BAU 1987; 295: t&!-3. ~orphyria. Dicloferiac sodrJm has been associated with acute droxydiclofenac, and 4'.5-dihydroxydiclofenac. It is
3. Yinn~ AM, et al. Ntphrotic syndrome assoc:iatcd ~ith di- attacks or porphyria and is considered unsafe in fX>rphyric pa· dlen excreted in the form of glucuronide and sulfate
dofenoc tc>Jiutft. BAU 1987: 295: 5$6. ticnts. conjugates, mainly in the urine (about 60%) but also in
4. Tattcrutl J, ~al. Mt1nhranous nephcopathy associ:Jlcd ,..·tth di·
clofenoc. Pos11rod Mui J 1992; 68: 392- J. Veterinary use. Veterina1y use ofdielofcnac in cattle in South the bile (about 35%); less than Io/~ is excreted as
Effects on the liver. Elewtions orscoum aminotransferase ac- Asia h:u been associated with severe decline in tbc numbers of unchanged diclofenac.
tivi1y and clinica l htpatitis, 1·1 including fatal fulminant vulrurcs. to v.1l0!1l the residues are highly lo•ic iftheyconsuine
!he carcasses.'-' Meloxicam !Jl.84) hos been su~cstcd as an al- 0 Rcfo-cnccs.
hq>atitisl-5 have occwred in ptllcnts laking diclofenac. TllCl'C has I. Fo\\ler PO. n al. Plasmo:> and S)'•\Ovial tluid c.onc<'nU'aliMS or
ternative.
also been a case rcp,ort or hqla1orcnal damage attributed to di- dicJofcnac sodMl1n end its nujor hydro~ylaited me&abolitu dur-
clofcnac.9 Analysis 0 or180 oftbe cases ofdicl~fenac·asooci>ted I. Shul11. S, t!l al. 01clorenac poisoning is widcspreod m dcclinilll: in,g long·1~rni lrtatment ot' rhtum:i1oid 8r1hritis. £1wJ Clln Pl10r•
hepatic injury received by the FDA between November 1988 vulture populacions •trou 1hc lndi;an subcontinent. Proc Diol Sci mtrcQl 193:\; ?S: 3&9-94.
1004: 271 (su.ppl 6): S4S3-S460. 2. Maui CA. l'I ol, Compdrali"e bioavuilubilil)' uf Jicloft:nX hy-
and June 1991 suggc.ied an increased risk ofhepaiotoxicity in
~.o~~~,:~1fr~~;i~i8~ ';,';~orenac: sodium in 1n•n. Eur J our
1
2. Sh3rp O. Mcloxicam 10 pKYCnl ratiic.s? Lo11Ci.!I 2006: 367:
female paticnL' and 1hose taking diclorcnac for os1eoarth1i1is. 817-a.
Hcpatotoxicity had been delec1ed within 6 months or starting di- 3. Davies NM. Anderson KE. ClmUI pharmacokhH:tics of di-
clofonac in 85% oflhe patients. The biochcm1cal panem of inju- do!enac: 1htrapeutic insi.ght.s and p11falls. CUJ1 Phormueokinel
ry w11s hcpat<X:dlular or mixed hepntooellubr in 66% of patients Interactions 199': 33' 184-213.
and choles1a1ic injwy W3S round in 8% of patients. Signs or hy- For interactions associated with NSAlDs, seep. l 03. 4, Rttnntr SS. rt nl. lnflucmoc of :"f.e W cytochrotne P4SO 2C9
~enot~ on 1l1c sacady•5Uile di!PoSilion <if diclofentc and
persensitivity were uncommou and it was considered thal the Diclofenac should not be given intravenously to pa- c..-c1ecosib. Cli11 Phormotokloe: 2003: 42: 283-92.
111Cchanism of hepatic injury wa.< likely to be a metabolic id10- S. Hinz8.~1al. 8ioo\•'3ilabilityof dictortnac potassiunl al lowdor
synen"ic reoctio1i rather 1han due to in1rinsic toxicity of di· tients ab·eady receiving other NSAlDs or anticoagu-
<>. Sr J C1i11l'IKr#locol2005: 59: 80-4.
dofenac. lanlli including low-dose heparin. 6. Staudiug JF. o ul. Popul01till'Jl phannac:c:tkinctks or oral di·
t. Dunk AA, e1111. Oiclofcnac hepatitis. BAU 1982: 284: l<lOs.-6. clorcnoc for a.cutt' pun in children. Br J Cl/11 PhannocoJ 2008:
Ciclosporin. Deterioration in renol function has been anributcd 66: 846-~3 .
?. Breei'I EG.11 nl. F:llal htfati1is: a.ssocia1cd with diclofcoac. c,,1
1986: 27: 1390-3. to ohe use of diclorenac with ciclosporin.1 Increased concallJa- 1. Miyat.t1kc S. ~' al. R~ndoaizod clinic-31 comp3risons or di-
l. Sc:~ra 0, ~' ol. Oiclofcnl\c.~induccd hcp:tt01o:otidty. Pusrgrad tions of diclofenac were also noted with cielosporin;2 licensed clorcnoc C(lnccnitatton in the so(11luucs nnd blood plasma be·
Ai.OJ 19&6: 62: 63-5. product 1nfonnation fot ciclosporin rccocnmends that 01e dosage l\\.ttn topic~I and oral :apj>Ji<'.:.1100.s. Br· J Clin Phannoeol 2009:
4. Ryley NO.~ ol Dielofcn:ic as:S<Kh11cd hef))lltis.. Gut 1939: 30: ofdiclofcn.ic should be reduced by obout one-half when the lwo 61: 125-9.
A708. ore gi,-en togcthct.
S. HtlfG(lll SM. rl cl. Oic.lc(1:n:>e•OS.~floCi:11N hiepatotoxicity. JA.WA
1990: 264: 2!\60-l. I. Branthwaitc JP. Nicholls A. Cyclo~p<w1n and didof~c in1trt1c.. Uses and Administration
6. Purcell P. elnf. 01dofcnac: hepalili:C. Ciut 1991; 31: ll$1-S. tio.n in l'htumaeoid arthri1i~. L1111rt1 \99L; l37; 252. Diclofenac, a phenylacctic acid derivative, is an
7. Bhogat:>ju A. ~' .ul. Oido!mx-n.soci:ucd hepatitis. So-tit AJnl 2. Kovarik JM. (ti al. Cyclospotinc and nons1eroidal acxiionamm:i· NSAID (p.103). lt is used mainly as the sodium salt for
J t999; 92: 711-13. 1ory dntgs: cxpkw'1"1 poctntinl drus inlcr.lc1ions and l.htir impli--
S. Greaves RRSll, l!.f nl ln..id.. enmt diclofenac rcchallcntt frMt cations for 1hC' lrtalnwnl of rhtumatoid 3rlhritis. J Clin PhorMo· the relief of pain and inflammation in various condi-
g.cn<ric Q_nd non-1cnCJic pr~scrihing. leading to li\rcr tro11uplan- col 1997: 37: 336-43. tions: musculoskeletal andjoint disorders such as rheu-
1acion for fulminant liver failure. Eur J Go1wocntcroJ Hepotol
2001: 13: 71-J. Corticosteroids. Concomitant use of ophthalmic preparations matoid anluitis, osteoanhritis, and anJ..-ylosing spondy-
litis; pcri-anicular disorders such as bursitis and
~i~°Jrc~r~n:~· :d~~!i~~!~~~~~;;'~":;~Ji~ a~9f~~~~
9 cootaining diclofcnac with those containing co1ticos1eroids in
' patients wi1h significant pre-existing comcal inflammation may
$01-41. tendinitis; soft-tissue disorders such as sprains and
in~ the risk of developing corneal complications.
IO. Banks AT~ c1 al Oiclofcn;mc-11uo<:i11c:d JiepatotU>.iciLy: anal)·sis strains; and 01her painful conditions such as renal colic,
of ISO cast:s reported 10 dle 'F'ood and Dru! Admimslration ris Diu~cs. Deterioration in renal function has ~en attributed to
adverse rcaccions. H'pou>loiy 1995; 22: 820-7. acute gout, dysmenorrhoea, migraine, and after some
the use c>f diclofenac with lriomtcrt!~. 1 surgical procedures. 1t has also been used in some
Effects on t:he skin. Self-limiting skin reactions such as <Mh or 1. Jliirk6nen M, ElblMl·Kullbcrg S. Rcveoibkdccctiorativn o(rc·
prurirus may occur in patients given diclofcnac. More serious nal flmcticm after d1clorc:-1\3c in patienr rcoch•ing ttiRmlc~ne.
countries for the m3nagement of actinic kerntoses and
skin reactions attributed todiclofcnac include bullousdcrmatitis1 B.11119S6: 293: 69'-9. fever. Eye drops of diclofenac sodium are used for the
The symbol t denotes a preparation no longer actively marketed
48 Analgesics Anti-inflammatory Drugs and Antipyretics
prevention of intra-operative miosis during cataract ex- lowed by one drop immediately after surgery and Actinic lceratoses. Oiclofenac sodium 3% in hyaluronic ocid
traction. for the treatment of inflammation after sur- then one drop 4 timcs daily for up to 2 days gel is uscd 1•3 in lhc lrealmenl ofactinic kcraloscs (S(!C Basal Cell
and Squamous Cell Carcinoma, p.733), and • mcta·analysis'
gery or ·laser treatment of the eye, for pain in corneal • to relieve symptoms of seasonal allergic conjunctivi- found ii to be ofbcn<:ti~ despite previous cuoccms tha1 the prep-
epithelial defectS after surgery or accidental trauma. tis, one drop is instilled 4 times daily as necessary aration may nol be significantly more e!fective 1han hyalW0<1ic
and for the relief of ocular signs and symptoms of sea- Diclofenac diethylamine is used topically as a gel con- acid gel alone.5 An open-label comparison involving 30 paticuts
sonal allergic conjunctivitis. wilh multiple actinic kcra1oscs suggesled that 90 days of treat·
taining the equivalent of I% of diclofcnac sodium for ment with diclofcnac sodium 3% iel (10 lesions on one side of
The usual oral or rectal dose of diclofenac sodium is the local symptomatic relief of pain and inflammation; 1hc race and scalp) was better tolcraccd. bul slightly less effective,
15 to 150 mg daily in diYided doses. In the UK the it is applied to the affected site 3 or 4 times daily; treat- lhan 28 daysoflIQtmenl with fluorourocil 5% cream (lo lesions
maximum dose regardless of rou te or indication is ment should be reviewed after 14 days or after 28 days on the ocher side).'
150 mg daily; however, in the USA a maximum oral ifused for OSteoanhritis. A topical spray containing di· I. Rivers JK. Mele.an 0 1. An open sLudy to aJ$CSJ di~ t"fficacy and
sart1y of 1opK:at 3% dielorenae ma 2.5% hyaluronic acid !!Cl for
dose of 200 mg daily is allowed in the treatment of clofenac sodium 4% is also available; 4 or 5 sprays (32 the trea1mcnt of ac1inic kcnitoscs. Arch Drrmatnl 1997: Ill:
t239~2 .
rheumatoid arthritis. Modified-release preparations of or 40 mg ofdiclofenac sodium) may be applied 3 times 2. R.i\'tfS JK.. tt cl. Topical uu1mcn1 of actinic keraroses wilh 3.0%
diclofcnac sodium are available for oral use. Di- daily, up to a maximum of 15 sprays (120 mg of di· didormac in 2.S% hy)1Utonan s;el. Br J lknno10/ 2002; 146:
clofenac has also been given in equivalent oral doses as clofenac sodium) daily; treatment shou ld be reviewed 94-100.
3. Ulrich C. et al. Tr~ttM'l\I or multiple actinic keratoses with top•
the free acid in dispersible preparations for short-term after 7 or 8 days. A topical solution of diclofcnac sodi- k1I diclofonac 3% Selin airg:tn 1rans11lant rtcipienlS: a stnes of
treatment up to 3 months long. Diclofenac is also given um 1.6% is available for the treatment of osteoarthritis six cam. Br J Derructol 2001; t S6 (suppl 3): 4~2.
orally as the potassiwn salt. Doses of the potassium salt in superficial joints such as dte wrist or knee; it is ap- 4. Pinrd D. ti ol. Three percent dido(cn3t in 2.S% hyaluronan gel
in lhe tratmc:nl of actinic kcratosts: .a mcca-an1Jysis of the re-
are similar to those for diclofenac sodium. Diclofenac plied in small aliquots to achieve a total of20 or 40 cent $1Ud1CL Ard Dermorol Res 2005; 2'7: t 85-9.
potassium is also used in the treatment of migraine in drops, depending on the size of the joint, and repeated 5. McE.....an L,E. SmiL"i JG. TopiC'a) diclofcnac/hyllun>nic acid gel in
the 1rea1men1 or solar kcra1oSCJ. Austmlas J Dermotol 1991; 38:
an initial dose of 50 mg taken at che first signs of an four times daily. Diclofcnac is also used in the manage- 187-9.
attack; an additional dose of50 mg may be taken after ment of actinic kcratoses; it is applied twice daily as 6. Smith SR. 11 ol. Bilateral comparison oflhc efficacy and 1olcra·
2 hours if symptoms persist If necessary further doses diclofenac sodium gel 3% for 60 to 90 days but the op- bility of 3% diclorc.:nac sodium &ti and S% 5-fluorouricil cream
m the lrC3lmcnt Of ,;,ctinic ktn\OSU o( the face and SCaJp J
of 50 mg may be taken every 4 to 6 hours to a maxi- timum therapeutic effect may not be seen until 30 days Drvp Dermarol 2006; S: t S6-9.
mum daily dose of200 mg. after the end oftreatmenLDiclofenac epolamine is also Pain. Reviews.
Diclofenac sodium may also be given by deep intra- used topically as a plaster containing the equivalent of I. McConnack PL. Scon U . Diclofenac sodiurn injection (Dy·
1% of diclofcnac sodium for local symptomatic pain :?~~~7)~ rof~opentive pain. Drugs 2008: 68: 121-30. correc-
muscular injection into the gluteal muscle in a dose of
75 mg once daily or, if required in severe conditions, relief in ankle sprain and epicondylitis. In the treatment 2. Derry P, er of. Sin&lt dose 0t1I diclofenac for ac"'t postopcralive
75 mg twice daily. Diclofenac sodium may also be giv- of ankle sprain, I plaster is applied once daily for a pain in adult.s. A\11lablc in The Cochrane DatabaseofSys1cma1.
ie RcvKws; Juve l. Ch i<:l~stcr: John WiJcy; 2009 (aceeucd
en as a continuous or interminent intravenous infusion maximum of 3 days and for epicondylitis, I plaster is 09/09/09).
in glucose 5% or sodium chloride 0.9% (both previous· applied twice daily for a maximum of 14 days. 3. Sianding JF. ~' ol. Diclofcoae for acute pain in children. Av1ila·
bk in The Cochrane Database or Systematic Reviews: Issue 4.
ly buffered with sodium bicarbonate) or as a bolus in· Diclofenac is available as a combination preparation Chicltest•r: John Wiley; 2009 (ICCUS<d l 8/03/tO).
travenous injection. For the treatment of postoperative with misoprostol (p.21 75) for pMients at risk of Preparations
pain a doseof75 mg may be given ovcr30 to 120 min· NSATD-induced peptic ulceration. BP 2010: O;c!of<!nac Get~ 0.dolonK Tzlf.eu; ~
utes or as a bolus injection. The dose may be repeated Administra tion. IN CHILDREN. In children I to 12 years old re!..,e Oiclofcnac Clp>Ulo!: ~td-r•I•.,. Oiclo,.,,ac Tr..tett
VSP JJ: Oitlofcnac Pow1iun T.tllcu: Oklolcnoc Sodium ~a se
once after 4 to 6 hours if necessary. To prevent postop- the licensed UK orol or rurol dose of diclofcn:>e sodium for Tob'e<s: Odolenac So6.wn Eictended-Relcas• Tablot>
erative pain, an initial dose of 25 to 50 mg diclofenac juvenile idiopathic arthritis is I to 3 mg/kg daily in divided
Proprietary Preparations (details are given in Volwnc 8)
doses. In children 6 to 12 years old diclofcnac sodium may
sodium may be given after surgery over 15 to 60 min· also be given rcc1ally for the trcatmtnl of aculc postopcra1ive
Arg.: Ainedif Alcliooinj: AldoronNF: Algocler;AIJio>ol><At>alle>eATM 101;
Alomo Oesinlhmlm• Gel6c: 8ancxt.ri; Sela!; BlrbJM: l!lolOu'Tl PY001; CM·
utes followed by 5 mg/hour to a maximum of 150 mg pain, either alone or as an adjuncl to opiate therapy; a usual rro11c>< ~ Cunnftam VL: D•mi»t O?N: Dias1one: o;-. Oicloge-
daily. Alternatively, dle initial dose may be given as a dose is I to 2 mg/kg daily in divided doses for a maximum of sic: O.Clof'>n<i O<lol;rn; Oiclomar: Ooetonooc Oien«:. Oli!Nc F«le: D~·
4 da)s. The parenteral route is not licensed for use in children •mt: Oioxoflex; ();oxaflex Protect: ~ ();stec; Colo Toroanot
bolus injection over 5 to 60 seconds followed by addi- Ool:lr.uc; Oo:oncitor; Oolvan: 0 - ExtclMlia Analge-.k0< F.iboflemj:
tional injections up to the maximum daily dosage; this although it has b«n used (see below). Aexrc Fltlaplcm; flogenact. flopsn " ' - Gentisal)'I; lglo<line: tmoncit
may be repeated after 4 to 6 hours if necessary al· '!be BNFC 1()()9 suggests slig)itly ditrc~t doses of diclofenac ~lolt: l<amox; Kinal&in; Klonof!noc: ~ lort>rcnac: Mc:Utltx Nf.
sodium: in the management of rheumatic disease, includingj u- ~""t: N.ii;ncx: Nit<r• rcnac; NQl'Viktn: o . a: o ..~ Pronix
though the 1010/ dose should not exceed the maximum "enile idiopathic arthrilis, in children from 6 months to 18 years Ou«·Out: llati Sahl O: Rod<\oc ~m F0<10: S.trox: 1om•nl: Vaalion:
daily dose of 150 mg. 'Ille maximum period recom· ·r,.rvt Nr. Vomttl,,,., Vrob<On Ge~ V.robron NF: Volforte; \'ol'$er<
ofage, it rttommcnds an oral dose of 3 to 5 mg/kg dally, in 2 or Volt>r•n Colr-.o; Volt:trtn Mov•t. Xe<lenol; Xfft: Austnol.: .Arttwotoc
mended for parenteral use is 2 days. Diclofenac sodi- 3 divided doses. For rtlicf of pain and ioOammation in, for ex- Clona<.t; D<nconb Anu-NlomrNtO'y; Diclacf : Oicbhox.ot ONc: ~nae
ample, soft-1issuedisorder5, 1herecommcndcd oralorrttlal dose lmllac; Solaf.ue; Vdo(en 1.lol'"""" Yott.fen Ophtho: Voltfm. Aulllfo: Ag·
um is also used intramuscularly in renal colic in a dose olomcdt: A'gri: Ar1hrotoc Oedol:>r: Oeilamat OenanYnt: Ck:.CHexal;
in children from 6 months 10 lll years of age is 0.3 to I mg/kg
of75 mg repeated once after 30 minutes if necessary. given three times daily; children 2 lo 18 years ofage may be giv-
~ Oiclo-Bt: O.Clobene: Cklom•lar< DClo<tad: Oiclo<)t ();fcnet:
Do'o-Voltan!nf; Oc:lfp.uic:. re.N•-mt:riectO""! Sot.rue: Tritut\.t:lttarct\ Zy·
For dosage details in children, sec below. en o similar dose once or twice daily by intrawmou.s infi1sion or mamcdt: ~'"' Artlwotec: C.Ullam: Ocloobolc: Od:iast Dicloletned. O.·
deep intramuscular (gluieal) injec/1011 fot up to 2 days fot post- clotop: Oocc11dofe: F',ector: MctWtne: ~~tdt Voharen: Broz.:
Diclofcnac sodium is used as a 0.1% ophtha lmic solu· A~ A.-nn: Augelitt: S.1-Gelt: 8eneww> 6olonac: C..1"1>m: C.1·
operative poin. •ftcx: C.Uftel<)'m C.talgemt Cr,.llanj: Oo/>t'lnf; Oolent: Clofenal;:
tioo in various situations: Regardless of roule or indication, a maximum daily dose of Oo'end Oeflatlogin; Oeituerc Oesdl<xf; o.ciact: Oitlo P: ();doff: 0..
150 mg should nol be exceeded. <Jo1tnaxt. ();clogcnotr< ~ DclcNco: Oiclonamnt. Oicbna><
• for the prevention of intra-operative miosis during 01c1cnt Oklc»odt: O..losocko: Oo""'1nt: o;O>C1ncx: 0naten: c:>oril>nt:
Diclofenac pot<lssium has also been usal in children aged over Oori<"t OoriR.int. Fenae.r. ~ ~btrl; Fi.;oren: 1-- Aatn.1-
cataract surgery, it is instilled in the appropriate eye 14 years fot the treahncnt of rheumatic disease, musculoskclcbl genj: Flamatrot P: Fianalcn _..,., Rex.1,.,,..,.f; f1ocln Duo: Flopr< Aoge-
4 times during the 2 hours before surgery disorders. and post0pcra11vc pain; it is given in an orol dose of75 O<t Aofirerc Flogonoct hr.x: Wlade<ent. lnllamtt Kitdrer>c IJfnnt:
to 100 mg daily in 2 to 3 divided doses. Luparent: Maxiei'g. Ncocon.r. Neotallan; Nee>W'M; Ollooc Opumaxt:
• for the treatment of postoperative inflammation after Ort~ Pollzx: ~ Plodortnaco: Prolenoct ~ Sclt Tonallanl:
cataract surgery, it is instilled 4 times daily for up to TOPICAL. References to the use of phisters.froviding sustained Trlc<>t. Venaec ~ Voltoflc>e VoltM'erc Voltaren Colrio< Vdlrhc: Zo-
topical release of diclofcnac epolamine,1 and reviews of the tac. <:on<>d.: Ap<>O<to: Anhrolec; N""°'OoC....C Nu-Odo; PeMsaid;
28 days staning 24 hours after surgery Voll3t'Ot1: V::>I'....,. Ophtlla: Chilo: 3A OfAM< /Vrdtrc ArVerc A"1dol:
use ofl 1opical solution ofdiclolCnac wi1h dimethyl sulfoxide cata'llm: Oo111m>t: Die~ ()c<>J.<l. Eliu'..-c &ca.mt Aimesan: Fl<:<tor;
• for the control of post-photorefractive keratectomy to treat ostcoanhritis. 7·' The latter was found 10 be cffeclive Ao1oc: ~ L..-lu< Merpat NcoUlext: otic ~ Pirollan~ Pro l.,.·
pain, it is instilled twice in the hour before surgery, and belles tolmted lhan oral use. 1IA: ~ Tvtogc>;c Voltaren: Cz.: ~ Aj»Octo: Atlhrctect: Or
I. Galcaui M. Man:olongo R. A placel>o«irltrollcd study or the <1orM: Oiclore...,-, OIKY: Oo!<nina: Oon:>sor>; ftiu<a11t: flec1e>·; lntlomicj:
then one drop twice at 5-minute intervals immediate- efficacy and tolcrabilily or a nonstcroidal anti-inOamm:uory HonoCltr< MJOail: Notlofj: ~ Ollet< ~ u n;.;lopher< U...
ly after the pmcedure, and then every 2 to 5 hours drug, DHF.P plu11:ter, in inOammatory ptri· and extra·)r\icuJar
Veal: Volt.;rorc Denm.: Ar11Yo:ec Oiclodan: Oicloit Oafc!net Eta:~
rhcumatologi cal di~il)n,Dr11p£xpClinR~ 1~3:
nacopc Flector. t1od•""""- So:ar..e: Vot..,.... Vorurf; Flo.: ~oc O·
while awake for up to 24 hours 19: 107- 15.
¢>metin'): ();domc>c Eoze: RK!orj: Motifcne: PennWdj: Sdit1llt vobo-
2. OrciKr RL. Tisnc-Camus M. OJIEP p•~jlerS as a topical lrcll· nat: Voharen; Fr.: Artottc: Oicloced: f leeter: Sotara?e: V°'cUitf:
• for pain control after accidental trauma, one drop is mc.nt of knee oste~rthtitAs-e double-blind placel»-con1ro1ftd \lolt.nnactiga ~ Voll.,..,.; Xcrid; Ger, A.l.orvc Ar\ho1t<:
instilled 4 times daily for up to 2 days ,.,11dy. D"'8-'Exp C/lnRn 1993: t9: !17-23. A,..,.,..x ();clobeto; Diclac; Delo: Doclo·Oi\;&x ();dc).Gctt. Oido-1'\nf•:
) . AfTaitati G. et al. EffttlS of1op1col didofenac: (DHEP plasla) on D<lo·IW: Oi:lodoc: Oiclol""6eu: Q;f•n: O°'li'-O;do; O.U""1enf; Effck·
• in the treatment of inflammation and discomfort af- skin, subcu1is aind muscle pain thresholds in subjects "ithout ton: jena!<Ncf: jtlt.lfenac; L•xobencj; Monollam: M)ogilf: Op1alidon
sp0nt•neot1S J»in. Dn<gt bp Clin Res 200!: 27: 69-76. :z.m.a.men mt Q;clofenac: R•wo&no: Sondoz Sctwner-.get Solarll1e;
ter strabismus surgery, 01Je drop is instilled 4 times 4. J~nourc P-J. £..,.luation d'un anti-in011mmA1ou·t: nnn stCroJdicn Voll""" \l:lltnn Ophlha: Gr.: Actisul')'; Arl:tnxiton: Arlhrotec. Sat•!t
daily for the first week; this is reduced to 3 times dai- topiq1.>e dans te ni1cmcn1 de- la douteur cl 6e l'infl:.mmation: CAWlatT< Oonac; Comralg: Declof0<t o.r;_,. o.n.c1o<: Oiclofast Qi.
cxcmp1c de Flcctor nuugcl'' 1% dispo$itir local bioedhesif de clo)et: CklopHoacnc Oiclcptast ()fend: O'Nclot'c Ew-q>on Eyeclot Fen.
ly in the second week, twice daily in the third week. diclorenac ipolamine. PrCtse Med2004; 33: l~t3 . octet F;gr.t Flcfarm;n; lnllalOrte; )<-;pr... l.inobol Moniflam; Optcbel: Pen·
and as required for the fou11h week S. Bn1hhnann P, ~' nl Shon.1cnn trear1ncn1 with topteal dictorenat' gee< A:nnsaict. ~n: Rl>eu...- - : S•nac: T~ t.k1c<>«
cpolaminc plaslcr in patien1s wi1h sy.nptomatic knl"C osh:c,nu1hri· Vil2ait •;o1on~:Voll"''"' Vurdorc Honr K011g: Afm~At A~ Apo-0.-
cb: Artlwen; ArtlYolcc; Aswn Crut.m: Coofec Clokn>c; ~ Oo-
• for the control of inflammation after argon laser tis: p00led analysis of two randomiw-d dinical ~tudics. Curr M~
clo o.nk: Oitlofenf: OCJosesict: Oifenac: o;iono!t, Erdon: E~
trabeculoplasty, one drop is instilled 4 times during Rn Opin 2006; 22: 2429-38.
6 Altssandri ~. et al. Topical dictor~nac p:;1tch for postopcr111ve Fena<fu'Tl: fle<tor: ~t Gtolena<t: ln~anac les11im: Olbt PainoK.
die 2 hours before the prooedW'C followed by one l\enulcn: Remetl\on. Ren: Rhtmaftnaxf: Ru""'1'1no><: Sl""en.x: Tak~
wound pain in lapar0$C0pic gyn«0loai1.· ;urge1·y:,. randomized Uno""'; Vartebrc Voclde<>ic Voll....,n: Voli.rcn Opl'rJ>.>: Voll..-; Vol.al.,,;
drop 4 times daily for up to 7 days after the proce- Mudy. J Min;,n /mwfrre GJ.,1ecoll006; 13: 195--200. Zolterol: Huor.: C.ti"....-n: Oiclac: Oclomet Flameri: Ftector: Foncdol;
1. Towhctd TE:. Ptnniaid therapy for CUICO~ rlhrilis or lhr L:r.tt: -- H\m"O:fcna¢ Qlfer.j: Ve..,.lt; VclU,... Voltarc• Ophto: Indio: Cofcoac:
dure s:yslcmo1ic ll:\ltW and mcl.a3n3ly1'iS or rtndomizcd COOlTOlled Oitlotnot OocloNc: Oic!o<>rc DoCex; Oolocidc IC: ~ Pius E~
trials. J Ri1<1.n>01ol 2006; 33: 567-73. ES£ipyl>n OS: '<tiodxt. Fensaide: ~Gesic: ):>!IOt t(.fenac. Nae; Nae Get
• for the treatment of pain and discomfort after radial
keratotomy, one drop is instilled before surgery fol-
S. Moen MO. Topical d;ciorcnac solutioo.
262t -32.
°"''' 2009: 69: ~ °""""'"D: o..Jtin-SR: Proierac; R.coctono: ~: Sol\lnact: Trc-
nugooic: Tromo>e Vo..oran: lndon.: .Ab6llwnt. A<lomc; M•m: Avanac:
All cross-references refer lo enlries in Volume A
 DidofenadDiflunisal 49
~ Spot.n: OcJ:l(t...;; Switz.: t'fea~ 'JObr4Jcll Vd-
noper.: VOt'Cf'o, body hacmOl)11c am..:mia has also been reported. 51.-.,: Hypcrsen-
lamoc"1< Thoi.: ~ Turlc.: Moget Ocubm;: UI:.-.: 3cl-R.n (&o,.p,M): si1ivi1y. below.
Q;dofon·Gel (Alo<"*'4): 0.Cloran Pl>,. (Al•<M>l>b< nNX): O;p.-.n
~;pc11Jt: Do«1tel"I (A~!: O::d:i.·a..< {0K'/6PM<CF V~tz..: Com- I. t:Jnbrtwc AM O.Ounis3l-anoci~l ed thromhoc:ylope!"lia 1n a pa·
We-i; Pa n(nii. TOdtnac Tr.ur~ . 1icm withrheuma1oidanhritis. Ar1hrllf.f Rhrmu 198S: l1: r4S-9.
Effects on the kidneys. Acute in1ers1i1ial nephritis, prcscnlin:;
as acule oliguric renal failure. c1'Ythrodenna, and cosinophilia
Diethylamine Salicylate has followed the u~ ofdiOunisal f
Dioethf.amn SaEcylas: Die'l)iamnsa"c)".at Dietyylizmoin&lisy· I. Ch.1.n LK. "' nl. AC:ulc 1nlcrs.111ill ~ri1is and eryOuodcrma U·
sociatcd withdiflunisel. BMJ 1980: 280: 84-S.
laatti: ~lo de d1etilamina: Sais.ilat D"etiamn
Al~)TW-.a.Mlt!"f C.V.M~T: CaAHU1o+MT Ato0nv.av"1Ha
Efied:s on the lungs. For rererence Lo po1oumoni1is associated
with diOunisal 1hcrapy, sec Hypersensitivity. below.
=211.3
C11 H1 1N03
o .s - 4419-92·5. EffeGts on die skin. Rc~11s ofStC'\<ens-Johnson syndrome as·
so<:ia1ed wilh dtflunisal. 1- Sec also Hypcrsc:nsith•ity, below.
I. Hunttr JA. t1 nt OinunisaJ and Stevens· Johnson syndrome. BJ.!J
1978; 2: 1038.
2. Qrolll JA. er al. OiOuniAl·1nduccd erythc:ma muhiformc niajor.
Hqsp Fomml 19&6: 21 : 3S3-4.
Hypenensitivity. Three cases of hypcrsensiti"ity 10 diflunisal
in which die main clinical features w<:rc fever. elevated liver en-
zyme values, Cl)1hrodenna, and cosinophilia, have been report·
ed.' Heinz-body haemolytic an""'llia occurred in one of !he pa·
1ien1S. Other hypc?Scnsitivity rcaelions associated wi1h diflunisal
Pharmacopoeias. In Br. and Clti11. therapy MYC included pncumonitis1 and fuhninant neerorising
BP 20 I0 (Die".h)lanw>e s.Jicyl.\1e). White or almost while, fosciitis.l
odourless or almost odourless cl')'Slals. Very soluble in water; I. CQvk OJ, "' nl, Three cases of diOu1usa1 hypersen.siti\•hy. Cou
li'ecly soluble in alcohol and in chlorofonn. Protec1 from light. M•d ASJ<X:J t9S8: 138: 1029-30.
Avoid co11tac1 wi1h iron or iron salts. :?. Rich MW. Thomas RA A c.-..se o ( cosinophilic pneumonia and
va~u l itis induced b) d1nuniS3I. Clies1 199/; 111: 1767-9.
Profile l . Krige JEJ. 1r1 nf. NccrotiRn,c (asciitis after dinuni,.:al (N' minor
Oielhylainille salicy'hue is a salicylic acid deriva1ive used topi· injury. L'mcei 19&5: ii: 1-43i...3.
cally in n1befacien1 preparations similarly to me~iyl salicylaic Overdosaae. Diflunisal poisoning has $0l11Climcs been fatal.1.2
(p.89) for rh~lic and muscular pain. A dose: of IS g hos been reported to ha\'C Cl used de<llh when no
Preparations 01ho-drup were involved bu1 a dose of7.S g has also been futal
BP 2010: ~ S.llC)-!a10Crcan>. whcn taken wi1h other drug$.
Proprietary Preparations (<lc:tails are given in Volume BJ I. CoUft H. ~ans GN. Poi!>oning ~ricr O\·trdose "ith non-s(eroi-
dal 1111i-innarnrn11ory dmp . Atlwr·n Drux Rmct Acule- Po&o1t-
8tlf.: Algesal: <An~ A>y>ogesi<: Fin.: Alge•a~ Fr.:~ Gr" A:~
ing Re-'' 1984: l: 1- 21.
Hunr.: Aciphen: lndi« ~ Noch.r A'?.•sal: Nww, >s~ Pol.: 2. l.evinc B. et al 010&1ni1:I r~lo led fa1:1lity:: C:3SC report FtHt'1tJ/c
SlJmm: Port.: Nginm AIP<mo. M.issa&im: Swe<f.: A'ge<..al rurlt: A!Je-
Sil: llq>zrl: UK: Alg<>sat. Lloyd's Crcom; V•nn.: Ne"I. S<i Im 1987: 35: 4S-50.
Precautions
~1 :;;-f;:~~~.~~~,-~~~z~:~:~
1
As forNSAJDs in gtncral, p.102. DiOunisal may need to be giv-
C~ 'il''"''mime111T1>11S<hot: IJ:'l...---.m.fUdt: Latc1yt P;.su N-
tu~ ~t. Rh-:u~..,,.i; TI~ lltlf.: P,epri: 8roL: R,par.;
en in reduced dosage in paticntS with signifrC<tnt renal impair-
ChRe:~ c .. : Alge,.1: Repard-Gol N: fr,~ Su-.ctive: Rcparit nlCOt and should nol be given when rerol impainnent is ~verc.
li-auma!!>lt. Ger" AJsesat Dolo·Menthonaimf: ~ot: fl.,.,.01-G<>I Aspirin and other acctylatcd salicybtes are not recommended for
N; Gr.:-Aficsol S...•ct.'ve; Poro>1op. Hon
~onr:R.,p;iri~ Rubesalt: ""' in children unless specifically indicated, bec111se of the risk
Huna.: ........, Repori N: lndon.: A~ ltoL: ~ L•· of Re)'c's syndrome. Although this preca111ion has not been •t»
otontrauma: ~ 01: F.fl>1rilt: Sl!dalp.>I\ ...,,., Tr.iuN: Moloysio:
fWl>a..;.c;.1N: Noth.: Alto-Al Forte. Philipp.: P~~ N; PoL: Repan1 N: eifically cx1e:idcd 10 diOuuisnl iris not generally licensed for use
Port.: Alsesat l.at..t M<da'.I""' ~nopll'il: S.A(r.: Repri; Spain: "'fe· in children.
~ Con'"'' " Ooim<th F~ Rdc>o Sala: Switz.: Al~~.
l"IMna ~>Gor< Rq>On< N: Repotilf: Thai.: Repri: V~ Turlc.: Interactions
~ S.,act;..; P1..;»2CL UAE: R.biahi: UK: Fiery )•ck li·w,,..,. HUI For inleractions 8$$0Ci3led with NSAIDs, see p.103.
Spoy. Ukt.: Roparil·Cof N ~f._,., H); Veno<.: LeMa><>I. Aspiri11 may produce a small dc<:r<asc in the plasm• concentra-
tion or diOunisal. Diflunisal has been repo11ed 10 increase 1he
plasma concenrraiions orindomr1acin and paracetamol; diflunis·
Diflunisal !&AN W.N. •INN) al wi01 indon1e1acin has been ossoci.11ed with fo1al gastrointesti-
nal hacm01Thage and 1hcre(OI'< lhe combination should not be
Q;fluni~I( Dl'llJnisalis; Difouni5"1<.m; 0.lluntsza : MK-6<!7. 5-(2.4·
DoOuoroplle~.ic acid.
used. Regular use of antacids may reduce the absorption of dif·
lunisal.
A"""y>111c;111
C11HeF;03 = 250.2. Benzodiazepines. for lho elli:ct or uiflunisal on plasma COil•
CAS -- 22494·42-4 conlra1ions or o.raupom, ;;c.-e p. I093.
AfC - N02BA I I. Probenedd. Average $1Cldy-statc plasma conccmr.nions ordi-
ATC Vet - QN028A 11. flunisal were increased by 65% when ii was given with probc1ie-
UNll - 7C546U40E.N. cid.1111is was due mainly 10 reduced fonno1ion of the phenolic
and ocyl aJucuronides. However. plasma conccnrTlltinnsofthese
glucuronides and the sulfate oonjuµte w<:re also increitsed C\'en
COOH more hcc:i= probenecid also reduced rhcir renal clearance.

•-Q-d-OH F
I. M :acdon~ld JI."' al. EtTcc:1 of pt'Obl:necid on the formatioo ind
cfimin:lO\ kine tic~ or thC1U)J>J1!1.lt and gJucuronidc C-Onju,aalCI
oft.linW1i:.al. £11rJ C/111 PJ11irmorol t99S; 47: 519-23.
Pharmacokinetics
Difltuiisal is well absorbed from 1he ga.stroinlcstinal tni<:I and
peak plasma concenlr.nions occur about 2 to 3 hours after inges-
tion ofn sinale dose. IL is more than 99% bound 10 plasma protein
Pharmacopoeias. In C'1i11.• £11r. (sec p.vii), nnd US.
aod has o plasma half-life of • bout 8 10 12 hours. Diflunis:ll e.~­
Ph. Eur. 6.8 (O.Ounisal}. A white or. almosl while. crystalline
hibil$ non-linear pharmac:ckinclic; so 1lrn1 doubling lhc dose
powdet It exhibits polymorphisn~ Pr.>c1ically insoluble in w'1tcr:
more than doubles drug accumulat1u11. Due 10 the long hair-life
soluble rn alcohol; dissolves in dilulc ""lulions or alkali hydrox· and non·linca1 kinetics. ~n<ntl clorys an: m 1uired to reach stcady-
ides. Pro<c:ct from ligh1.
Sllltc plasma concenlrntions oficr multiple dosing, llic time to
USP 33 (r>.b-.i>aQ. A while 10 off.whi1e. practically odourless, sh:ady·Slal• "oricenll"•lions can be reduced by giving on ioitial
powder. lnsolublc in water nnd in hexane; ti'eely soluble in alco- loading dose. COOO!ntnuions of di0u11isal in synovial Ouid re.1ch
hol and in me1hyl alcohol: soluble in acetone and in ethyl accme; about 70-A of those in pl:isma. Diflunisal iscxcrcled in the urine
slightly soluble in c..rhnn ie1r:1chlmide, in chlorofonn. and in mainly as glucuronidc conjugates. Some bilrary recycling may
dichloromethane. also ooour. DiOunisal is disrribulcd into llrca.<t milk wilh concen·
Adverse Effects and Treatment lr3tioni rcponcd 10 be aboul 2 IO 7% or !hose in plasnu.
As ror NSAI~ in general, p.100. The commonest :><!verse ef.
ORcfcm1<.-c.<.
tecls occuning wilh diflunisal arc gns1roimcs1inal dislurbanccs,
I l.ocw~n GR.. ('/ o/. Effccl ordose: on lht ih1curonid3lion 3nd SUI·
headache, nnd rash. Peptic ulcera1iori ond g~s1rointestinal bleed· phation kine1ics or d1flun1S1I in min: single dose studies. Br J
ina have been rerorted. Dizziness, drowsiness, insomnia, and Clin Pharmacol 1988~ 2Ci: 31- 9.
tinnirus may also occur. 2. Eriksson L·O. (!' "'· lllOucncit of rmi.J (aih.1tt, rhe\.lma1oid 1nhri-
1is and old a~c on the phar1n~C-okincttCS of difiunis:il. Eur J Clitt
Effects on the blood. Haema1ological :>dv~ eftects Msoci·
Phorm«<>i 19~Y:36: IA!-74
a1ed wilh diOunisal appear 10 be infrequent. Tltrombocytopcnia 3. Vtrbt'ttk RK. r1ol. The i:ffec1 ormu1tiplt' dos.3,t on the k lne1tcs
associaled with dtRunisal-indnced pcriphernl plaieta destruction of ~lucurorhd.11100 11nd sulphatio11 of diOunis;al in mim. Br J Clin
has been reported in• pal~! with rheumatoid arthritlS. 1 Heinz- Plto,.m«ol 1990: 29: 381-9.
The symbol t denotes• preparation no longer actively marketed
50 Analgesics Anti-inflammatory Drugs and Antipyretics
4. Macdonald JI,"-' ol. Sc:x·diffcrcn.;e and the effecrs of smoking deine Tanrate BP 2010). A white or almost white crystalline Pharmacokine tics
and oral conl.rlceJ>'ivc 1tcroids on the kinetics of d1flun1ul. £11r powder. Freely soluble in water; <paringly soluble in alcohol;
J Cf;,, Phormocol 1990: JS: 175-9. Peak concentrations ofdihydrocodeine occur about 1.2
practically insoluble in cyclohcxane. A 10'!. solutinn in warer
S. Nuemberg B. ' ' ol. Phamucokinctics of dillunisal 1n pa1icn1s:.
has a pH ofl.2 to 4.2. Protect from lig)lL to 1.8 hours after oral doses; oral bioavailabi lity is only
Clm Phorn-l•,.t 1991: 20: 81-9. about 200/o, probably because of substantial first-pass
USP 33 ~odeine BiUnnt•)- pH ofa 10% solurion in
U ses and Administration water is between 3.2 and 4.2. Store on airtight containers. metabolism in the gut wall or liver. Dihydrooodcine is
DiOunisal is a salicylic acid derivative (sec: Aspirin, p.24) but it metabolised in the liver via the cytochrome P450
is nor hydrol)'1'ed 10 salicylarc and iis clinical effects resemble
more closely those ofpropionicacid derivative NSAJDs such as Dependence and Withdrawal isoenzyme CYP206, to dihydromorpbine, which has
ibuprofen (p.68). Diflunisal is given in the acute or long-tam As for Opioid Analgesics, p .105. potent analgesic activity, a lthough the analgesic effect
management of mild to moderalc pain, and pain and inllamma- Dihydrocodcine has been subject to abuse (see under ofdihydrocodeinc appears to be mainly due to the par-
1ion associalcd with OSICOal1hritis and rheuma1oid arllui1is. The ent compound; some is also coo"-ened via CYP3A4 to
usual initial ontl dose for pain relief is J g followed by a mainte- Precautions, below).
nance dose of 500 mg every I2 hours although some patients nordihydrocodcine. Dihydrocodeine is excrc1ed in
may require 500 mg every 8 how-s. ln others, a lower initial dose Adverse Effects and Treatment urine as unchanged drug aod metaboli lcs, including
of 500 mg followed by 250 mg every 8 to 12 hours may be suf· /\s for Opioid Analgesics in general, p. I 06; adverse ef- glucuronide conjugates. Elimination half-li fe is repon-
ficienL The usual oral dose for arthritis is 500 mg to I g daily in fects of dihydrocodeinc are less pronounced than those cd to IlllJge from abou1 3.5 lo S hours.
2 divided doses, adjusted according to response. Maintenance
doses gicatcr than I.S g daily arc llOI recommended regardless of of molllhine. 0 References.
indication. Doses may need 10 be redllC«I in patients with renal 1. Rowell FJ,~t al. Phannaeokirw:tics o(inlrl\'tnou.s tMonl dihy-
Overdosagc. A 29-year-old man who had taken 2.1 g of dihy- drocoOeinc and its acid meubolitC'$. E11r J CJin Phar-mocol 1983;
irppairmenl, sec below. drocodcinc had biochemical evidence of acute renal and hepatic 25: 419-24.
Difluoisal arginine has been u.<ed similarly given orally or by in- impainncn! when admined 13 hours after the ovcrdo5c. 1 Severe 2. Fromm MP, ~1111. D1h)•drocodeinc:: a Qcwopioid" substnlc for the
uainuscular or intravenous injection. life-tbreatening rcspinlOry depression subsequently developed polymorphic CYP2D6 in humans. Cl/• P'-"'«ol Tltor 1995:
36 hours at\crtheo,..rdose and only responded to treatment with SB: 374-412.
Administration in renal impairment. Diflooisal may need l. Ammon S. ~/ nl Pharma.cokinctics ofdihydtocodeinc: and iu ac·
to be given in reduced dosage in patients with significant renal naloxone aflcr large d05CS (a total of 46.6 mg of naloxonc) O\'cr
a long period (106 hours). Commenting on this report some rive metabolite aliC"r single and muhiple dosing. Br J Clin Pliar-
impainncnt and should not be given when renal impainncnt is tnOCOl 1999; 48: 317-22.
severe. questioned the evidence for hepatic impairment and considered 4 . Webb JA, ti ol. C0t11ribU1ionord1hydtoi;odcine and dihydromor-
that the ntiscd liver enzyme values were of muscular origin as a phine 10 analgesia foll~"ing dihydroc:odei:ne administntion in
Pre parations result of rhabdomyolysis. '~ Rhabdomyolysis may also have man: a PK-PD modcllin1 a.Nlysis. Br J Clin Phormocol 2001:
BP lO IO: OoA.ris>I Tablets; contributed to renaI failure. S2: 35-43.
IJSP U: ~I Tablets.
An anaphylacloid reaction after an overdose with an unspecified Renal impairment. Tbe pharmacokinetics of dihydrocodeine
Proprietary Preparatlons(dmilsaregivcn in Volume 8)
Austn>l.; Dolobidj: Avstrlo: ~ &rg" 0;flu.alt, Otnm.: Oono-
number of dihydtocodcine tablets' appeared 10 respond to intra· uirtrate, given as a single oral 60-ma dose, "= all'ecled in 9
t>ctt. Gr" Analeric; o;.Flu; /rol" ~ N ech.: Oolobidt; Oclociclj: venous naloxonc. patients with chronic renal failure 1tea1cd with haemodialysis
1
when compond with 9 healthy subjects. Time to peak plasma
Norw.: Oonot><tf: Pon.: Oolol>iclj: Andert Spain: Oolobidt: SW.d" t. Red fem N. Oihyd10C"ode1ne overdose 1rta1ed wi1h ruiloxone in-
Oonot>c!t Thai" ~ T""" OotplWI: IJK: Dolobi<tt: IJSA: Oolo- fusion. BAI./ 1983; 287: 751-2. concentration in those wid1 renal fa~ure was 3 hours compared
b<lt. Venez.: Oolot>df. 2. 0tKk1ey .BM, 'Vale JA. Oihydrocodcinc O\'ndosc 1re1l:d with with I hOUt in healthy subjects: the area under the plasma con-
naloxoot infU$ion. /JMJ 1983; 287: 1$47. centration-time curve was JP'Cltcr in those with renal failure; and
3. Dlain PG, lane RJM. Dihydrocodcint overdose treated with after 24 hours dihydrocodcine w:is still detectable in the plasma
natOJ<ont infilsion. BMJ 1983; 287: 1~7 of all renal failure patients, \Jut in only 3 of the healthy subjects.
Dihydrocodeine Phosphate 4. Wen P. Dihydrocodeine overdose lrt"ltcd with naloxc>ne infusion.
I . Barnes JN, et al. Ol'hydrocodcinc in 1c:tl1I failure: further C"·i·
BAI./ 1983; 187: 1548.
(BANM rlNNM) dcACc for on import.ant rote oft.he kidnty in lhe handling of opi-
S. Panos MZ 1tf al. Use or naJoxonc: in opioid·induccd ana.phyla~ oid drup. BM.J 19&5; 190: 740-2.
toid reaction. Br J Anocsth 1988; 61: 371.
Oih)&ocodt!ine. Phosphate de; Dfydtocodciro Phosphas: fos-
Cato de dhidrocodeina; 1-fydrocodeir.e Pnosphate. Pain. For reference to increased postoperative pain associated Uses and Administration
A>tn<ApoKOAeHHa <Docij>IT
with the use ofdihydrocodcine. see under Uses and Administra- Dihydrocodeine is an opioid analgesic (p. I08). It is re-
tion, below.
c,,HnN03.H~Po. = 399.'I. lated to codeine (p.40) and has similar ana.lgesic activ-
CAS - 1420•-13-S. ity. Oihydrocodeinc is used for the relief of modcralc to
ATC - N02AA08.
Precautions
As for Opioid Analgesics in general, p.107. severe pain, often in combination preparations with pa-
ATC Vet - QN02M08. racetamol. It has also been used as a cough supprcs-
Abuse. D1hydrocodeine has been rcponcd to be widely abused sanL
by opiate 1ddie1S.1..

H3CO~
I. Swodi fl, ct al. Mi•u<e of dih)'drocodeint """''• (OF 118)
For analgesia the usual oral dose of dihydrocodeine
amongopiaoe oddicL<. BW 1990; 300: 13 13. tanrate is 30 mg after food every 4 to 6 hours; up to
lb 2.. Robcrl5on JR, P.t al. M1"U5C of dihydrocodcioc 1ar1ratc (Of 1ISJ
among opiate addicts. BUJ 1990;301: 119.
240 mg daily may be given for severe pain. Modified-
3. Sorong J. Cl •I. llfausc of dohydracodeine tanrooe (OF 118) rclease preparations arc avai lable for twice daily dos-
o,_ H
•morrg opiote oddic:os. BMJ 1990: 301 : 119. age in patients wi1h chronic severe pain.
. NCH3 4. ~eymour A. cl al~ The role of dihydfocodtinc in causing death Dihydrocodeine tarlTatc may also be given by deep
~~~°,l drug \lscrs in th.r wes-tof ScNhind S«/11 MedJ2001; 46:
subcutaneous or intramuscular injection in doses of up
Ho·· The elderly. Dc:spile some renal impeirmenl an elderly 1,>roup to 50 mg every 4 to 6 hours.
(drhydrocodeine) of patients' appeared 10 haodlc dihydrocodcioe similarly to For details of doses in children, see below.
healthy young subjects. There was marked variability in all
measurements and on the basis ofthis study no clear conclusions As a cough s uppressan t d ihydrocodcine tanrate may
Pharmacopoeias- Jn Jpn. on guidelines for dosage in elderly patients could be dra\\•n. be given in oral doses of I 0 to 30 mg up 10 tluee times
However, die reco1M1enda1ion that small doses be given ini1U.lly daily.
Dih ydrocodeine Tartrate (8ANM. rlNN/~J with •uhscquenl d~ according 10 response was endorsed. Dihydrocodeine phosphate has also been used. Other
Oihodrokodein-hidroge<>-wtr.it; Oihidrokodcino-v.indeRlio tar· I. Oo\'ics KN, t!t ol. Tht> effttt o( oacin& on the phannacolineties
or dihydrOC'Odeine.. £11r J Clin Pltormocol J9S-9; 37: 37.S-9. salts of dihydrocodeine used, mainly for their antitus-
tratas: Oihydrocodcine Acid Tartrate: Dihydrocodene sivc effects, include the hydrochloride, the polistirex,
Bitartratc: Dihydrocodene Hydrogen Tartratc: Dlhydrocodeine. Renal impairment. Caution is necessary when giving dihy-
drocodcine to Jl<llients with severe renal impainnent. Severe nar- and the thiocyanate. D ibydrocodeine polistirex has
hydrogeootanrate de; Oilydrocooeine, Tarvate de: ()iyydroco-
deini Bit.artras: Dih)odrocodeini hy&ogenotartras; Oihydrocodei- cosis occuncd in a patient with anuria and on maintenance also been used in modified-rele3SC preparations.
ro Tartras;; Oit)'drd<odei nivetytarmmi: Dt>)<lrol:odc.n-tanar.lt; haemodi3lysl• aflcrshc had received dihydrocodeine orally for4 Administration in children. In the UK, dihydrocodeine tar-
DihydrokodeirMitetartrat DihydrolcodeS>y wodorowinian;
days. 1She responded 10 1teatmen1 with naloxone. trate may be &iven orally, or by deep subeuUtnCOUS or intramus-
Drocode Bitartrate: Hydrocodcine llitartr.rte; Tartrato de dihid- See also.under Pharmacokinclics, below. cular injection, for analgesia in children aged from 4 IO 12 years
rocodei'la. '1.5..fpoxy-3·methoxy-l 7-methylmorphinan-6-ol hy- I. Barnes JN, Oo('ldwin fJ , J)1hydmcodc.ine narcosis in re:na1 fail· in usual doses ofO.S to I mg/kg (to a maximum of30 mg) every
un. BMJ 1983: 286: 438-9. 4 to 6 hours; older children may be given lhe usual adult dose
drocen tartnte. (sec above). Although unlicensed in children aged under 4 ycBrs,
At<n<AP0t<OAC11Ha TapTpaT
Interactions the BNFC 2009 suggests giving those aged I 10 4 ye•rs
c,,HnN01.C.H,O, = ~51.S. SOO micrograms/kg every 4 to 6 hours.
CAS - 125-28-0 (d1hydrocodeine): 5965-13-9 (dihydroc· For interactions associated with opioid analgesics, see
odeine <artrote). p.107. Dyspnoea. Dihydrocodeine has been rcportcJ 1 to have pro-
UNll - 8LXS958SA9. duced benefit in nonnocapnic patients severely disabled by
Quinidine. Dihydrocodcioe is metabolised vfa the cytochrome breathlessness due to chronic airllow obstruclion. A dose of
NOTE. Compounded ~parations of dihydrocodcinc tartrate may P4SO isoenzymc CYP2D6 to active metabolites, which may per-
be rcprc$Cllted by the following names:
15 mg was uikcn 30 minutes befon: exercise up lo three times
haps play a role in its analgesic activity in extensive meuiboli~ daily.
• Co-dydtamol (8AN}-dihydrocodcine tartratc I part and P3· crs; quinidinc impairs this metabolism, but a study in 11 healthy I. Johnson M Ai ~/ ol. Dih)'drocodeine for br~athle>sne:u in 'p•nk
19CClamol SO parts (w/w). subjects did 1101 find any reduced analgesic activity wbcn diby· puffers'. 8Al/ 19SJ: 186: 67S-7.
St reet names. The following terms have been used as ·street
drocodcine was given with quinidine, despite a thrte- IO fourfold
reduction in plasma concentrations of tlie metabolite dibydro- Pain. Dihydrocodcinc is used in the rna11agcmcn1 ofmoderate 10
names' (seep.vi) or slang names for various forms ofdihydJoc.. morphine.' severe pain. However, dose-relaled increase in postoperative
odeine uirtro1c; pain has been scent in patients given 25 or SO mg dihydroco-
DFs; Dill's; Duncan Flockharu. I. Wilder-S1nith CH, ~I ol. The visceral 1nd som.a1ic antinocicefr
lh·c clfcc11 of dihydrocodcine and its mctabo1itc, dih)'dromor- deine tanrate inlrlvenously after dental surgery, and it has been
Phannacopoeias. ln Eur. (sec p.vii) and US. phine: a uoss-o"cr s.tudy with c-xtcnsive and qu1n1dinc:·tnduccd proposed that dihydroeodeine might·ac:t as an antagonist in situ·
Ph. Eur. 6.8 (Dfydrocodeine H)'dro&-en Tar1rate: Ohydroco- poor metaboliurs. Br J Cli11 Phormoco/ 1998; 45: 575- 81 . alions where acute pain was accompanied by high opioid activi-
AII crnss-refercnc:es refer to entries in Volwne A
 Oihydrocodcine Pnosphate/Dipyrone 51
ry.! Systematic r<\'ie" Clftho use <'f single otal doses ofdih}'droc.- D ipyrone (dl.N. IMNJ
odeinc- ha~ indicated that these are in5.u fficient to provide Metami2ole SodUn (!JINN): Aminop)'rine-sulphoni".e So:l'um:
adequate r<licfof postoperali~oe pain, and that dihydrocodeine is
Analginvm: D1p;rM; Dipirona: OiP'fl"On: Dipyroni: (),pyrcn:rr~
1= elfcctiv< than ibuprofen.'
Mcamrtsolina~·1um; Metarrilol; Meam:1o1 s<Sdico: Metamizol
I. Se:)"nM"Ut RA. C! ol. Uihydrocodciot-1~ hy~ra l gesi3 in >OdN s:i monohydrat: Met~ sodowy: Me:amiiol Sod)'U"ll:
J>'l»ilop:r.tuw dt.:ntal pain. ltmcrt 1982; i: 14?5-6.
~zole sodiqvc; Meta~;rium; Metamizol.l'IMrou."'
l. Henry JA. Oihydrocodeinc mcreucs c:kn<1I pain. Lh1ttt1 I982:
II: 123. Mct1mizolo r.atno druska: Meurnzokim natncum: Metami·
3. Moore RA. rt al Sini~ dose dih)•drorodcinc for~ pOSloptr· zolum t~um Monohydricuni; Me:hampyro'le, Methylmelu·
ttlive pajn. Availat'ttc in Th~ Cochrnnc Databuc of Systematic brio; Natti.m Novamin1Vlfonicum; No-ar:-odazopllrum; No-
Review,: IS.SU( l. Cbichutcr- John Wiley; 2000 (accused vamidaicfen; N<>Yami05Ulrone Sod'um: NSC-73205; Sodium
26/0610&). Noramidop)'me Me!Nnesulphoo.ate: S<AP)'rine Sod'ivm N-(2,3·
Preparations oimeth)4-S-oxo-1·~3-pyrazolin-4-yl)·N~·
nomethanesulphonate monohydrote.
BP 20 IO: Co-dydramol Tat:lm: Dil)dl'ocodtine lrjection: ~
Oral SoM""" o:hyd=.ooeone Tab!PU. MeTaMH30/\ ~aTpi.!iit
Proprietary Preparations (details m Ci\r:n in Volume 8) CuH 16N 3Na01S,H 20:: 351.4.
CAS - 68-89-3 (anhydrous dfpyrMe): 5907-38-0 (dipy-
Aurtrol.: "-"'O<Wtt: Ri<odc•-..: Au.nrlo: Coddol: OeNce: Panco~on:
Belr,: Cockmtn: l'>r.Kodinc: CJ.: OHC eo..,...,,. Fr.: Dicodin: Ger, rone mo.iohydrote).
0HC: P;...,odn P,.xodin N: l\cm<d&cent: Toomon Mono: Gr.: Oolcon· ATC - N026602.
tire Hong Ko"" Of t t8: Hun1.: 0HC: Hydrocodrc lrl.: Of 118' OHC ATC Vet - QN02B602.
CQntil>'JSt: P..-.codn: 1141.: Pancodf\a; Malaysia: Of t 18'Suncodin: N Z: UNfl - 6429LOL52Y (dipyrone); V5U62Z740N (anhy-
OHC Ccrnnis: Pol, 0HC Cont;..," Port.: Dic1ort. $.A(,, Of 118: p.,.,. drous dipyrone) ..
ccxJn Spain: P - i a : Tos.dm Switz.: Codicontin; Pncodn UK! Of
118: DHC Co"""11: USA: j-Hox OHC.
11uld·lngrcdlent: A'J'" i . - . - Awtnrl.: Codo><t: Auruia: Pincod-
nj; G•r.: An\iluSlNVm Burger NI: Mokatu..;n Trcpfen fontj: H Ol!J
Konr; Codaewon: lrl..: Paramol /1ol.: Qr~-Paracodioa; ParocodN:
'sP:...<;"1~~,: ~~.;.7,,'~-~:~·~~7.t~~
~USA: Ali!list OHC: Ot<pec.fXP. OHC O.. PM. c:»iy<tro.CP: • HzO
H)odro·GP: ~"E; Oon.'IMS 0C ~ OJi; &idceof.OH: J·COf
OHC: ~ OH: P•ncof POt: Paned~ Pancoft: P•nlor: Poly·
Tus'"104CS~ T~•ix.

Oipipanone Hyd rochloride (81\Nb.\ 11NN1AJ NOTE. Confusingly !he tcnn dipyrone sodium also appears to be
used synonymously for dipyrone itself. Dipyronc is refcncd to in
~panone. Chlom)'drate de: Dip~noni Hydrochlotidl.ITC I-id· some countries by the colloquial narne ' Mexican aspirin'. The
rotioruro de dipipanona: ?~Hydrochloride; Piperi· names noraminophc:nazonum and novaminsulfoo have appar·
d)4 ~done Hydrochlondc: Plperidylamidooe Hydroch!o- cntly been applied to dipyronc. but it is not clear whether these
lllc the sodium sail.
ride. (:t:)-i.4-0i;ihenyi·6·piperidnohepw\-3-one hydrcxhloride
mo.~e.
Pharmacopoeias. Jn Chin, £11r. (seep.vii). and Jp11.
P h. Eur. 6.8 (Metamizole So<f..n: Oipyrone BP 20 10). A white
A"'™na»ClHC r...po'°'oP"'A or almost white cryst•llinc powdcc. Very soluble iu water; solu-
Ci<Hi 1NO.HCl.Hi0 404.0. = ble in alcohol. Protccr from light.
CAS - 467-83-• (d1p;ponone): 856-87-1 (d1p1ponone hy- Ad verse Effects and P recautions
drochloflde). Use o(dipyronc is associated wilh an increased risk of agranulo·
UNll - BVYOOAjORL c)l1osis and wilh shock.
0 References.
l. Levy M. Hypcrsensi1ivfl) 10 pyrav.ilones. Thora:< 2000: SS(sup-
pt 21: S72-S74.
Effects on the blood. Data collected from 8 populatio'1 groups
in Euro~ and lsr.1cl br the lntcmational A~nulocytosis and
Aplastic Anemia Study revealed dl3t lhcrc was a SillJlificant re-
gi0tl3l variability in d1e rate-ratio estimate for agranulat}10Sis
and dipyrone (0.9 in Budapest to 33.3 in Bsn:elona). Although o
Jarr:c rclati11e illCl'C2se in risk between agnnulocytosis and use of
dipyronc was found, the incidence was less th:m some previous
reports had sug_,,"CS!ed.
Blood dyscrasias such as a&mnulocytosis and granulocy1opcni11
have continued to be rcpo<ted where dipyronc remains availa-
(d1p1ponone) blc.2''
I. The: lntcrnrttionnl AgranuJC\c.)"10$is and .~ lastic Anemia Study.
Pharmacopoeias. In Bi: or
Risl:.s or •i&Hl llUIUt..'ytu~iJ 0tnd aplutic anemia: :J firsl l'CflOC1
SP 20 I 0 (Dpopanone Hydl'OChloride). An odourless or almost their rcl01tion to drug use with sptt~l rcfctcncc to analgesics.
J.IAIA t9S6: 256: 1749-57.
odourless, white, crystalline powder. Sparingly soh1blc in water; 2. Hodenmalin K. Spig•c• 0. Asranuloc)'losu and other blood dy-
freely soluble in alcohol and in acetone; incucally insoluble in aCT11i1u aHociaicd with diJJyronc (me11n1i.1olc). Eur J Clin
ethc1'. A 2.5~. solution in water has a pl I of 4.0 to 6.0. P/tnrm-12002; 58: 265 .. 74.
J. Maj S. Lis Y. Tht incidence o( tnct1mjzolc sodium-induced
Profile :11.mnuloc)'lOSis in Poland. J Im M<"d Rn 2001; 30: "SS-9S .
Oipipanone hydrochloride is an opioid analgesic (p.IOS) SUUC· .a. Maj S, Ccmk0'-1rsti P. A p1os1>«1h·e s:1udy of the inc;idencit t'r
rurally related to 1ne1h3donc (p.86). Us.d alone it is reponed to ~granulot:ytosis and 1plastic :.nemi3 :>ssoci;itcd "'i1h the' oral ux
be lesssedaling than morphine. Ir is used in 1he treauncntofmod- of nH!l<'mitolc s:od1u1n in Pol:ind. Mei( Sri Mcmil 2004; 10:
Pl93-Pl?S.
t.Titc to severe paiu. S. lb~mc>:. L. er ol. Airanulocytosis as.wciatcd wilh lli1))ronc (1nct-
Oipipanonc hydrochloride is usually give" in combination prep- ainizol). E1wJ Cli11 Pharo1ot'Oll()OS; 60: 821-9.
6. H~mc~hlak N, Ca,·alcanli AB. Nculropcni:s, :igrunulocytos:is
arations wilh the anticmetic cycli1Jne h)'drochlotidc to reduce ind d1pyronc. Sno Paulo Med J 200.S~ 113: 247-9.
lhe incidcn..: or nausea and vomiting, but the use of such prepa- 7. Garci1 S. ti al. Oipyronc-indu«d 11anulocyto1>enia: a case f'or
rntions is no1 recommended for the management of chronic pain, .-w~1C'ntSS. PhormaC'olhttmtT.'' 2006: 1': 440-2.
as the amien1ctic is usually ooly r~oquired for the fU'SI few days of Effects on the skin. Oipyrooe hM been considered responsible
treatment. Tiie US\131 orol do«e of dipipanone bydrocJdoridc is
for a case ofdrug-induC<.'d toxic epidcnnal nccrolysis. 1
10 mg, repeated CV"'} 6 bClurs. The dose may be increased if nec-
essary in increments of S rng: it is seldom necessary to txcccd a I. Roujcau J-C. C'I nl Sj&s.ren-like 'yndrome after dru1·i1~uced
1oxic epidermal MCTOl)''\i'\. /.ancer 1 9~5: i: 609-11.
dose of 30 mg. Aller an oral dose 1he analgesic effect begins
wilhin an hour and lasts about 4 to 6 hours. Hypersensitivity. Cross-scnsiti,·ity between aspirin and dipy-
rone occutTod in a paticnL1 Oipyronc producod an exac:crbati0tt
Preparation~ of dipipanonc hydrochloride with cyclizine hydro- of dr.;pnoot, cy•nosis, and respiratory mTCst.
chloride are subject to abuse. I. Bartoli E, ti u l. Orug-induced as1hma. /A!K'et \ 976~ i : 1357.
Preparations Porphyria. Oipyrone bas lx.-cn llSSOCi¥1cd wilh acute attacks of
llP 2010: ~and Ci<:h2"10 Tablm. porphyria and is considered unsafe in porphyric patients.
P roprietary Preparations (details ore given in '\l'.llume 8) Ph armacokinetics
After oral doses dipyrone is rnpidly bydrul)'Sl:d in the gaso·oin-
Multi-ingn.die nt Hani Kon1: Wel::ooalj: S.Afr.: ~UK! D- tcstinal tract to the aC1i110metabolile 4-mclhyJ.amino.antipyrine,
conal.
which atlcr •bsorpcion undergoes metabolism to 4-fonnyl-ami-
no-antipyrinc and Olber metabolites. Dipyrone is also rapidly
The symbol t denotes a preparation no longer actively marketed
52 Analgesics Anti-inflammatory Drugs and Antipyretics
flammatoiy disorders of the skin. !TIQUth. lhrollt, and recrum.
Enoxolonc potassium (pota~ium glycyntownaie) has been used
Etanercept (BAN. usm rlNNJ
similarly. funercept EU!nercepll.lnl Etanersept Etancrsep11; rhu-
TNFR;Fc; TNR-001. Ad"'nero( 1-235 tumour neCl'OS'S factor re-
Derivatives of enoxolonc; including its aluminium sak (p.1880)
and carbcnoxolone (p.1864) have been used in the treatment or ceptor (human) llsiorl protein with 236-467~tobulin
G I (humanyl-<NC-1 Fe fragment).
benign peptic ulcer disease and other gitstrointestinal doorders.
Elte nac (rlWJ) '.:ha,~epuem
0 Enoxolone is a potent inhibitor of the eazymc I IJl·hydroxys· CAS - 18520-69-0.
E~enac: Ellenaco: Eftmacum 'o·(2.6·DichloroanMc>)·3-lhoophe· tcroid dchydroacnasc, which inactivates cortisol. and use wilh ATC - l04A801 .
neacetic acod. hydrocortisonc has been shown in animal slUdics to polcntiate ATC Vee - QL04A801
311!>Te><aK the acti,~ty or hydroconisooe in slcin. 1 Whether this also in· UNll - OP401G70JC.
C 12H,Cl2NOiS = 302.2. creased the systemic absorption and toxicity of hydrocortisone
CAS - 72895-88·6 was unclcar.2 However, for refettnc:e to adverse effects attributed
UNll- .A,153L3JA99. to systemic inhibition orcortisol when enoxolonc (glycyntoelinic
Adve rse Effects, Treatment, and P re cau·
acid) is produced during metabolism or ingested liquorice, see tions
Mincralocorticoid Effects, p. l 892. As for lnfliximab, p. 72.

o~N~
A cream containing enoxolone with hyaluronie acid, telm· Mild to moderate injection site reactions witli symp-
esteinc, and a ppc extract. has been investigated with apparcnl toms of erythema, itching. pain, or swelling are com-
benefit in the management of mild lo modentc =ema.l.4 How· mon with etancrcept Other common reactions include
•ever, topical applicntion or cnoxolone bas been associated with headache, dizziness, asthenia, nausea and vomiting,
l(J
HO
s
Cl
contact dermatitis.s
I. Tcclucksins,h S. ttl ol. Po~n1iation of hydrOiCortisone activ-ily in
skin by g!ycyrrt.e1inic acid. Lon«I 1990; 335: 1060-3.
abdominal pain, dyspepsia, and allergic reactions. An-
tibodies to etanercept may develop.
2. Ore1vcs )1W. Potcntiotion of hydroconisonc '-C"!ivity in skin by Etaaercept should be used with caution in palicnts with
Profile
~l)'CCCTh<linic acid. Lane<! 1990; 336: 676. heart failure.
3. BeRoru G. et al. A randomised. doubk·blind, VC"hicle..controllcd
Ellcnac is an NSAJD (p.100) used in veterinary medicine. srudy IO evaluate the efficacy and safely of MAS0630 (Aoopi· O Rererenccs.
clait•) in the 1rca1mcnt of mild to moder1tc atopic dcrmati1i1. I. Sinc-hci Cara to J L. tt al. Safety otetanerccpt in psoriai:sjs; a nit·
Eur J D<rmotol 200S; IS: 31-6. ical review. Dn1g S../tty2006; 29: 67S-8S.
4'. Abramovil$ W. Boguniewicz M. Adult 1\topicl1ir Study Group. W egener's granulomatosis. The addition or cunera:pt to
Embutramide (BAN us.tX ~ A muhicen1er0 rwndomizcd. vehicle-controlled clinical srudy lO standard lhcrapy (including cyclophosphamide 0t melhotreXale
fmbutramida; EIT'butrarridurr Hoe· I8·680. N-(ll.~-Dietl¥-m­ examine the efficacy ind aafcty of MAS063DP (Atopicbir} in and corticoslaoids) was not shown to be effective in patients
methoxyphcoelhyf)-4~tr.amide. the management o( mild 10 modcmte alopit dtn'l'\lhl1.s in adults. with Wegeocr's granuloma1osis and was associated with an in-
J Df'llgs /)ennato/2006; 5: 2lH4. creased incidence of various non-cutaneous malignancies.' Li·
3M6)'TpaM>\A
S. T~l'IJka S. rt al. Allcreic contaet dermatitis &om tnoxolone. ccnsed producl inronna1ion recommends !hot etanen:•pt should
C 17H27NO; = 293.'l. COlfl«I ~rmatitis 2001; 44: 192. not be added 10 therapy in patients with Wcgcner's granulomalo-
CAS - 15687-14-6.
sis.
UNll - JP4TQG94TI. P reparations
J. Wc:gcncr's Granulom1losis Et.anerccpt Trial (WGET} Rcscuch
Proprietary P reparations (details are given in Volume 8) Group. Etanercept plus standard 1he1"8py foi Weg.cncr's granulo·
S.lg" Demiano>c Fr.: /\t1h'odon1: Hounidoo..t, PO 12; Huor" Arho- motosis. N £"11 J Mtd200S; 352: 351 -61.
don1; S.Afr.: Arthrodontt
Multi·ingredient: Arf,: Anastirn: Empecid P'c Auttrol.: Alo;>iclait: Interactions
Chile: Geklar.~ert. ~~ Seb;...,Al:N; ~Fr.: ~e; As for lnfliximab, p.74. The use of etanerccpt with sul-
Dermeot E'>11"°' Hcxa~fSO, Hysckc: H)'Seke Sol.>..., Mounkologoc;
Mo<.""""5o Sobe.Noumssont. Nliht l'l!ol "'°""""ne St. NCMlphanet fasalazine has resul1ed in decreased white blood cell
PNeboa-. f'tlebo5up: l'llotod...,,, flWlt: l'tlCXOderm Lasct'j: P)rel'crt. counts; however, the clinical significance of this is un-
Sd><rl MN: Sodc:nho;dc; Toq'Jlwtaf; Vb<•dy>; Hong Konr: A!Qc He<· known. For an increased incidence of malignancy
olyse: lt>don.: Alocl.0-: A!cpdar. lbll<f: lsra.I: Aphta.X: Aphtasone. /u-
op;clait: C..lclAirt; Xtll..: Ito/.: Ac....-j, Ba<tl°"" e;oi..-Jc TS: ~ when etanerocpt was added to standard immunosup·
05; Flogo(Of'I Cremoitl fbxri l e,.41>a111t: letlirosej: Lisomuc~ Galo: pressive therapy in patien1s with Wegener's granulo-
Noo-Sto~n: Pan.1ie Wdat: fuOuxi Cremaget Prur= Sl:2b 2: v.gincl:
Profile Mex.: An~ l'tnod-J>l)t Port.: Oc~"llc: Rus.: He><:1lyse matosis, see above.
Embutramidc is an opioid analgesic used in veu:rim11y malicine (fe•caoo): Spoin: Anfleptol: ~g Robe<farn UK: Atopodoir. Gel-
ror euthanasia. clor: X<tar. lll<r~ Hexolyw (rc«;wo}: USA: AU>pCW: C.,Jda;r: Vene%.: Pharmacokine tics
Sebu'n AKN: Scti,;ti;o DS.
After a single subcutaneous dose of etanercep1, UK li-
censed product infonnarion states that the mean half·
Enoxolone (SAN; dNN) life is about 70 hours, and lhc time 10 peak serum con·
Acido gliom!tico: Acido g'.icirrelkloco; Enoksolonas: Enolcsokri:
Epirizole (VSAN. :>l'INJ centration 48 hours. In contrast, US infomiation gives
Eno><olon; Eno><0lona: l:noxolone; Enoxolonum; G~ DA-398: Epl'izol: ~pnzole: fprizolurn: Mepn2ole. 4-Melhoxy·2· tJ1e half-life as 102 hours and tJ1e time to peak concen-
Acid: Glyc:yntietinic Arid Kw;is ghc:yryzyn"Mf. 3jl-Hydrol<)'-11- (5-me1hoxy·3-mo!lhy!pyrazol-1·yl)·~e. tration as about 70 hours, although with a considerable
o><o-olean- 12-en-»oic acid. 3nMpt<30ll range. Repe.ated dosing was noted to result in a two- to
3HOKCOAOH
C 11 H 14 N 102 =
234.3. sevenfold increase in scrum levels of etanercept in
C10H.,O. = '170.7. CAS - 18694-40-1 . some patients.
CAS - 471-53-4.
ATC - D03AXl0. UNJI - 3B4602FH81 0 References.
ATC Vet - QDOJAXIO I. Konh·B.,.dky JM. t:t al 111e- ph1m1111cokinetics of em"tetecpl in
healthy voluntccn. Ann Phonnoco11'N' 2000; l4: 161-4.
UNll - P540XA09DR. 2. Zhou H. Clinical pharmacokinctics ofttanc:rcc-pt: a fully hu man-
ized solubk recombinant 1umor necrosis factor n:ccpt0< fu5ion
protein.JC/in Pliormocol 200S; 45: 4~7.
l . Yim t)..S. e1 al. Population pharmacoldne:tic analysis and simu-
lation ofthe lime·concenlrahon profile or e1anercc:pl in pcdia1ric
paticn1s with juvcnitc rheumatoid arthritis. J Cli11 PhormOCOI
lOOS; 45: 246-56.
4. Don BR. ~'al. The pharmacokine:tks of e:tancrcepl m patients
with cnd-Slage renal disease on h3c.nodialysis. J Phonn Pho,..
mocul 200S; 57: 1407-13.
5. Nc"oroY I. CJinical ph2rm:icokinetic1 o(tumor ne.crwis foc1or
antagonasu. J Rhemnatol 200S; 74 (~uppl)'; 13-18.
6. Sunivan JT. tt al. Biocquivatcnce of liquid and n:cons1i1u1c.d
tyophili.zcd eiancrccpt iubcut1ncous injections. J Clin Phonno·
col2006: 46: 6S4-61.
7. NeslOfO\' 1. •t nl, Ph.arm1coktne1i.cs or subcu11neously a<lminis-
tered e:tancrccpl in subjects """·ith psoriasis. 81' J Clin Phorruacol
Pharmacopoeias. In Jpn. 2006: 62: 43s-itS.
8. Ek..-.'Ski 8, ct ol. Companson of clinical 3.nd pl\annacokinctic
NQT£. Do not conl\lse with glycynhizic acid (p.2537). Profile profiles of ctanerccpt 2S m11wtce weekly and SO me onet week-
ly i11 patients with psoriasis. hr J De.r11101ol 2001; 156: t38-42.
Pharmacopoeias. In E11r. (see p.•ii). Epirizole is an NSAID(p. 100) that has been gj\'en in a usual oral
Ph. Eur. 6.8 (Enoxdone). A "fote or alm0$t white, crystalline dose or l50to 450 mg daily in divided doses; larger doses or up
to 600 mg daily have been u.o;cd in patients with rheumatoid ar-
Uses and Administration
powder. II allibits polymorphi~m. Practically insoluble in water; Etanercept is a recombinant version of soluble human
soluble in dehydrated alcohol; ~ngly soluble in dichlc>- thritis.
romcthane. Protect from light. 1NF n:ceptor that binds specifically to tumour necrosis
Preparations factor (p.865) and blocks its interaction with endog-
Profile Proprietary P repar~tions (details arc given in Volume B)
Eooxolonc is n complex tritcrpene prepared from glycyntoi1.ic enous cell-surface TNF receptors. This interaction pre-
8"'z.: MellrootJpn: Mebrof'c Venez.: O.tex. vents the imponant effect ofTNF in the inflammatory
acid (p.2537), a conS1itUC11t orliqooricc (p. 1892). Enoxolonc is
used locally in preparations ror the treatoncnl of noo-infecti\oe in- processes of rheumatoid arthritis; elevated TNF levels
AJI cross-references refer lo entries in Volume A
 EltenadEtanercept 53
are also found in psoriatic plaques, in the S)'Tl<lvium of o,,mentia. A small pilot study' and indi,.jduAt ca.oe repons1 8. Cheon Y·f. .:t al. NHS He:.ilth Tcchnn~y Assessment Pto·
have suggested !hat perispinal injection nf elaoercept, io doses of sramm~. A $)'~Cmatit review oflhc crrcctivcOC'» Uf Dd~JitnUnl·
patients with psoriatic arthritis, and in the serum and ah, c:1nncn:ept and intlisimah for 1hc trcMmCftt of rhculliatoid
synovium of patients with ankylosing spondylitis. 25 to 50 mg wccl:ly. may improve <igns of dcmcnti• in patients :mhri11~ in :adullS and an ecooon'lic t)'tluuian or then c('l5t-4:r-
with Alzhei1T1er's disease. However, l'llndomised cnntr0lled stud- rcc:1i\•cncu (is:sucd Novcmlxl' 2006). Auilable at: bllp:/I
Etanercept is described as a biological disease-modify· ies arc required to confirm any benefit. www.huu1t.uklfullmonG'mon i0 .3~.pdf'(1cceSK-d llA>6IOS)
ing antirheumatic drug (DMARD). I. Tobinick £.Cl of. TNF..alpha modul~ion for trt::Hn'ICnt of Alzhc- 9. Wel1man MH. et al. A pla«~co1molled. rllndomizcd~ double·
E1ancrcept is used in the treatment of moderately to se- 1rner·s dista.$c; a 6-month pflo;. Rudy Af~dGtmMed 2006; X: 2S.
Av;ilable at: ht1p:f/www.ocbi.nhn.nih.~ ov/pmcfo r ticlcs /
~~:~,~tt~dir~~~~i:~~g ~:~e.~ta~~ :,~1C:~~1 ~is=R=~
1"010/~· (0.~ford) 2007: 46: t 11~-l.
verely active rheumatoid arthritis (below) and active PMCJ7SSl82/'?toot•pubmcd t•«cn<d 28107110)
2. Tnbinid:. EL. Gross H. Rt1pid cosni1ivc improvement in Althe·
10.. Dhillon S. c1 ul. E1tncrccpc 1 rcvi'--""'" of il.S u~ in die m.a.nasc·
and progressive psoriati<: arthritis (see Spondyloar- irncr·s d~ followina perl1pin.al etonerccpt administrrnifln. ,J mcn1 of rheumatoid anhritis. Dr-ugs 2001~ 67: 12 1 1~1 . Corrcc·
lion.ibid.; IM9.
tltropathies, below). In the UK, it is licensed for use in Nt:11,.ofr1./fo•watio1t 2008~ 5: 2.
11. \•an dcr Hiijd' D. ti"'·
Et~n'-'f'C<Pt S1udy400 lnvcs1iauors. TI1e
patients who have had an inadequate response to stand- A"ailablie: aa: hup:l/www.jneu roinO~mnution .comlcontcn1/pd(I ~rc1y and cllicacy of :iddinz erancrctpt \O 1nclholrcxaie or
1742-2094-S-l.pdf (OCC<MCd t 3106108) mctholro.aitc to etum.-rccpl i1l modcrttcly a<tivc rheum11oid ar-
ard DMARDs although, in severe rheumatoid arthritis, thri1is p1ticn1s previously 1rct1Ltd with monothcr<1py. .41111
Psoriasis. Et~ncrcept is etrec1ive in pa1ients with moderate to
it may be used in patients not previously treated with sc\'Cre plaque psoriMis (p. I 7?..3). 1·1: It has also been successfully
P.hm1m D11 2008; 67: I82-3.
methotrexate. In the USA, it is licensed to treat early 12. 'nn dcr Hcij<k D. ~ul. Di~<i.s< n.:miss1on and sustained hahina
tried in the ueatmenr of er}Wodcnnic psoriasis," and of plaque Of rAdiographfc: propasion Wilh Combin:uion C':;)OCrCqU and
meumatoid arthritis or psoriatic arthritis. In both indi- pso..;asis in children and adolesce1t1s.t' me1ho1rcX3te in p31ic.nts with rhtum11tcud :tnhri1is. ArthritlJ
cations, it is given as a subcutaneous injection in a dose Rl;c1m1 2007: 56: 392S-39
Elficacy may be dose-related, in one study.' 25% of patients in 13. NICE. Ad"3linlu1n3b. ei.antrecpt and intlixinl3b forthc1rcamtnl
of25 mg twice weekly at intervals of3 or 4 days. The the low-dose (25 mg once weekly) SJOUP showed at least a 75% af rhcumal<'id anh11t1s: Technology Appraisal Guid.Ancc 110
equivalent weekly dose of 50 mg may also be given improvement compared with 44o/o in the medium-dose group (issued OclObtr 2007). A\-a1l11blc at: http:l/www.rucc.ori.uk/
(25 mg twice weekly) and 59% in the high-dose group (50 mg Ri<emed;alpd(ffA t 30suidonce.pdr (acc....,d 13106106)
either as asingle 50-mg injection or as two separate 25- twice """'kly) after 24 weeks of Clanercepl ucalnicnl Howe'""'· 14. Ganldmcr Cl II al. Biolo1ics (or the lrc:.uncn\ of ju ....c111tc idio--
P3thie\ anhrhit: a S)'Jltmatic review and critical onalyais of the
mg injections (given al about the same time). Jn the a later multiccnttt study
in patients with chronic plaque psoria- C\idm« Clio Rhl'mnatol 2008~ 27: 67-76.
UK, NlCE recommends that treatment for rheumatoid sis found that the therapeutic ctfoet ofctancrccp1 was maintained 15. lovell OJ. ~I of. Pedi:ltric Rhtum:at01oSY Collabora1ivc St udy
or psoriatic artluitis be stopped if there is no adequate when the dose was reduced after 12 weeks from 50 mg twice Group. Safety and efficacy or up 10 cif.ht )"nrt of continuous
weekly to 25 mg twice weekly. An open-label e.<tension8 of c1;111r-rccpt therapy in pacicn1s wi1hjuvcn1lc rtleum3to1d :arthti1is.
response after 6 months or 12 weeks, respectively. these 2 studies found that efficacy was also sustained when pa·
Arthl"llls R,_,,, 2008: 58: 1496- l 504.
Etanercept is also indicated in the treatment of severely 16. Emc:ry P. ei ol. Cornpuison or m~ tho1rcxa1t mo:Lothcupy with
ticnl\ who had received ctancrccpt 25 mg twice weekly for at 11 combinallon of mcthOUcxMc and ~t;in<.rce pl in active, tarly,
active ankylosing spondylltis (seA: Spondyloarthropa- least 24 weeks had their dose altered 10 50 mg once weekly. mudera1c 10 severe rbeumuoid a nhriti$ {COMEn: a r~n·
thies. below); in the UK, its use is again limited 10 those domised, double-blir.d. p~rallel tT.:•unent 1rial. LoMC'I lOOI;
1. ;;::~~;. ~'E:~;j A~~200f;' ;.:,~~~~Y in p3tienu with 372: 375-82.
who have had an inadequate response to conventional 2. Papp KA. t!l nl. A global phase lJl randomiicd con<rolled h'i1I Spondyloarthropathies. Reft1en=•·11 to the use of ttaner-
therapy. Doses are similar to those used for meumatoid of dlnctcepl in psoriasis; sarcty. efficacy. a1ld effect Of dO$C re- ccpl in the treatment of ankylosing spondylitis and psoriatic ar-
duction. Br J ~rN10101200S; 152: 1304-12.
arthritis. In the UK, NICE recommends thal treatment 3. NICE. Et&M:rccpt and cfalizumab for the rre11mC"nt or :>dulls thritis (p. I 4).
be stopped if there is no adequate response after 12 with psonasis. Technology Approiis.al Guidance 103 (i~ucd July t. Davis JC. «cl. Enbret Ankylosin& SpMdytitis Soudy Group.
weeks. 2006). Available at: http://www.nicc.ora.uk/ni«m-edia'pdf/ Rccombinan• 1tuman tumor necrosis factor rccce1or-(ccancrccpt)
TA I03i:uidoncc.pdf(0<:ccssed 13106/06) Cor treating 2nkylosins cpondyH1is: a random1..tcd. controlled
Etanercept is also used in the treatment of chronic, 4. Dnehncke W·H. t1 al. Europc1n Otnn1101ogy E10pctt Group. trinl. Arthriri$ R~11m 2003; ..,8: 3230-6.
2. Mca.sc PJ. e1 al. £1.ancrcepl ll'catrnent of~riatic enhti11s, safe·
moderate io severe plaque psoriasis (below). Jn the :::~~;:~~~~:::!:-~~;:,:':c!~~=~~~~~ 1ls:;~~ ty, efficacy. and tffttt on diseue progres:-:;ior.. Arthritis Rh~11nt
2004; 50: 22"4-72.
-UK, its use is usually limited to patients in whom other to/ Vt11t,.ol 2006: 20: 98S-9S.
l. ~;:!:;t~~ ~il!~ ~~~~,:'!r l~:;; !.i~~·:,:~~:C~k:~~~~
S. Woolncou N, ef al. NHS Hcallh Tc:chnology A!ISCi$1Mnt Pro· 0 1
systemic treatments are not suitable. The recommend- pam1nt:. Etancrccpl ond ef11izumab for the tteit111cnt o(psori..
ed initial dose is 25 mg twice weekly. Alternatively, an sis: a sys1cm1tic review (issued NoVbnbcr 2006). A\•1ilt11blc at: and mt1g11c1ic rc£Onancc inutging data. Ar1hrl1is Rh~Nm 2005:
h1tp:/iwww.h1a.ae.uk/fol lmono/Jnon I 046.pd f (acccued 53: 856-63.
initial doseof50 mg twice weekly at intervals of3 or4 l:i/06/0$) -I. MCl5C PJ. 01 al. Contimk:d ir.hibition o(radio~mphk pr<>!:,'T~$-
days may be given for 12 weeks; the dose should then 6. T)T[n.a s. ol. Long-term safety and emcacy or 30 ins or
#I
~~,.i:~i~~l~c~~~r.s;~~;~::!!';;l~;o;;~n/1 ~_:i~~s of1rca1-
ct:mcrttpt 1wtcc w-cckly in patients "'ith psoritdis. Arch D~mutt-
be reduced to 25 mg tw ice weekly or 50 mg weekly. 1011001; 143: 719-26. S. NICF.. F.tanercept Jnd intlix1mab for the tre:acmeot of adults
Initial doses of 25 or 50 mg once weekly have a.lso 1. Romero-Ma~ A. el nl. Efficacy and s;i((t)' of etanetttpt in psCI· whh psoriatic al1hriti$: Tc:c-hnulu,¥)' Appnisal Guidance 104 (is-
riasislpsor'11ie lirthritis: au updated revit.w. •4m J Cl111 DtrmotiJI sued July 2006). Av:ailable ~l : hnp:i!www.nicc.org.uk/
been shown to be effective. Tl"eatment should continue 2007: S: t43-55. nicem<:diaipclfJTA t04guidoncc.pdf (accessed Ol/1 t/U8)
until remission is achieved, for up to 24 weeks. Etaner- 8. Elewski B. c/ al. Comparison of C'liuical ond ph&nnacokintli( 6. Woolacou N. 11 ttl. NHS Hcftllh Tcchnolugy As.sn.smenl Pro-
srainme. Et.anc«q)I nnd inniximt1b foT lht ~lmcn\ orpsoria.t·
cepl should be stopped after 12 weeks in patients who ~:[~~s j~fp~;i~11~t~~,;~u1~i;.c~r"J~!~11~;;,s~Oo1tf. f5'~ ic an hrilis: a S)stcnunic 1tvicw :ind economic cvah.Qt1«1 (is-
sued Scpl,mbc r 2006). Available. at : http;I/
show no response. 138-12.
9. Ahinl!d K. Roa&cr11 s. Two years or experience wi!h CIOnC'f'(!Cpt in www.hla.ic.uk/fullmonolmon I031.pd f (acccucd 13!06l01)
For details of uses and dosage in children, see below. rttalcitranl psoriasis. BrJ DCJmato/2001; 156: 1010-14. 7. v~n dcr Htijdc D. ~'cl. Etan.ercept Study )14 ht\l'Cshg:nors
10. \-an dt KerkOOf P<.:M. " al. Once wet:kly administration or Ettncr<.-cp1 50 nig once wcdcly is ru cffccli\'c as :?5 m.:, twice
Administration In children. Etancrcep1 is used in rlie treat- eta~ 50 mg is efficacious and "eO 1oftt1tltd i1l pa1i~ms
"ttlly iu p:ui~nts with 21okyJO$in~ spondyli\is. Atm Rhemn Dis
wi1h modtratc-co-se"crt! plaq1.tc proriu4s: o nrido1nizcd con· 2006: 65' 1572-7.
ment of moderately to severely active polyarticular j uvtnile idi- &. CMtini F. 1:1 ti/. $\\.itching from inni.Jci1n1h to onc:e-wcddy ad-
op•thlc ortl\ritis; UK licensed product infonnotion limits its use 1roflcd trial "ith oren-Jabe:I ex1cn111on. /Jr J Dermmol JOOS; 1nini5'rat101l O( 50 ITU! C'lllACf':tf)l in rts:iiUlftl Of intO)CfaJlt J>a-
I59: t 177-85.
to those who have had an inadequate response IO. or who arc ll~nlS "-i1h inkylosin~ spondyluis: ~ha o( a fifty.four-week
t I. Ortonnc J-P.~ al. PJC.i~nts wilh modcr.110:-lo-scvcrcpsoria.sis re·
intolerant of, the disease-modifying antirhcumatic drug mctbo- s1udy. Arthriti.J Rl1<11m 2006; SS: 812-'6.
uc~ate.
8~.~uD:r~~::}~~:~: t;~8!s~~-neatmc:nt Y.ilh mnerccpt. \l. Woolacot1 NF. ~I nl Et~l'\fl'CCpl nnd inOlximzb foe the trc-atmcnt
ur psuTiatic anhri11s· a sysmn:llic rtview·. C/i11 E.tp Rhcwnmnl
12. Sten'y W. ct al. Comp1rison of two ctancrccpt rc11n'CnJ (or 2006: 2A: S87- 93.
In the UK, it is give11 subcutaneously iochildrcn aged 4 ycmand trf'al mcn1 of' psor1a111 2nd psoriatic arthrili$: PRESTA r.an-
o""rin a dose of400 microgra1nsll<g(up to a m:IXimum dose of 10. GoulicllAB. wnl Use: ofttancn::cpl forpsoriauc arthrtlis in the
domis~d \louble blind mukiccntre trial. Abri d~ed ''crslon: BM.I
~~;~• ~~~o~~:!:~~t'~1~t:::~~~~~f,"~~~·E~~d':.~:;
13
25 ins) twice weekly at intcr\-als of 3 or 4 d:Jys. In the USA, 2010; 340: 300. Full ''ersion: http:Jiwww.bin,1.co1nlci;i/reprinc/
etanerccp1 is lic:enscd for use in children as young as 2 years old .lol-O!reb02_2'ct47 (•c.:<ssed 06/0S:IO)
11. o~::t~i. 7:,'1:~. :~~J~!:~;~;·pati<nt·n:puned 0UICOmt$ for
2
ll. Esposito M, ttt nl. Treatment of ery\hrodcrmic: psori:iisis wi1h
Similar dos« are used although they arc expressed as d.ancrccpc. 81· J Dcrmo1012006; tSS: IS6-9.
800 micrasnms/kg (up to a maximum dosc of SO mg) weekly: pati~nu with 11:nkytosing s.pondylicis trc11ed with et:tncrupe
14 PQllCr AS.,., al. Et:me-rccpl Pedi11ric Ps.oriu.is Study Group. SO mi once-weekly :Jr)(J 25 n1a twtce~wttk l y. Xhe11111or()fogy
doses to be given llS 2 separate injoctions may either be given on EtaMr«pt lreatment fo r childrCtl 01nd adolc.sc~nts wi1h plaque (0>/0t•dJ 2007; 46: 999-t004.
the some d:Jy or 3 to 4 days apart. p$0ri..is. N £,,gf J M<d 2 008; 358: 2• 1- 51. 12. Rornet0-M3tC A. er al. Efficacy and SOJJttyof ctancrccpt in pso·
In the UK, NICE l"C<:<ltllIJlcnds that trcaunent be stopped i11 chil- Rheumatoid a rthrit is. Some rcfcrenccs..,6 IO the use of riasislpsoc-i.31tc :mhritis: an upd:itcd r~vicw. Am J Clln Dcrmutol
dren if there is no rcspoose af1<r 6 months, or an initial ~nsc ctanercept in rlicumatoid uthritis (p. 12) and ju\"eni~ idiop."hic 2007: 8: 143-SS.
1l Franke-I EH. <1 nl. E111u."rccpc improves psoriatic :uthrhis pa-
is not maintained. arthritis (p.11). ti.!nt-<eponed ouecorncs: rc:suhs from EDUCATE. Cu1i1 2001;
Etane~pl is also used in the ueouancm of chronic ~eve re plaque I, NIC'E. Guid:mc<: on the use of e1ancrccp1 for the &rcalmcnt of 79: 322-6.
~~~~;::. ~da':u~UJ:.~sei~~:;~~~"i~~~~·i:::;;,~~C.:~:
jnv.-nilc idiopalh!C arthritis: T«hnology Appr.r.iul Owidantt JS 14
psoriasis in children aged 8 years and over; its use is limited to (is.$ucd M1m.:b ~002). Anilablt :u; h1Lp:l/www.nicc.org.u.k/ .
those in whom other S)'Stemic treatments are not ruiiablc. TI>e niccmcdilllpdf7JIA-PDF.pdf(acc<$$Cd 13106/06) nl(ill or nnkyloJing spondylitis.: ;I systcmctic review and cco.-
UK licensed dose is 800 micrograms/kg (up to a maximum dose 2. Kl.artst.01 l. (!/ 1rl. The.rapeucic effect of the combination or nomic cvnlua11on (issut'd Au2ust 2007). ,4,v11il:tblc at: bup:i/
ofSO mg) subcutaneously once wcckJy for up to 24 weeks; treat- et•ncrcc)){ and in e 1ho1 ~;;.11c compared wi1b coch trcatmen.c '""ww.htu uc.uklfullmonotmonl 128.p<lf (occeucd 3J/IOI08)
~rOflC m~litnl$ wi1h rhnim:iitoid 1rdwitl$: double-blind ran·
ment ~Id be <topped after 12 weeks 1n those who show no dnm1sed controlled trinl. Lunc~t 20CM: 3'3: 675-81.
1
!'. :~n!~·o~~~~}~~i~~a~';,!Xi.~1'~"~~!~~!fc u~~hi~l~.c;;
rcspo1~e. 2007; 67: 2609-33.
3. Gcno'-ese MC. et al. l..on£1C'rm s:arrt~. effica(y. and radiognph ..
Asthma. TN!' inhibitors such as ctanercept ha"C been investi-
ic outcornc with ct~nerccpt lrcalment in patient$ wi1h early 16 NICE. AdnlimunHib. ~t31\tref'PC 2nd innl.,im3b for :inky1os.i1\J
gated in the lre:itment of refnctory asthma (p. I220)-1"" There is
ri\cumatoid :wthritis. J Rlt~umotol 200S; Jl: 1232-42.
~=~·~~:~iT:~:~n~!~i~t~.~J::~!.'.n9~~~:k~:~c~i1~~J~1~~
some evidence that only a minority of patients "ill respond to 4, ~~~hrr; ~bj~,~-;:~c:~::.~~c1~~a~~~r~l~~~~!::'2~~~ TA I43G•ocl•nc:< pdr(oc.:u•cd 3 llt0.113)
17, Sterry w. '"'ol Comparisoo nf 1wo ((3nc1ccpt r~im('llf lhr
such therapy, and that the benefits and risks must thcrcfon: be
can:fully assessed.'
33: 234-43.
5. van Riel PLCM. n ol. .. DORE (Add Enl>rcl or Repbc.: Merb- tn:-atmC'l'I' or psoriuis
.ond psoriatic
arth1111s: PRESTA 1an-
dNn1scd doubk blind mul1icen1re tri31. Ah11<ffcd vmion: BMJ
ocrcxat~) S1udy lnvcs1ig:3tors. Efficacy and sorCT)' of combina-
I. Hov.-~rtb PH. ~' al. Tun1our necr<nis factor (TNFn) as a novt-1 tion etanc:mpl and mcthotrexatc versus ctt1ncn:ep1 alone in pa. 2010; 340: lOO. full vtrstol\: hnp:l/www.bit\).Ct1mlc--g.W1·eprint/
lhenpwtie targel in symp1omaric: con)c0$te-roid dependent as1h- 1itnlS wi11\ rlicuma1otd anbri1i$ "ith an iru1dcqu'2tt response IO l~Ol(eb02_2/c t47 (acces>C<I 06/05110)
111a. n.o...... 2oos; 60: to1 2-1s. mt\hotrexntc: the ADORE study. Amr Rh1tum Dis 2006; 65: Vasculitic syndromes.. for a p<elimin&ry report on tbc use of
2. 8cny MA. ~101. E,·idenee of a role or1umor nce:ros;s factor u in 1~711-U
etancr.::cpt iu Takayasu "s anentis, see p.1653.
' f!he~ ~~~~~1:i; ~T~1~~~i~~cf >: :rn~1~~i~~¥ !;;;:i~~~~~
rer,..ctooyMlhm•. N £<18/J Mcd2006: 354: 6<n-1os. 6 3 1 1 1 1

3. Morjari.J JB. ~al. ~ role o( a soluble l'Nfo. rt«plor fus ion R1-• .,.1ol 2000: 33: 3S4-6 I. P reparations
protein (euncrc~pt) in cor1icostcroid ttfrac:1ory a.sahma: a double i. vim dcr Heijck D. '"al. Com.parisoo of ctaMTCepc and mietJl. Proprietary Preparation• (ddails are given in Vol11~1e ll)
blind, randomised. placebo ..:on1roll~d tri411. Thorax 2008: 63: otrex.atc. atone and con1bincd, in 1hc ~ment of rhc:umaco id At;" &bet Austral: Enbret Austria: Enbrd 11ei,, Enbrel Broz.: Enbt-d
584-9 1. :inhritis· two-~ar clinical and ra diog:r~phic ttsullS from lhc Conod.: Eril<<f; Chllt: Enlxot Cr.: &b1't Denm.: Entttt Fin.: Enbrd
4. ::~~11 i~~ ~~h~:':, !~~"~,~~!u!o;'~~~;'~r:r~t1i~- ap- T EMPO )1udy. a double-bli11d. randomiz.cd mil. Anhritis
""'""' 2006: $4: l06J-74. f~~;~:,~~!:=..t~~::=.t·e".t~'1~~
The symbol t denotes a preparation no longer actively marketed
54 Analgesics Anti-inflammatory Drugs and Antipyretics
laysia: En1>rot M.x.; Erbtt Ne<h.: E~ N orw.: Enord; NZ: Ert>-ot: Preparations Preparations
PhWpp.: En!>re! Pol.: &.bret POl't.: Er.brot s.Afr.: &Q'd; s;ngopore:
E~t Spoi"" ~Swed.: Enbrct SW1tt.: trb-cl Thai" E,.,,..1; Turk.: Proprietary Preparations (clcuils are giY<n in Volume B) Proprietary Prepara.tion.s (details a.re given in Volume B)
Cnbm: UK: &>Int USA: Enl>'Ci: Vcnex.: &c-d. Aunna: Muo:cth<rm Arr" l);oMa; Belg.: ~ C..: Dolult: fin.: C«if;.,,._ Fr.:~
M ulti-ingredient: Au1trlo: Thermatt: Belg,: Transvan•: Hunr.: on Toux Sed..: Peter's !Wop; UK: Cd""' Eixi<
Nicoolt>e lrl.: Tninsva<on: SWlu.: 8a<.rne EKo F<>rte: Fnxo-Dr-..cn lle<:f; Mufti.ina;redtent Austria: Hods,opt. Betg.: Saume ~ Lcng-
Knobe: Muilc N; Tl-.efmOCUIJnf: z,.ceh.
UK: PR Heat SCx'>r: "l_,, ba!scmt: S..-.bcis. TU>"j; cruk: Codetan: Fin.: lnda!V< fr" E~t.
Ethenzamide (BAN.....,.,, H.,.tll<b. Humeo<t, T"""*" """"°"'r''"" HonII Konf. Fm.u!.w< Hung.: Doi:><: In-
dio: Bell o;o...o ~ntj; Bell Re""'1en\ • No.w.: Cos)l>n; SC>Mpect
Ac1ho><ybenzamict.Jm: Etem5.YY11di: E1enzamld: Etenu:nida: <°"ll< Spain: o...uin. ~t: s-" Coalbn>-Etyin; LeP'>l'fon:
Etenzamidc: ~.za.-nide: Elhenzamid..-n: Ethoxybenzamide: Swia.: !pear. Pho!-Tu><: $.tnboisj: Slwlo Tu": Turlc.: FenoloOn: Neoce>-
EtJ'1)1saliC)4amidc: HP-209. 2-Etho><ybenzamide Ethyl Salicylate ditt. Vene;i.: No4c-°"'
3TeH3aM~ Salicilatode etilo. eih)4 2-hydr~e.
=
C9 H 11 N02 165 2.
CAS - 938-7 3-8.
3Tw\ciW1U'11\aT

ATC - N02BA07. c.H100i:: 166.2. Etodolac (SAN. USAN. rtNNJ

ATC Ve1 - QN02BA07 CAS- 118-61-6.
UNll - 555U6TZ2MV. AY-24236: EtodolaalOO: Etodolac: Etodoli!co: Etodolac..-n;
UNll - L929ZCK4BF Etodol<ik; Etoclol* Etodolakas; Etodollc Aci::I. f .8-Dielhyl·
l,3,4.9-:~Clp}'l'ano{3.4-b}indol- 1-y'.acetic acid.
3TOAOMK
C11H21N03 = 287.<I.
CAS - 4 I 3~0-15-4
ATC-MO!A808.
ATC Vet - QMOIA808
UNll - 2M36281008
Phannacopoeias. In Jpn PYofile
Etbyl salicylate is a salicylic acid derivative that is used similarly
Profile to methyl salicybte (p.89) in conccnll'atioos of up to 5% in topi-
Elhenwnidc isa salicylic acid dcrivative(sccA!pirin, p.21) si•· cal rubcfacicnl preparations for lltc reliefof pain in musculoskel·
en orally in painful llJld inOammatOI)' conditions and to reduce etal,join~ and sun-tissue disordcts.
fever.
Preparations
Preparations
Proprietary Preparations (details arc given in Volume 8)
Proprietary Preparations (d«aib are given in Volum<: D)
Multi·ingr.,cHenc Aumol: Oc<p Heat Radlan-Bt. 8el1.: Rodo·S.ll
Multi·ingredienc Aus<rio: Ccl:kdolinj: Dotm.xt: Helopy"rc Nai::urj: Chllt: Cllontb Sport Hun1.: Oe<p Hen Spray. lrl" Ooep Heat Rolge>e
Scloc: Cz.: Cephy!f: lndon.: f u•f!O"._Neo No\ropon l'b;/pn: Son Col~ broel: OoepHe>tSpray. ltol.: Remy. Pol: OoepHeacS.Afr" O«:-pHeat Phannacopoeias. Jn Eur. (sec p.vii), Jpll, and US.
K.ov.Q Ka<et. POI:: &b; Elem.a,-, Elopiry.'>a: Port.: ~ Ru~: Nextrom Soroyt: 5;nJOPOre: Ooep Heating Spr>yt; Switz.: Algine><t: UK: ~
AlcW (HOKCT'pHM Alm1o~ Ph. Eur. 6.8 (Etodol>e}. A white or abnost white crysuillinc
Hut Sjny. Dvl>otn: N..mari: ~i. Scny. R.f&tx. powder. Pnctieally insoluble in water, freely soluble ;n dehy-
drated alcohol Md in acelone.
USP 33 (Etodolac). Store in 'ainight containers.
Ethoheptazine Citrate (~tl'IN'AJ Ethyl morphine Hydrochloride (MNM)
Otralo de etoheptaciria: Ethohcptazine, Citrated': EthoheptaZn Aethylmorphinae Hydrochloridl.rn; Aethyl-norpt-Oni H)d-ochlo- Adve rse Effects, Treat ment, and P recau-
Glras; Wy-101 . Ethyl 1-methyl-<l~rllyduazepine-+ur­ riO.tm; Chlortiydrate de Codethyline: Etlvtrnot1i~lorid tions
boxylatc dnydrogen cittotc. di~t Elll)'lmorph1ne, chlorllydrate d'; Elll)'lmorph.-ii hydro- As for NSAIDs in general, p. l 00.
::horcma3....a U>npaT chtoncbn; Ethf.morphini Hydrochlorid\.m Dil'o>dncum; Ethyl- The presence of phenolic metabolites of etodolac in the
C"H23N01.C,Ha01 = <153.S. morpNnium Chloride; Etitmorlina, hidrocloruro de: Etilmorfo-
CAS - 77-15-6 (ethoheptozinc): 6700-56-7 (ethohep- hidrol<Jond: Etilmorlino hidrodilotldas; Etylmorfinhydroldorid; urine may give rise to a false-positive reaction for bi-
toz1M citrate): 2085-4 2-9 ((.t-j-ethohepto2inc citrotc). Etytomorl'iny chlorowodorck: EtyyWnor(inihydroklori6. 3~ lirubin.
UNll - lXK8~E245D.
Ethylmo<ph1ne hydrochloride dihydrate; 7.8-D~ S- Effects on the blood. ArrnulocytO!:l~ has been reponed in a
cpoxy-3·etho><Y· I7-melh)4morphinan-6-ol hyd-ochloride d1hy- patient recei ving ctodolac. Coombs-positi'< haemolytic anae-
drate. mia due to sensitivity to ctodolac mc1abofites has also been re-
3 r....,,,,,pcp....a f llAPOXl\OPHA ported.'
C,,H13N03,HCl.2Hp = 385.9. I. Cramer RL. 41 of. Agruoulocytc»is associ111ed with c:1odolae.Ann
Phonnocolhtr 1994; 28: 4S8-«l.
CAS - 76-58-4 (cthylmorphine): 115-30-4 (ethylmor- 2. Cunha PD. ff ol. Immune hemoly1M: anemia cauStd by scn~lfrvi·
pltmo hydrochloride). ly to a rnctaboli1e o( ctodol11t, a nonsteroid31 anti-inOammacory
ATC - ROSDAOI; SOIXA06 drug. Transfudo11 2000: -40: 663-8. "
ATC Vcc QR05DAOI ; QSCIXA06.
Effects on the gastTointestinal tract. 1-:todolac is reponed to
UNll - MFM5450PJT (ethylmorphine hydrochloflde):
407XJNQV4N (ethyimorphine hydrochloride dihydt0te).
be a prefcrcnlial inhibitor of cyclo-oxygenasc-2 (COX-2} and
consequently it may produce fess gastric toxicity lhan lltc non·
selective NSAIDs such as naproxen. •·3
(ethohepiozinc) l. Taha AS. tt ol. Effcc1 or repealed 1berapcu1ic doses of naproxen

Profiie H3c............ o~
I~
Md ttodolac on gastric and d\l~I mucosa! pr0£l1glandins
(l'Cs) in rheumatoid anhritls (RA). Gur 1989; 30: A7SI.
2. Bian1.:hi Pono Q. et of. A doubk·blind gast-roscopiccvatuation of
Ethoheplllinc ciiratc is un opioid a.nalgesic (p.105) Sln1cturally the cfTe<:ts of rtodolx Md naproxcn on the gastroinlestinal mu·
related to pethidine (p.1 18). It has been used as an analgesic in cosa or rheumatic pa1irn1.s. J lnr~m Med t991 ; 229: S-&.
the short.tenn treatment of mild to moderate pain. usually with q. ). Weideman RA. ~' ol. Risks or c linially significant UJ>P(T gas-·
Olh<r druss such as aspirin ond meprobam3te. • NCH3 trointestinal evcnl.S ~:ilh c:todo)ac and n.apro>.cn: a hiuoria.I co·
hon •nalysis. COJ1ro<m1rol<>GY 2004; 127: 1322-ll.
Preparations
Proprietary Pre.pa.rations (de1oils arc given in \t>l\.true B) HO" ~ Interactions
Multi-ingrodlenc Indio: Equagest<; 5.Afr.: Eq,..,..:f. For interactions associated with NSAI Os, see p.103.
(ethylmorph1ne)

Pharma.copoeias. Jn Chin., Eur. (seep.vii), Md Jpn. Pharmacokinetics

Ethyl Nicotinate Ph. Eur. 6.8 (EthylmorphO'le H)d'ochloride). A white or almost Etodolac is a chiI31 compound given as the i:acemate.
Nicotnato de etilo. white crysrallinc powder. Soluble in water and in alcohol. A 2°/o Peak plasma concentrations of the active S.enantiomer
3TMN,MK0l~T solution in water has a pH of4.3 to 5.7. Protect &om light. and of the inactive R-enantiomer usually occur within
C,H,N02 = IS 1.2. Profile
CAS - 614-18-6. about 2 hours of an oral dose but plasma concentra-
Elltylrnorplnne hydrochloride is WI opioid analgesic (p.105) and tions oftheR-enantiomer have been reported to greatly
UN/I - Nl}JH35JYH.
has properties similar to those ofcodeine (p.38). It is used mainly
as a <XJUgji suppressant It has also been used for iL• analgesic and
exceed those of lbe S-enantiomer. Both eoantiomers
antidiarrhoeal propcnies. fl was formerly given in eye drops u a are highly bound to plasma p roteins. Both are also dis-
lymphagogue. tributed. to the synovial fluid, although the difference in
Elhylmol)lhine free ba$c and the camphorale and camsibtc have their concentrations may not be as large as the differ-
olso been used. ence in plasma concentr4tions.1be plasma half-li fe of
0 References. total etodolac has been reported to be about 7 hours;
1. Aasmunclsald TA, c1 '''· Biotr:insform.ation ~nd phannocokincl· excretion is moinly in the urine as hydroxylated metab-
ics of ethyJmorphint afltr a single oral doK. Br J Clin Phormo·
col t99S; 39: 61 1-20. olites and glucuronide conjugates; some may be ex-
Profile
Bhyl nicotinatc is used in concentrations of up to 2% in topical 2. Jonas.son 8, ft ol. fatal poisoninp "Ahctt cthylmorphiJ)e frot1' creted in the bile.
an1icussive mcdicaition' contribuicd to dulh. /111 J LPgol Med
rubefacient prtparations R•r 1he rehcfof pain in musculoskeleta~ 1999; Ill: 299-302. 0 References.
joint, llJld soft-tissue disorders. It has also been used as supPOSi· 3. Helland A.~' al. l>caah of 1 IO-mon1h-otd boy after exposure 10 I. Brocks OR. et ol. Stcf'COSClcc1iw: dispO!ilion of ctodolK enanti·
tories in aoorecial disorders. cthylmotphin<. J F'omufc Sci 20 IO: SS: SS 1-3. omcrs in syno.-i11 Ouid.J Clrn Phormoc-ol 1991; 31: 74 1-6.
All cross-refe~s refer to entries in Volume A
 Ethenzamide/Etoricoxib 55
:!. Brocks OR. e1 "' ~ $\Cttc>Stlectivc pham1acokl.ndte' of drJ'ir.g: Honi Koni: f'&osoP..olen. Rhfuma·Cknlc: Hun1.: Actr;°": cant increose in the ml< or heart failure v.ith etoricoxib 90 mg
etodollte in yuuni; and ckSerl) subjccls. ind :inl!r chol«)"l'C«t\l- Rheomon; TrN~ Ital.: 6ayrot: Gemidot /vtex.: Bayttt Pot: Rheu- daily comparl'd with diclofenac; withdra"als due 10 oedema
my. J Clhr PlwrmttcV>l 1992: Jl: 9S2- 9. n~ TrauN'IOn; Port.: ~ ....a'&ex: Reumon; Tr&i..rnen. Spain: k.~
; l\rOC'IU L>tt fa mAli F. E:~lac clinica! phomn'3cokbctiC'$. Clin pitopic: Fio-4opro~I'( 7,.~ Sw~ f'.hcvrnon: Tr1vmab: Turlc.: Del~: were also more fi'equcnl with high-dose ctoricoxib lhan with di-
Pbor#HK'oAl11N 1 99~; 26: 2~9-74. f'teXO. ~ine..c: ~umon; Vitoe:z..: Tri~ clofenac or etoricoxib 60 mg daily. In addition. the number of
... Boni J. Cl al. Pham1;,cokinciic :ind pharmacodymonic action or Muld·in1redient: Art'.: ~f'i Austrio: Thcrmo-Rr.e:lt'T'().°'I"; Ci.: lhe..... patients stopping tl'C3llllCtll because or hypertension was higher
c1odolK in p.Jli(:nts after oral SAl'l-tfY· J Clm Phornurrol I?')9~ with both doses of ctoricoxib thon wiOt diclofcmc. Similar re-
39; 729- ll. ~~~;,'.;'=-=:~~:T~~;.,";,,_~t= 1ults were seen in the othct 2 Sllld1cs.
s. Boni JP. ~I al. Pham13cokinclics or ctodotac in palirr.ls with Sta~ f!llevmon: Thermo~>.: Yenci.: ~
Mc jU\oCrtil(: rhcuma~oid ·ar1hri1i11. Cliu n1er 1999; 21: Ii I 5-.24. In another study' that pooled pre-licensing data, the risk of
thrombotic cvcnL~ with otoricoxib, gi"en ot o dose of 11 least
Uses and Administration 60 ing daily. was also found to be similar 101h31 for placebo 1re:1t-
Etoricoxib (SAN. USAN. rlNN) meo1, ibuprofen (2.4 g daily), diclofcnac (I SO ong daily), and
Etodolac, a pyrano-mdoleacetic acid deriva1ive, is an noproxcn (I g daily), although there was 3 trend towards more
NSAID (p.103) reported to be a preferential inhibitor Eto1icoxib: Eto-xoxO.rn: Etori.'-.oksib: faorokoksb( Etoril<oxib: L- C\~nts wilh Cloricoxib thon "ith naproxen. For details on the rel-
of cyclo-oxygenase-2 (COX-2). It is used for rheuma· 791456: MK-663: MK-0663. 5-Chloro-6'...-octh)-1·3-(p-(methyl- ative risk of thrombotic events associated with non-selective
toid arthritis. includingjuvenile idiopa1hic arthritis, and sulf°")'i)pt>cnyQ-2.3'-t:ipyricn. NSAlDs, see p.100.
osteoarthritis and for the treatment of acute pain. 3-Top«•o•c•6 After a r<:<:ommcndation from the EMEA"s Committee for Me·
For the treatment of rheumatoid arthritis and osteoar· C,,H,5CIN20~S = 358.8. dicinal Products for Human Use (CHlvlP).3 licensed product in-
CAS - 202409-33·4. fonnation for etoricoxib states that ii must not be gi\JCO to .,._
thritis, the rerommendcd oral dose is initially 0.6 to l g 1ients whose blood pressure is persistently above 140/90 nunHg
ATC - MOIAHOS. and inadequately controlled; in addition. high blood pressure
daily in divided doses adjusted according to response;
ATC l'et - Qf.o!OIAH05. should be controlled before starting trcalmcnt and monitored for
single daily doses of up to 600 mg may also be given. UN/I - WRX4NFY03R 2 weeks afb?rwtrds then regularly lhereofter.
Modified-release preparations are available for oncc-
daily use in these conditions. For doses in children, sec For discussion and ~dvke on the u.., ofselcclive COX-2 inhibi-
tors in patienlS with cardiovascular or ccrcbrovasculor disease,
below. see under Celecoxib. ?.35.
For the tl'catment of acute pain, the recommended dose 1. Cannon CP. er al. Cardiovasculat (IUtcomcs -.·ilh ctoricoxib aod
is 200 to 400 mg every 6 to 8 hours to a maximum of diclorenac in pattec'its wilh ostcoatlhritis and rheum:uoid atchrilis
in the Mullin.:uion1J ElorlCOX'b and OiclC1fcnac Ar1htiris Lona-
I gdaily. lt:nn (MEDAL) proW1Jftme. 1 nndomised comparison. Lo.nttl
0 Revic..,•s. 2006; 36&: 1771-81.
I. Tirunagari SK.~' 111 S1ngtc <l01>c oral ecodolx for acute pos,op· 2. Curtis SP, c' ol. Pooled analyslS of 1hrombc'ttic: cardiovascular
e~·~ts: in ~linic1 l 1riils of the COX-1 s.clccth·c inhibitot ctoricos-
cr.tli"c pain in aduh,_ Available in The Cod\rane Oalabasc of
ib. C•rr M:d Rt.t Opi11 2006; 22: 236S-74.
S)"'tcmatic RC:vlC'\\S, Issue 3. Chiche1iter: John Wik)-: 2009 cae-
ccmd 09/09/09). 3. EMEA . EMEA r~ommends strcngtM:nina wanlings and con-
traind.c:alions for ctoricoxib.,comainms mtdicil"les used in 1hc
Administration In children . 111 the tJSA modified-release Cl 1rct1mtnl of rheumatoid arthrl1is Md ankylosing. spondylitis (is·
prepar.nions of eiodolac may he given for 01c oral treatment of sued 26th June,. 2008). Available a1: hHp:l-"'-ww.cmea.europa.cu/
juvenile idiopathic anhriris in childrtn aged 6 10 16 years. Doses pdf$/humanlp=s/pr/3J363~08cn.('dr(1<ttssed 16!07!08)
are ~ven once daily accor<1ing 10 body-weight as follows: Adverse Effects, Treatment, and Precau- Effects on the gastrointestinal tract. Jt is generally accepl-
• 2() to 30 kg: 400 mg tions cd 1hal the inhibition ofcydo-oxygcnase-1 (COX-I) plays a role
• 31 1045kg: 600 ml! As for NSAIDs in general, p. I 00. in the adverse gastrointestinal effeclSofthe NSAIDs, i nd !hat the
• 46 to 60 kg: 800 ins sdeclivc inhibition of the odier isoform, COX-2, by NSAIDs
Hypersensitivity reactions including anaphy laxis and such as etoricoxib may cause less gastrotoxicity than that seen
' OYer60kg: 1 g
angioedema have occurred in patients receiving etori- wilh Ille non-selective inhibition of the tradilional NSA!Ds.
Preparations coxib: it should be stopped at the first signs of hyper- Ho,.evcr, licensed product information states lhat upper ga.s-
BP 20 I 0: Etodol>C '-'°"" E:odola< Tableu; sensitivity. trointeslinal perforation, ulceration, and bleeds, in some cases fa-
USP 31: Etodolat ~ EtOOoi>c Ext~td·llolrue l"<!lll!:s: Ete<i.o:•c tal, ha"c occurred with ctoricoxib treatmcnr; consequently. it
Talllets. Etoricoxib should not be used in patients with ischae- should be used with caution in JXJlicntS wilh a hisrory of, or at risk
Proprieta.ry Preparations (d<uils are given in Volume 8) mic heart disease, peripheral arterial disease, or cere· of de.eloping.such e\'cnts. In addition, etoricoxibshould not be
S....: Fbneox; Denm" To<loli<; '"'"' LO((ne: Fr.: lodhe Gr" E~ used in patients with ac1ive g;mrointestinal ulceration ot bleed·
ftobc: ~~ Looint: l.ubd)I; Oln-.t:rt Sif:<>V.no: Hong Koni: Et~ brovascular disease. It should be used with caution in
ing.
oc: ~t lndon.; l.of'.eflOt: lsrotl: Eloiw< Jpn: Hypen: Ph11ipp.: &o- patients with significant risk factors for cardiovascular
fi>rn Port.: A<:vdo". Ao·t<uill\[. Du~..-.: &<odolan; Lodinet: l.odott: Results from controlled siudies have suggested that NSA!Ds
Me".utj. Sod<Uc Switz.: Lod""'"' Thoi" Et<JnO:<; Turk: Edolar: Etodon: disease such as hypertension, hyperlipidaemia, and di-
Etot: Loe.-..; Tadoi.11( Tol•c: UK: Et«»<cbc: Etopon: lo<lnt: Ul<r,: Etol selective for COX·2 were :mocialed with a lower ineklence of
abetes mellitus. E1oricoxib, particularly at high doses, serious gastrointestinal effecls. In a study' of the pooled data
(:ff°' ~T~ USA: Lod.nef; Venez.: LoOnej.
may be associated with more frequent and severe hy- from 3 randoinisoo clinical studies, c1oricoxib (in doses of60 or
pertension compared wirh olhcr NSA IDs and selective 90 mg daily) was associated wilh signilic:rnlly less rrcquenl up-
cyclo-oxygcnase-2 (COX-2) inhibitors; blood pressure per gas1tointestinal clinical c\'cnts than diclofenac (ISO mg dai-
Etofenamat:e (61'.N USAI'{ rlt-INJ ly). "The resuh wos attributed to the lower rote of1u1complicated
monitoring during etoricoxib treatment is recommend- ulcm "itb etoricoxib comJXJred with diclofenac; there wos 110
B-~77; Bay-<1-1107: Eto'et•amuru; Etofenamat: Etclenam.n:
Etofenamatas; Etoferumatc:: &o<enamato: Etofe-iamat...-rc lY- ed. Etoricoxib should not be used in patients with hy- difference io ~rate or complicated gastrointestinol events be·
'48S; TVX-435; WHR-5020. 2-(2-Hydroxrethoxy)eU-.yt N-{oon· pertension whose blood pressure is not controlled (sec tween the 2 clru@s. The lower 1-ote of u11complicated events with
Lriluoro-m-tolyt)anU"anolatc. also Effects on the Cardiovascular System, below). etoricoxib compared "'ith diclofenac was not 3ff'ec1cd by treat-
ment with low-<lose aspirin or proton pump inhibirors. An
3T'*"'°"'JT Etoricoxib is also conlra-indicatcd in patients with in- onalysis! by the manufacturer, of pooled &ta from 10 ran-
C 11H,,riNO, =369.3. flammatol'y bowel disease, moderate to severe heart domised clinical studies, fo.,od Ulat cloricoxib (in daily doses of
CAS - J0544-n-9. failure (NYHA class JI to IV), and renal impainnent 60, 90, or 120 mg) was associated wilh a lower combined risk of
ATC - M02M06. associated with a creatiuinc clearance of less than UPf'Cl" gas1roinlcstin:il pctfontions and bleeding, and symp10-
ATC Vet - QM02M06. 1ro1ic pstroduodenal ulcm when compared wid1 11on·sclccrive
UNI/ - KZFOXM66)C. 30 mUminute. lt should be avoided in patients with se-
NSAIDs (diclofcnac 1SO mg daily, ibuprofen 2.4 g daily, or
vere hepatic irnpainncnl (Child-Pugh score of 10 or naproxen I g daily) •s a group. This reduced risk w•s seen even
more). Therapy should be stopped if persiste11tly in patienlS with known risk factors for such con1?lico1ions such
ab1101mal liver enzyme values are seen. Caution is rec- as 1he elderly and th05C with a histo1y of g;is1tointestinal reac-
ommended when using etoricox ib in dehydrated pa- tions.
tients; it may be advisable lO rehydrate patients before t. Lai1u: L. ~' ttl A5"i:Snlttat of upper gas1roinld1inol s:arccy ol"
ctorico~ib and diclofooac in p:ments whh oi1eoanhri1i1 and
giving etoricoxib. rhcuma1oid artho1is in 1hc MuhinatiCln:ll E1orkt.J:<ib and Di·
clorcnnc Arlhritis Long-term (MEDAL) progt~mmc : a ran·
EffecU on the cardiovascular system. There ha,•e been domistd com~rison. IA«n 2007~ 369: 465-73.
conc.:rns about lhe adverse cardiovasculareITecls ofselectivecy- l . Ramey DR..,.,'''· The i1lcide:ncc or U'pper gastrointeSlinal ;idvctw
Pharmacopoeias. In £111: (sec p.vii). clo-ox)'gtnasc·2 (COX-2) inh1bi1ors ofter 1hc worldwide with· or
c,·~nts in clinical tri~ls etoncox1b \$.non-selective NSA IDs:
Ph. Eur. 6.8 {Eto""2male). A yellnwi$l1 vis.:otJS liquid. Pracli· drawal ofrofeco:.ib (see p.125). The C3rdio"3SCul>r safe1y of an updated cC'mbincd a1u1ly1i .. C,,,.,. M«I Ro· Opln 2005~ 11:
cally in~lublc in water. miscihle with alcohol and with ethyl ac- ctoricoxib has been assessed in the MEDAL programme,' which 71S-?2.
thlle. pooled data from 3 studies in"olving over 30000 p.tlicnts with Effects on the kidneys. Limit<."<! evidence ofthc renal toxicity
Profile ei1heros1eoanhri11Sor rheumatoid orthriris. PatienlS "ith os1eoar- of 01e sclecth-., cyclo-oxygenase·2 (COX-2) inhibitors such as
E1ofenama1< is"" NSAIO(p.IOO)that has beeu applied topically 1hri1is were i;ivcn ttoricoxib 60 or 90 mg doily; those "ilh rheu· etoricoxib suggestS that such ~SAIDs appear 10 have cff'e<:IS on
in a cun.;cntralicm of Sor 100!. for the relief of pain a.nd inOam- matoid anlu-itis received 90 mg daily. Jn all srudies, diclofenac renal function similar to tho5< oflhe non-selective NSAIDs (see
mation associated wiOt musculoskelctal, joint, and soft-tissue 150 mg dnily was given as the comparator; low-dose aspirin p.102).
disotclcl$. h has also b<.-en given by deep intramuscular injection (100 mg doily'" less) was also allowed where indiC'1ted. After
in sin~le doses of 1 g. an a'erage ttcntmelll duration of 18 months. the rates of throm-
botic events such as myocardial infarction, stroke, and sudden or Interactions
Preparations unexplained death \\ith etoricoxib were similar to those for di- The metabolism of etoricoxib is mediated by the cyto-
Proprietary Prepuations (dt1Ail~ 1're gi\'tn in Volume B} clofcMc. (It has hccn sug£csted tlu.l diclofmac itself may in· chrome P450 isoe11zyme CYP3A4. Use with other
.Arg.: Cootcut: flor.ot Austrlo: Rheum:>o: T.-.unon: S.(r.: Flexi'""'; crease dlC risk of some thrombotic events; for further details, sec
8roL: l!ayTv. O.ile: llot~ flosojet Mutet"·Geit;Valoret Ci.: EIOlClt: p. I00.) Tix programme also found lha1 lhc rate of sonic other drugs that inhibit or induce this isoenzyme may result
R'l«lma Oc<11¢ ~Trwmorc Ger.: RhaJIT.l·Get ~ 1'nou- in changes in plasma concentration of ctoricoxib. In
mon: Gr.: c.laoit: Cim.ll (t°"'1ol Etoge!: ff<\<m. f...,..p.11: ~ iro- non-thrombotic cardiovascular events was increased with ctori·
l'cne; l(o.othcrm: MelfeM. Parerpcet ~10; R.,..,,na. lloipb"C - coxib: one oftlie 3 S!Udies showed thol lhere was a non-signifi· addition. in 1·i1ro studies suggcs1 that several other
The symbol t dc1101es a prepar.nion no longer actively marl:eted
56 Analgesics Anti-inflammatory Drugs and Antipyretics
isoenzymes may also mediate the main metabol ic also used in gouty arthrilis (p.600). However, in the UK, it is rec- Adverse Effects and Treatment
pathway of etoricoxib. Rifampic.in, a potent inducer of ommended 1ha1the use of selective COX-2 inhibitori; is limiled As for Opioid Analgesics in general, p.106. Etoiphine is not used
lo paticnls wilh good cardiovascular health and al hiJ:)t risk of lhcrapcutically in humans.
CYP isoenzymes, has produced decreased plasma con- developing serious gastroiniestinal problems if given a non·se· E1orphinc hydrochloride is highly potent and rapid acting:
centrations of etoricoxib. lective NSAID(sce p.101). minute amowus can exert serious effeciS leading to coma. It may
Etoricoxib is an inhibitor of human sulforransferase ac- References. be absort>cd through skin and mucous membranes. !1 is thus ad-
tivity and has been shown to increase the plasma con- I. Cochrone DJ • ., of. Etocicoxib. l>rHgs 2002; 62: 2637-SI. visable to inject an aniagonist immediolel)'afte-conlaminatioo of
2. SchumKhcs HR. ., ol. Random;scd double blind 1riat of ttori· skin or mucous membranes with pttparat.ions containill! ctor-
centration of ethinylcstradiol. Interactions with other phioc hydrochloride ond 10 wash the atrccled areas copiously.
coxib and 1ndomtu.cin in ueatmcm of acute goucy arthritis B•U
drugs, such as oral salbutamol and minoxidil, also me- 2002: 324: ICSB-91 Accidental injection or needle scnudi injuries should also be
tabolised by this enzyme may be a possibility and li- 3. Con<Sdicncr K• ., nl Rcsuhs oh ...,,dom~ -·nni:inc uial treated immediately by injecting an antagonist. Naloxooe is pre-
censed product iofonnation advises care with such of ctoricoxib in ~dents with ~~rthritis.. RM11Motn/osry (0¥- femd as the an\agonist in medical treatmcttl However, veteri-
fonf) 2002; 41: IOSl-61. nary preparations of etotphinc arc SUJ>plicd wilh a preparation
combinations. 4. Wl~nnhutte:r CW, ti al Eva1ua1it1n of the: tompara1ive effictc)' (Rl!llivcn) containing diprcnorph inc hydrochloride (p. l 585) aod
For interactions associated with NSA!Ds in general, or tloricoxib a.nd ibuprore:n for U'Ulmtnl of 1)3licnts wich osto• this should be used for immediate first-aid antagonism if
01nhri1is: a randomited. double-blind, placcb<rcontrollcd tri1I. naloxone is not available.
see p.103. Mayo C/f" Proc 200S; 80: 470-9.
5. van dcr Hcijde o. 11 al. Evaluatton of the efficacy of c.1oricoxib Uses and Administration
Pharmacokinetics in ankylosina spondyliris: rcsuhs of a fifty·l w~weeJ.:, nind- Etoiphine hydrochloride is a highly potent opioid an•lgesic
omized, controlled study. Arthritis Rheum 2005; 52: '205-IS. (p.108) used for revCJSiblc neurolep!Anolgesi• (see Anaeslhelic
Etoricoxib is well absorbed from the gastrointestinal 6. Cunis SP, ct ol. Elorleoiib in the treatment of osteoarthritis over Techniques, p.1936) in veterinary medicine. It is given.with ac:e-
tract after oral doses. Peak plasma concentrations oc- S2°wec:kt: I doublf•blind, ::ICliVf..COtnp&ralor controlled trill promazine maleate or le,-omepromaiine (Jmmol>ilon) to rco.11"ain
cur in about I hour in fasted adults; food delays absorp- JNCT0024?489). BMC Musculask•I" Dlsord 200S; 6: SS. animals and before minor veterinary surscry. The duration ofac-
Avoil1bJe: 11: Jmp://www.biomedccntral.com/contcntlpd(/
tion by about 2 hours, although it has no effect on the 1471·24 74-6-SS.pd( (accessed 01/11!07) tion of etorphine is up to about 45 to 90 minules depending on
the species but ii may be longer in man, especially if the large
extent of absorption. Plasma protein binding is about 1. Bina,h1m CO. ti al. Efficacy and .safety of e1oricox.ib 30m1 and
1nimal preparation is i1wolved.
celeecu1:ib 200 mg in thctreaune:cnofostto3nhritis i" 1wo KStnti·
92%. Al steady state the half-life of etoricoxib is about cony d<Slsn<d. randomized, plaabo-c:antrollcd, non·i•ftrioril>
22 hours. Etoricoxib is extensively metabolised with studies. RhntMatolOf:'l !0¥.fonlJ 2007; 46: 496-507.
less than 2% of a dose recovered in the urine as the 8. Croom Kf. Siddiqui M.AA. Etoocox.ib: a review or its use in the
parent drug. The major route of metabolism is via cy-
symp1omauc Lreaunent of osteoarthritis.~ m,umatoid •nhri1is.1n.• Felbinac t'MN. l.ISAN tff.?
~~:~~~.spondytitis and ac:u1e goo!)' 1rthritiJ. Dr11gs 2009; 69:
tochrome P450 isoenzymes including CYP3A4 to CL·83S44; felbi:ia•kki: Felbinaco: Felb<nacum: fetinak; LJC-
form the 6' -hydroxymethyl derivative of etoricoxib, 10141. Biphenyl-4-ylacetic: a<:id.
Pain. A systematic review' found thal a single 120.mg dose of
which is then oxidised to the 6'-carboxylic acid deriv- ctoricoxib, given orally, provided effective pain relief after sw· CJleol6... ax
ative, the major metabolite. Both are inactive or only gery. When compared indirectly, cioricoxib was considered 10 be C,.H1201 = 2 12.2.
weak cyclo-oxygenase-2 (COX-2) inhibitors. Excre- al le:i.~1 3S effective as other commonly used analgesics. CAS - 5728.52-9.
1. Cl~rkc R, ti ol. Sins le dok Or-31 etoricoxib fot acule po1t0pero.- ATC - M02AA08.
tion is mainly via the urine (70%) with only 20% of a tivc pain in adults. Available in The Cochrane: Database of' Sys-
dose appearing in the faeces. Studies in animals sug- 1cm:uic Reviews; ls.sue: 2. Chichester: John Wiley~ 2009 {ac- ATC Ve! - QMOlAA08.
gest that ctoricoxib may cross the placenta and that m••~ 09!09/09).

some is distributed into breast milk. Pre paratio ns

OH
OReferences.
I. A~w•I NCD, ~• ol. Single- •nd multiple-dose phannocolinet-
Propt'ietary Preparations (details are gr...,, in Volume B)
A.i.: Nccoo: AvJtn>/.: Art:OIOI; Austria: Ar=xia; A<ool>. B•'r.: Art:<Mo:
""""'°" o=( n ;=\
ics of elorico;xib, I stkctiYe inhibllor o( cydoo.xygen.St ·2~ in
mon. J CHn Phnrmacol 2003: 43: 268-76.
&oz.: Art:oocia: C..: M(IO<'.a; Denm.: At=.a.; Fm.:
Mox.at: G•,..: Attox..a.; Gr.: An:oxil= Tixox. Honi Kone; Alc.O»I:
T"'*' Fr.:
Hunr.: Arcooo: tncllo: ex..; E<O><Of; Etoxilx Et.._ ICrcloo.. N..oeetdo; 1,..
\J-\_j
2. Agrawal t\'GB, n al. Phlrmacok1ne11e.1 of clOriCloxib in p;Jlit'nts don.: lvwiR:. lrl.: Meo<a. lsra•I: Am»Ooc Ital.: Al&oc Mocio: TN!b
with hepatic impairme:nl. J Clln Phorlf1acol 2003; 43: 1136-48. Malaysia: Moooa. M u.: An:oocio: N•tlt.: Aroma; Au>iO. Norw.: !Va»<· Pharmacopoeiu. In Eur. (sec p.vii) ~nd Jp11.
l. A&ra'A'3.I NOB, Cl al, Phann1cokinetics or etorioo:tib in p:atients
with r¢n31 irnpainnc:nl. J Clfo Phonnocol 2004~ -14: 48-58. '°""
io: NZ: Al<O><io. Philipp.: llr<cooo: Port.: hcO><ia: E>OCiv. T'"'°" Rus.: ,.,._
(~°""'•k S.Afr.: Art:<»<io: Singap0<e: hcO><ia: Sj>oln: Ar<...a:
Swd.: Arc.O>ci~ Thal: Art.Qeli: UK: Artoxia; VeneJ..: ~OO(ia
Ph. Eur. 6.8 ( Felbinac). A while or almost while, aystallinc
powder. Practically insoluble in water; spru-inilY soluble in alco-
4. Takemoto JK, n ol. Ctinic;il phom1acokinetic and pharmacody· hol; soluble in methyl alcohol.
narnic profile of etoricoxib. C/ln Pho1·mctc0Hnt1 2008; 47:
703-20. Adverse Effects and Precautions
Mild local rcaclions such as erythema, dcrmaiitis. and prurirus
Etorphine Hydrochloride (BANI>\ t.NNM)
have occurred in pi1tienis U$lng felbinac 1opically. Mor<: serious
Uses and Ad ministratio n
~torphine. Chlomydrate d': Etorphini Hydrochloridum: Hidro· adverse cffccis including bullous dcnnatoses such as epidcnnal
Etoricoxib is an NSAID (p.100) reported to be a selec- cloruro de etor<ina: M·99: 19.Prop)'forvinol Hydrochlo<-ide. necrolysis and erythcma multifonnc, photoisensilivily, anaphy-
tive inhibitor of cyclo-oxygenase-2 (COX-2). It is used (6R.7R, I ~R)-7.8·();hydro-7{(I R)-1 ·hydroxy- I·methf.butyl)·6- laxis, and bronchospasm or wheeziness have also been reported.
in the symptomatic relief of rheumatoid arthritis, oste- ().melhyl.6. I 4o.·C\heoomorphile hydrochloride; (2R}-2{(-)- Gastrointestinal disturbances may occur.
oanluitis, ankylosing spondylitis, and acute gouty ar- (SR.6R.7R. t 4R)-4.5-Epoxy·J.hydroxy-6-methaxy·9a-metll)'t- Felbinae prcpardliuns should be avoided in patients wilh a hist<>-
thricis. 6.14~1'1nan-7·ytjpent2r~2-0I hydrochlonde. ry ofhypersensirivity n:at1iun<; lo aspirin or other NSAIDs.
In osteoarthritis, etoricoxib is given orally in a usual r
:noi+o<~ 'IAj)O""°l"'A Incidence of adverse effects. The UK CSM had received 49
dose of30 mg once daily, increased to 60 mg once dai- C1~Hi~O •.HCI =148.0. rq>OrU ofad,..,rsc n:actions associated with felbinac by October
1989,about II months after it was reluscd on 1he UK market.'
ly if necessary. The recommended dose in rheumatoid CAS - 14511 · 96· 1 (ctorphme): 13764-49-3 (etorphine
BronehospaStn or wheeziness was reported in 8 pa1ic:n1s using
hydrocl>lofl<1c).
arthritis and in ankylosing spondylitis is 90 mg once felbina<; gel. Four of these pa1icn1s had a hislory of aSlhma of
UNll -· 8C8E.OIN748. whom 3 were reported 10 have had a similar reaction to aspirin or
dai ly; higher doses of 120 mg once daily are u:SCd in
gouty arthritis allhough such doses should only be.used other NSA!Ds. Other reported reactions included roshes (17 cas-
03). locol opplicotion sile reaclions (7), Gnd dyspepsia (6).
for the acute symptomatic period and for a maximum I. CSM. Fclbinat (Traum) and bron cho11~sm . Currfnt ~robltm1s
of 8 days. For dosage recommendations in patients 17 t989.
with hepatic impainnen" see below. Use s and Administration
0 References. Felbinac, an active metabolite of fonbufen (below), is an NSAJl)
(p. t03). II is used topically in !he symptomalie treatment of mus-
I. Patrlgnani P, c-t ol. Clinical pharmacology or e:toricoxib: a no"cl
sckaive COX2 inhibitor. Expcrr Opln Phofmooorhv 2003; 4: wloskclctal pain including that due to soft-tissue injuries. II is
265-84. applied as a 3% gel or a 3.1,..4 foam 10 wibrokc:n skin over af-
fected areas 2 to 4 times &ily. The tol1I daily dose ofgel or foam
2. [bUob A. <'I nl. ChlrlCltri~tion of ete>moxib.. J novel. selecthe
COX-2 inhibitor. J Clin Phor#IO<OI 2003 43: Sil-SS. should nol exceed 25 grcgardlcss of the siu or number ofaffect-
3. M311ina SD. ~t al Etoricoxib: • hi.Ahl> s.c:Jcc1ivc COX-2 inhibi· ed orcas. Thetapy should be l'CVicwed after I 4 days.
toe. Ann Phormncoth<r 200S; 39: 8S4-62. Diisopropanolamine felbinac has bea1 used similarly.
Administration in hepadc impairme.nt. The maximum 0 Rcfer¢nccs.
oral dose of etoricoxib in patients wi1h mild hepatic impairment (etorphine)
1. Hosie GAC. The topical NSAID, ftrbinac. versus oral ibuprofen:
(Oiild-Pug)I score of 5 10 6), regardless of indication, is 60 mg a C('lmpari~on of cffic.Jc:y in lhC lt'Utrnenl f'f ftCUtC: IOWCI' back
once doily; those with moderate impaim1cnt (Child-Pugh 7 to 9) Pharmacopoeias. In BP(Vet}. injury. Br JC/in Res 1993; 4: 5-17.
should be given a maximum of60 mg every other day or 30 mg 8 P(Vet) 20 10 (Etorphine l-l)'drocllloride). A white or almost
once daily. Etoricoxibshould not be given to palient• wilh ~evcrc white microcrysialline powder. Sparingly soluble in water and ln Pre parations
hepatic impairment (Child-Pugh 10 or more). alcohol; very slightly soluble in chlorofonn; practically insoluble BP 2010: Felbinac Cvunoous Foain. fclbinac G.:l
in cUier. A 2% solution in water has a pH of 4.0 10 5.S. Protcel Proprietary Preparations (dc\ails ore given in Volume B)
Musculoskeletal and Joint disorders. TI1e selective cydir from lighL
oxygenase-2 (COX-2) inhibilor etoricoxib is used in the ln:al· 8•11~ ffexf- Ger.: Spalt Schmerz·Gclf: Gr.: Ootinac: lrl" Trv:am: Ital.:
001r1>c Traxamj; /pn: Selouch; Switz.: Dalo li'lett. UK: T,.._,,
mcnt of ankylosing spondylitis (sec Spondyloarthropathies, Dependence and Withdrawal
p.14). os1coarthrilis (p.11 ), and meuinaloid arthritis (p.12); it is As for Opioid Analgesics, p.105.
All cross-references refer lo entries in Volume A
 Etorphine l-lydrochloiide/Fenoprof~ Calcium 57
Fenbufon (BAN. llSAN. clNN) Pharmacokinetics Effects on the blood. Hac"fliatological 3dYer$C eff'ccrs includ·
Fenbufen is absorbed from the gastrointes1 inal trac1 af- ing auranulocytosis. 1 aplastic anacmiA,' and thrombocyto-
Cl-$2204: rerb,'cerir. ~enbuie:-:Fen:>JfeNs: renl:></ere: F..,.. penial• have been reported in pa1ic111s taking fc11oprofen;
bufcNr",. 4·(Biphen)'.·4·yl)·-1-<>Ycbutyri( aCld.
ter oral use and peak plasma concentrations occur in liumseu prodo<1 infonna1ion also re1>0ris haemolytic anaemia.
about 70 minutes. Fenbufen is over 99% bound to plas- I. Simon SD, Kosn>in M. Fcnop'Ofcn 01nd a~nHu.1loc-yco,.is. N Engl
(Ile~
ma proteins. lt is metabolised in the liver to the active J Mt:d 1978: 299: 490.
C,.H,.O;"' 254.3.
metabolites, biphcnylacetic acid and 4-hydroxy-biphe- 2. Ashr3f M. r-1 ul Aplastic a.,,attlllll i1:t)()Ci3h:::d with renoproftn.
CAS - 36330-85-5. BMJ 1982: 284: 1301-1.
nylbutyric acid. Fenbufcn and its metabolites are re-
ATC - /\101AE05 3. Simpson RE. c1 tit. Acute: dtrombcc)10p!nia usoci31cd w11h
poned to have plasma half-lives of about I 0 to 17 f<r.oprofrn N £>111.I J M~d 197&; 298: 6~9-30.
ATC Vet - QMOIAE.05
hours and arc mainly eliminated as conjugates in the 4. Kati, ME. Wans P. Fenoprofen·assoc-i.alcd lhmmhocylopenia.
UNH- 9815RIWR98 urine. Metabolites of fenbufen have been detected in Aim lntem J.ktJ 1980; 9?: 262.

breast milk in small amounts. Effects on the liver. Choles1a1ic jaundice and hepati1is devel-
oped in a 68-ycar-0ld woman after receiving fenoprofen 600 mg
0 four times daily for 7 weeks. Sul>S<:qucnl use of naproxen and
Uses and Administration indo1ne1acin did not rcsull in hepaloto>icity.1 However, !hen: has
COOH Fenbufen, a propionic acid derivative, is an NSAID been a repo11 of cross-heperotoxicity between fcnoprofen and
(p.103). It is given for the reliefof pain and inflamma- naproxen.'
tion associated with musculoskeletal and joint disor- I. Stmnttt OJ. 11 trl. Fcnoprofen ..induc:t'd hcpacoto)'Cichy. Am J
ders such as rheumatoid arthritis, osteoarthritis, and an- Hcnp PIKJrin 1978; 35: 90 I.
2. Andrcjat M. ~I al. Cross hc~loto>.icity ~en non-Mcroidal
kylosing spondylitis in oral doses of900 mg daily; the 1n11-innomm•1<1<y drup. BMJ 19S7; J95: 110-t.
dose may be either 450 mg in the morning and evening Efl'ects on die skin. Toxic epidermal neaolysis was associated
Pharmacopoeias. In Grin, £w: (5"C p.vii). nud.ljm.
Ph. Eur. 6.8 (Fer.bulen). A white or almost while, line crystil- or 300 mg in the morning with 600 mg in the evening. wi1h fcnoprofcn in 2 patients.'
line powdtr. Very slightly soluble in w:uer; slightly soluble in al- Preparations 1. Stotts JS,~' ol. fc-00Pfofcn·lndt1ccd 1oxic epidermal necrolf$i\.
cohol, in acclonc. and in dichloromelhanc. J Am Aeon Der11101ol J9"; 18: 7SS-7.
SP 1010: f=bu'cn Of>wlc• F""""°" Tab:.ets. Overdosage. Coma, rcspirarory depression, hypotensooo, and
Adverse Effects, Treatment, and Precau· Proprietary Preparations (deails are givtn in Volume Bl 1nctibolic acidosis occurred in a palicnl who had ingesred bc-
lndon.: Cybllent. lrl.: Lc<l<rfent; Port..: ~ Rou1Htt: Tho/.: Ctpet tw- 24 Md 36 g offenoprofcn.1 lbc patient responded IO gas-
tions Foroufer< Turi<.: Cir.opolt: UK: lederf<nj.
As for NSAIDs in ~enerdl, p.1oo;·ahhough the com- tric bvagc and activared charcoal and intensive supponivc care.
monest adverse effects offenbufen are rashes, usually I. Ko4oc:tz,k JM."' al. Nonslcroidal 1nti-1nftamm:ttory drugs ond
co1na: a case report or fe11oprofen ov~. ..tnn Emerg Med
occurring within the first 2 weeks of therapy, and par- 1~90; 19: 313-81.
ticularly in women and in pat.ients with seronegative fenoprofen Calcium (BAN1v,, USAN. rfNNMJ
rheumatoid arthritis or psoriatie arthritis. Disorders Calcii Fenoprnfen111n: F~ Cakique; Fenoprof:no cMo· Interactions
such as epidermal necrolysis, erythema multiforme, co; llly-69323: lilly-53858 (fcnoprofen); l iDy-61169 crenoP-o<en For interactions associated with NSAIDs, sec p. I 03.
and Stevens-Johnson syndrome have also been report- sxiu'n~ Calcium (.1:)-2-(3~propionate dt>y- Aspirin is reported 10 reduce plasma concentrations of
ed. A small number of patients who develop rash may crate. fenoprofen.
go on to develop a severe illness characterised by pul- K._,...·, <lleHon~"
Antiepileptics. Phenoba1·bi10/ migill 1ncrense the rate of nic-
monary eosinophilia or allergic alveolitis. Treatment (C1sH1101hCi.2Hp = SSS.6. 1abolism of fenoprofen.1 US licensed product infonna1ion sug-
with fenbufen should be stopped immediately if a rash CAS - 31879-05-7 ((enopro{en); 34597-40-5 (anhydrous gests that dosage adjuslmcnl or
fcnoprofcn may be required
appears. {enoprofen colcio;m); 53Hb-4S·S (fenoprofen colcium do- when given with phe:nobaJbila1.
nydrote). l. HeUeber:g L. ct ol. A ph;irmccokinctic interaction in men be-
Breast feeding. UK licensed product infonnaliOn advises lhal
ATC - MOIAE.04. tween phenobatbitont end (moprofen, a new anti-intlammocory
fcnbufen shoutd be avoided in brcas1-fecding molhcrs, because agent BrJ c//n P,,_«CI 19i4; J : 371-4.
ofd>e presence of its mc1aboli1es in breast milk. ATC Vet - QMOIAE.04.
Effects on the blood. Haemolytic anaemia' and aplastic UNil - OX2CW I QA8J Pharmacokinetics
anaemia? ha'-e ~1 rcporled in p;ilienlS rccc1V1ng feubufen. Fcnoprofcn is readily absorbed from the gastrointesti-
I. Martl:lnd T. Stone WO. H;icnioly'ic an:.cm1a associated with (ct1- nal tract; bioavailability is about 85% but food and
b.,li:n. DAI.I 1988. ?97: 9:?1.
Andrew,. R. Ru.s.seU N. Apl.3s1ic a1Hh.~1nia usc.ciatc:-d with"' non·
milk may reduce the rate and extent of absorption.
steroid.ii Mti·ionamn.tatOfy dN1: rebpsc ufier cxposu1c 10 1.n· Peak plasma concentrations occur I to 2 hours after a
olhcrsuch drug. BAU J~ 301: 38. dose. The plasma half-life is about 3 hours. Fenoprofen
Effects on the lungs. In Jonua1y 1989 •hc UK CSM rcponcd is 99% bow1d to plasma proteins. About 90"/o ofa dose
lhat ii had received 7 reports of• suspa:1cd association between is excreted in the urine in 24 hours, chiefly as the glu-
rash and an allergic i111ers1i1ial lung disorder in patients receiving (fenoprv(on)
curonide and the glucuronide ofhydroxylated fenopro-
fcnbufcn.1 In S p;1tients, the lung disorder was dia8J1osed as pol-
mona1y cos.nophilia; in tl1e 2 other pa1i..11s the pulmonary coni-
fen. Fcnoprofen is distributed into breast milk.
Pharmacopoeias. In Br:, Chin•. a11d US.
po11ent ofrllC reaction was described os allergic alYt:Oli1is. Sever- BP 20 I 0 (f.eoopro(en Calcicm). A white or ahnost while odour-
al ofrhcse reae1ions have been rcpo11cd in 1hc litcranire.2-' Uses and Administration
less or almQSI odourless cryst.illinc powder. Slightly soluble in
I. CSM. f(nbufcn. rash ind pulmon:1ry cosinophi1ia. C11rrttn1 waler and mchloroform; soluble in alcohol. Fenoprofen, a propionic acid derivative, is an NSAID
Problem114 1989.
USP 33 (Fenopro(en Calciun). A white crystalhnc powder. (p.103) used in the management of mild to moderate
2. Swinbum CR. AlvtolfltSand hllc1noly1ic :anMemia induc:.:d by at· pain and for the relief of pain and inflammation associ-
Slighrly soluble in water, 111 merhyl alcohol, and in n·heXJ1J1ol;
apropaion<. BAI.I 1987; ?M: 375.
3. Burton GH. Rash a"4:1 pulmonary tcSinophilia 1$Jt0Ci111cd w11h
practically insoluble in chlorofom1. Srorc in airtigh1 containers. ated with disorder:; such as osteoarthritis, rheumatoid
f<nbuf.n. BMJ 1990: 300: S2-;. anhritis, and ankylosing spondylitis. It is given as the
Effects on the skin. In &plemb<r 1988 lhe UK CSM reported'
Adverse Effects, Treatment, an d Precau· calcium salt although doses are expressed in terms of
tha1 i1 was still receiving large numbers of reports of adverse rc- tions the base; fenoprofen calcium (dihydrate) 1.2 g is
oc1ions 10 fenbufcn when such reports were expected 10 have de- As for NSA!Ds in general, p. I 00. equivalent to about I g of fenoprofen. A usual oral
clined. Fenbufen was the most commonly reported suspocl dru11 dose is the equivalent of300 to 600 mg of fcnoprofen
Dysuria. cystitis, haematuria, interstitial nephritis, and
in 1986and 1987. Al the rime of1he rq>0rt morcUian6000 such three or four times daily, adjusted thereafter accord.ing
rcpo1ts had been received, 80% conceming mucocutlncous reac- acute renal insufficiency have been reported with feno-
1ions and most invoh-ing a generalised florid eryd1cmotous rash, profen. Nephrotic syndrome, which may be preceded to response. ln the USA, lower doses of200 mg every
oflen witl• pntritus. 'There were 178 reports of erythema multi- by fever, rash, artbralgia, oliguria, azotacmia, and anu- 4 to 6 hours are recommended for mild to moderate
foone. 30 ofS1eve11s-Johnson syndrome, and 2 tlttaliries. ria, has also occurred. Upper respiralory-tract infection pain. It has been recommended that the Iota! daily dose
J. CSM. Ft-nbufcn and mucocuta.neous rtaclM>.u. Cun'<'nl Pn>/J· and nasopharyngitis have been·reported. There have should not exceed 3 g (UK) or 3.2 g (USA).
l~m~ 1J 19SS.
been reports of severe hepatic reactions, including Preparations
Hypersensitivity. See under Eff'CCIS 011 dlC Lunss (above).
jaundice and fatal hepatitis. BP 2010: fenoprolen TilllleU;
USP 33: fenoprofen C.lci"" c.p.uloi: f_,.,,.,r.., Cal;"'m T.d>leu.
Interactions Breast feeding. f'cnoprofen is dislributcd into breas1 milk al-
though the amount is considered by the BNF 59 to be 100 small Proprietary Preparations (det•ils arc given in Volume B)
for interactions associa1ed with NSAIDs, seep. I03. Fr.: Na1g<1ic: Gr.: Exprort N>Z;P""'" Mex.: Nalont: UK: Fcnci><Ort USA:
lo be h•nnful to a brca•t-fed infant Jn contrast, licensed produc1
Use of fenbufen with aspirin may result in decreased Nal'On; V•ne&.: ftrqi<ont.
infonnalion docs no< recommend its use since safely has not
serum concentrations of fenbufen and its metabolites. been established.
The symbol t dcnoles a prcpararion no longer aclively marketed
58 Analgesics Anti-inflammatory Drugs and Antipyretics
Fentanyl (BAN. ttNNJ ® An admixture of fcn1anyl citrate and bupivacainc in sodium throat irritation, e pistaxis, nasal ulcers, and rbinor-
chloride 0.9% appeared' 001npatiblc and Stable when stored for rhoea.
Fentani; Fenunlo; fentan1lo; Fentanylum Feo1anyyl1 N-( I· up to 30 days at 3° or 23° in a ponable infusion pump. In another
Pherclllfr'l-pipericfyl) propionanilde. study' the stability of solutions containing fcntanyl, bupivacainc, EffectS on the cardiovascular system. For a reference to lhc
CDeliTl."iK.'\ ":"d adn:naline, alone and in combina1ion was studied over a pe- effects of fentanyl 011 histamine release compared with so1nc oth·
n~ of 56 days when stored at various temperatures in lhc light er opioids, see under Pe1hidine. p.118.
C22HnN20 =336.S. or 1n the dark m PVC ba~ Both fcntanyl and bupivacaine were
Effects o n mental function. Fenronyl had so~ dOl5e·"'latcd
CAS - •37-38-7. adsorbed liom solurion onto the PVC for lhe first 3 days but clTecL~ on mental function and motor acthity in heallhy sub-
ATC - N01Alf01; N01>.803. thcreaflc~ concentrations of these drugs remained relatively sta-
jects,1 but immediate and delayed recall "ere not aJfec1ed. Sec
ATC Ver - QNOIAHOI : QN01A803. ble; frcew& appeared to slow the concentration change for bupi- also under A lfcntanil (p.17).
UNll - UF59978SJZ. vacaine but not for fcntanyl. Solutions containing adrenaline be·
ca me more acidic during the studv as the adrena line Acute toxic delirium has been reported oRer treatment with
progressively _detcrionlled but this was gr;,.tly reduced by frcct· transdcrmal fentanyl.l
mg. Autoclavmg produced a funhcr redutlion in the conccnu·•· J. Scamman FL, ~I al. Vcn1tlatory a:\d mtntal cffccLS ol' 1ffcnllnil
tion of all drugs. There was no sign of precipi1ation from any of and (cn1anyl. Arw Anttts,htmal Sc:and 1984; ?8: 63-7.
the solutions studied. l. Kunna PJ, et al. Acurc IOll:ic dclinum: a uncommon rcK1ion to
iransdcrmal feutanyl. Atwsthaiolog,Y 1995; 83: 869-11.
An admixture of fonianyl citrate, ketaminc hydrochloride, and
dropcridol in sodium chloride 0.9"1. was stable6 for at least 30 Effects on the nervous syste m . 111crc have been rcpo<IS of
days when stored in glass bottles at 25°; lhc minor decrease in the seizures wilh low and high doses offcn1anyl orsufentanil.1There
concentrations of all 3 drugs was attributed to either hydrolytic was, however, no EEG evidence of conical seizure acti\ity in a
de~dation or ad~rp<ion. This admixture also appeared com- patient who had seizure-like muscle movements during a fcnta-
pattble when Slored UI PVC bags at 4° and 25°; the sm1ll increase nyl infusion;2 die muscle movements migltt have been due to
m drug concentrations over 30 days may be a IC$Ult ofwater per. myoclonus produced by depression of higher CNS inhibitory
mearion and cvapor.>tion through lhe bags. ~nlrc$ or to• pronounced fonn of opioid-induced muscle rigid·
Fcntanyl is potentially unstable in PVC eotitainers when mixed 1ty.
wilh alkaline drugs (sec Incompatibility, abo-.-c). For a report of encepbalopalhy 1$SOCiated wilh prolonged use of
Street names. Tbe following 1cnns have been used as 'street fcntanyl and midazolatn in infants in intensive care, see Enceph-
J. Kowalski SR. Gourl-1y OK. Stabihty or rcmany1 ciuatc in g.Jas:s
names' (sup.vi) or slang names for various forms offentanyl : and ~.nltc containers and in a paaient-con&rollcd delivery sys- alopolhy under Adverse Effects of Diazepam, p.1091 .
Apache; China &itl; China town; China whire: Dance fever Fen- l<m. Am J Ho1p Phorm 1990; 41: IS84-7. I. bc("ara <l ct ol. Clin.tcaJ features, pathoscnesis and management
lllnest; Friend; Good fellas; Great bear; He-man; Jackpot;'Kino 2. AJltn LV, ff al. S1ability offt:Rtanyl citrate in 0.9% $.Odi-um chlo-
ivoiy; MW'der 8; Poison; Tango & Cash; TNT; T.N.T.
0
of drua-indueed sti211n:s. C>rvg Safcl]l 1990: 5: 109-SJ.
ride solution in poraabloe infusion pumps. Am J Hosp Pharm 2. Seo~ JC, SttnCfllisl FH. Seizure-like movements duriog a fcnta-
Pharma copoeias. Jn Eur. (soc p.vii). 1m; 47: 1s12-4. nyl infusion wuh absence of seizure ~livi'Y in 1 simuhaneous
l. Ch:tpa l ~i~· Par~ade S. et ol
Microbio1og.ical 11nd ph)"Sicochcmi- EEG recordin&- .4Milh.siology t 98S; 62:81?-14.
Ph. Eur. 6.8 (Fen1.Y>)'~. A white or almost white polymoiphic c.al s1ab1 hl~ oJ rent1nyt ~Pd
sufrntnnil ~lutfon.s ror petitnt-<On-
powder. Pracli"'1lly insoluble in water, freely soluble in alcohol ~~~e.d deh\·cry systems. J Puin Symptom Monugc 2006; 31: E_ffects ~n the respiratory system. Fcntanyl, likt other opi-
and in methyl alcohol Procect from light oid agomsts, causes dose·rela1ed rcspiratoiy depression; it is sig·
4. Tu Y-H. e1 ol. Stability0Uen11nyl citrate and bupivacain~ hydro- nificant wi1b intravenous fentanyl doses or more than
chloride in portable pump reM:J'\Oirs. Am J Hosp Pllllrm 1990:
Fe ntanyl Citrat e (SANM. USAN. tlNNM) ® 47: 2037-40. 200 micrograms and may be more prolonged than analgesia. An·
Citrato de fe:f.anilo; Fentani-citra~ Fentanitoo citraw: Fcntanyl, S. 1?3....,10n PJ, ~t oi. Stebilily o( fent1nyl, bupiucaine and adrena- acslhcsia wilh fentanyl may result in either prolonged or delayed
citrate de: Fentanylcitrat; Fent•nyl-Otral: fenwtyi ci:ras; Fentan- line sol'Utions for cxlradural infusion. Br J Anocsth 1992; 68: respiratory depression pos1operati"ely.' Consequently, patients
414-17. should continue to be monitored postoperatively until spontane-
ylu cytrynan: Fentanyylisitraatti: McN-JR-4263-49. Plientanyt Cit- 6. Ltt DKT, ~' al, Compatibility of fmtanyl ci1r1tc, kctaminc h,._ ous breathing has hccn re-established. Severe respiratoiy depres·
rate; R-4263. N·( l-Phenethyl-4-~proponanil1de dihy- drochloride, ond dropcridot in O.~~ s.odimn chlotidt inject~ s10n ma 14-month-old child after intravenous sedation with fen-
ct-ogen citrate. ~;';~~;~~~yvinyl chloride bags. Am J H.a/1h-.~1., Phorm 200S; ianyl and midazolam has also highlighted the necessity for
<Dctrr•...,,. L.l>lrpaT careful moniroring when giving with other respiratoiy depres·
C 11H 21 N,O.C6 Hs0 7 =S28.6. De pende nce and W ithdra wal sants. 2 If present at the end of operation respiratory depression
may be reversed by an opioid antagonist such as naluxone; alter-
CAS - 990-73-8.
UNll - MUN5LYGi6H. As for Opioid Analgesics, p. I05. natively. a respiratOI)' •timulant such as doxapram that doo:s nOI
Pharmacopoeias. Jn Chin., Eur. (sec p.vii),Jpn. and US. Fentanyl and illicitly manufacrured analogues are sub- reverse anal1!"5ia has been given.
Ph. Eur. 6.8 (fen1Anfl Citrate). Whire Of al~! white powder. ject to abuse (see under Precautions. below). !Ugidity of the respiratory mu9Clcs (chest wall rigidity) inay oc-
Soluble in water; sparingly soluble in alcohol; freely soluble in cur during fentanyl anacslhcsia. TheelTeclS can be ininimised by
0 Plasma concentrations ':quired to produce satisfacrory seda· using a s low intr•vcnous injection but a neuromuscol3f blocker
methyl alcohol. Protect from light. non "3ve been reponcd to increase!'lcadily in nl'Onotes recei"ino
USP 33 (f'eltanyt Ci1ratc). A white crystollinc powder or white may be required 10 allow artificial ,..,nrilation; rigidity has been
continuous infusions, sugges1ing the development of 1oler01ic: reversed postoperatively by naloxone. Similar muscle rigidity in·
glistening crysials. Sparingly soluble in water; slightly soluble in to the sedating effects of fcnt1n)~. 1
chlorofonn; solubk in incthyl alcohol. Store at a temperature of duced by alfentanil could be anenualcd by pre!Rnllncnt with a
Mo_""!"ei11 disol'rkrs, cJmnc irrirabiliry, and symploms clwac- bcnzodiaz.cpine whereas small doses of neuromuscular blockers
25°, excursions pcnnincd bcl"ctn 15° and 30°. Prolcct fr°'" lenslic of opioid abstinence syndl'Ome have been rcponed in chi I·
light. appeared to be ineffective.I
drcn afterwitbdr.lwal ofp<olonged fentanyl infusions.:J Similar- Coughing has been associated' wilh intra\-enous fenranyl; inci·
ly, withdrawal symptoms ond, in one case. myoclonus have dencc was decreased with a longer injt<:lion time.' in lighl ciga·
Fe ntanyl Hydrochloride ~ t:NNM) ® occurred in adults when rcn1anyl transdennal patches have been rcne smokers,M and in older patients.• For the use ofbcclometa-
Fen;anyl, C'.hlom)'drate de: Fentanyli H)'drochloriclJm: Hidro- stopped.•..! Acute opioid withdrnwal syndrome has also been sonc and lidocaine to prevent rouglt associated with intravenous
doruro de fenan.lo. Sctn in c:anccr poticnts switched from modirlCd-r.Jcase oral mor- fentanyl in 1nacsthcsia, see p. l 656 and p.2014, respectively.
phine to transdennal fcntanyl despite adequate aoalgcsia being
OleHTaHW\a r"APO""°P"'A ina.intained.6 Tbe risk ofrespiralory depression associated with epidural dose$
CnH 28N 20.HCI = 372.9. I. Arnold J~-f. et ol. Ch1nges iA the pharmacodynvmic u.·$pon.e 10
of fcntanyl, a highly lipid-soluble opioid, hos been considered
CAS - 1443-54-5. fcntanyl 1n 1lCOR3tcs during continuous infusioo. J P~<fl01r J991; relatively sm11ll and only slight ventilatory depression was noted'
UNll - 59Hl56XY46. 119: 639-43. after a dose of 50 microsram,s. However. profound clclaycd n:s·
Incompatibility. Fcnlanyl cilrlle is inconipalible with thi~­
2. Lane JC. Cl <JI. Movcmt'nt dlsorder aftn withdraw·a1 or f~nianvt piratory depression hu been rqio11cd in 2 women 100 minules'
infU$ion.J Pedialr 1991; tit: 649-SI. • and 80 minutes,• respectively after fontanyl 100 microg111ms had
til sodium and methohexitJI sodium. ), Oomin,guez. KD. e1 oL Opioid -...·i1hdrawal in critically ill nc· hcen given epidutally for caesarean seel.ion. No ad\-cr$C effects
A thick while precipitate formed in the intravenous tubing when onults. AnnPhorm«Other 2003 37: 473-1. on ncona1al respiration or ncurobehaviour were detected in a
fentanyl ci1rate wid1 dropcridol was gi"cn shonly ofter nafcillin 4, lian PKJ. ~t oL Myoclonus secondary to withdta.lvil from
transdc::nnal fcnta-nyl: t3.SC rt:PQrt 11nd lileraturc review. J Pain study 10 of neonates of mo1hers given q>it.lural infusion.' of bupi·
Sodium. There was no prceipitatc when fontanyl citrate alone s,...
1p10"' Monot.• 2002; 23: 66-72. "acaine and fcnianyl during labour. However, a later repon 11 de-
was mixed wilh nafcillin sodiwn.1 S. bhih1r1 C. tt ol. WilhdrawaJ symplom aOcr d1JCominua1ion of scribed 2 neonates who developed respiratory depression ancr
Fenunyl citrate underwent rapid and cxte~ivc loss when ad· transdcnn~I rcntanyl at a daily dost' of 0.6 mi. Plwrm World Sci their mothers were given epidural fcntanyl during labour; the ef-
mixed wirb fluorour.icil in PVC containctS.' Tbe lo5s wa$ due to 200S: 27: 13- IS. fect was reversed by intram1L«:t1lar naloxonc 400 micrograms.
sorptioo offentanyl to lhe PVC as a result oflhe alkaline pM of 6. Anon~ous. Opi:ih: wt1hdra•11I "'ith ll":ll"ISdc:rmal (cnt;i.nyl.
Pl>0rm J 199S; 255: 680. The authors noled that the doses of fentanyl used were higher
the admixture, and presumably could occur froni admixrure of ~"'n those in the previous study.
fenl>nyl citrate wilh any sufficicnrly alluiline drug. Respir•tory depression is also a risk with 1opica//yapplied fcnm-
See alJO Stabi lity, below.
Adverse Effects and Treatment
nyl preparations. Severe hypovcntilation with some fatalities has
I. JeghJm EL, et ol. Nafcillin sodium incomsx11ibilily v.-ith acidic As for Opioid Analgesics in general, p. I06. occurred in patients given fcntanyl ••a trnnsdmnal patch for mi·
solurions. Am J Ho.•pP/tan# 1981; 38: 461, 464. Respiratory depression, which occurs especially with nor painful conditions. 11 More recently, Beallh Canada had re-
2. Xu QA, tt ol. RipH:l 1oss of fcnta11yl citnHe odmi.xcd wilh nuor· ceived 2 rcpons of fatal respiratory depression associated with
ouratil in polyvinyl chloride conu1iner~. Ann Phormacotht:.r high doses of fentanyl, responds to naloxone (see also
1997; 31: 297- 302. Effects on the Respiratory System, below). Atropine 1hc use oftransdennal fcnta,nyl patches in 1dolescents for rela-
tively minor conditions (cluonic headache and throat pain):ll in
Stability. In a 48-hoor study fentanyl citrate in glucose 5% or may be used to block thcvagal effect~ offentanyl such bolh ~ the respiratory depression developed within 24 hows
sodium chloride 0.9".4 was stable when stored at room tcmpcra- as bradyeardia. Unlike morphine, fentanyl is reported of applying the lirst and only patch. Set also AdminiSlration,
tun: under usual light conditions in glass or PVC containc!l;1the not to cause significant histamine release. Transient Transdennal Route, under Pn:cautions below.
concenntion of fcnlllnyl delivered by a patienHontrolled sys- hypotension may follow intravenous dosage. Muscle I. Bennett MRD, Adams AP. Pos1opcM1tive respiratorycnmplic•-
tem was relatively consiant tlvoughou1 a 31>-hour study period. tions of opiates. Clln An«tlhuto/ 1983; 1: 41-56.
Femanyl citrate injcc1ion diluted to 20 micrograms/mL with so- rigidity can occur and may require neuromuscular 2. Yastcr M, 1:1 ol. Midnol0lrn•fcn1anyl intravenous scd:aition in
dium chloride 0.9"1. was stable fOf 30 days at 3° or 23° in PVC blockers. :~~~~~n: case rtport of tesplratory an-es1. Pctliotrics 1990; 86:
reservoirs for ponable infusion pu1nps.' In another studyl fenta- Local rcactions.$uch as rash, erythema, and itching
nyl ciliate diluted to SO micrograms/ml with sodium chloride 3. Sanford TJ. ~'al. Prctrcatmc:nl whh scda1ivc-hypa01ic$, but not
have been reported with transdennul use. Gum bleed- with nondcpol•rh.ing muscle relnxa.1'1\S.. tllcnuatcs alfentaniJ.in~
0.9% remained slab]< fOf 11 lcas1 14 days when stored at room dueed musd~ rigid icy. J Clin Anes'h. 1994, 6: 473..SO.
temperature in PVC resc,rvoi!l for ponable patient-<0ntrolled ing and irritation, and taste perversion have been re- 4. T~u~ WA, 0.kin 0. £>plosive courhinJ ofter bolus fcnlanyl
sysrems. ported with transmucosal use. Intranasal use may cause mJccOon. Auath Anolg 2001: 92: 1-'42-3.

All cross-rcfercnus refer to entries in Volume A

 Fent.any! 59
~-Lir. J-A. ,., a!. Prol"o•"<'CI 1njc<"lion lime ~nd ligb1 s.moL.ma de· adviS1.'> thac used patch<!< should be fold<d linnly in half, adhe- Breast feeding. The Amcric•n Ac>demy of Pedfotrics1states
c.:rca-S4." tl1c i11cidcncc ;,>( (~nUJnyl-indm:i:d ~ough. A11t'.,tl1 A1tt1lg sive? side inwards lO conceal the re least membrane-. and disposed that 1here ha"e ~ no repoits of any clinical elf~ in infoncs of
2:>0;: IOI : 670-4.
of safely. breaso-focding mothers given fentanyl, ond that therefore it may
6. Oshim3 T. tt1 ol fdcnlifte011on of ind<'rcndcnt 11~k rac'~ klr
r.:m~nyl-1nJuced ((IU11h. C.>11 J .-lm.·srf, 2006: ~3: 7'3-8. I. Buchom1n ,IF. Urow,, CR. ·Oesipicr drua• ' : n problem in cliriica1 be considered 10 be usually compatible with brcut feeding. Tite
7. Mori.wt P. ,., ul. Vcntil:::lory ~Po"\C \0 c31~11 d ioxide durins IO"<ICOloUY· Mc•c1 Tu:rll:ol1988: 3 : 1·17. BNF 59 olso considers thal the amount of' !Cntanyl disiribtJCed
<'"<trad1.trnl :rna<'Slhcsi" \\·ilh hsnou1nf' ond (cn1anyl. 9,. J 2. WHO. WHfl r:1tptn oommilliec on dnis depc:nd~ncie: lv.'f'nty- into breast milk is too small to be h~nnful to a breast-fed inf.lnl
"'"'m• t989: 6.•: 97-t02. (ounh rcpon. ll'HO Ttth R<'J) Sw 761 1988.
3. WHO_ WHO c-"p.::11 conuniucc N «us dependence: 1w.::nty-
However. licensed product tnfonnation states that. since: fentan}I
~- ~~!:i1:.!~)~:j;~·J~~,~~:,•Jt ~~~ft~~ion aflcr <'X- s1<1h n:pon. H'HO T-.h RupS<r J87 t989.
is distributed into breast mclk, it $hould be avoided in nuning
mo~rs because of the possrbilily of sedation or rcspiraiory de-
'). <ifprcssinn a rt('T C~lr3dural ftnlanyl. Br J
W~r"J;. CY. Rcspi.talOl}' -1. ScRN. AJL. «I al. lllicil l'Cntanrl in Ei.Kope. LA11e,, 1996: 347:
Anti t!Slh 1992; 69: 5.C4. t334-5-. pression in breast-fed infants.
10. Porter J. "' "'· Effect of tpidural f<ntanyl cm nconalll rc.spm1- S. Rc:~vc-s MO. GimlC-rCJ . Fatol intra\'enous misuse orvouudtrm31 A studf usini: fentanyl 100 tnicrograrns intravenously for in-
1ion. Amt~thcsiol~· 199S: 19~ 79-S). fc-ntan)"I. Al...'11J Aus1 ~002~ 177: 552- 3. duction ofanaesthesia in 5 mochers concluded that the amount of
ti. Kt•mvr M, Paes B. Epidural opioid ana ls~sia and nronat:il f'H- 6. Tharp .\M. ~I al F"1tal lnll'3'\.'Cnous fenU.n)'I abvse~ four CAS<S fentanyl oxcretcd into breast milk within 24 hours of induction
piratory dcprc.ssion. J P~rlnatol 2003: 23: 425-7. im«'llvins ex1rac:1Kwt of ftnlanyl frnn1 1r::in$dcna11 1>3\C'hes.Am J was less titan 0. l'Y. of tlie matcmal dose, and hence unlikely to
12. FDC Rfpm·rs Pinl· Sh,el 1994: Janu:lr) 24: 12. Fol'<!nJi<' Mtd Pathol ~004: lS: t 18-S I.
affect a healthy full-tttm breost-fecdi11g infant
13_ ~~!!~hi~=~:Sc!~~~~~~~"'':,~~~~~~~~c1~0~~P~r;'«i: Administration. INTllAYENOus ROUTE. Fentanyl is much I. AnH:rican Academy of Pt<lb.ltic:s. 'Ou: trnns(cr of drugs and oth-
1-2. Also a ... ailable :n; hup:/fwv.·w.hc·sc .£-c.ca/dhp-mps/ more lipid-soluble than morphine and aner standard single in- er ehcmicaht into homan Milk Pt"1Ju1rit?.· 2001: IOI: 716-89.
ah_f<N'TOOtslhplb-dgps.:i./p<I f/mcdcfT/c:irn-bcci_ \. ( 4n4-~ng .pd r travenous doses has a rapid onset and short duration of action rRctircd May 2010} Corm:tK>n. lb/ct: t029. A l:i.u O\.aiLlbk 11:
toc«U<d ?6/06.'llSI . However. fentanyl is rapidly redisuibuted in t11e body and its h up:// a:a ppoli c: y. ooppubl ica ti ons.o rg/cg i/co nt ~ralfu 11/
half-life (see under Pharntacokine1ics, below) is longer lhan p<diotrics%3bl08131776 (ac<CSS<d 2MJ6i0Sl
Effects on the skin. A patieni develop«! amacular rash cover-
2. Nitsut1 M. "' ul. Ph11nn1cokinchcs of 11\idnol:un. proporol. and
ing che whole body. except for the face arid scalp, while using that of morphine. Hence, with high nr repeated doses, fenta- fen1a.nyl tran.~ fct l(\ human breast rnilk. Clln Phormocol TM,-
transdennal fentanyl patches.' nyl becomes a relatively long-acting diug; to avoid accumu- 2006; 79: 5-49-.~7
t. Stoultidc-s CA. Stepan M. Oiffuse ruh associated with lation patients ~hould be monitored and doses adjusted ac-
1ran$Clcr1nal (cncanyt. Clin PJ;cnu 1992: 11: l22. cordingly. Children. TI1e BNFC 10/0/// states thll the ltalf:Jife of fen13-
nyl is prolonged in neonates and accumulation is likely with pro-
Effecu on che urinary tr.let. Urinary retention Je...,loped in Repeated i11tra-qicrative doses of fe1t1a11yl should oo given with longed use; muscle rigidity may occll' and the use of muscle re-
2 ptcm~rure infants after sedation "'ith fentanyl infusion ata d - care, since nnt only may the rcspiralory depression persist into laxams may be required. Sec also under Pharmacokinctics,
of 3 mierogr.nn~g per hour.1 In both cases cathe'terisation re- the postoperative period but it may become apparent for the firsl below.
liC\O:d syrnpmms. time postoperatively when the patient is away from immediate
nursing atte111ion. Exercise. Opioid tO.'<ieit)· rcquil'ing naloxonc tn:atment oc-
1, Du UG. $.uidharan P. Bfa ddtr ttknt.ion o( urine :is .i. result o(
cnntinuou~ inlravc n()u~ 1n(u!tinn of f<'nt:anyl: 2 c:asc rt:poris. curred in a p;itienl who"°"' a fentanyl patch while engagins in
TftANSOERMAl ROUT4. fatalities have been associated with the
J'ediotri<> !001: 108: t012- t0t S. vigorous outdoor exercise.1 Physicia1is should be aware that
use or stindard fenta11yl transdennal patches (sec Effects on along with fever and ext•mal heat soun:es, physical nc1ivity may
the Respinitory System, above). lncorrecl or inappropriate cause inetcascd absoJ')ltion of lransdernlal fentanyl.
Precautions use resulting in serious adverse effects and fatalities had
I. C111rr KA. Heitt .. as~oci.i!:lcd 1ncr"se "'~Mckm1:1I fen1anyl ;ib-
As for Opioid Analgesics in general, p.107. prompted regulatory authorities to issue warnings and rccom· 14.vpi1on. AmJ Ht'Ultll•S,1~·1Phttt'ln100) : 6(1; 191-2.
mendations for changes lo product labelling; in particular
Caution is advised in patients with myasthenia gravis; transdcnn•I fenumyl patches are nol appropriate for the treat- Handling. Avoid contact with skin and tho inhalation of fcnta-
!he effects of muscular rigidity on respiration may be ment of acute or postoperative pain . Nonetheless, reports of nyl citrate particles.
panicularly pronounced in these patients. fatalities Md life-thrcatenin& adverse reactions have contin-
US licensed product infonnatioo contra-indicates the ued to be received'_, and, in txcembcr 2007, the FDA 1 reit- Interactions
erated that: For interactions associated with opioid analgesics, see
use of standard transdennal fentanyl patches in opioid- • f•ntanyl p:uches are indicated for the management of pcrsist-
naive patients because of the risk of fatal respiratory p.107. Use offentanyl with non-vagolytic neuromus-
cn~ modcrote to severe chronic pain in opioicl-lolenuu patients
depression (sec Effects on the Respiratory System, cular blockers may produce bradycardia and possibly
• li<:enscd product in!Onnation must be consulu:d when deter-
above and Administration, Transdcnnal Route, be- mining the initial dose as o"erestimating when converting pa- asyslole.
low). Similar conrra-indications apply to transmucosal tients from allC)(hcr opioid analgesic can result in fatal over- Fentanyl is metabolised via the cytochrome P450
formulations of fentanyl (see also Administration, dose "ith the fir.;t dose isoenzyme CYP3A4; use with potent inhibitors of this
Transmucosal Route, be.low). The use offentanyl intra- • use with any inhibilofS of the cytochrN11C P450 isoenzymc isoenzyme, such as ritonavir and other HlV-protease
CYP3A4 may result in an increase in plasma-fenL,nyl con· inhibitors, may increase !Cntanyl plasma concentra-
nasal spray is contra-indicated in opioid-naive palients, c~ntrotions, which may cause potentially fatal respim!Of)' de-
and in !hose with previous facial radiotherapy or rc<:ur- pression; patients who ere raking CYP3A4 inhibitO<S and us- tions.
rcnt episodes of epislaxis. ing fcntanyl pa1ehcs for an e:<tcridcd period of time should be Antidepressants. For reference to a possible~ of serotonin
Absorption of fentanyl from standard transdennal monit<'rcd and the dose offtn1anyl adjusted if necessary syndrome associated wt th ust of fcntanyl and SSR/s,..., Opioid
I. FDA. lnfonmttion IOr healthcare professionals: fcnti.nyl Analgesics under lnternc!ions ofFluoxetine, p.428.
patches may be increased as the temperature rises and tntnsdCfmal lY51CITI (inarkeled U DuraitSIC Ind aencric$) (is·
patients should therefore avoid exposing the patch to Sufd ~Ill Deccmb-:r, 2007). Antivin>lt. Ritonnvir, an inhibitor of the cytochrome P4SO
c.>xtemal heat; similarly. pa1ie111s with fever may require Av11lablt at: hllp://www.fd3. gov/Druas!l>ru:::S afctyt 1soeriZ)·me CYP3A4, might prolons fent•n}l-induced respirato-
Pos1 1n:i.rl..:1Dru~Safrtyfnfurm1uion(orl'atientsandPro\'idcrsr ry depression. The plasma clear111CC of fen~nyl was dec""'sed. •
monitoring because of increased absorption. It may 11<1110$4307 (an:CSS<d 021081 I0) 01>d the elimination half-life ~nd area undef the plai.1110 concen-
take 17 hours or longer for plnsma concentrations of 2. 11..:!lhh C.-nada.. Fentan) I tt:tnsdc1·,n~I pa1ch :and (:.bl ach•tt$C re·
:ictil'\11s. Cun Athv!r~ H"-o N,w• ::wo~; t8 (3): t-2. Also 11\·•ili- cratiou..t.imtcurvt incrc.ascd. when gi'-m with ritona,·ir in n study
fentany l to decrease by 50% after removal of a blc oc: ht1p://wwwtJC-SC.f<.caldhp-ntp"alc_forn»ts1hpfb..dl!)W in healthy sul!jccts. 1
trnnsdennal patch; patients who have had adverse ef- pdt::mi:dt:fltcam-bcc:i_v 18A3-cn;;.pdf (3cccsscd l)./07/0S) I. 01kkola KT. C'f al. Ritonavir's role in reducing fcntanyl dt11nocc
fects should be monitored for up to 24 hours and those 3. MHR.! \/CI IM. F<.ntttnyl p1tchcs: $oetious :ind fatol overcklK ft0m and proton1in1 llJ halr lifc .•foes1heJio/og•· l999; ' l : 681 - 5.
0

dosin2 crrots, :iccidcnt:il cxposutt-. and i11appropdo.tc use. Dr'¢

requiring replacement opioid therapy should initially Sufery Updar. 2008: l tlJ: 2-3. Available at: Benzodiuepines. For the elfocts of opioids such :IS fcotanyl
receive low doses increa~ed gradually thereafter. Sim- h11p·/lwww, m hra. gov u k/Publica1 ions/SI (c tyg u idancc/ with benzodiazcpines. see An:tlgesics under lntcmctions of Di-
OmgSar.1yUpd>1c.'CON02$6; t (accused 03/t J/(19) IZl!P301, p. I093 ond EITtcts oo the Respiratory System. obo\'C.
ilar advice has also been given for patients receiving 4. Hc1l1h <.::a:n-ad:a. Ftmanyl tr.msdttrnal p~uchf't tnd accidental
fentanyl via an iontophorctic drug delivery system; the ch1kl c~posur.:. Om Acfr~ru Rt'«I N.-ws 2009; 19 (3): 3. Propof'ol. For reference to the effect !hat fcntonyl has on blood
Also anibblie tl: hnp:J/''''"""·hc:·sc.gc.c:aldhp-mp$1alt_form:stsl collccntr.uions of propofol. see p.1949.
mean half-life offentanyl in this system is 11 hours. h ptb...d~ps:Updllmede(f/ca m ·bc<'i_vi 9n3-..cn~ .pdr (:l('CCstC'd
The bioavailability of different transmucosal fentanyl 03111:'09)
Pharmacokinetks
preparations is not equivalent and consequently they T•~NsMucosAL «OUT£. The FDA' has received reports of 5C· After parenteral doses fcntanyl cirratc has a rapid onset
should not be substituted on a dose-per-dose basis. rious adverse effects, including fatalities, in ~rients who
have taken the fentanyl buceal 1able1s, Fentoro (Cephalon.
and short duration of ac1ion: After transmucosal deliv-
Abuse. Severo I synthetic analogues of fcnlanyl, so-called "de- USA). 1~sulti111: from inappropriate use in 11atients who were ery, up to 50% of the dose is rapidly absorbed from the
signer drugs', have "'-"en manufactured ilhciily for recreational not opioid tolerant, misunderstanding of dosing instructions.. buccal mucosa; the remainder is swallowed and slowly
use. panicularly in the USA. They are highly potclll. and respira. or inappro~riate substitution for other fi:ntanyl-containing absorbed from the gastroimestinal troct. Some first-
tory depression ond death may occur '<>'Y rapidly. 1 The ' fcnta- fonnulations. The FDA rei1erated that Fmtoro:
nyls" ha\c been smoked or sno11cd os well as inj«lcd intrave-
pa'>S metabolism occurs via this route. The absolute bi-
• should only be us.!d for breakthrough pain in opioid-tolerant oavailability oftransmucosal delivery is 2bout hal f that
nously. cancer p:itienls
Fentanyl analoSU<S iJontilicd by WHOu as being subject to for inuavenous fentanyl but varies between fonnula-
• should not be used in those who only need an opioid on on
street obuse or likely 10 be abused mclude: <t·m<'lhylfenuonyl (al- inte:nnittent~ or as ~uired, h3s is and who arc not on aroond~ tions. The absolute bioavailability of inuanasal deliv-
so kno"11 as 'Otina whne· 0< 'synthetic heroin·), 3-nicth)ICenl._ ohe-clock orno1ds ery is about 89% and fentanyl is absorbed very mpidly
nyl, acetyl-a·mcthylfentanyl. u-methylthiofemanyl. p-OUO<ofen- through the nasal mucosa. Absorption is slow after
tanyl, P-hydroxyfentanyl, 11-hydroxy-3 -methyl fcntanyl, • should J\Ql be used fO< 1he manogemenl of acute O< postopcra-
thiofontanyl, anJ 3-mcthylthiofentanyl. ··
ti\'C pain including headaches, migraines, and pain due to in- transdennal application. Fentanyl is metabolised in the
jury liver by N-dealkylation and·hydroxylation via !he cyto-
Fentanyl itself is also subject to illicit use. ll is chemic•llY UtlrC-
• should not be directly subsliruted for other fcntanyl-cootain- chrome P450 isoenzyme CY P3A4. Metabolites and
lated to m0tphine and does !IOI reacl in screening tests for mor-
ins fonnulation.< some unchanQed dntg arc excreted mainly in the urine.
phinc-ttlole:d opioids. ll has thcn:rorc been R<C01nmended4 that
fentan)•I$hould be tc:sted for spc<ilically in QSeS with suspected Sin1ilar restrictions a1-e also mentioned in 1hc licensed produa The short du;:ation of action is probably due to rapid
opioid misuse. infonna1ion for other iran!muCOSll prcpar:ttiOtis of fcntanyl.
I, FOA. lnCorm;acion for hc~ hhcare profh!ionals: fcn1a11yl buccal
redistribution into the tissues rather lhan metabolism
Used ICntanyl tr:msdenno l systems may contain significant and excretion. The relatively longer el imination half-
tt1bkts (monkc1¢d as Fcn1on1) (1s:suc-d 16th September, 2007).
amounts of fentanyl and hav" been subject to abuse. In some cas-
es clic contcncs of the P3tchos have been injected intravenously:
A \'ai l:.iblc u : hup :/lwww.fd:),g0\ /0rug1i Oru1Safcly/
0
life reflecl~ slower release from tissue depots. About
ros1ma1kttDruaSaftlylnfonn<1tionfotP:tticntundP1ovidtrs/
<uch abuse has resulted in do:llh."" Licensed product information 11cm I 2f)0$2 (a~ 0"-108!10) 80% has been reported to be bound to plasma proteins.
The symbol ® denotes a substance whose use may be restricted in ~enain sports (see p.vii)
60 Analgesics Anti-inflammatory Drugs and Antipyretics
Fentanyl appears in the CSI'. It crosses the placenta and Cardiopulmon ary bypass. ln general, studies•.? indic:iJe that lt is more lipid soluble than 'morphine and after an in-
has been detected in breast milk. scrum concentrations of fentanyl during cardiopulmonruy by· travenous injection of 100 micrograms the effects of
pass decrease initially and then remain slable. The fall in concen·
0 Marked differences in resuhs of pharmacokinetic studies of trations has been attributed to haemodilutioo although adsorption fentanyl begin almost immediately, although maxi-
fentanyl ha\'e been atU'ibuted 1 to differences in assay methods. to the bypass apparatus has also been found. mum analgesia and respiratory dep~ion may not oc-
The need for sensitive assay methods has been emphasised be- J. Suylocn WA. ct of. Cardiopulmonary bypass and the phnm•· cur for several minutes; the duration of action of fenta-
cause the potency of fentanyl means that small doses are used. eokinc.tics of dNp: a.n update. CHn PhannacoAi,,et 1989~ 17: nyl depends on the dose and die intensity of the pain
Howcvet, there are differences in phamlacokinctics between bo- 1()...26.
lus doses and prolongccfinfusion with highly lipopbilic drugs l . Gedney JA, Ghosh S. Phannacotdnet:cs of aftllgcsies, sedatives involved, and may vary from JO minutes to several
such as fentanyl.? Tenninal half-lives ranging from 210 7 hows ind anatsthctic a,cnts durina, cardioputmona.ry bypau. Br J hours.
Anamh 199S: 75: 3'4-SI.
have been reported in healthy subjects and surgical patients. For premed ica tion <he equivalent of 50 to
However, the duration ofaciion offentanyl after a single intrave- Children. The disposition of intnvcnous fcntanyl 10 to I 00 micrograms of fentanyl may be given incram11sc11-
nousdoscofup IO 100 micrognms maybe only 30to60minutes SO micrognunslkg in 14 neona~ undergoing various major sur-
as a resuk of rapid redistribution into the tissues. US licensed gical procedures was highly variable.' The mean elimination /orly 30 to 60 minutes before the induction of anaesthe-
product information has gi'lll:ll "alucs for a three-compartment holf·hfe of 317 minutes and other pharmocokineric panimctcts sia.
phannacokinetic model with a distribution time of I.7 minutes, a including \'Olume of distribution and total body cle31"ancc were As an adjunct to general anaesthesia, fcntanyl is usu-
redistribution time of 13 minutes, and a terminal elimination greater than reported in adults, but both pharmocodyn11111ic and ally given by in11-aveno11s injection. Dosage recom-
half-life of219 minutes. Gi"ing repeated or large doses, or con· phannncokinc!ic rncx:banisms appeared responsible for the very
tinuous infusions. may result in accumulMion and a more pro- prolonged rcspinuory depression that can occur in nconntcs after mendations show a wide range depending on the tech-
longed action. fcntanyl anaesthesia. Jn 9 premature neonates gh'Cn fentanyl nique.
The clinical significance of secondary peak plasma-fentanyl 30 micrograms/kg intravenously for induction of anaesthesia~ • Patients with spontaneous respiration may be given
conccnHations and the possible role of entero-systemic the elimination half-life ranged from 6 to 32 hours, but cautious SO to 200 micrograms as an initial dose with supple-
rccirculation3 has been conD"Ovcrsial, but some' considered that interpretation was advised because of the method of calculation.
irregular decay curves were not unlikely for lipophilic com- or m
l . Koehntop O!, «( " '· Pharmacokinc1ics fcplanyJ nCOf'lttCJ. ments of 50 micrograms. In the USA it is recom-
pounds such as fentanyl, cspccially in patien1S undezgoing oper- Ann•h Anolg 1986; 6~: 227-32. mended that doses above 2 micrograms/kg be ac-
ations and subject IO luge changes in blood Row. Unc.-.pcctedly 1. Collins C. ~t ol. FcncanyJ phannacokinetits and h.emoctyn1mic companied by assisted ventilation. Significant
high plasma-fcntanyl concentrations U1 a patient following epi- effects in preltnn infants during ligation of pattnl duclus 2rtcri-
osus. Anuth Anof1198S; 64: 1078-llO. respiratory depression follows doses of more than
dutal use were thought to be a result of aortic clamping and might
re.Rcct lbe effect of changes in blood flow.' The elderly. In one ~ludy the climinalion half-life of intrave- 200 micrograms
Tbe main mctabolitcS of fcntanyl, wbich arc excreted in the nous fcntanyl 1n~-n:ucd from 265 minutes in patients with a • Patients whose ventilation is assisted may be given
urine, have been identified as 4-N-{N-propionylanilino) pipcrid· mean •ae of36 ycan lo 945 minulcs in lhost "'ith a mean•&• of 300 micrograms to 3.5 mg (up to SO micrograms/kg)
inc and 4-N-(N-hydroxypropionylanilino) pipcridine; 1-(2- 67 ycars. 1 The authors of another study were critical or lhc rcla· as an initial dose, with supplements of I00 to
phcncihyl)-4-N-{N-hydroxypropionylanilino) piperidine is a mi- tively sh0<1 sampling time used and in conrrast found that major
fentanyl phannacokinctic parameters did not com late with age.2 200 micrograms depending on the patient's re-
nor metabolite.• Fentanyl has no active or toxic metaboliles.'
I. Mather LE.. Clinital pharm1cokincliC:S of fcntanyl and its rM:wer However, elderly patients had increased brain sensitivity to intra· sponse. High doses have been reported to moderate
derivatives. Clin Phormocol:fnet 1983: 8: 422-46. venous fentanyl, as ~hown by EEG chang~ and lower doses or attenuate the response to surgical stress (see An-
2. Scholz J, et al. Clinical pharmacokinctic! of alfentanil, fentanyl might be indicated in older patients for phannacody03mic ra1hcr aesthesia, below)
and Suf en1anil: ao upd11c. Clfo Ph,Jrmocoltinet 1996; 31 : than phannacokinelic reasons. -
275-92. I. Bentley JS, ~t ol. Age and feotanyl pharmaiookinetics. Anuth Fcntanyl may also be given by intravenous infusion. in
3. Benncn MRD, Adums AP. J>ostopcr:uive respiratory cornplica· Ano/11982: 61: 968-71. ventilated patients a loading dose of about
tions of opiitcs. Cli11 Alt()tsth#1io/ 1983~ I: 41-S6. 2. Scott JC, Stenski OR. Oec.-..sed fcn11nyl and alfcn,.nil dooc: re·
4. Moore RA~ et ol. Opiate me11bolism and excre:tion. Bolllieres quiremenlS with age: 1 simu.ltancous pha.rm11cokinc1ic and phar..
I microgram/kg per minute is given for the first I0
CJfo Anoes11>u;o/ I987: I : 829-58. minutes followe'd by an infusion of about
mac.odynamic cvtlu.31ion. J Pho.rmocol Exp Th~r S987j 240:
S. 8ullingham RES," ol. U""xp•<1cdly hiih plumo fm1anyl kv- ISll-66.
clsafttt cpidUl'al ..,.. l.oM<t 19&0: I: 1161-2. 100 nanograms/kg per minute; alternatively, the load-
6. Goromaru T. et ol. fden1ifa1ion and quarnilltive dccmnination Hepadc Impairment. The phannacokinetics offentanyl were ing dose may be given as a bolus. The infusion rate
offcnlanyl mmbolilc:s in p.atitntl by g.u dlt0matography-ma.ss DOI affected sianilicantly in surgical patients with cinhosis of the
spcctrom<Uy. Anathalolorr t98~ : 61: 73-7.
should be titrated according to response and rates of up
livcr. 1 A 1987 revicw2 considcnd that fentanyl Md DOI been as- to 3 micrograms/kg per minute have been used in car-
Administration. Some references to the plwmacokinetics of sociated with clinical problems when given IO paticnis with liver
fentanyl after constant rate intravenous infusion,1 tmlSdcrrnal dysfunction. diac surgery. Infusions should be stopped about 40
application,,.. use of the 0tal ~ublingual6 and transmucosal" 11 1. H:abttet JP, tt ol. Fe:rv:anyl phannac.okinecies in an1e:s1he1tzcd pa· minutes before the end of surgery unless artificial ven-
routes, inO'anasal dosage, •:Lil subcutaneous infusion." and epi- ticnts with cirrhosis. Br J htocs1h 1982: 54: 1267-70. tilation is to be continued postoper.nively. In patients
dural use. 1 "" 17 2. Moore RA, tt ol Opiate metabolism and excretion. Bolllfetu
with spontaneous respiration, tower infusion rates of
I. Ou1hie OJR, et al. Phum1cokineiic1 or rentanyl durin& coiutant Clin Ano<Stltt.1/011987; I: 829-58.
r.ue iv infusion ror the rcJie(of pain after surgery. BrJ Anatsth SO to 80 nanograms/kg per minute arc used.
1986; 58: 950-6. Renal impairment. Clearance offentanyl from plasma was re-
2. Grond S, 11 ol. Clinical ph~rm:1C.:okinc1ics of tninsdcml31opio- ported to be enhanced in surgic:il palients with cnd·stage renal Reduced doses are used in the elderly or debi litated pa-
ids: focus on transdermal fcn\anyl. Clin PhormacoH11e1 2000; disease,' altl1ough clearance was rcdu~ and elimination half- tients.
38: ~9-89. life increased in patients with renal failure undergoing transplan- Similar doses to those used for prcmedication may also
3. So1assol I, ~I al Inter- and intr1lndiv1d1111I variabili1ies in ph<!r- tation,2 possibly because of the inRucnccofuracmia on metabo·
mac.okinetics offcn11nyJ 1Rcr rcpe:11cd 72--hour LransdcnnaJ ap·
Iism in the liver. Ncva1hcless, a 1987 rcvi°"'2 noted toot fcntanyl be given by intramuscular injection postoperatively,
plictnions in cancer poin JXUicnll. 71'cr Dn1g Moni1 JOOS; 27:
491-8. bad no aeti\-e or toxic metabolites and had nOI been associaled and by intram11Scular or slow intraveno1JS injecfion as
~' of.. Ph1nnac:okinctk1. l~le~bHily. and pcrfornl-
4. Marier J.. f. with clinical problems when given to paricnts ,v;th renal d)'S· an adjunct to regional anaesthesia.
ance of# novd matrix t.nnsdCN'Nll dch\"Cry $)'$1cm of fentanyl function.
rclatiw 10 the commercially 1vailablt f'C$Cf'VOir formulation in For the treatment ofintractable chronic pain in adults
hcal!hy subjects.JC/I• PllonolXXJI 2006: 4G: 642-53. J. Con II JM, tJ ol. Plasma concentrations of fmUn)1 in normal
s:urs1C11I pedcnts and lhosc' v..iLh scvc" renal ind hf:Pllic disuse. when opioid analgesia is indicated rransdermal patch-
S. M:irin J-F, ~t al. Compenti\.t btotquivtlcn<:e str.ldy bc.1ween a
BrJAnoath 1910;52: IOIP. es delivering amounts of fentanyl ranging from 12 10
:~c!::•!1fy ~':i~~J:':~~i:7or:!;::rc,:.rl:J~J! P~'!r~ 2 Moore RA. II o/_Opiate metabolism and c-xcretion. BoilliO"ft
I00 micrograms/hour are available. In the UK, fcnta-
mocol 2007; 63: 121-4. C/ln A110t11ht1iol 1981; I: 329-58.
6. Lenncm:is 8. et at. Ph.arm1cokincti« 01nd tolcrabiliry of dirra- nyl patches may be used in strong opioid-naive pa-
cnt doses of fentanyl followina sublingual admini.s1raiion cf a U ses a nd Administration tients; however, in the USA, use is rcslricted to patients
::~~~e~:s:f i~~fd~:. ~, ~~~~~ b~~e~l~~,,~:;~i~~~~
1 1 1
Fentanyl, a phcnylpiperidine derivative, is a potent opi- who are already tolerant to opioid therapy of compara-
249-53. oid analgesic (p.108) chemically related to pethidine ble potency.
7. Streisand JS, et"'· AbSOl'plion and bioa\'ailability of oral lrans-
mucosal rcntanyl citra1e. Auesthcslology 1991; 7S: 22l-9. (p. I I8) and is mainly a µ·opioid agonist • Doses should be individually titrated for each patient
8. Darwish M, et ol, PhGrmawkinc1ics ond dose proportiom1li1y of according to previous opioid usage. Initia l dosages
fentanyl cffcrvtscent buccal tablets in heahhy votuntecrS. cu,, Fentanyl is used as an analgesic, as an adj unct to gen·
Phonnacokinet 200$; 44: 1279-86. eral anaesthetics, and as an anaesthetic for induction should not exceed 25 micrograms/hour in opioid-
9. Darwish M. et al. Comparison of equivalent dO$t~ o( re-ntanyl naive patients; in addition, it is recommended that
buccal tabJcc.sand ancrio\'cnoU.J. differences in fenranyl phanna· and maintenance. It is also used as a respiratory depres-
cukineties. Clin PhontlOCOl/ntt 2006: 45: S.3-50. sant in tl1e management of mechanically ventilated pa- these patients are initially titrated with low doses of
10. Darwish M, ti of. Sinslc-do"' ond >t•ody-st•te pharrnacokinct- short-acting opioids before transfening to fentanyl
ics offentanyl buccal tabl<I in healthy voluntecn. J CJin Phar- tiei1ts under intensive care. When used with an antipsy-
muco/2001; 47: ~. chotic such as droperidol it can induce a state of patches
11 . D:irwi$h M, d ol. AbJOltde ind rel11ive bioa,·ailabilily of fcnta·
nyl bucc::1l 11ble:t and oral t11nsmucosal fcn&anyl citrate. J Clin neuroleptanalgesia in which the patient is calm and in- • Forpatients who have been receiving a strong opioid
Pharmaco/ 2007: 47: 30-SO. different to his surroundings and is able to cooperate analgesic the initial dose of the fentanyl patch
12,, Walter SH, et ol. Pharmacokinc-ttc:s of inlrtnual fcruanyl. Br J
.4nouth 1993; 70 (:!Uptll t): IOI. with the surgeon. should be based on the previous 24-hour opioid re-
13. Foster 0, rt ul. Ph1rmacokinc1ics and pharrnacodynamics of in· Fentanyl is usually given parenterally, intranasally, or quirement. Use of a patch providing 2S micrograms
~~3:::,~~:n~~:;!a:,r:~:a262~~ c1~;:o._v;i.th P2in aOer by 1hc transmucosal route as the citrate, or in transdcr· of fcntanyl per hour is equivalent to about 60 to
14. Miller RS, et al. Plis:rnt concenlrations of femanyl wilh subc~ ­ mal patches as the base. The hydrochloride was avail- 90 mg daily of oral morphine sulfate. During trans-
taneou.s infusK>n in pallialive core p:nicnis. Br J Clin Pharmocof
1995: 40: SS3-6. able as an iontophorctic transdennal delivery prepara- fer to treatment wi th fentanyl patdlCS previous opio-
I5. GourlJy GK, et of. Ph111nnacokint1ics or fcn1anyl in lumbar and tion but this was withdrawn from the market because id analgesic therapy shou Id be phased out gmdually
cervical CSF following lumbar epidural and in1r.t ..·cnous adn1in-
is1ra1ion. Poiu 1989; 38: 253- 9, of a defective delivery sys tem. Fentanyl citrate in order to allow for the gradual increase in plasma-
J6. Bader AM. et al. Maternal and ncona1~I fcntanyl ~nd bupi· 157 micrograms and fen tanyl hydrochloride fentanyl concentrations
vac:aine contcnlrations tflcr epidural infusion during labor. An·
esth Anofg 199S: 81: 829-)2. 11 1 micrograms are each equivalent to about • More th:fn one patch may be applied if doses greater
17. ~o;ses EC, et of. Pharmacokjnclics and 1nn.splaocn1.:.I distribu- JOO micrograms of fenranyl. Doses are expressed in than JOO micrograms/hour a,re required (applied at
tion of fcntanyl in epidural ancs1hui1 ror nonnal pregnant
women. EwrJ ClioPhormocof200S; 61: 517-22. tenns of the base. the same time to avoid confusion); additional or al-
All cross-references refer to entries in Volume A
 Fentanyf 61
ternative analgesic therapy should be considered if An in1ranasal spray fom1ula1ion of fenl3nyl is a"ailablc for 1he 6. Rauc1t R. do.I fcn1.:inyl buccal sotuMc film ~FO.SF) for brcnk·
rrcatmcnt ofb-k1hrough cancer pain. 7 through pain itt ptuients with cancer- a randombcd. double-
doses greater than 300 micrograms/hour are re- blind, pl1cobo-<on1rolled siudy. Ami O"':oJ lOlO: !I: 1308-14.
I. Stri~bclHW. "1 nl. lntnnasal fcntaoyl tilro.1ion ror postoptnnin
quired. Patches should be replaced every 72 hou_rs pnin muna.gc:mtnl in an un.sclcct~d populolion. Anarsthaio 7. Anonymou$. Oral lran~nucos.11 fenUm)·Icurate. Med Ufl Dmg:r
with the new patch being applied to a different site; t993; 48: 7SJ-7. TllCI' t994: 36: 14-5.
2. Stncbcl HW, <'/ al. P:uicn1<0ntr0Htd imr:.muol ~nal~esla: a S AroutifT GM. tot of. E•idcncc·bMCd nral 1ransmucmal fen&:anyt
use of the same area of the skin should be avoided n•tthod fot noni1lvasi"·e postopcnrilvc roin mana):;etm:-111. .•ut'~·Jlr ciuiw: (OTFC) dosin~ ~HJeline1. Ptrl11 Mtd2005; 6: 305-14.
for several days AMlg 1996; 83: 546-S f. Administration in child,..n. lndicatioos for femanyl therapy
l . Toussaint S. d ed. P~1icnt~ootrolkd innnasal ;inalsesia: .:rt«·
• Elderly or debilitated patients should be observed tiveaJterrwiw 10 inlT3\'CnOU$ PCA ror posiOper:itive p:iin relief. in children are similar lo lhose in adults (see Uses and Admm1s-
Cu11 J Anath 2000; 47: 299-302. 1ra1ion, above).
carefully for siJ,'flS of toxicity and the dose reduced if 4. MarJushru R. ~'al. lfltr:inas;al fcn1anyl provides *'equ:110 po51•
necessary Fentan)1 is usually given by inrra>enoitS injec1ion us an odjuoct
operative an.atccsia in pedi,1ric l'<iuen1s. Cnn J A~:tlh 2002; 411: to general anaesthesia. In the UK recommended initial doses
190-3.
Fentanyl patches arc not appropriate for acute or post- S. Borland ML. d al. ln.tran;Qal fentan)'J is 1n cquiv1tcnl an~lgesic range Crum 2 to 3 micrograms/kg in cl1ildren aged 2 to 12 years
operative pain. The bioavailability of different brands 10 oral morphine in pacdiauic bum.s patients for drenini dumg· with spo111oneous respira1ion: supplemenu of I microgram/kg
es: a randomised double bli:td crossover ~l\Jd)'. Bums !OOS: 31: may be 11:iven. ('{heBNFC 20/0111 suggcm initial doses of I to
of fentanyl lransdcm1al patches may not be equivalent 831-7. 3 micrograms/kg for those aaed from I monlh to 12 years.)
and patients should not switch brands without fu1ther 6. Bortaod M. e1 al. A randomized controlled lria.1 comparing inua- When ve11f//01ion is ass1Strd, 1he iniliol recommended dose is
advice. naut feQlnnyl to intravt-noi.rs m«phine (or mal'l;igjng Xlllt rain elso2 10 3 micrograms/kg. with supplemen1s of I nticrognmllcg.
in children in the cmeri:rncy dcpanntent. Ann Emerg Med 2007:
~9: 335-40.
(The BNFC 2010111 suggests an ini tial dose of I 10
A lozenge-on-a-stick dosage form of fentanyl citrate 7. Kress HG 11 ol. Efficacy and tolcr.thtli1y or intranasal fcn111nyl S micrograms/kg for n00l1ates and children up to 12 years ofasc,
for transmucosal delivery is used as an analgesic in the spray 50 10 200 mic.roa fnr brcalnbrougb pain in patients with wilh supplemcnls of I 10 3 microgrnmslkg.) In U1e USA doses
management of breakthrough cancer pain in those uncc:r: a phuc Ill. mullinational. nindomi:ttd. doubJe·blind, are simil3r 10 lbose licensed in lhc UK.
p1acebo<Oatto1Jtd, crossover lri'11 v.ith • 10.montl\, opcn--ltbd
already receiving and tolerant to opioid treatment. Loz- c~tensioA lrt~lmtnl period. Cli11The1·2009; JI: 1177-91.
Children may also be given fenianyl by intravenous infusion: li-
enges co111aining the equivalent of200 micrograms to cen$CCI product infonnation implies that doses are similar to
tNTRASPINAl ROUTE. for a discussion cm the in1rupinal use of those used in adulU (see above).
up to 1.6 mg of fentanyl arc available. An initial unit ft111a11yl. sec Postopera1ivc Pain, below.
1i't111sdam10/ patches deliveiing amounlS of fcntanyl ranging
doseof200 micrograms may be taken over 15 minutes TltAN SOERMAl ROUTL Tnmsdcnnal fcntanyl is used for chron- from 12 lo JOO micrograms/hour may be used for the uca1men1
for an episode of breakthrough pain and repeated once ic in1ractable cancer pain in adults and children.'·' h is also of Intractable chronic pain in children aged 2 )'Cars and older
if necessary after a furtl1er 15 minutes. Doses arc sub- used in the treatment or chrome non-cancer pain ;•J.S howev- who are already tolerant 10 opioid therapy of comparable poten-
sequently titrated according to response, up to a unit er. such use is contra-indicated in the management of acute or cy. The initial dose should be based on lire previous 24-hour opi-
pos1opera1ive pain because the problems of dose tilration in oid requirement. Use of a patch providing 12 micrograms of fcn-
dose of 1.6 mg if necessary. Once the patient has been the short term increase 1he possibility of development of sig- bnyl per hour is equivak:n1 10 about 30 to 44 mg daily of oral
stabilised on an effective dose, no more than4 unit dos- nificant rcspira1ory depression' (sec also EffeclS on 1he Res- morphine sulfate. See Uses and Adminis1mtion, nbovc for fur-
es should be taken daily. piratory Sys1crn, above and Transdermol Route, under Prc- ther details. Patches should be applied 10 1be upper backs of
cau1ions, above). young children to minimise the potcntral for l'C1noval.
Buceal and sublingual tablets containing fcntanyl cit- Although die licensed dosage inlerval for transdcrmal patches of Although 1he 1ransm11cosal lozenge-on-a-Slick formula1ion is
rate for lransmucosal delivery are also available and li- fcntanyl is 72 hours studies have suggested that up to about 25% n111 licensed for use in children, 1hc BNFC 10/<Yll suggests a
censed for the same indication as the lozenge. Tablets of cancer pa1ients may require niore frequent application wid1 single dose of I 5 to 20 micrograms/kg (maximum of
containing the equivalent of 100 to 800 micrograms of some palients requiring fresh patches every 48 bo=.9·'" Equally, 400 micrograms) for 1he managemcm of breaktbrougll p•ln
in on anempt to supply lower doses than arc alloW<XI for by ex- and as premedicarion in lhose aged 2 years and older, and who
fcntanyl are available. An initia l do se of isting iransdennal do.sage forms. patches have somclimcs been weigh more than lO kg.
JOO micrograms may be taken for an episode of break- CUI, fold<:d, or partially masked wilh non-porous dressings; the
through pain and l'Cpcated once if necessary after 30 manufacturers do nol recommend such practicesas 1hcy consider Anaesthesia. fentanyl and its congeners alfcntanil. remifon-
the dose supplied will be unreliable. and there is potential for iani~ and sufenuinil arc shorter-acting tl\an morphine and appear
minutes; dicreaftcr, palients must wait al least 4 hours 10 produce fewer circulalory changes; Ibey are preferred for use
before lreating another episode. Jn the USA, a buccal O\'Udosage.
An iolllophott1ic drug delivery preparallon cootaining fenianyl as supplements during anaeSlbesia v.ith inhalational or intra'~
film containing fentanyl citrate for transmucosal deliv- hydrochloride \\'as also available for 1he rnanagemcnr of ac111e nous drugs. fcnianyl is widely used as lhe analgesic component
ery is also available; the films contain the equivalent of moderate 10 severe pa.<toperative pain in a hospital setting (see of balan<lcd anaesthesia. It bas been used 10 attenuate cardiovas-
200 micrograms to 1.2 mg of fcntanyl. An initial dose Postoperative Pain. below for some referenees) but was witll- cular stress responses to in1uba1ion (see Anaesthesia, p.2064),
drawn from 1he market becaus.: of a defective delivery S)'Slcrn. and may be used in higher doses in an attempt to redJcc the car-
of 200 micrograms may be taken for an episode of diovascular, endocrioe. and me1abolic changes th:ltmay :w:com-
breakthrough pain; thercafier, patients musl wail at I. kal W. Benfield P. Transdttmal f~nl:in yl: :. review o( its phar·
macologic:il properties and thttapnnic ~Oicacy in p3in control pony surgery. When ~ncnuation of surgiC31stress is cspeciolly
least 2 hours before treating another episode. Doses are Drn&J 1997; SJ: 109-lS. importa111, for cxnrnple in cardiac surgery, intravenous fcn!J!nyl
2. MllijSC"rs RBR 1 W1gs1:arr AJ. Tr211sdennal fen12nyl: on updated 50 10 iOO micrograms/kg with oxygen and a neuromuscular
subsequently titrated according to response. 111e dose l"CVK\V o( ic.S ph•rmucological propcrttCS and lhCfllp.!Ulic <ffiCI• blocker. and sometimes up to I SO microgni1nslkg. may be used
of lhe maintenance opioid used for persistent pain cy 1nchton1c citnccr pain control. Dntf,> 2001 : Gt: 2289-2307.
for gaieral anaesthesia. Total intravenous anaes1hesia with fcnia-
should be re-evaluated if U1c patienl has more man 4 l. G~rlay CK. Trtalmt:nl of cancer ~in "'ilh tmn$dermal fenta-
nyl and propofol has been succcssful. 1
~~;,~A~!~. ~~~;.~.~i~~-~ s~~is1nmt oruansdcrmal fen·
2 7
episodes of breakthrough pain dai ly. -1. Sar1sfactory a11aes1hesia has been reported? wi1h high-dose fen-
canyl lor lht treatment or chrooic p:t.in. Dt·ug Sofety 2003; 26: tanyl citm1e (30 to 50 micrograms/kg) in pnnl(Jfure iefo111s when
Caution must be exercised when switching between 9~ 1-73.
used as sole anaesthelic, with pancuronium, for ligation ofpcnenl
the different transmucosal preparations as the extent of S. Zcrnikow 8, <t ol. Tnn.!-dct11l3l fcnlanyl in childhood and ado.
1e~ccoce: a «>mptthtM1ve literll\urt' review. J Pain 2001; I: ductus arteriosus; cardiovascular stability was moincaincd
absorption may be substantially different. 187-201. throughou1 the procedure. However. others' found significant
6. Hoy SM, Ke~tina GM. Fent1nyl lransdcnl1al matiix pa1c9' ([)i,.. hypotension in prctcnn infa111s given cilhcr fen1any l
lmra11asal sprays containing fentanyl citrate, equiva- roecpe M1. p.itch. Dorogesice OTr;ms~ Oorogcsic* SMAT): in
20 micrognunslllg, isotlunne, halolhane, or kctaminc; systolic
adults wi1h ctuu.:er.r·ela1cd pain.Drugs 2008: 69: 111 1-21.
lent to 50 to 200 micrograms of fentanyl per dose, are 7. Hair Pl. ti ttl. Tronsdennal matrix fcntanyt nlC1nbn1.nc patch arterial pressure was bcsl maintained wilh the kclamine lech-
available for the same indication as the transmucosal (M~lr1fcn•): in se~ere cance:r-rela1td chronic pain. Dr11g¥ 2008: nique. 1l1e suigical stress response in prctcnn b.1bies was abol-
68: 2001-9. ished by 1he addition of fent3llyl 10 rnicrogromsikg i01ra\1:0ous-
preparations. An initial dose of 50 micrograms is s. Allan L. "' ol. R3ndomised Cf'OHOvet lri:I of 1run~dmn:1 I renU· ly lo 111 an3csUielic regimen of nitrous oxide and tubocw-arine.'
sprayed into one nostril for an episode of breakthrough nyl :and sust:un~d relc<'sc ornl morphine for treating chronic
Dost responses of fentanyl in nrono1:1/ anaesthesia have been
11011-c.>n«< poin. BA/J 200 t; 321: 11S4-&.
pain and repeated once if necessary after 10 minutes; 9. Donner B. ~' al. Long·ltnn lr1!'3Unent of c-anc:tt pain with diseussed.s
thereafter, patients must wait at least 4 hours before 1rnnsdennal f~t3nyl. J l'oln .\)•mpltu" J.lcm~1gt! 1991~ IS: for details of dos<s in neo<intes and children, sec ahove.
t68-7S.
treating another episode. Doses are subsequently titrat- I0. R~dbr-uch L. ,., ul. Tr:msdenn:il rcn1unyl Cor lhe m~stment of Ncurolep1011algt:Jio. ,\n injection of short-acting fc1uanyl
ed according to response; up to a ma:-timum of 4 epi- cancer 1:>:1.in: :t wn·ey of 100~ pati..:nts. f'tJ/lj"' MM 2001: IS: 50 microgran1slmL with the lo11gcr-ac1ing a111ipsycholic droperi-
;09~2 1.
sodes may be treated daily. The dose of the mainte- dol 2.5 mg/ml has been us<:d for ncurolep1analgcsia, prcmcdica-
nance opioid used for persistent pain should be re- TltAHSM UCOSAL /IOUTL Transmucosal fe11t:1nyl hos been lricd tioo, and as an 3djunc1 10 3llaeSlhcsia. However, the use of such
for sedation und •iialgesia trefort anae>thesia or painful pr~ a frxcd-ra1io combina1ion cannot be 1·ecornrnc11ded.
evaluated if the patient has more than 4 episodes of 1
cedures in odults and children?..l ood is used for breakthrough I. Jtnstrup M. et al. Tcital iv ~hcti" wilh propofo ...alfenl;mil Of'
breakthrough pain daily. c:mcer pain in opioid-toleranl palicnL<.'"' II has been noted' propofol-feut:inyl. 9,.; A1NJC'.slh 1990; 64: 717-22.
1ha1 this dosage method can cause all the adverse effects of J. Robinson S. Gregory GA. fcn11nyt-oir.c:tygcn anesthesia ror h·
For details of doses in childr~n. see below. parenter~I opioids: n~usca and vomiting :ue cornmon and po- Jtlllion of p3lcn1ductus a1·1er1os"' 1n JWCtttm infanu:. Anf!stlt An·
1entially lethal resp1m1ory depression can occur (sec also un- olg 1981;(.0: 331-4.
Administration. IHHlll.ATION ROUTE. In a s1udy1 inhaled fcn- 3. Friesen RH. Hcury 1)8. Card1ov3sc11lar chan:e,cs. in preccrm ."c·
ianyl provided plasma COllCCnlrations similar 10 ll>OSC after in- der Precau1ions, above). Dosage guidelines have been sug-
onatu ~i' Mia 1$UOur:rne. hulo1bane, fcmanyl. and keuanune.
rrnenous doses; use ~s pa1ient-con1rolled analgesi• was sug- gested.$ · ''""'h"'iolocr t9S6; 64: 238-42.
ges1ed. lnh~led forrnulallons of fenianyl are under 1. Macaluso AO, et a(. Oral t1aruanu<.vsa' fon1anyt ciU'lte few prt· ... Anand KJS. ,, "'· Rondomised trial or fc:nlanyl MIHthc-sio j,,
in•.sligation for 1he treatment of breaklhrough cancer pain mcdie4tion in adults. Attath A11clg I?96: Sl: I5&-61 . pretcrm babies u"dc:rgoing surgery: dlttts on •J\e strus r(-
2. Nel.>on PS, ~'of. CoinpJrison of or:al trtns1nucoul fe-Nanyl cit· SpOnSC'. Umcc-1 19S7: i: 243-8.
and acute pain. rale and nn oral solution ofmepe:rid1nc. diazcpan1, and atropine S. ''aslt:r M. The: dose rcspomeoffCruanyl in ncona1al ancslhcsi1.
I. Mather LE.,., al. Pt1lmooory administnattOft of acro11oliscd fonta· forpremcdieation in childrcn..4nntMJ/o/ogy •989; 70: 616-21. .411r:t'h~!tiology 1987: 64: 41)-S.
nyl: ph~rmacokirtt:tic: analysis of S)'Mcm1c de-livery. Br J Clin 3. SchcdU(r NL, et al. The use or OD1 ltltUtnUieOHI fcntanyl cilQtt
P/;(11'WttlcvH 1998; 46~ 37-43. few painful prnc:edures in ch1ldrtR. p,diorrks 1995: 9S: 33 5-9. ,HAIOCHROMOCYTOM A. Unlike niorphinc and some olbcr
~ Olide SKA. Wigsu1fT AJ. fent11nyl bl>cnl tablt=c: in brc:akthrouKh opioids, fentanyl and 1lfen1anil do nol release histamine and
tNT1tANA$AL ROUTE. Sludics M hove shown lhat intranasal fcn- paio i.n opiotd·tolcr~ nt patients "ith n.Dtt1'. Drugs 2006; 66: m:iy be used safely in the a11>e5lhc1ic managemcnl ofpo1ients
uinyl is as effective as the intravenous rou1e for postope1ativc 23S7-9;.
5. leCJ1K\clla G Ribeiro :v1DC. Opioid~ for the: management ('I( wi1h pbaeochromocy1c11n•.'
pain management and that it can be used in a J>3licnt-conlrol- breakthrov;h (q>1sodk) pain in c:mcer P'itients. J\-Yail~bk in the I. Hull CJ. Phat"Ochromocytoina: diagnosis. pm)pCrGtive pre.para·
lcd anal~esia sys1em. Intranasa l fentanyl has also been Cochrane 0;ibhase ofSystem31ie Reviews~ ls.sue: I Ch1-chc:51cr: ai•d ainactthetic managcmcn1. Br J
lio11 AfUldllr 1986; S.8:
studied'· for the management of acute pain in children. John Wiley; Z006 (:o«ouod 26.'06108). t45:k>S.
62 Analgesics Anti-inflammatory Drugs and Antipyretics
POSTOPERATIVE SHIVERING. As pe1hidine appears to be cfTcc- 3. OraSJ JA, tf ol. A randomiicd, double-blind, dose·rtspun.sc Fepradinof (t!NN)
livc in the treatment of postoperative shivering. other opioids or
compiflrison epidural fcntanyl versus sufcntanil anal~csi ai ar-
1ercos1.1run lCCtiM. Ancslh Analg 1997; 85: 365-7 1. r <!pradioot Fep<adinoluin (±)·0<·{((2·Hydc-oxy- I, l-dimcthylc·
including fcntanyl have also been tried. Nol all opioids are
necessarily effective but fc111an~I has been reported to be so,1 4, Swarm RA, ~' ol. raiin tn:atmcnt in 1hc periopc:rali\'c period. thyl)aminoJmethyt}benzyl alcohol
altliough information is scanty.· . Curr Prob/ S11rg 2001; 38: SJS-920. <IlenpaA>1110A
S. RoUJsicr M, c.1 of. Pattcnt<:c>ntrollcd cer.·ieaJ epidural fcntanyl C,,H ,9N0 1 = 209.3.
l. Alfons-i r. el"'· r-cnt1nyl, .., pethidine. inhibilJ po.sa. an;icS1hcsia compued with pacicnt-controHed i.v. fcntanyl for pain 1Acr
shh ering. Br J A""'sth 1993; 70 (luppl I): 38. CAS - 63075-47-8
pllorynaol1ryngc1I surge(). Br J .4noesth 2006; 96: 492-6.
2. KranJc.e P. e1 ol. Ph:mnacoloa.tcal trc~menl of postopcr.lli\-r UNll - 860MHl4W8A
$hi~crinf: a quanhllth-c syi&ematic fC\i ew of randomized coo- 6. Cooper OW, • ' o1 PaUe.n1-eonu-olled cxttadural analgesia wlth
trolled tnals.. Allcsth A1)(1/g 2002. 94: 4Sl-60. bupiveca1ne. fcnt.anyl. or a mixture ofbolh. afttr cat$1run sec-
,..,,... 8' J Anomh 1996, 76: 611- IS.

H~CH,
Intensive care. Ocspile the shon duration ofaction of feutanyl 7. Ltjus C. tt al. Post0pentivc utradural analgesia in d1ildrc:n;
after single doses, rapid rcclismbuuoo in the body results in an c:omparison ofmorptunr with rcn:.anyl. BrJ Anonth 1994: 72:
elimination half-life longer than that of morphine. Consequently 156-9
(fl
~H
fen111nyl is not a shoit·acting drug when used for analgesia in ii.- S. Sud:trshain G. •t ol. Jn1n.lhecal fcntanyt for potMhonicotomy
tensive care, and may offer linle advantage over mO<]lhinc.1 pain. B,J Anamh 1995; 75: t9-22.
9. Chclly JE. An ion1ophorttic. fontanyl HCI pnticnH~ontrotlcd
CHs
I. Aitkcnhead AR. Analgesia and sedation in intcnsh~ car~. Br J OH
Ammth t 989; 63: t 96-206. trf!nsdcrmal system ror acute postopera1ive paiTI m~n:1gement.
Exptrl Optn Pliarmncother 200S; 6: 120S-14.
P.,jn. CANCER PAIN. Transdcrmal fcntanyl is used iu the man· 10. Koo rJ. Postopcr111ivt pain man~gctnenl \li:ilh A rmienl-conu·ol- Profile
agement of chronic intractable cancer p3in; for references sec lcd 1r-4nsdcrmal delivery syslcm for fen1anyL Am J 11tolll'l•$yst Fepr•dinol is an NSAID (p. I00) that has been used topically in a
Administration, Transdermal Route. above. For references to Phorm 2005; 62: 11 71-6. concentration of6% for the relief of pain and inflammation. TI1e
the use of intranasal and transmucosal fcntanyl in lhc man· 11 . Mayes s. Ferrone M. Fentanyl HCI piticnt--controJJcd ionio- hydrochloride has been u>cd similarly.
agement of breakthrough cancer pain, see Administration, Jn. phorctic 1ran.tderm1I 1ysttm for the managemcnl of acute P'('S-1•
tranasal Roule and Transmucosal Route, above. opcra1ivc pain. Ami Phormoco1her 2006; 40: 2 liS-S6. Preparations
Proprietary Preparations (delllils are i:iven in Volume 8)
usouR •AtH. Fentanyl has been reported to be an effective Preparations Mu.: SN1gia: Spafo: D>igon.
inttavenous analgesic during acti\-c labour. Epidwal fcntanyl
is unreliable wbcn used alone,•-> although it docs enhance the llP 2010: e..p.....,. ar>dffN~~Fer~ll'jeaion:
USP 33: f~ C.,.,e lrfe<'""'
epidural analgesia achieved with the local anaesthetic bupi-
vacaine. lbc reduction in the mmimum local analgesic con· Proprietary Preparations (details an: givco in Volume 8) Feprazone (8M( tWNJ
ceouation of epidural bupivacaine for labour pain increased Arr·: ~ Fern»e Gnyoft Na;\,.ent s..tlmue: TUu; AMnral.: ()11..2370; Feprazona: fepruooe; Feprazonum; Phetl)lprena-
with increasing dose offentanyl added to bupivacaine.' How- Ac"'J ~; SublrNzr. Awtrio: A<:'d<; C>.n>gesic: knlomed Fen:<> zone: Premrone. 4-(3-Methylbut-2·er¥)-ll-d1phenytpr.azoid-
ever, the incidence of pruritus increased SiitJilicantly with n:>r< Matrlcrc Bets.: ~ loosysf: Motrifer< Bra>.: Durogeoc Fttrt·
illbo<t. Fent.,.,,, femat.4: t.Milcntat Canad.: ~; Chile: OuroeesJ<: ine-3,S-dione.
fcntanyl in a dose of 4 mierognms/mL and therefore the op- Cx.: DoKotn c:Nrottsic Efrenwro; fentigcsc Fent..,.,..I: Fen~ Inst~:
timum dose of fcnlJlnyl may be 3 microgramsfmL for bupi· <De<ip.iX>M
vacaine-sparing epidural analgesia during labour. Respiratory
lons)st: Matr~ffl Tocr\l: Winunytt Denm.: Acliq; OurOjl<lic: HaW:
MWilenc Fin.: Actoq: Ourogesic knton)losant Matrilen: Fr.: Atmril; Actiq: C20H10N202 = 320.4.
CAS - 307<8-29-9 ((eprozone): 57148-60-4 ((eprozone
depression has also been reported with the combination.• CAiro&esic: Ellentorl: lnstanyl! lotlsyst M>tlifen; Gtr.: Actiq: Ouroge1'C.
F~nU>dolon; 1'11trilen; Ribofcotul)'I; Gr.: Act'q: Ourog«ic Fentadur: Ion· piperozine salt I : 1) .
I. Reynolds F. Exir:1durol opioidj in h11bour. Br J AmJt$lh 1989; 63:
2St-l. •Y't. M.ttrife1t Mei•11)11: Hon: Kong: C>.JfO;;<sic: Hung.: Dolbin; Ourog<· ATC- MOIAX18: M02AAl6.
2. LlndO\\' SW. ~I of. A randomised double.blind comparison of •ic Mw>fe1t Sedaton; Indio: Ouroiesoc: Trofentyt lndon.: Ouroges<: lrl.: ATC Vet - QMOl/o.Xl8; QMOZAAl6
epidural fentanyl versus ftntanyt and bupivjcainc [$;c) for pain Abnrot: llctiq: Dvoaesk: Ellcnt0<>: Fenut fetal\eoc; tnstanyt M•trilen; UNI/ - 7BVX6jOCGR.
relief in lhe setond suse of labour. 8,. J 0'111~1 G.-..,wecol 2004: Mytan)t S<A>limatt; lsroe/: Aeliq: Dvrogcoc: Fenta: Tanyt: Ital.: Actiq; Ou·
111: 1075-SO. rozoK; Fem•~ Mllnt.n: Quwclen:Jpn: D..-cnepc Malaytia: Dura&•
3. l.)'(lns G, t!t al. Extradural pain rthd 1n labour: bupiH1cairlt Spar- "" ,~ M u: Ourotesc Fonoc!d FenWleSI: Fillzter< Neth.: Actoq:
ing by extr-.dur.-1 fomimyJ i> dost: dependcn1. BrJ Anoe:s1h 1997; D.iroges<; lonsyrt: Norw.: Aaiq: 0.n>g..C: LepU<1'1t Matrolen: NZ: Ou-
78: 493-7.
4. McClure JH. J('l'leS G Comparison or bupivacainc and bupi~ bilt °"""""" r.,,.,.
"'l!"C ~; Philipp.: Ourog.,OC S<bSmax: ~ Pol.: Dol-
MX: F.,,.,...C ~~ Port.: Ac"'J
vataine with'°'''">';,. conianuou• otradural analgaia d\lring
l>l>O<JT. Br J An«.Slh 1989; 63: 637-40.
Atdoca~ ~ Elftntora: ~ lon>)'Sf: Nlfene: Rus.: ~
~; $.Afr.: Clurogt<C:~ Tan,lt:Sinppott:
Spoin: Aa"J~ftf'Un<>t:Ma:r*'1:QWdcri:r< Swed.: A<tjq:Ou­
°"°"""
roSYOPEAATIYE PAIN. Small intravenous bolus doses of an opi· ~ l.epllnlt Mrrlert Switz.: Acbq: ~ s;r.enyt Th<ri.: ~
oid analgesic may be injected immediately after surgery for l""" Turlc.: Ac\iq: Outoiesi<: UK: l'bstrot Acbq: CllJ:o&esic: Elltntcra:
postoperative analgesia and faster acting opioids such as fen·
Fentu.: ,.,,,.,,t
lons)'>t ~trilet\ O!mach: Osma'>it Sut>imur. T""'1t.
Ulu.: Matrlen (Mar~t, USA: Actoq: C>.K01gesi:; Fentoro: ~t: Oris·
t•nyl may be preferable to morphinc. 1 Fentanyl has also been ok Sublitn1M: Vt nu. : Ouroges;c.
given by epidural injection in doses of I00 or 200 micrograms
or by continuous epidural infus ion in doses of 20 to Mutd·ingrt<llcnc Arr.: Ooifeit: A.,,..,.al.: MartaW> with FenWl'(t Naro.
pin with r<l'IAn)I, Brc,..: ~ridot Gr.: Thalamonat Ital.: l<:ptolent. NZ:
80 micrograms/hour; paticnt ·contl'Ollcd systems have been S..parcn: Ma,,.,., with Fcntonyt: Naro?<O wit.h F""1anyl Profile
used.' Fcprazonc, a phcnylbulazonc (p.121) derivalive, is an NSAID
Epidural fentanyl or sufcntanil provided effective postoperative (p.100). It has been given orally in Ilic treatment of mild to mod-
analgesia after caesarean section with comparable adverse cllect erate pain, fever, and inOammatioo associated with musculoskel·
profiles.' The sugge sted optimal dose. of fentanyl was Fentiazac lllAN. uYw. rWNJ etal and joint disorders. Feprazone has elso been given rectally
I00 micrograms. For references comparing epidural fentanyl and used topically as a 5% cream.
with alfentanil, sec Postoperative Analgesia under Uses and Ad- BR-700: Fentiazaccx F~n11azacum: Wy-21891. (1·(~-Chlorophe-
11)'1)·2~ol-5-)f)•tetic acid. Pinn.one, the piper.07.inesalt offepraz.onc,has been used similar-
ministration of Alfentanil, p.19. In• review' of pcrioperativc
ly.
pain management epic!ural opioids "<ere considered to provide <Ile.m.ua•
cffecti>'C analgcsi• at lower doses than systemic opioids. Fcnta· Preparations
nyl may be given throug)i a lumber epidural eoithctcr that is often C11H11CtN01S = 329.8. Proprietary Prepa rations (details•~ 1Pven 1n VolOOle 8)
inserted im""""iatcly posiopcrativcly. After an initial loading CAS - 18046-21 -( Ito/.: Z~ Spoin: ~ Ven oz.: V>j)<W\
dose of I to I .S microgr.unsllcg offentanyl, infusion at the rate of ATC -MOIA8 10; M02AAl4
0. 7 to 2 micrograms/leg per hour is begun and continued for ATC Ver - Q.'1101A810; QIA02AAl4.
about 48 hours on average. Some prcfcrto use intemiincnt injcc·
tion. A small studyS comparina 2 pa!icnt~trollcd routes of ad·
UNll - OYHF6£6NLS. Firocoxib (t.'SAN. rlNN)
ministration found that cervical epidural fcnianyl prO\'ided better FirocC»<ibum: ML-17857 I3. 3.(Cyclopropylmethoxy)·S.5-dime·
postoperative pain relief al rest than inuavcnous fcntanyl; how- tll)'l+[~·(methylsulfon)l)phe'l)1j(urar>-1(5H)-one.
ever, there was no decrease in the total dose r(.-quircd and tl1e au· <iMpOKOKCH6
tl1urs considmd thal the bcncfi1s of epidurol fentanyl did not out· C11H200)S = 336.4.
weigh its pot~ntia1 compJica1ions. CAS - 189954-96·9.
Combined opioid and local anaesthetic epidW111 infusions have ATC Vet - QMOIAH90.
also proved effective, for e.. mple fcntanyl I microgram:'mL UNll - Y6VZW4S4WT.
with bupivacaine O.lo/.; both could be infuseda1lower rates than
either drug alone. Allhough a srudy' comparing bupivacaine-
fcntanyl combinations "ilh ~drug alone for epidural anal~
sia after caesarean S«tion conrumcd an additive analgesic effect
for the combination, there "as no demonstrable clinical benefit
compared with fentanyl alone in this patient group who expect
early mobilisalion. However, the combination moy be of greater Profile
benefit in patients for whom eorly ambulation is not routine. Fenti11.ac is an NSAID (p. I00) that has been used for the relief
Fcntanyl has also been gi\'en by epidllt:ll injcc1ion to children for of pain and inflammation associated with musculoskeletal,joint,
postoperati\'C analge.<;ia.1 peri-aiticular, and soft-tissue disorders. It has also been ~ in
Fentonyl has been tried by intnthecal injection for postoperative the tre:i1ment of fever. Fentiazac has been given orally; it has also
pain.s been applied topically and has been given rectally as the calcium
As mentioned in Administration. Transdcnnal Route, above, an salt.
iontophorctic transdermal system for postoperative pain was also ProOle
available.•· 11
Preparations
Firoc.oxib, a selective cycJo.oxygenasc-2 (COX·2) inliibitor, is
I. Mirchcll RWO, Smith Q The cot11rol of acute po11opua1ivc Proprietary Preparations (details are given in Volume 8) an NSAID (p. l 00) used in ""terinary medicine for the treatment
rain. Br.I Anau1h 1989; 63: 1~7 58. /101.: 0.Fl;nlt: Port.: ~ IORt: Nor\'Odont. of inflammation and pain as!;OCiated ~ith ostcoat1lvitis in dogs.
2. Morgom M. The rat~nal use or 1ntraiheco1 ind txtraduri:l opio-
ids. B, J .4nawh 1989; 63: 16s-88.

All cross-rcfcrencts refer to entries m Volume A

 FentiazacJFlurbiprofen 63
Floctafenine (l>IW tr.W -N1.r. Uses and Administration There has been so11-.: interest in the potcn1ial of llupi11inc to trc.i1
Flufenamic acid, an antbranilic acid derivative rela1ed to prion diseases such as Creutzfeldt-Jakob disease: (sc.: below).
Aocta'.,,..;na: Flocurer-;r.e; Floctafen.num: R-'\318, RU- I5750.
mcfenamic acid (p.&4), is an NSAID (p. 103 ). Flufenamic acid is 0 References.
l3-Dihfdroxyp1-opyt N-{3-tnf00ro.-nethy~1..quinolyl)anthrar0- mainly used topically in a concenlration of 3 or 3.5% for the re-
late. I. Frit<kl HA. Fitton A. flupittioc: a tcvitw of its ph:wmac<'lfogicRI
lief of pain and inflammation 3SSOCiated v.•ilh muswluokek1al, ptopcrtie.s. and thcraprulic cffic..t1cy in p11in $1-iltCJ. Dr.gs 1993~
(!)-~ ....... joint, and soft-tissue disordess. Aufcnamic ucid and its alomini- 45: S4S-69.
C?oH 1FiN;O, = 406.4. wn salt have also been gi,·cn orally. 2. Klawc C. Maschke M. Flupirunt:'. ('hDl'lt'l:lCfl1ogy 3nd clinical lp-
CAS - 13779-99-9. plications <.' f a nunupioid 1no.l=<)ic and po1en1ia lly neuroprotcc: ..
Preparations 1i\'e compound. E:<perl Opl1t Pharmu<:nthtr 2009; 10:
ATC - N01BG04. Proprietary Preparations (deUils are givai in Volume 8) 149$-1;00.
ATC Ve1 - QN018G04. Ger.: Mcbia< ltun!;Jpn: Opynl\
UNI/ - 004HVXoA9Q. Creutzfeldt-Jakob disease. A double-blind plaC(bo-comrol-
Multi-ingre<hllt Aunrio: Mobilisin. Mobm '*"- Rhoupsal: B•lg.: lcd study' !rom 2004 in 28 patients with CrcutZftldt-Jokob di,;-
Mobilisirt &oz.:~ Compo~to; Gr.:~ MlM,_: ~ilisin t:
Ito/, M~ Pon.: utnt Mobili<in: Spain: McMliso-l: Sw!U.: Algesalo- casc (CJD) found Oupininc 10 have beneficial elfe(ts on cogni-
nat Assan: AsS1n 11wrm<x l".obiisin. tive function.
I. Ouo M, ti ol. Eflic;acy of OiJpin ine on cotnili\<t function in pa-
tients with CJD: a doublt·blind s tudy. NtNro/08.,r 2004~ 62:
714-18.
Flunixin Meglumine ~ USAN. rlNNMJ
Ove rdosage. A 17-ycar-<ild girl who h3d bad symplOms of
FU-clcsitnimeglumiini: Flunixin mcg\Mninova sul: Ftunixine rregu- headache, blurred "ision. shivering, drowsiness, disturbed
rnone: fUlixini meglvminum, Flunixivnegtumin; Aunixino n~­ speech, aiaxia, and syncope wos found to have bright green urine
mina; FlnoQnum Meg!umin-cum: Megk.mini Flvnixinum: Sch- and high conC(ntrations of Oupirtine.1 Another palicnl who had
147I4 (ftunOcin). 2-([2-Methyl-3-(tri~J>yl)~ny!)amino)- taken an overdose of Rupinine was drowsy and on neurological
3-~ a<id comJ>OV!lded with 1-deolcy-1-(methyl- examination hod conical hyperexciubility with intemiineot my-
Adverse Effects, Treatment, and Precautions amino)·D-gL<itol (1:1~ 2-(o.3,Cll.al-Trifluoro-2.l->C)'l'dir>a)nico- oclonus, ucmor of the extremities, nysugmus. and a pronouncod
As for NSAIDs in gener:U, p.100. cerebellar syndrome.2 Blood-Oupininc concentrations were
\inic acid c~ with l-<:leoxy· I ·(methytamino)-0-gluchol
Anaphylac1ic shock has been reported, and may be prcccded by (1:1). I0.9 micrograms/OIL nine hours after ingtstion, compared with
minor allergic manircsrations; floclafeninc should be stopped in a 1herapeu1ic range of0.5 to LS microgrnms.lmL. Aupirtinc was
any patient who develops signs suggestive of alleigy (such as f'1erl\yMHH3 <DAYH1"1KC1tH
undetectable at 3 days post·i11ges1ion. No specific lreatmcnt was
prurirus or urticaria). Reac1ions may also involve 1hc li"cr. C,.H 11 F}N;O;.C1H 17N01: 191.5. given.
CAS- 38677-85-9 ((luni•i11); -42461-84- 7 ({lunixin meg-
Porphyria. Floe1afenine is ooMidctCd to be unsafe in patien1s lumine). l. Hufsehmidt A, e1 ol. A sirl wilh headache, confusion and £(ten
with porphyria b<cause it has been shown to be porphyrinogenic urine. J Ncurol2009; 156: 1169-70.
UNI/ - BY3jKOjW3U. 2. Hoffmann O. '11 Qf, Ptridoxic•I cerebral corl ical hyperexcitabil-
in i1t-'Virro systems. il)' followina Oupini11e o"erdosc. J Toxicol Cllo1 T<>xlcnl 2004;
Interactions 41: 913-16.

~~CF,
For inleractions associaled with NSAIDs, see p.103. Preparations
Pharmacokinetics N Prop.ietaty Preparations (deiails arc &•Y<1> in Volume ll)

CCcoo~
Bro&.: KIUdolort Ger.: i<atadolofl: Trl11C~ Tranc:opal Oola, Po/.: l<;t-
floctafeninc is aboorbcd from the gaS1rointe81inal tn1c1 and peak •dolor< Pore Meanor: Nowxttr'i'< Rur.: ~ (l<r.>A"'°")·
plasma concentrations occur I to 2 hours after ingestion. Its plas-
ma half-life is about 8 hows. It is metabolised in !he liver to
Roccafenic acid. It is excre1ed mainly as glucuronide conjugates
in the urine and bile. ((.uni•"') Flurbipv-ofen (BAN USAN. rlNN)
Uses and Administration BTS-18322: Fk.111>iprof_.. f\J1lipo-ol'en: Aco'b1proienas; Fbti-
Floctafenine,an anthranilic acid derivative, is an NSAJD(p.103) Pharmacopoeias. Jn Ew: (soc p.vii} and US for vcterinory use
only. prolene; Aurbip,-ofeno: Fk.rrbiptO(enum: U-27182. 2·(2·Fluorob>-
used in oral doses of up oo 800 mg daily. in divided doses, for the
sho11-tcnn relief of pain. c>h. Eur. 6.8 (Flr\ixin Meg'.umine for \lelerina.-y Use: Flunixin phenyl-'i-yl)propionic acid.
Meglun'line lll'(Vet) 2010). A white 10 almost while crystalline <JlA)'1)6~H
P reparations powder. Freely soluble in w31er and in rncthyl alcohol; practiC.11- C, 5H 13 F0 2 = 244.3.
Proprietary Preparations (details arc given in Volume Bl ly insoluble in acetone. A 5%solution in wa1erhas a pH of7.0 to CAS - SIO•i-49-4 .
Fr.: lcWac; lrl.: ldar>ct; Thai.: ldn<. 9.0. ATC -MO IAE09: M02AAl9; ROZAXOI; S0i6C04.
USP 33 (Aunixin ~). A white to off-white Crysl•lline
powder. Soluble in waler, in a.lcobol, and in methyl 3lcohol; prao- ATC Vet - QMOIAE.09; Qiv102AAl9; QRO]AXOI:
tically insoluble in ethyl •eetale. pH of a 5% soiu1ion 1n water is QSOIBC04.
Flufenarnic Acid (0--\f'l UW( tllNJ between 7.0 and 9.0. Soore at a temperature of25°. e;cursions UNI/ - 5GR0578KLP.
Acide Ftur.!nunique: km OufeninOc:o; Acidum Flufenamicum: pennittcd between 15° and 300.
Cl-'140; CN-275~; FlufeMamihappo; Flufen;wnsyn: INF-1837:
Profile
Kwas flu'enirrowy. NSC-82699. N-(ao.Cl·Tnftuom-m-1olyl)an- Flunixin meglumine is an NSAID (p.100) used in veteri11ary
thranilic ac•d. medicine for the relief of pain and inRammation in acute and
<DJ1>"1>et<aMC11a• Kv.<:MTa elvonic disorders and as adjunctive lherapy in the treatmcnl of
C,.H,oFiNO, = 281.2. cndo1oxic or "'J>lic shock and masti1is.
CAS - 530-78-9 ((lu(cnom1c acid): 6!891 -34-7 (flu(ena-
mate aluminium): I 6419-51-0 ((lu(e11<1mote olumm1um)
ATC -MO!AG03. Pharmac.opoejas. In Eur. (seep.vii), Jpn, and US.
Flupirtine Maleate f'aMl'-1 WN. dl-JNM) Ph. Eur. 6.8 ~).A white or alniost wh11e ~rys1:11linc
ATC Ve: - QMO I AG03.
UNll - 60GCX7Y68H. D-9998: Flvpirtine, Maleate ce: Aupirtini M<lleas: Maleato de~­ powder. Practically insoluble in w•ler; freely solu~le 1n alcohol
pi1ina: W.296'4M Ethyt 2-amino-6-(4-!luorobcnzylamir>a)-3-py· and in diehloromcth3nc; dissolves in aquccus solutions of alkali
fi<M.carbamate maleate. hydroxides and carbonates.
USP 33 (Flu1iiprofen}. A white crys!allinc powder. P~lly
<DAyrt~™"" M2ACaT
insoluble in water; freely soluble in dehydrated alcohol, m ~­
C,1H11FN,o,.c,H,O, = 420.1.
CAS - 56995-20-1 ((lupinme): 75507-68-5 (f!upircine tone, in ether. and in metliyl aloohol: soluble in ace1oni1rilc. SlOR:
malea1e). in airtight containers.
ATC - N028G07.
ATC Vee - QN028G07. Flurbiprofen Sodium (6ANM. 1fNN/AJ
UNI/ - OVCIS3PK4A Flurbiprofene Sodqo.ie: Flurbiprofeno s6d<.o. Natni Flurtlip1·ofe-
Ad..erse Effects, Treatment, znd Precautions num. Sodium (~)-2-(2-~1-bipnc~iyl)propoonate dhydrate.
As for NSAIDs in general, p.100.
Hnp>1,;, (l),,yp6Mnpocl>eH
18reast feedinc. No adverse clfects haVi: been seen in breast- C 1 sH,~fNa02.2H;O =
302 3.
fed infants whose mothers were receivi11& Oufcn•mic acid, and CAS - 56767-76-!.
1hc American Academy of Pediatrics considers' thot ir is there- ATC - R02AXOI .
for.: usually cornpa1ible with breast focding. ATC Ve1 - QR02AXOI.
Ane:u-ly study' found that only very s1n•ll amounts of0ufa13m- UNI/ - Z5897MU9/<.4
ic acid were excreted into breast milk after oral doocs. Pharmacopoeias. In Br: and US.
1. Amt::ri(.-an A(.'»dc1ny of Poc:hatrics. The transfer or dr'UJi and oth· BP 20 IO(lbbvokn Sodium). A whire to creamy-~hite, crys-
u chemicals into l1um1n milk. PedioJr;cs 200 1: 108: 776-89. talline powder. Sparingly soluble in water. soluble tn alcohol;
(R<1ired Moy 2010) C-orr«:tiCft. ibid.; 1029. Also av11loble •C (flupirtine)
hn p ://Hp po 11c y. aa ppublica t ions. Otf.IC ~i/contcnl/ [u 11/ practically insohble in dichloromelh:we.
pedia1tiu%3b l0S/3n76 (accessed 01111/07)
2. Buch1~n RA. Cl of. The bfu.sa milk ~1crc1ion or nuf(nnmic ac- Profile Adve rse Effects and Treatment
id.°'" TMr R.s 1969; 11 : 533-S. Aupininc maleate is an analgesic lhal has been given for the re-
lief of pain (see Choice of Analgesic, p.2) in usual doses of As for NSAIDs in general, p. I 00.
Effects on the gastrointestinal tract. Acute proclocolitis 100 mg three or four time.~ daily orally, or 150 mg three or four Minor symptoms of ocular irritation including_tra~­
has been associated with oral flutenamic aeid.1 times daily as a rectal supposi1ory: daily doses of up to 600 ma
I. R1wi S. ~t al.. Coti1is c.austd by non-stero;d1l :nti·inflommotory
sieot bwning and stinging have been reported on msul-
orally or 900 mg rectally hove hcen used when: necessary. Flu-
drugs PostgrodM<dJ 19~6; 61: 77)-6. pirtine has also been &Jven by intramuscular injeclion as the glu·
Jation of flurbiprofen sodium eye drops; there may be
Porphyria. Flufenam1c acid has been associated wi1h acute 11- eonate in the management of acute pain. ItIs also being inv~.sti­ increased blccdinl! from ocular surgery and wound
tacks ofporphyria and is considered unsafe in porphyrie p:1ticnrs. ga1ed for 1hc trc..anent of f1bromyalgia. hea ling may be ddayied. Local irri1ation has also fol-
The symbol t denotes a pcepannion no longer actively marketed
64 Analgesics Anti-inflammatory Drugs and Antipyretics
lowed rectal use, and local effects includ ing a sensation Flurbiprofen is a chiral compound given as the race- Fosfosal (rlNNJ
of warming or burning in the mouth may be seen after matc and the above pharmacok.inetic characteristics re- Fosfosalum: LR· 1521 2-Phosphono-o><)Oenzoic acid.
using tlurbiprofen lozenges. fer tO the raccmic mixture. Allowance may have to be <Docij>oCM
Incidence of adverse efl'ects. Repor1S from the manufac1nr- made for the different activities of the enantiomcrs. C1H104 P =
218. 1.
crs on the range and incidence ofthe adverse effects offlwbipro- o Rclerenc:es. CAS - 6064-BJ-1 .
fen.12 UNI! - I 24X2V25W4.
l. All'Ofls L. et ol. Plasma and synovia.I fluid kinetics of f1urb1pro-
I. Shelduke FE. <1 ol. A looa-1em1 uscssmcnt of flurbiprofen.
fen in thcum:noid arthritis.. Br J Cliu Pl1arn10,ol 1986; 21:
CrurMcdRa0pinl911; 5: 106-16 ISS-63.
2. BroobCD. ""'· Clinical safotyofOurbiprofen.JCTinPbam>a-
co/ 1990: JO: 342-51. ?. Smith 11, et ol. Flurbtp<ofcn Jn post-partum women: plasma and
tMeasc milk d19P0'1ti0tt~ J Clin PborMocol 1989; 29: 174-14
Effects on the C NS. A seven: 1)1lllJleoical par!cinsonian syn- ). Kean WF. ti ol The pharmac:okinttics of nurbiprofen in younicr
drome developed in a 52-~-old man who had taken flurbipr<>- :ind elderly patients with rheumatoid anhritis. J C/;n PMrmocol
fen far 7 days. 1 t992; 32: 41-S.
I. Enevoldson TP. ~'al. Aculc: parkin.sonllm assoc:iaied with Our.. 4. Davies NM. Clinical pharmacokincttcs of flurbiproren and its
bibrofen (•ic]. BMJ 1990; 300: 54()...l. en1n1iomcrs. C:llo Pltorm1.1ctMi~t 1995: 28: I00-14.
Efl'ects on the kidneys. Renal papillary necrosis has been de-
scribed in a palicnJ who had used flurbiprofen for many years. 1 Uses and Administration
Acute flank pain and reversible renal dysfunction has been re- Flurbiprofen, a propionic acid derivative, is an NSAID Profile
ported in 2 patients treated with flurbiprofen.2; Membranous ne- (p. l 03). It is us,e<l in musculoskeletal and join! disor- Fosfosal is a salicylic acid derivative (see Aspirin, p.21) that has
phropathy also developed in a parienl who took flurbiprofcn dai·
ly for 12 lo 18 months.' ders such as ankylosing spondylitis, osteoarthritis, and been given or11lly for !he treannent of pain.
l . Nafria EC. <I al, Rcn1l papillary necr0<is induced by Ourbipro· rheumatoid arthritis, in soft-tissue disorders such as Preparations
f"'1.DICP Ann Plumnocotl>«r 1991; 25: 87()...1. sprains and strains, for postoperative pain, and in mild Proprietary Prepantions (details art given in Volume B)
2. Kaufhold J, ~t al. Fturbipro(tn•.associatM tubuk>inctrs1i1ial ne-
phritis. AM J Ntplt,.,, 1991; II: 14-HI.
to moderate pain including dysmenorrhoea and mi- Spain: A)dolidt: Oisdol!nt. l'rotJlpt.
l. Mcintire. SC. er al. Acute OaN: plJn and ~vusible renal dys- graine. Fturbiprofen is also used as lozenges in the Hulli·ini~ienc Spoin: A)doid Cod.;n¢ Oi-.i Coc!Mat.
function assoc:,i ated with noni.lcroadal anci-inOammatory drug symptomatic relief of sore throat Flurbiprofen sodium
use. Pttl,io1rics 1993; 9'2: 4$9-6().
4. Mac:Kay )(. Membranous ntphropathy 1ssociatrd with tht vse of
is used in eye drops to inhibit intra-operative miosis
Ourbiprofen. C/i• N•p/>rol 1991; 47: 279-80. and to control postoperative inflammation of the ante· Glucametacin (tfNN)
Efl'ects on the liver. Cbolcsllllic jaundice probably due to flur· rior segment of the eye. Glucametacina; GJcametacine: Glucameucinum. 2-{2-(1-(1-
biprofen has been n:porled. 1 Chlorobenzoyt)-5-methoxy-2-methylindol-3-yl)acetamido}-2-
For pain and inflammation, flurbiprofen is given in deoxy-o-glucose.
l. Kotowski KE, Cnyson MF. Side effec:11 or non-steroidal anli-
inflammatory drugs. BMJ 1982; 185: 371.
usual oral doses of 150 to 200 mg daily in divided dos- r NOl<aMCTau~H
Effects on the skin. Cutaneous vasculitis apparently due to
es, increased to 300 mg daily in acute or severe condi- C21H21CIN20e = S 18.9.
flurbiprofen occurred in a 59-yur-old woman wilh long·<Hand- tions if necessary. A modified-release preparation for · CAS - 52443-2 1-7.
ing rheumatoid arlhrili.s. 1 Contacl ~crmatilis ha~ also be.:o seen once-daily use is also available. Patients with dysmen- UNI! - NIE.XE.SE.HAN.
in a 22-year-old woman who applied a pouhice containing flur- orrhoea may be given an initial dose of I 00 mg fol-
biprofen to her wrist.2 lowed by 50 to l00 mg every four to six hours to a
t. Wei N. Flurbiprofen and eu11ocous \"ISCUlitis. Ann l111em Med maximum total daily dose of300 mg. Flurbiprofen has
1990; 111: 55()...1.
2. K.awada A.6 of. Corn.act dermttitis due 10 Ovrbiprofcn. Comoc1 also been given rectally as suppositories in doses simi-
Du1n01itis 2000; 41: 167-S. lar to those given orally.
Hypersensitivity- A diffuse, pnlritic, maculopapular rash de- For the relief of sore throat, a lozenge containing
""loped in a poticnl 48 hows all« taking• second dose of flur-
biprofcn. 1Two days later, !he rash had become wticaria~ and on- 8.75 mg of flurbiprofen may be sucked or allowed to
giocdema and bypo1ension ""'" also nored. Parch testing wirh dissolve slowly in the mouth every 3 to 6 hours to a
nurbiprofcn powder was positive. maximum daily dose of 5 lozenges. It is recommended
See also Effects on the Skin, above. that treatment should be limited to a maximum of 3
J. Rom:ino A. Pie1rantonio F. Delayed hype:rsensiti,•ity to flurbi- days.
profen. J1n1cm M•d 199i; 241: 81-3.
To inhibit intra-operative miosis during ocular sur- Profile
Glucamecacin, a derivative of indoanciacin (p.69), is an NSAID
Precautions gery one drop of tlurbiprofen sodium 0.03% is in- (p.100) that has been given orally in musculoskeleial,joinr, peri-
As for NSAIDs in general, p.102. stilled inlo the eye every 30 minutes beginning 2 hours - anicular, and soft-tissue disorders.
Breast feeding- Small amounts of flurbiprofcn are distribu1ed before surgery and ending not less tl1ao 30 minutes be- Preparations
into breast miUc; licensed product infonnation advises to a\'oid in fore sui&ery. To control postoperative inflammation
Proprietary Preparation• (dcuils are &iven in ';Olumc B)
breast-feeding mothers. the same dosage regimen is used before ocular surgery 8roi.: l'e°"'1'1irT; Mex.: Teoren\IC
Herpes simplex keratitis. Whether flutbiprofcn c:m e.ucer- followed 24 hours after su~ery by the inst.illation of M u ltl-inirc<l~C OHi.: Fit>rcrclox-
bale infeclion "ten used IO tre31 ocular herpes simplex is unclear one drop 4 times daily for l to 3 weeks. Flurbiprofen
fromm1imal studies, •.l but licensed prodUCI infonnation for llur- sodium eye drops have also been used in the topical
biprofcn sodium eye drops recommends that they should not be treatment of cystoid macular oedema.
used in patients with active epithelial herpes simplex keratitis. Glycol Salicylate
Patients with a hisiory ofhelpes simplex keralitis should also be Flurbiprofen axetil has been given in some countries Ethylene Gl)<ol Monosaiqlate: Glycol· Salcytas; Gty!tolisalisylaat-
monitored closely when undergoing treatment with lhese eye by intravenous injection for severe pain. ti: Glyko:S.,icylat Kidrolcsietilo salicilatas; Hid-oxiWl-sdteilat Hy-
drops. droksiet)')llisafisylaatti. Hyd-oxietylsalicy!at Hydroxyae>Jlyti Salicy-
I. Trousdale MD, Cl al. Effect of nurbiprofen on herpes simplex The R-enantiomer, tarentlurbil. has been investigated las; ~yle, salicylate cf: H~ylis salicylas: Hydrox-
kcratitis in r.1bbils. l11V<stOphtholmol Y'rs S<i 1980; 19: 267-70. in the management of Alzheimer's disease but the re- yethyt-sal~t; Salcilato de glicol. 2-H~thyf salicylatc.
2. Hendricks RL, et al. The cffecl of Ourbiprorcn on herpes simplex sults of phase Ill studies have been disappointing.
virus type: I s1romal keratitis in mice. Jnv~11 Opltlholm<>I Vl.s Sci f i\MKOAb UlAl1UW>aT
1990; 31: 1503-11.
Preparations =
C7H 1o0• 182.2.
BP 20 I 0: FIJll>pio"n E)<! Drops; Flvrb;profen Svpposito• ;.., ~ofcn
CAS - 87-28-5.
Interactions Thblets:
For interactions associated with NSAIDs, see p.103. USP JJ: f\ri>iprolm Sodi¥n Ophrli•lmi< Solution: AJl'boprofen T~leu.
Parasympathomimetics. Ucenscd product information for Proprietary Preparations (details are given in Volume B)
:iccrylcholinc chloride ophlhalanie preparations and for Ourbi- Atz.: ""°®t Fbbc. L"""""'enof: To!rnne: Aurtrol: OolM; Screpftn:
profen sodiwn eye drops statC$ lha1 there have been reports that Aunt!o: F<obenf, S~ s./t" ~ Otubt Bnt>.: 0aJon Tr-
ocetylcholiM and oarbachol have been ineffeclive ...11cn used in guo: Conod.: Ansoict ftobent Noo-o-F\rrprc(er< <>c..fe<t Chit.: -
Oislox: ONlln C>.: Anladf; ~i'of: Orulbt Strq>fen: TranoA<tlATf:
patients treated ,.;th topical (ophthalmic) NSAIDs. Oonm.: Fb'oterc Fr.: Cd>Wd: Ocufen: Sl1""1: Ge<.: ~~
Oobroknf: Oc\Ar. Gr.: Sedce: Bono1ol-R; °'"1o¥ot fyet.r, l " -
Phannacokinetics l'lldolol·B. flocldona: fUclon fboplic: lnhlb-; io.c KKk ~ Oru-
IU': Pin.-; ~ Huni.: f~ Ocub'f; S~ Indio:~. Pharmacopoeias. Jn Eur. (sec p.vii}
Flurbiprofen is readily absorbed from the gastrointesti- Cadi!Ur; fteb<n; O:Ukr, lrl" frotien Sb'cp<is Int~ Ito/.: 8enacl¥. Ph- Eur. 6.8 (H)'d'oxye'Jlyt Saic)Qte), An oily, colourless or al-
nal tract after oral doses and peak plasma concentra- fltb"': Frob<t-< ~ T•ntum A<t;v Go!>; T.-.nsact l•t Jpn: Rq>on, niosl colourless liquid or colourless erysuls. M.p. about 21°.
Malays/a: Acustop Ca~ Mu.: A•Qd: Ocurcn; Mon.: Amady>;
tions occur about l to 2 hours after ingestion. Absorp- N eth.: Frobc<'< NZ: h-<lbo"f: Ocuren: Stropf"1: Pol.: Aupin: Strepsils fn. Sparingly soluble in waler; freely soluble in alcohol; very soluble
tensM>: Pon.: Edoltene: FroU<n: Ocuflurf: RaJpa><\: S1ttpren; Transact Lil. in acetone and in dichloromethanc. Prorcer. from light.
tion after rectal doses may be more rapid. It is about Ru~: Slr<p(en (C1pe1*'4r. S.A(r.: f•<>be1•t: <Xufenl: Sctepsi11 ln1cn1ivr.
99% bound to plasma pro1eins and has a plasma half- TrarY.Act Slnjapo,.: Aa.s1<lp C"'2plasm>t Ocvfenc Spain: Frobcn: Noo Profile
life of about 3 to 6 hours. It is metabolised mainly by Artrolt OcvJUrt: Switz.: Frobeo: Oc\Jlu<i: Thai.: Fl..-om: Turlc.: Ans»d; Glycol salicylate is a salicylic acid derivative u:;ed similarly to
Forline. ft"'1<; Majezilc M~ M...,..1.11: Ocur""' Zero·P: UK: FrobOI\ methyl salicylale (p.89) in topical l\lbefacient preparations in
hydroxylation (via the cytochrome P450 isoenzyme Ocufen( Str.Cen: Ul<r.: Strepsis ll'l<•lSlv (Crpencw.c IA••OH011): USA; AA· usual ooncen1ratioos of 5 to I So/o for lhc relief of muscular and
CYP2C9) and conjugation in the liver and excreted in wet O..uron; Venn.: Fkll>6'lt. Ocufenf. rheumatic pain. Dipropylenc g)ycol .salicylate has been used in
urine. Flurbiprofen is distributed into breast milk. simil11t prepara1;ons.
All cross--referencC$ refer lo enlriC$ in Volume A
 Fcsfosal/Hydrocodone Hydrochlo1ide 65
ing spondylit1s who have had an inadequate response to conven· l-tydrocodone Tartrate {BANf.\ "~.I
tional ther:t1>y. For alt the abo»e indications, 1 dose of SO mg is Ditrfdroc~ A:id Tartrate: H,.0.-c.codonc lv;1d Tartrate;
given by subcutaneous injection once a mond1. h should be £iven
Hydrocodonc B<tartrate 1'J~•Wj; Hydrocodone. Tv>.rale d·; Hy-
with me1hotrcxntc in patients v.rith rheumatoid arthritis; in those
drocodoni Bil3'1rtt i-!ychxodon• Tarti-.s:" Hvdrocone
with pooriatic arthritis or ankylosini spondyli1is golimumab may
be given alone or wi1h other non-biological DMARDs. Re- Brtal"lfi te: Tai1r<to de ciihid<ocodt:inona: Tartrato de hidtocO<io-
g1rdl~s of indication, concurrent thcropy with corticosleroids, na 6-0eoxy- 3-0·methyl-6-0xomorphine h~·~ lart'2te
non-biological OMAR Os, and/or NSALDs may be continued. In hemipenla-'"tydrate: (-)-(SR)-1.).f:l'OXY· 3-methoxy-9a..-iethy'•
the EU, licensed produc1 infonna1ion recommends thal conlinu- morphin211-6-or.c hydrogen t.rtrate hemipentahydrate.
ing d1e:rapy should be reconsidered if thcJe is no adequate re- r""f!Ol<CA::>"1! rapTpaT
sponse v.-ithin 12 to 14 weeks of starting 1rea1mcn1. Patients
weighing mon: lhan I00 l(g with an inadequate response during
C. 8H2 1 NO;C -H,0<.-2 '~H;O ~91.5. =
CAS - 115-]9.J (hydrocodone): I 43-7 I -5 (on/!ydrovs hy-
this pci'iod may bcnefil from a higher dose of 100 mg once a dro(odone tor:rote); 34 I 95.34. I (hydrot odone tortrore
monlh; continuing therapy should be reconsidered iflhcre is no llem1penrohydro1eJ.
adequalc response wi1hin 12 10 14 weeks of ~eiving this dose. ATC - ROSDAOJ.
Golimumab is also being sll.ldicd for 11le 1tcatmen1 ofchronic:sar- ATC Vee - QRC5DAOJ.
coKJosi$. ulcerative colitis, and psoriasis. UN/I - N070W886KK.
'IOTE Compounded prcporallons ofhydrocodone 131ua1c may be
O~fcrcnces.
represented by the lollowmg names:
I. Kay J. et al. Golimumab in pc.ticnts with acti\-c rheumatoid ar·
thrj1is d~1C trtalm~nt with metholrexatc: a nDdomizcd, dou- • Co-hycodAPAP (PEN}-hydrncodone 1aruate and paraccta·
ble-blind. pfaccboacontrolled. dosc-.ra...,1iog 1t11dy. Artlm'1i1 mol
llh<l>m 2008. 58: %4-75.
Street names. The following !Clms have been used as "street
2. lnmBn RO, tt ol Efrte<11cy :ind safety 0>f ~limumab in pl'ltitnts
with Qnkyloc1ng 1pondylicis: rcsulls of• r1ndorniud. doublc- names' (sec 11.vi) or slang names for ,...nous forms ofhydroco-
blind. pl1ccbo<on1rollcd. phase Ill trial. Arthritis Rheum 2008: dooe tanratc:
58: 3402-12. Cough Syrup; \likes.
3. Kcyslonc .EC, ct al. Golimumab, ~ hum:m amibody lo tumOur Pharmacopoeias. In Eur. (see p.vii) and US.
ncctO!lS factor o. gi,·cn by mon1hly s ubcutaneou~ injections.. in Ph. Eur: 6.8 (Hydrocodcne Hydrogen Tartrate 2..5-Hydrne).
ac1ive rhctsmetoid :i.nhritis dc•phc mc1ho1rexatc therapy: lhc
CO-FORWARD Study. '411tt /Uwu•1 D>.< 2009; 68: 769-96. White or almost whi1c, hygroocopic, Cl)"Slalline powder. Freely
4. K_a,-anaugh A, et al. Oolimumlb. a new human cumor nocro1i1 soluble or soluble in wa~ sparingly soluble in alcohol; pracli-
ra.etor alpha omtihody, Ad1nini.1tt"ttd every four wuks as I subcu• cally insoluble in cycloliexanc. A 2% soluiion in waler has a pH
t3.nt<1us injtetion in psorb11c arthritis: twtnty-four-weck effica- of3.2 10 3.8. Store in airtight containers. l'rotccl from light
Gold l(eratinate cy and sarc1y rcsultl or l,t randomi~d. pl~\."Onlru llcd )tud:y. USP 33 (Hydrocodone Bil4.'Vale). Fine. while crySlJlls or crys-
Aurolhiopolypepbde: Queratinato de oro. Arthri1u Rit<un1 2009; 60: 976-S6. talline powdtr. Soluble in wotcr; slightly soluble in alcohol: in-
5. Srnolcn JS. tt nl. Oolimumab in p:aticnts "11hactivc rheumatoid soluble in chlorofon11 and in ether. pH of o 2% solution in water
CAS - 9078-78-8. ~nhriliJ aft.er u-ei1.rmn1 with tumour ncct0siJ factor alpha i11hib-
Profile i1ora (0()..AFTER study): a muhiccn,re, nu•domtscd. doublc:- is between 3.2 and 3.8. Store in ainighl oont:iincrs. Protect from
Gold keralinale is a gold compound wi1h a gold content of about bl ind, pl1ccbo-controllcd, ph;st Ill 1ri1I. Lo11C~t 2009: 37-1: light.
2 10-ll. Corr«iiOll. ibhl; 1422.
13%; it has similar actioos and usa lo 1hose of sodium •wothi- Profile
omalate (p.127). It has been g1wn by intramuscular injection as Preparations Hydrocodone, a phen:uithrene dcri"1lti,•e. is ao opioid anolgcsic
the calcium salt fot• the rrcannent of rttcwnacoid arthiitis. Proprietary Preparations (dcuils arc given in Volume 8) (p.105) rela1ed to codeine (p.38) and has similar ac1iau, bul is
Preparations Cz.: 5'mponi: fr.: Si~1 USA: s..poni. more po1ent on• wei&ht-for-weight basis. Hydromorphonc (be-
low) is one oflhc 111elllboli1csofhydrocodone.
Proprietary Preparations (details~ given in Volu1ne 8)
Arg.: ~ Hydrocodonc is used mainly as the taitratc it1 combin3tion prep-
Hexyl Nicotinate arations for the reliefofirritanl cou!!h. d1ou11.h ii has no P"nil.1.1br
advan~c uvcr codeine. Hydrucodonc tannulc has been used
Hel<syyMi~..otir.aa:ti: Hexyln:cotin;:t...-n; Hex)jnikotinat: Nicoti- similarly. Hydrocodone iartmtc is 1IS<1 used for the relief ofmod-
Golimumab (V>A.'{ ~"l nato de hex~:> n-He>.)'i n.<:otinate. emie 10 n1odcr91ely severe pain. usually wilh paracetamol. TI1e
CNT0-148: Golimumaburr. lmmuno&lobutn GI, arti-(1-..xnan f e1<tMAHi'll<OT1....aT usual orol dose of hydrocodone tartratt in such combination
IU'T>Or necrosis factor a) (lumn monoclonal CNTO 118 yl • preparations is 5 io 10 mg cl'ery 4 to 6 hours.
C 1H11NO, = 207.3.
ch.lin). disulfide with human monoclonal CNTO 148 o<-Chan CAS - 23597-82-2. For details of doses tn children, ~ee below.
cjmer. UN!/ - 8N07P844/V, HydrocodOllC hydrochloride is given orally•nd also by injoction.
f ONlt..()""".a6 The polistirox dcrivalivc (a hydrocodonc and sulf0fl3tcd dicthc-
CAS - 476181 -74-5. nylbenzcnc·clhcnylbcnzcnc copolymer complex) is used in
ATC - L04A806. modified-release preparations.
ATC Vet - QL04A806.
UNI/ - 91 XI KW43E.
Adverse Effects and Precau tions
"N~
~O~CH3
Hydrocodone has also been used in the treotmen1 of dyspnoea
Abuse. The aoose or O\'Crusc of prcporations containing hy·
drocodone and paracc1amol has been associa1ed wi1h >ert·
As for lnfliximab. p.72. wrimmrol heari11g loss. 13 Coc:hlcar impl•nts impro...W lh<: hear-
Most il\icction site reactions 10 golimumab are mild, "ith ery- 0 ing 1.,,,-. in some of the pMicnls.
diema being the most frequcnl manif<station. lnlranasal abuse of preparalions of hydrocodone and pa"'ceta·
Interactions Profile mol has also been rcponcd.}.<
As for lnffaimab. J>.74. Hexyl nicotinatc is used in usual conccnlralions of up lo 2% in I. Frit.":dman RA, rt ol. Profound hc·aring Joss 11soc~1td woh hy-
topical preparations as a rubefacient. drocodonc/..,,tami1>0jllt<n abusc . .4mJ Ounooo: 21: 138-91.
M.:an sie:idy~scate trough concentrations of goli11111111ob arc re- 2. Uo T. ,.., of. H)Jro..vdonr:: ll)C :.inrJ Knwrin..:t1r1,1l )l('.'.aring lms.
1iortcd to be up to about 52% higlier wtien a•wn wid1 methotrex- Preparations · Paiu PIJ.t'.fichm 2007~ 10: 467-72.
ate but lical.«d product information (or 1he fonner states that Pt"Opf'ietary Pl"eparations (dct:ails art gwen in Volume B) J~wtrs WM. l!I nl. P.;i.la1al pnf'or11lon associated wi1h inrDn2UI
dOsaiC adjusimem for cid1er drug docs nol appear 10 be neces- prcscrip1ion narcotic abuse. Ortil St"f Om/ M,~,1 Otul Pothol
Muki..fnircdient: Belg.: Tt7l'l!.Vi"IC; lrl.: Tl"lnS'~un; Port.: H:podort.
sa1y. UK: r,_...,... Heat Rub. 0.-.1 Rod;o/ £1ulod 200;: " ' .S94-7.
-4 . Sloln PA. Kliinkina 0. lnlranas.il ~bu.Jc orpr~ription hydroc·
PhZlrmacokinetics odone/ace1aminnphc11 rc~uhs 1n oronas:al fiscul:l1: ;a case rcpnrl ./
G111imumab shows linear pharmacokinetics. Ali.er subcutaneous Opioid Monog 2009: S: 3S3-5.
inj.uion peak co11centnmons occur in about 2 to 6 days ind lhc Hydrocodone Hydrochloride (BANfA.1"1NM/ Administration in children. Hydrocodonc tanratc may be
absolute bioavailabilily is esiimated 10 be obout 53%. Tiie mean given as p:ut of. CO<llbination prcparnlion for the reliefofirritanl
1e1minal half·life is nborn 2 "-eeks. Hid'Oeloruro de Ndrocodon3; Hydrocodone. C~te d': cough in children aged from 6 to 12 years in usual orol doses of
Hydrocodoni Hyd1·octtoridu:n. 2.5 111g C\"CI)' 4 to 6 hours. Older children niay be givC11 lhc usual
O Rcfi:rcm:cs.
I. Zhou It. <I'"· Ph;;mn3c(lkinetic1 '-nd Rfny or ¥01illl\llnl'lb. 3 ful- r""llo•oAo"a 1 '<APO"""P'IA adult dose (sec above).
t)' human anfr·TNF-u mo1loclon.al amibody, in subjctls with C1/i;1 NOi.l ICl.2';1H20 = 3€0 9 Pharmacol<inetics. Rcfcmices.
1hcum::1101d 1rthritis. J Cf;,, Phbrmarol 1001~ ~7: ;~0-96. CAS - 25968-9 ! -6 (onhydrcus h1drocodone hydrochlo·
2. Xu Z. fto/, Population phlnn11cokint11csofiohmmnab. 3n an1i- I lhnchinson MR, et al. CYP206 and CVPJA4 i1wolvcmcn11n the
hut1ur uc:cros:is: facwr-o. human monoclun11 antibody~ in patientlt
rrt!t) prim:1ry oxidative lllClnbollsn' or
hydrocodon~ by hum•>n lh-.cr
with prorfatic :1rthri1i1. J ('J;,, Plutt•111t;C'ol 2009: 49: 1056-70, /'.TC - R05DA03. mkrosl"lnleS. Br Jen,, Phm'dWtrol :004: 57: 2&/-97.
:;. Xu Z. et'"· Subc:ubncou' bioa,·ail~bil ity or ~imurr.ab M 3 d1f· ATC Vet - QM5DA03 Preparations
ICrc1u injmioo s11H in htahhy subjects J C!in PfP<Jf'lfl«'Ol2010: USP 33: H)<tococloolC llllari•·ate ar.d A<f~ fab'OI>. H)'droco·
SO: 276-84. :lo~ Bcar.rC.< ilnd 1lomatrqi;n. Me~-ndc Ta!WJ. Hydro<odone

H~O~
Uses and Administration Sitartt'1te T.tiim
Golimumab is a human nionoclonal an1ihody t(l TNF o. a pro- Propria:tary Preparations {details :'lrc W''C'O in \btumc B) .
. inflammatory mediotor and has actions similal' 10 Other TNF in- I# Bola.: Bioce>Oonet. Coned.: H)codan: Gor.: Otcodd Switt: tt,odrc:cod.,·
oon.
hibiton (see lnnixiinab, p.74); ii is described as a biological dis-
Multi-Ingredient: Arf.; Hdro'10Y~8 Comp~)(: Canad.: D.arnlca:
ease-modifying antirheuma1ic drug (DMARDJ. It is used in the ~. 0.-noune E~<Y<nt OC.1-')<onne. Nov.,1;.te< OH: ~OH;
trcatmcnl of moderately to severely acti-e rhC\lmatoid arthri1is ..1t10·Calmydooe: n;\jo·Coris".ec-Ott Tuswneic: V~frWiic Dl-t Indio: Car·
(p.12), aCli,•e md progressive P50riatic onhritis, and severely ac-
. NCH3
-.01tod<dt: USA: AIC>t A~ex 1-0t: AncYJi>. Aw.s Gf. AMS
tive ankylosingspondylitis (sec Spondyloarthropathics, p. 14). In HCf; AM> HOt: AMS HSj. Atw HX; Bara:> Hct: Ceta Piu>j: C.0.
1he EU. golimumab is hccnscd for use in patients with rhcuma- c.sC Co-T..s, V: COO.~OHj: Codde..- C»t CoOmol 0Hf:Copil<ne xP:
0 Co-dron·HCt: Cyndal HOj: C)'lvss 1-'Ct: C!"U'S·HC NR·~ 0.mason·P:
ioid or psoriatic anhrilas who ha'<e had an inadequate response to Oe-CNo< Gj. Ot-Oiloo- HCt: Dt·Cnlo< fOr. Oe-Olor l'V'.t: Oc-Chior
standard DMARDs (including the non-biological DMARD (hydrocodone) NX; ~ CX; Oolac.et Don>11.,., 0C Oroccn-CS. Ovocct: Ou.
mctho1rexatc for rttcuma1oid arthritis) and i111hose with anl-ylos- muss HO. O,tar-HC. ED Tv" HCt: EO·TLCf; ~110: Endal-HO;

The symbol t denotes a preparation no longer aclively marketed

66 Analgesics Anti-inflammatory Drugs and Antipyretics
Dependence a nd Withdrawal onset of analgesia is usually within 30 minutes. It is
As for Opioid Analgesics, p. l 05. given by subcutaneous or intramuscular injection in in-
itial doses of I to 2 mg every 4 to 6 hours as necessary.
Adve rse Effects, Treatm e nt, and Precau- It may also be given by slow intravenous injection or
tions by intravenous or subcutaneous infusion, with doses
As for Opioid Analgesics in general, p.106. adjusted according to individual requirements. Higher
UK licensed product information contra-indicates the parenteral doses may be given to opioid-tolerant pa-
use of hydromorphooe hydrochloride in patienlS with tients using a highly concentrated solution containing
hepatic impairment; however, product infonnation in JO mglmL that allows smaller dose volumes. In the
the USA permilS its cautious use although doses may UK, the initial oral dose is I.3 mg every 4 hours; there-
need to be reduced. It should also be used with caution after the dose may be increased as necessary. Jn the
and given in reduced doses to those with renal impair- USA, initial oral doses of2 mg may be given every 4
ment. to 6 hours; doses may be increased to 4 mg or more for
severe pain. Modified-release preparations are availa-
Effects on the nervous system. Myoelonus has been
reported ' in a .SS-year-old man given relatively low do.<e., of in·
ble for less frequent administration, but see Alcohol,
travenou., hydromorphone wi1h a total daily dose of 4 mg on day under Interactions, above. By rectum, the usual dose is
Hydrom orphone Hydro chloride t and 6 mg on day 2: symploms resolved when the drug was 3 mg every 6 to 8 hours.
(6ANM. rlNNM) @ Slopped on day 3. A chon revicw2 for neuroexcitatory symptoms
0 References.
in 48 patients wilh 1erminol illnesses on hydromorphone found
Dih)'dromorphtOone Hydrochloride: Hic:lroclonJf'o de dihidro· 13 cases ofagitation, 9 ofmyoclonus, and 4 ofsciZUTCS; maximal I. 9Nera £. ~I OJ. A randomiz.cd. double--blind. double.dummy.
morlino:>a: H1drocloruro de hidromono:>a: H.c'romorfono hid- dose and treatment duration were no1ed lO increase lhc risk or crossover uial compari:ng the safety •nd effic.acy of oral 1ur
tainc<J...rclusc hydromotphone wi1h 1mmcdia\c•rclcHe hyd"°"'
rochloridas; Hydromorlor>-l'l)'drocNorict HyOt>morfontry- neut'O(oxicity. morphone in palicn\S wilh cancer pain. J Clin Onc.ol 1996; 14:
droldorid; Hydromorlon~orido. Hy<romorphone. chlomy- I. Patel S. ti ol A myoc.lonic ruc:1.ioo with low-dose hydrorncw- 1713-17.
drate <f: Hya-cmorphcri ~ 6-0eoxy-7.8-dly- phonc• .c~~ Pho,.,.oanhu 2006; 411: 2068-70. 2. Miller MG, '1 ol. Con1in-.ssubcut1ncouo infus1Dn ofmotpllinc
dro-6-0xomorphine hydrocNonde; (-)-(SR)-...S.Epaxy-3-hy- 2. Thwaites D, 11 ol. Hyctromorphonc ncunxxcitation. J l'olllo1 •s. hydromorphone: a conuolk<I uial. J Poln SJ"'ptom M°"og~
MN2004; 7: 5'15-SO. 1999; t8: 9-16.
droxy-9a~r>-6-ooe hydrochloride.
3. Quigley C. Hydromoq>honc for •cute and chronic pmjn, Availa-
r ~ rl'.APOXMlP'A ble in The Cochrane D.lt~Msc of Systemaiie Rtvtews~ Issue I.
C 17 H,,N01.HCI = 321.8
Interactions Chichesm: John Wiley: 2002 (accessed 26/06IOl1).
O.S - 466-99-9 (hydromorphone): 71-68-1 (hyd<omor-
For interactions associated with opioid analgesics, see .-i. Murny A. Hagen NA. Hydromorphone. J Poln Syt11p1om Mon-
phone hydrochlo<ide). p.107. og12005; 29 (suppl): SS7-S66.
S. Grosset AB, ti ol. ComPQl'llive enicac)' ofOt'ftl CAlcndcd-rtlcuc
ATC - N02AA03. Alconol. TI1e F'DA received data from phannaeokinctie studies hydromorphonc and jm.mcdiatc-relell$C hydron1orphone in pa-
ATC Vei - QN02AA03. in heahhy subjects which showed !hat sigiiificanlly bir,hcr peak licnts with persistent modcra:tc 10 liC\"Crc pain: two rondomiz~d
UN/I - t960UP2KRW. plasma concentrations ofhydromorphonc were achieved, as n re· com.rolled trials. J Poi,, Symptom Ma1tag1 2005; 29: 584 ...94.
suit of dose-dwnping, when alcohol was ingested wilh once-dai- 6. Du Pen $., el al. lnlratllecal hydromorphonc ror jntractablc l'I On·

HO.M
ly hyd!omorphone modificd·release capsules (Pollod-OM; Pur- malisnanl p3in: a rc1rospcc1h•c study. PafoMtd2006; 7: 10-15.
due Frederick, USA); these increases were considered 1. Chang AK, II ol. Safety and effic1cy of hydromorphone as an
potcnrially lethal. C\>Cn in opioid-tolerant poticnls. 1 Subsequent- analge.~ic ahemalive to morphine in acu1e pain: a randomized

:~~H,
ly, this formulaiion was \-Olwitarily \\itbdrawn by the US manu- clinical trial. Ann £mel"Jl. Mu/2006; 48: 164-72.
facturer in July 2005. Preparations
I. FDA. l•fonnau«> for hutlheare rrofessionals: hydromorphone
hydtochlondc u1cnl.lc:d·relusc c-.psules (marketed u Pall•· USP 33: H)odioino<pno"e I ;.t.xNonde ~ f+tdlo1opto"' H)'-
done) (issued July 200S).
Available 11 : ht1p:llwww.fda.gov/Orugs/Dru2Safe1y/ -T-~
Proprietary Prepantions (deuils ••• gh'Cn in Volume 8)
Po$1m1rkctOrugSafctylnformationrorPa1ien1s1ndProviders/ kJ.: Oclcnovag Aurtrol.: Di1aucSct ~ Mrtrio: Oil.M.dctt: Hid>I; p.
11<m 129288 ( acces.!ed 02108110) rnsu; S./1.: Pabclone: Conod.: 0 liod<t Hydromor'j)I'< Ci.: ....,.a;
~ O•nm.: ._......, Opidolt PilCadon: Fin.: Pall•dor< Fr.: SopliClone:
P>I·

(hydtomorphone) Pharmacokinetics Ger.: Oil.udldt; )ffln.; P.l>don: Gr.: Pallodonc: Huni.: jumista; Pal!a-
done: lrl.: P.tladcne: lsroel: Pan•done: Ital.: Jumista; M u.: Libeta>Qm.
Hydromorphone hydrochloride is rapidly but incom- N oth.: Palladon: Norw.: PaQadon: NZ: maudidt; Philipp.: J"""5ta; Port.:
pletely absorbed from the gastrointestinal tract a fler Jumisa: Palodore: spo;n: J<.misu: Swod.: Op<lott: Pall.ldon: Swlt:<: P:illa·
Street names. TI>e following terms have been used as 'slrcel dot'< f1,,/c.: jutn;,ta; UK: Pal ~done'. USA: 0 1laudld: Exalgo.
names' (seep.vi) or slang names for various fonns ofhydromor- oral doses; peak plasma concentrations occur within Multl·ingredlent: Swed.: Obudld·A\ropinf: Paladon Compo USA: [)i.
phonc: 0.5 to I hour. Oral bioavailability is about 50% as it
Dillies; HillBilly Heroin; Hospital heroin. loudid C~t-
undergoes extensive first-pass metabolism. Hydromor-
Pharmacopoeias. In Eur (seep. vii) ~nd US.
Ph. Eur. 6.8 (H)'dromorphone Hydrochloride). A while or al-
phone is about 8 to I9% bound to plasma proteins. A
most white, crys1allinc powder. Freely soluble ;,, water; very plasma elimination half-life of about 2.5 hours has
slig)llly soluble in alcohol; practically insoluble in dichloromelh- been reported after oral or intravenous doses. Hydro- Ibuprofe n (8AN. USAN. rlNNJ
anc. PrOlcct from light. morphone appears to be widely distributed in the tis- bJprofeeni: Ibuprofen; lbuprofcnas: lbupro'.ble: ib14>rofcno: tbu-
USP ll (H)'dromo<phone H,odn:xttooic:le). A fine white. or sues; it crosses the placenta and is distributed into pro!enum: R[).1362 1: U-18573. 2-(~-l~nyt)propionic
pr.idically while, odourless, crystalline powder. Soluble I in 3 of
waler; sparingly soluble in alcohol; pnctically insoluble in elhcr.
breast milk. It is extensively metabolised by glucuroni· acid
Stor1' in airtight containers •l a tcmpcrarurc of 25°, excU?Sions dation in the liver and excreted in the urine mainly as 1'15ynpo4>et4
pennitted between I 5° and 30". Pl'C(CCI from light. conjugated hydromorphone, dihydroisomorphine, and C11H1102 = 206.3.
lncompa.tibility. Colour change from pale yellow to light green dihydromorphine. CAS- 15687-27-1 .
oceum:d when solutions of minocyeline hydrochloride or tetra- 0 References. ATC - C0/£816: GOZCCOI: MOIA£01 ; MOZAAI 3.
cycline hydrochloride were mixed wilh hydromorphonc hydro-
I. V3llJ'\cr JJ, ct of. Pharmacokine1ic-s t1nd bimvailabilily of hydro. ATC Vet - QCOIE8/6: QG02CCOI; QMO I AEOI;
chloride in 5% glucose injce1ion.' Mixtures of hydromorphone morphonc followins intravcnou$ snd or.ti administnuion 10 hu-
hydrochloride and dCJ<amclhusone sodium phosphalc showed QM02AAl3.
man subjects. J Clln Phormoco/ 1981; 21: 152-6.
eonccl\tration-dependcnt ineompatibilily.l While cloudiness, 2. Parab PV. ti al. Pharmacokinctic5 of hydromorphonc after inIra· UNll - WK2XYtlOQM.
haziness, or prccipita1ion developed 4 hours after mixing tl1io- venous. peroral and rectal administnnion 10 hu1nan subjects. n;..
pental sodium and hyd!omorphone hydrochloridc.1 • opho,.., Dn-1Dllpot1988; 9: 187-99.
3. V.:u~.hi v. et al. Clinic.al pharmxology 3nd ph:umacokinelics of
Stability of mixhJ<cS of OuoroW'llCil and hydromol]Jhone hydro·
chloride in0.9'Yo sodiumchloriclc or S%gluooscdc:.-pendcd on !he
once..daily hydtomorpho:ne hydrochloride extended.release c11.p..
sulcs. J Clin n .....ocol 200S: 45: 547-54.
concentration of Ouorouracil present' Hydromorphone hydro-
chloride 500 micl'OgJllrnslmL wilh lluorouracil I mg/ml. was
siable for at leasl 7 days at 32" and for al least 35 days at 23°, 4°, Uses and Administration
or-20". When Ille concenuation ornuorouracil was increased 10 Hydromorphone hydrochloride, a phenanthrene deriv·
16 mglmL, hydromorphone was no4cd to decoo1pose incurring alive, is an opioid analgesic (p. I08). It is related to
unacceptable 105SCS after 3 da)'S al 32° or after 7 days at 23°, but morphine (p.93) but with a greater analgesic potency. Pna.rmacopoefas. In Ch111., Eur. (see P.'ii). /111•• Jpn. US. and
was siable for at least 3S da)'S al 4° or-20".
Hydromorphone hydrochloride is used for the relief of Yiet.
I. Nicves-Cordcto AL. rl nl. Compatibility or 11arcotic. anaJgesic Ph. Eur. 6.8 (~fen). A white or almost white, crystalline
solutions ";th vaTious 11ntibiotics during simulated Y-si1e injce- moderate to severe pain; it has been used for the relief
1-.0n. A.m J Hosp Phorm 198S:4l: 110&-9. of non-productive cough. powder or colourless crystals. M.p. 75°10 78°. Praclically insol-
2. Walker SE. e1 ol. Compa1ibility of dexamelhasone sodium phos· uble in water; freely soluble in ace1one, in dichloromethane, and
pha1c with hydt01norphonc hydrochloride or diphc.nhydraminc. In the treatment of pain, hydromorphone hydrochlo- in melhyl alcohol; it dissolves in dilule solutions of alkali hy-
hydr<><.hloride. Am J Ho.<p Phorm t991: 48: 2 16 1-6. ride is a useful ahemative to morphine for subcutane- droxides and carbonates.
3. Chiu MF. Schwanz ML. Viwal cCltnpatibilily o(injtctable drugs USP 33 (Ibuprofen). A white to off.while crystalline powder
used in the intensive care unh, Am J Htol1h $)'ft P/Jarm 1997;
4
ous use since its greater solubility in water allows a
ha•ing a slight characteristic odour. Practically insoluble in wa-
54: 64-S. smaller dose volume. After injection onset of action ter; very soluble in alcohol, in acetone, in chlorofonn, and in me-
4. Xu QA, ~t al. Stabili1y and compllibilily of fluorotJ.raeil wj\h usually oocurs within 15 minutes and analgesia is re-
morphi~ sulfate and hydromorphanc hydrochloriJe. A11n Phm-· 1hyl alcohol; sligl1lly soluble in ethyl acetate. Siorc in airtight
moe<>IMr 1996; 30: 756-61. ported to last for more than 5 hoU1s; after oral doses containers.
All cross-references refer to entries in Volume A
 ~dromorphone Hydrochloride/Ibuprofen 67
Ibuprofen Lysina (VWJj aled aseptic mcnal\,gitis; l 7 rcporLs involved ibuprofen, 4 Effects on the skin. Rashes niay occur during hypc1-scnsilivi1y
!oupro'en I ys1!'l~1e: Solupt-.ene. Lysone 2-(-1-isobutylpl>en)'l)prop-- sulindac. I naproxen, and I 1ohne1i11. Or O>e 23 reports, Il were reactions olthough serious dennatological efl'cctS ottribu1ed to
in palien1s with• diag11osis ofSLE. Typically tl>e reaction is seen ibuprofen arc rare. Reports ofmore serious effects have included
onate. $1evcns-.lohnson syndrome (oficn ossociatod v.ilh lk.'pa!OtOxici-
in pa1ients who have just r$artcd NSAID therapy aflera gap in
!•16ynpo¢&< /\,.)..H their rrea1n1ent. Within a few hours of rcs1anins lhe NSAID the tyl.' .. pho1oscnsi1ivi1y.~ and bullous lcucocytoel8Slic vasculitis.6
=
C, 9 !-'i;"-:0 , :S52.S.
CA.S - 5 7469-77.9.
pouent develops fever. headache, and a s1ifT neck; abdominal I. Stcmlicll P. Robinson RM. Sum.~n.) ·John son syndrome plus to:d c
hep:Jtitis d\te to ibt1profcA. fJ Y Slot~J Mtd 1978: 78: 1~9-13 .
pain mny ~ present The pa1ien1 1noy become le1hargic and
ATC - CO t E8 16: G02CCOI : MOIAEO I . M02AAIJ. eventually comaoose. Symptoms resolve if the NSAI D is 2~ Sr1va$l~l\·u M. ~' Clf. Dn11-as:sociate-d acutc·onset vanishing bile
AiC Vet - Q<:O l f616: QG02CCO I; QMOIAEOI: duct and Stevens·Jolmson S)·rKlroma in a chiJd. <io.tfrtW!lJt~'f>lr>·
stopped. It is believed to be a hypcrscnsiti~ily reaction bul 1hcre
QM02AAf3. gv 1998: tlS: 743-6.
docs nOI appear to be eross-rcac1ivi1y between NSA IDs. 3. T~i::an M. ct of. Acult' vanishin1 bile duct syndrome nOer ibu·
UNI/ - NOIORX9D6S.
Similar conclusions have also been reponed onore recenlly.1 Af- profc:n thcnpy in a ch;ld. J Pedi<11r 2004: 145: 27)- 6.
Stability. Solulions or ibuprofen lysine in Water for Injections ter experience or2 cases, a review of 1he liter.mire idenlificd 71 ~. Hcalth c....ct:. lbliprofen: Stcvens-JohmM syndrome. Con Ad-
stored at room temperature were found to l>e most stsble when episodes of ibuprofen-induced aseptic meningitis in 36 patients; 1vru Rtoct N.-u"1 2005; JS (3): 3. Abo anilablc ai: l1Hp://
protected from light.1 22 paticnls hod recunm1 episodes after repeated ibuprofen use. WW'\o\'.hc« .gc.a/dhp-mps/:alt_form=icslhpl'b·dsp~pdf/m~dcff1
c•m-bee1_• l5n3-eng.pdf (accC$S<d 29/08/08)
I. 'A>k>nrt MG. ~' nl. Stobilily of ibuprofen in irticction solutions. An underlying auto-immune conncc1ivc tissue disorder was no1- ' · Br:rincr T. Przybi'lla 8. Phot*nsititation ~used by ibupro(cn.
,.., J H"1/rl1·Spr rlrorm 2005: 61: 630-3. ed in 2~ pa1ients or whom 14 had SLE, 6 had an undifferentiated JA111AC'ttdl>er1ua1ol 199'2~26: 114-16.
or mixed disorder, I had meuma10id anhritis, and I had SJ6- 6. Davidson KA. r:1 ~I. lbuptofcn·induccd buUous leukocyiocta.s.ic
Adverse Effects, Treatment, and Precau· ircn's syndrome. In mosl C&Se$, symptoms developed within 24 vasculi1is. Cmi.f 2001 ; 67: 303-7.
tions hours of s1arting ibuprofen although I patient had been iaking Hypersensitivity. A fatal ISllJ1mi attack occurred in a 6S-year-
As for NSAIDs in general, p.100. Ibuprofen may be ibuprofen for 2 years before tl1e oosct of symptoms. Cr0$s-rcac- old woman, wilh adult-onset asthma. 30 minutes after ingestion
better tolerated lh:in other NSAI Ds. 1ivity was reported in only I patient "'ho had also developed of ibuprofen 800 nig. 1
Adverse effects that may be associated with the use of
aseptic meningitis wi1h both naproxen and rofc:coxib.
I. Hoppm~nn RA,.,"'· Ccntr;JJ nervous syac-1n side cfl"ec1t of non-
For Olher hypcrscnsitivily rcaclions or possible rcac1ions •lso =
EffcctS on the CNS and Effects on the Skin, above.
ibuprofen injection in premature neonates include in- stcro id~l anti--inOammatory drugs: asep.1ic mc1ungi1i.J., psychosis.
a nd co;niuvc dysfunc1ion. ••rt:h Jmttrn Mtd 1991 ; ISl : I. Ayres JG. et al. ~a\sthma de::11h Jue to ibuprofen. U:mcet 1987; i;
traventricular haemorrhage, periventticular leucoma- 1309- t3. IOS2.
lacia, bronchopulmonary dysplasia, pulmonary haem- :. Ro<M~uei SC, et al C'harx.ccri.stici. of mcnins,iti.s call$Cd by ibu- Meningitis. For repon.< of a~ep1i c meningitis after use of ibu-
orrhage. necrolising entcrocolitis, intesti nal profe1\: report of 2 usu ¥>1ch rtturrcnt cpisc>dcs and rc,·itw of prorcn, sec E6Ccis on the CNS, above.
1he literature. Medi<:itte ~006~ 85: 214-20.
perforation, ol iguria, fluid retention, and haematuria; Effects on electrolytes. Hyponalraemia has been described on
Overdosage . There wu a substantial increase in the number of
hypoxaemia and gas1roin1eslinal haemorrhage have cases of ibuprofen overdose reported to lhe Na1ional Poisons ln-
palienlS laking il>uprofen;'·1 other risk factors such as p~xist­ fonna1ion Service of lhe UK in 1he 2 years after its inl!Oduction
also been reported. In addition ibuprofen injection ing renal impa.innen1 or use wilh desmoprcssin were generally res an •over-the·-countcr' medication. 1 However, no concurrent
should not be given to neonates with lifc-llueatening prcsenL incn:ase in severi1y of poisoning was found and in only I of203
infection, with significant renal impainnent, or with I. Blum M. A\·iram A. Ibuprofen induced hyponaiD<mia. Rhe1mw· cases '''IS ibuprofen thougb1 to ha''C caused scriollS problems. 11
rol Rthf>bll 1980: 19: 2511-9.
known or suspected necrotising entcrocolitis. Infants ~. Rnuh RM. CIK report: hyp0n::1treo1i111ssoc11ted wi1h nonsceroi- was concluded that ibuprofen appeared to~ much less toxic in
who are bleeding (especially gastrointestinal bleeding dal on1iinOainm:iitcr1 dru!s. An,J Med Sci 1993: 305: 318-20. acute O\erdosc lhan either aspirin or parscctaonol. Current odvicc
or intracranial haemorrhage) or who have tluombocy- 3. Oarcia EBG. ~' al. Hypon:nncmic coma induced by deJm~ is 1hat doses below 100 mg/kg are unlikely to cause to~icity in
prcssin nnd ibuprofen in a.woman wilh \'On \Villcbrand'scfise.aK. childr~n. wh..-eas clinical fearurcs will occur in children who
topcnia or coagulation defects should also not be given Ho~mophifia 2003: 9: 232-4. have ingested more than 400 mg/kg. In odults the dose.RSpOnse
parenteral ibuprofen, and those given it should be mon· Effects on the eyes. Reversible amblyopia has ~en reported etfec1 is less clear cut, but those who have ingested less lhan
itored during trealment for signs of bleeding. Renal in pa.ticms taking ibuprofen.'.? For reference to effeclS on the op- 100 mg/kg arc unlikely 10 require ueannent
function should be monitored and if anuria or marked tic nerve associated with ibuprofen, sec p.101. Nonelheless, rcpons illustrate the complexii)• or major °'"rdos-
oliguria is evident at the time of a scheduled second or I. Colhn11 LMT. Bowen DI. Oculor side-el'l«is or ibuprorcn. Br J ogc wi1h ibuprofen. A syndrome of coma, hyperkalacmia wilh
Ophrbol-' 1971: 55: 471- 7. cardiac orrh)l1hmias. me1abolic acidosis, pyre<ia, and respiratory
third dose, it should be delayed until renal function has 2. Palmer CAL. Tox;c ainblyop;a from ibuJl<Orcn OM.I 1972: 3: and renal failure was reponed2 in a 17-year-old man af1cr major
retumcd to normal. · 76S. O\'Crdosage with ibuprofen and minor overdosage wilh doxcpin.
Symptoms of nausea, vomiting, epigastric pain, and Effects on the gastrointestinal tract. Ibuprofen may be as- Hypcrlallaemia was not evident until 14 hows after hospital ad-
!iOCiatcd wi1h a lower risk of upper 2os1roin1~inal dfcclS than mission and was though I 10bedue10 a combination ofpoiassium
tinnirus have been reported after ibuprofen overdos- repluccmen1 for initial hypokalacmia, aeidosis, muscle damage,
age. More serious toxicity is uncommon, but giving ac- some 01her NSAlDs, bul nonc1heless it can cause dyspepsia,
nausea and vo01iting. gas1toin1es1inal bleeding, and peplic ulcers and ibuprofen-induced renal failure. A 6-year-old child
tivated charcoal followed by supportive measures is and perforation . Colilis nnd ilS exacerbolion have occl.WTcd.1.z developed1 shock. coma, and me1abolie acidosis after ingestion
recommended if the quantity ingested within the previ- I. Ravi S. fl al Coli1is C.8U$t'd by non·stc:rQidal auti-inRhmmet.ory or a dose of ibuprofen equivalent to 300 mg/kg. Trcahnenl con-
ous hour exceeds 400 mg/kg. dru3s. p.,,,g,od Med,/ 1986: 61: 774. sisting of intubation. mechanical velltilarion, fluid rcsuscita1ion,
2. Clon1<nts D. "' t1/. eo1;1is usocia\cd WJth ;buprorcn. BMJ 1990: g;istric lavas:<:, Md activated charcoal proved successful. In an-
Breast feeding. No adverse ellC:cts ha•-.: ~n seen i11 breast- 301: 9'1. other rcpon.• in which a 21-monlh-old child had ingested 1he
fed infllnlS whose n101hers were rcceivins ibuproren. and lhc eqtnvalenl or 500 mgikg or ihnprofen. the prescn1ing symptoms
Effects on the kidneys. Rcpons of ed\'Crsc renal cffcclS wilh
American Acadcmv or Pedialrics considers' lha1 ii is therefore w.:reOCUle renal f.lilure wid1 SC\'d"CmctaboliC acidosis. Tiie child
usually compatible ~ilh breasl feeding. The ONF S9alsoconsid-
ibuproren include an increase in scrum crcahnineconcentration, 1
acule renal Jail..-c.'" ond ncpilro1ic syndrome.' Cystitis, hacma- developed 1onic-clonic seizures 4<I hours after ingestion. with
crs lhe •moun1 ofibuproren dis1ribu1cd into brcasl milk k> ~loo significant hypocalcacmia and hyp0magnesaemio, which may
turia. ond intcrs1i1ial ncplui1is 1n6y occur. Acu1e flank pain and
small to~ honnful 10 a brcul-fcd infant. A studf esti11\3lcd thal hove been exacerbated by use of sodium polystyrene sulfona 1 ~
rcvc1~ible renal dysfunction has been 1eponcd in some palienlS
a brcost-fod infan1 would ingest obout 0.0008% of the niatcm31 and furoscmidc. 111c seizures, which could not ~ controlled
lrcated wilh ibuprofen.'-' See also Effects on ElcctrolyleS. above.
dose. However, licensed product infonnation for some prcpara· wilh diazepam, pheny1oin, and phenobarbi!al, ceased on correc-
I. Whehon A, ~I ul. Renal cfftt:lS of ibuprofen. piroxam. ond
tions. including $01llC lopical preparations. rccom1nends 1ha1 SlJlindac; in pa.1icms with asymptomatic 1c:nal failure: a prospcc- tion of dec1TOly1c bal>nce.
br;:ast feeding should be avoided during ibuprofen t1~n1inen1. cive. randomized, t:rouo\'er comparison . .A1111 Jmcm Med J990; I. P<:rry SJ, ti al. lbuprofm o,·erdose: the fir~ l'-''O ya.rs of
I. Amer-On At.ldemy or P4.:di~trics.. 1'tk tr.tR>fcr o(drul!-5 and odt- 111: S6~·76. ovcr-1he-coun1cr utes. Hru• To.tkol 1987: 6: 173-&.
~r chcmic:lls into human milk. Pcdlotra 2001 : 108~ 776-$9. l. Drands1cnec RO, Mar DD. Rc-\·e:rsibleofiguric rcn:il failure asso· 2. Menzies DO. et al, Fulmin:ml hypc:rkl'll3tinia ond multiple com~
lHeHred Miy 2()10) CorrcC'tioo. ib;d: 1029 AIJO availablt at: ci•tcd "ilh ibuprofon ln:atmcnl. BMJ 191&; l: I l94-S. plic:uions following. ibuprofen O'Ycrdou. Med Toxicol Adwne
h up:lluppoticy.aappubl icu 1i o.u .or1,/ c1i/con1cn ti fu 11/ J. Kimberly RP. rt al. Apparent acme rcNI failure IS$ociatcd with 1»1'S: E.tp 1989: 4: 468-71.
J1Cd;1trie1%JblO!lr,J776 (o<cc.sed 07111/07) thcnpc-utic aspirin and ibuprorcn 1dministration. Artl1ri11's 3 ZuckC'fTN.o GS, Uy CC. Shock. nK"Uboli<' :acidosis, and COJna
2. W::.hcrK. OilgerC. lbupcofcn in hu1nnn milk. BrJClinPhon,,d• R/1<111n 1979; ll: 281-~. following. ibuprofen O\•erdos;c 1n a ~ ild.. Ann P/l(lrmC1coUrcr
ro/ 1997; 44: 111-12. ·I. Spic-nu RJ. ct al. A"-utc renal failure a.ssociatfd with 1hc use or 1995: 29: 869-71.
4. Al-Harbi NN. el ol. Hypocalccmia and hypom::isncscnlit n(tcr
Children. An analysis' of the outcome ortrealmcnt ur83 915 ovCr·d>e~counlcr ibuprofc-n. Aun PlwnimC'other 1992; ?6: 714.
5. Fernando AHN. no/. Renal f.!lilure after topicoJ u.seofNSAIOs. ihuproft<n ovcrd~e Aim Pllm·11mt:o11wr 199i: 31: 4 3 2~ .
childi-en round thnt the risk ofhoopi1alisation for gnSlroin1«1i~
B~f.I 1994; 308: 533
bleeding, renal failure, or anaphyla.•is was no greater in children 6. Moghal NE. tt ttl lklprofen alld acute renal fl'ilurc in~ toddler.
11iva1 ibuprofen thun in 1hose given paracclnmol. Int eractions
Arch Di.r Child 2004; 8': 276-7.
t . Lc:skoSM. M1tcl1c:l l AA. An3':~~qncn1 o(lht sofctyof petli:itric 7. Jus1iui1mi FR. Ovu-lhe-counttr ibuprofen tnd ncphroti.e S)"n· For interactions associated wilh NSALDs. see p.103.
;\xojloor•• JAMA 1995: 273: 929-33. dronlt Am1 htlf'nJ Mrtl J986; tOS: 303. Antineoplastics. For lhe elfc<:t oribuprorcn on 1he melabolisin
Effects on the blood. Blood disorders including agranulocy- S. Mclndrc SC. "' nl. Acute flank J)9Jn 1nd re.ver.liible ren:il d)'S- orpemt!IYl!)(ed, see p.838.
(unctit'n associ.itC'd with non,h:roidat ~ti··inOa inmatory drug
tosis. aplastic anaem ia .' pure white-cell aplasia, 1 and use. PN°HJtrics 1993; 92; 4 S9-60. Aspirin. II has been suggested lhat ihuprofen may reduce the
1hro111bocy1openial have b.:cn rcponcd in palicnts taking ibupro- 9. Wanad A.~' nl. A unique c~mpl 1cllion of nonsteroid3I antt-in· catdioprotcctive effect or asi1irin bu1 see NSAIDS, under lnter-
fen. Fo1al l"1emoly1ic anaemia occurred in a man laking ibupro· Oanunatory drui us.r. Pcdfotrlc1 1994 : 9l: 693. ac1ions of Aspirin. p.24.
fen and oxazepam.•
Effects o,, the liver. Raised liver 1ransaminase wh.><.-s were Lipid regulating drugs. for n repon or rhabdo01yolysis and
t. Gr) re Cl. Ru~n.ahl S. A1rur.ulucy1osis and aplasuc ancania
pj>Ssibly due to il'luptof~'· C"" Mtd AssocJ 1976: 114: 877. nolcd in 3 r,1icnts with chronic hepatitis C infe<:lion after 1aking renal failun: attribu1cd 10 an imeraction bclwccn ibuprofen and
~. M:;unu.s SW, fl ttl, Jbuprofcn..associa1c-d pure whi1e--ccll 1plu1a. ibuprofai. Values mumed to nonnal on stopping 1he drug; the
ciprojil>ro1t . see p.l 3S7.
N e..1 u M~d 1986: 3 "' 6H-~. effect rccWTed in one p111ien1 who was re-e)(poscd. Other hepatic
3. Jain S. lbuprol'Cn-iodun:J lhnxnbuc:y1Upcl'liJ1, Br J C/lu Proct adverse cffccis reponed "ilh ibuprofen ioieludc hepati1is2 and Musd e relaxants. /Jodofe11 1oxicity may dcvelOfl after starting
199~: 0: SI. . liver failure.' ibuprofen: for further deiail!<, see p.2052.
4. Gufdry JB. ~'al Fatal autoitnmunt' hcmaly\ic ancmi3 :iuocia1ed
w11h ;t>uprofcn. JAMA 1979: 242: 68-9 See also Effccls on lhe Skin, ~low.
I. R'ltyTR. Smith JP. lbuµrofc1\·induccd hcpatotoxicity in patient• Pharmacokinetics
Effects on the cardiovascular system. For a discussion of 14•Jth chTonic hcp.1tili.s C: a c.:is.c ser•cs. AM J Go1trocnlet'Ol l Ql)S; Ibuprofen is absorbed from the gastrointestinal tract
1he cardiovascular effcctJ ofNSAI Ds, including ibuprofen. Se<: 9J: 156:>-5 .
and peak plasma concentrations occur about I to 2
p.100. 2. ~:~!;n~~ t,!;,'J!~ 2a~~~~ :r::~o~~~ prise d.ibuprorent. hours after ingestion. Ibuprofen is also absorbed on
Effects on the CNS. Asep<ic mcni11gi1is has oc:cu!Ttd in pa· .~. Rodrigucz.-GonU ln FJ, et of. Orthot0pic liver uansplt1ntl\1ion
1icnls 1oki11g NSAIOs. A review 1 of NSAID-rcla1cd CNS ad- l\Hcr subac,uc lh"t"r (•ilurt" indu~cd by therapeutic dosn of ibu-
rectal use. It is pa1tially absorbed after topical applica-
verse dlec1s summarised 23 lilerature reportS ofNSAID-associ· prorcn. A"' J Gosr""'n"ro/ 2002: 97: 2476- 7. tion to the skin; some licensed product infonnation
The symbol t denotes a prepara1ion no longer actively marl<eted The symbol ® deno1es a substance whose use may be restricted in cenain sports (seep.vii)
68 Analgesics Anti-inflammatory Drugs and Antipyretics
state that percutaneous absorption from topical gel is 500 micrograms/cm2 of ibuprofen for the managemcnl Single dose, ornl ibuprofen is an cffee1ivc analgesic for the trcat-
about 5% of that from an oral dose fonn. Ibuprofen is of ulcers and superficial wounds. 1ncnt of postoperative pain.~
90 to 99% bound 10 plasma proteins and has a plasma I. Underwood M.,, ol. Torie-al or on1I ibuprottn (or d1ronic knc.c
Ibuprofen is usually given as the base but derivatives, pain in oklc1 people: the TOJO 11udy. 1Jral1h TC'cltnol Assc.u
half-life of about 2 hours. l.t is rapidly excreted in the including various salts, esters, and other complexes, 2008; 12: 1-176.
urine mainly as metabolites and their conjugates. 2. Omy C. ~ ol. Single dose oral ibuprofen (or acute ponopcrati\'C
have also been used. 'These include lysine (see Patent pain in 1duhs. Available in The Cochrane Dat~basc o(Sys:ccmal-
About 1% is excreted in the urine as unchanged ibu- Ductus Meriosus, below) and sodium salts, guaiacol ic Rc\•iews; Issue 3. Ch.tchc-s:tcr: John Wiley• 2009 (accessed
profen and about 14% as conjugated ibuprofen. There and pyridoxine esters, and mabuprofen (ibuprofen J.S.'09/09).
appears to be little, if any, distribution into breast milk. aminoe1hanol), isobu1anolammonium, and mcglumine Patent du«us arteriosus. Ibuprofen or its 1)-sine sail niay be
gh'Cll parenter.iUy for the lttatment of palent ducluS artcriosus
The above figures refer to racemic ibuprofen. Howev- derivatives. (p.71) in pn:tcnn infants of less lhan 34 weeks' geSlattoo; doses
er, ibuprofen's disposition is s1ereoseleclive and there Ibuprofen is usually given as a racemic mixture but arc expressed in tenns ofibuprofen. Tuceilltnvcnousdoses(in-
is some metabolic conversion of the inactive R-(-)- preparations containing only the S-(+)-isomer dexibu- fu5ed over 15 minu~) arc given at 24-hour in1ervals; lhc initial
enantiomer to the active S-(+knantiomcr, dexibupro- dose is equivalent to 10 mg/kg of ibuprofen followed by two fur-
profen (p.41) arc available in some countries. lher doscs of 5 mg/kg. lf,48 hours afterihiscou~ofthcrapy the
fen (p.41).
Administration in children. In the UK. 1he following oml ductus remains open, a second course may be given, bul if 1his
0 References. doses of ibuprofen, given according to age, are recommended by produces no response surgery may be necessary. Ibuprofen injec-
I. Davies NM. Clinic.al pharmocokinc1ics o(ibuprof~n: 1he lit s.I 30 01e BNPC 1010/l I for lhe 11ea1men1 of pain, inOammalion or tion, when give11 as the base, should be used undiluled, bu1 if
years. Clin Plwrm~okinwt 1 998~ J.4: 101 -54. soft·tis~ue injuries, or fever in children: necessary ii may be reconstitu1ed wilh sodium chloride 0.9"/o or
or
2. Sh.3mL3 PK.1tt ol. Ph1nnacokinclics or1I ibuproicn in prcma· • I to 3 months: 5 mg/kg 3 or 4 times daily
glucose 5% for injection. When giwm o.t the lysine salt, it should
mrt inlanlS. J Cl/" Phormocol 2003143: 968-73. be diluted wilh sodium chloride 0.9% or slucose 5%.
3. Gregoirt' N. et ol. Popul11ion phamlttokineti.c:s of ibuprofei1 • 3 to 6 months: 50 mg 3 times daily For a suggestion that ibuprofen migh1 be a better choice than in-
cnantiomers in very premature neonates. J Clin Phormocnl • 610 12 mon!hs: 50 mg 3 or 4 times daily dometacin for lhe trea1men1ofpatent ducrus aneriosus,sce p.71.
2004; 44: 1114-2~.
4. H..n EE. et al. Phannxokirw:tks of ibuprofen in children with • I to 4 years: 100 mg31imes daily P reparations
cystic fibrosis. CUn PhonltocoAintt 20CM; -43: 14S-S6. • 410 7 )'QIS' ISO mg31imcsdaily Bl' 10101 lbup<o!on~~c.t~Or.. ~lbu­
S. Hao H. et al. Enan1.iosckc:1ivc ~macok1nc.tK.s of ibl."Profen prolen T-ts: ~ b.Or'Ofen ~ ~'tt!e
and involved mrchanis.rns. f>n,g Mttob R,.,2oos; 31: 21S-34. 7 10 I0 years: 200 mg 3 times daily lbuptofon Toll!e'.s
6. Kyllonen M. <1 ol. P<riopcrlliw plltnnKdciooi<S of ibuprof.., • I0 to l 2 years: 300 mg 3 linies daily USPJJ:~lcnitld~H)O-oc-Tabteu:lt>Jpt'olen
~s._..;:,n:~ Tlt>lds.
cnat\tiomers aner redal adminiMrthon. PtHdtOlr Anottth 2-00S:
IS: 566-73. • 12 to 18 ~ars: ini1ially 300 IO 400 mg 3 or 4 limes daily in· Propriet..ry Preparations (deuils are given in Volume D)
7. Kokki H, t1 al. Ce,.,brospintl Ou1d d,.1riboition or ibuprofen af- creased, if neccssasy, IO a maximum of 2.4 g daily; mainte- Arr" Ad10tt AcUl!em; Afebril Alii<>l>t'olt":t: Atomo Desin.'bmontc lb-<
ttr incra.venous adininiJlration in children. Abstract Ptdiatrics nance d06es or200 tll 400 mg 31imcs daily may be adequa1c BOWytt. Butidiora: C.usolon lbu CoO<on: UOIOCCO<t. Dolonyrc Drui.e:
2007; l?O: 882. F1bop; Fet>ritic: font<Jt lbu; lbu fvanot: lbu-l.adyt: bu-N<Mlp>o: lblbe-
for more stiotre sympton1s iu children aged between 3 months nitot lbutalmin: llxJclet: lbufab<a; lb.lb; lburull lll<Jl>m: lbulNt; lb.,,.Jltin;
Full version: http://pedi111rics tutppuhlica1ion5.or31cgifreprinlf
120/41c!002 (a<eesscd IS/09/09)
and 12 years, a dose of30mg/kg(maximum 2.4 g) daily in 3 lbupf; tiupir.ic: lbupire-ulS: tluprolenh<; lbuprofel<: tbul( lbU1¢I: lbu!umalf;
or 4 divided doses may be given lbvtenl<: lbuxim; lbuzid'1e: 1<.esinf; Matli><: Novo Goniol: o.bll: P•l.<.n~
8. Gregoire N, et al, Population rhumacokinc1ic analysis of ibu- f'lonnj 11ujer: F\lnst>-< F\lnslnet1<: S.IMo: S<fldot TC(l(i>c; Ton>I: V.fren: Aus-
profen eoa1l1iomcrs in prctcrm ncwbom infan1s. J Cliu Pb(Jrmo·
co/ 2008; 48: 1460-S.
Jn the USA, suggested doses for children aged 6 monlhs and over
arc: for fever, S 10 IOmglkg (depending Oil the severity of the
tral.: ACT-31: Ac1pofcnj: AO.' 8'vf<<r. D•net1pp Poin & F...,. Relief:
N"'°lon: PrOYCI'.: Rafe>: Tri-Prolen: Au11rlo1 Advilf; Aktrto; .-.,.1onet;
(ever) and for pain, I0 mg/kg; doses may be given every 6 10 8 en.rm: Di.,,.not Neu: Delp: Oolbut, Dolofort. Dua:cn: lbllj: llludolt:
Uses and Adm inistration hours up 10 a mL•imum daily dose of40 mg/kg. Wemt; lbull"tt; lbumotJn; l!>upronj. lbut"f" lmb<.nf; l<ntalzjr< Motne11t0<
Nvrofie>c Nurofen. l'e&!o; nlioDolor: Tb:.nf; Bet1.: Adulftn l)'Sin<: Adv;I
Ibuprofen, a propionic acid derivative, is an NSAID Jn Oie treatment of rheumatic disease includingju•-enile idio- Mon« BNfer< l!upmphar: Oolol<lc ~ ~ lbu,Slc>.Nf; _ ,
pathic ar1hri1is, 1hc BNFC 1010111 recommends a dose of flMq>: p-.ilcnf: l".a'afene; N"""'°"'t. Nu°Of<n: Optaklon ~ for.

=
(p.103). ltsanti-inflarmnaiory properties may be weak- rn.Ao:Pedeo: ~ ~ ~Pro.encff:~t $pd-
er d1an those of some other NSAJDs. I0 mg/kg 3 or 4 limes daily (maximum 2.4 g daily) in d1ildren ""Bro<.: An!""!en: Ad'~ A'&dt>c.l'll)l•'llrodbij. AIMunt NvlOalsy.
aged 3 lllOllths and over; if neccssa1y up IO 60 n>g/kg daily in 4
Ibuprofen is used in the management of mild to mod· IO 6 divided doses (maximwn 2-4 g daily) may be gi\·en in sys. ~L~~~~~-~
crate paiii and inflammation in conditions such as dys- Jemie juvenile idiop:illiic anhritis. A usual daily dose in 1he USA Cot>Od" Moot Mo>.'"1: Mori< No<o-froWc p~
"'4>t<>fcr<
Chli.: Acttor< J.6<dj; Bedatl Deucodot Oolot\Alt E..,,tcm< Forto;>i.'j:
menorrhoea, headache including migraine, postopera- for jll\.,nile idiopalhic anhritis is 30 to 40 mg/kg in divided dos· II><~ lbu-6t: ~ rpso.-c l<i<Motm.Niolcr( ~f'Wooat
es. l')t>pect Uent; c..: A<Ml &roe: ll<'\l<r< Do1ii<: lbllv< 11><.t>ett llludolc<:
tive pain, dental pain, musculoskeletal and joint iburrwc lrl'c1>j: NJolen; ~Advill<Ct~S'topinxP>biprofenj;
Similar dosage regimens are also suggested by UK licensed
disorders such as ankylosing spondylitis, osteoarthritis,
and rheumatoid arthritis including juvenile idiopathic
product information for all the above indica1ions; however, ibu·
profen use is nol gener•lly recommended in children weighing
~~i~~~~~~~~~~:t,";~~.;.t~:
N: tJum»< 1i...r..-~: tlusat t>wi>I. l>u>art f,, AcJ,d; A~ AA'""et1C:
arthritis, pen-articular disorders such as bursitis and less 1han 5 kg or under 3 months of age. Biatain·lbu 6<ufet1: Oolgit Oo~aquef: Erg;x: E•panfc11: Gclufc,.,., He·
tenosynovitis, and soft-I issue disorders such as sprains m.genc Talleuc: lbutop: lnttalgi' N1Rllcx N<Nofe11: ~rof01lll.uh: Nuro·
For post·hnmunlsation pyrexia, a dose of50 mg has been rec· fenpro: Nurofentlb~ Pede a; SoUfen; Spc6fcn: S(>'ferc Tiburon< Uplen; Ger.:
and strains. It is also used to reduce fever. om1nen~ed; a scoond dooe may be given after 6 hours. If the PY· A<M!1: Al<\ren; Aoco; Biatain-1>1.< Con~rineurtlt. Dismcnol 1~: Dolrit: Dole
rcxia pcrsisL• after !he second dose, medical advice should be S.nol: Oolo·P'-""'< Doloberie !1'1; Dolodoc Oclorrnon: Esprot1it; tud0<lin
Ibuprofen is also used as an alternative to indometacin sough1. Infants aged 2 10 3 month.• may also be given a SO-mg Extra; Eud0<lin Migr•ne: Gyno-Ne'-"•'8irc ~u·iort lb..< lbu 8eru-ont. ot>u-
Auntin: tbu..-•llopllarm b<tj; lbl.>bela; l>.dolor: lbulun: IW:iexol: lbumer·
in the treatment of patent ductus arteriosus. dose of ib11profen for post-immuni'3tion pyrexia on 1hc advice of def. lbuprort; but>d lbvtop; lmbun; Jcnaprofcnt: Kont.>.-l>JX Mensoton:
The usual oral dose for painful conditions is 1.2 to a doclor. Moitra'WI lbuprol<rc Netnig<>...,.. mA lbi4".rolcn: l'U'ofon: Oplahdon lbu.
Ibuprofen or i1s lysine sail arc also used in lhc lreahnenl of pat- Opturem: P•soit Pede>: Plelt Sch.'"""·OolJll: Spill t': 1\boion:r-11>u-
1.8 g daily in divided doses ahhough maintenance dos- 00: 10ga1 Akut lbuptofeot T~ Tus..,,,.. 1",.._ undSchm<n·
es of 600 mg to 1.2 g daily may be effective in some ent ducfus artcriu•w. in prct.-011 infants; dosage de1ails for this ••lll<nm Ur= Gr~ A<Mt Al;!oCrer< Sn.It« BuK.....,.. Chrcblcrc OM:
indicli1ioo arc aivcn below. fo<us; ~ lbodczit~~ l.ondoclact: ~ f'Nfor: Ro-
patients. Jfneccssary the dose may be increased; in the
UK the maximum recommended dose is 2.4 g daily Cachexl11. For refUtllce to the use ofibuprofen wi1h megestrol
,..,... Hone Kong; AcWt S'-. &..pogcsict: Con.al
~ tb<Jac lbupenf: W.C.h'C~~~of:~·
"""°""" Oob-

lo treat cancer cachexia, see p_2322. dm Prdtrt IWer< Sch.lent~ Si<l>l'Ofett Zo1enc Huni.: Mlt Al-
whereas in the USA it is 3.2 g daily. Modified-release fl>llo>< Oolgit: fbno.Prttt..f: Wost: lbuml>C brtop: Mellerc """"""
preparations of ibuprofen arc available for once- or Cystic fibrosis. In potients "ith cystic fibrosis (sec p.176), 1he Solpo'le>cf: Spc-. India: !!ruble B.Mlenf. ~ tlu&OllC bipol In-
inOammotory response to chronic pulmonary infection wi1h don.: An>!<n: Anl'den: Sol<ct; Oofcn: Do:cle"-f: E1t.fcn: r..,.r.n: fe.
twice-daily dosing, ahhough acrual dosages vary with brynf: Fe«11; lprox: l""'P"'"''" Mor... Nofemt: Osu.rrc Prifent Pr°""'
different preparations. Pa1icn1S with rheumatoid arthri- Pse11domo11as organisms contributes lo lung dcslruc1ion.
NSA1Ds have been studied in patients with cystic fibrosis os an
Proni; Pr""1al: Rl-..wtn. Ribunat Slldrorc<if; Sped''"'" Y•l'W1: Ir/.: Advil
llrufe<>; Bvfigent; &.11!cx; Easolor< fCIY.)!lin..-; lbufel: M•lft« N...-o!en: N...-o-
tis generally requin: higher doses of ibuprofen than ahcmalivc to cor1icos1croids to reduce pulmonary inflammation. fen Adv.10r.r. Pedea: Fhot'ptlirc ProP.ex; Prol-J'IC {o.1'ent. Israel: Adex. Advt
those wiU1 osteoarthritis. The recommended dose for Sonic revicwsl.l found evidence in supporl of using high-dose ArlofOtX lbuf<r< lbtleve: N1.ro"'1 lrol.: Algofc.'fl: Antalfcbal: Anl.olfO<t /Jvi.
,.ll!il: Anialisin: Men; Benflogint; &-vferc BU!Cofcn: Catminc: Ciba!gina Doi:
fever reduction is 200 to 400 mg eve1y 4 to 6 hours to NSA lDs, mos1 notably ibuprofen, 10 slow the prosression of
a maximum of 1.2 g daily. For oral doses in children, lung damage in pa1ients wi1h cys1ic fibrosis. However, !here a.re g~i~~ ~~~ ~~t=~"~fi:~~~:~:~
limited data about lbe long-Jenn safety of high doses' and some ~;olv, flodo; ss-.oev. Spidifcn: Stb.1ene: Moloy•lo: &le" SNr.,,. Jbuf•c:
see Administration in Children, below. oonsider tha11liis may have limited such use ofNSAIDs;> olliers lbuftnt: Nurot'or< Peror.n: RLpont: Spediren Mu~ ABl<t. AarcN1 "6vont.
M<l Afl..&'t A.t1exf: Aldo!er< Algjdol. eesufetl< Carone: C..:g>n: Dadd
Ibuprofen may be given parenteraUy by intravenous remain to be convinced that a benefit has been shown.• Fwther-
mon: there were suffocicn1 dala lo ra:ormnend 1ha1 NSAIDs be
O.ys: Dioufent o;por.n; o;;irodo>, Oolpt"' Oolprof«'c t)ol,.?J:
E<Mn1: febralict. Fdoir>Q: fl<><af<n: Gelidol: Gotrowi-c lbu:l;m; bh>C
°""""'=
infusion for the management of mild to moderate pain 1cinpon1rily stopped when inttavenous aminoglycosides llr other 11-t~Ma>ale<'(~Mep\Jl'.raf;Mo!MNo~-t:
and as an adjunct to opioid analgesics for moderate to ncphrcM~ic drup are used.' J'ro.XB: F'ro>nNt l'robl.o<i. Quochx Reolch>c Rbifr>t: Til>M>n: Noth.:
severe pain, and for reduction offever. For painful con- A6.t Br-.ifen: F~ 11xsn: R>Jgrf; "-\roltn Pede.. Rot0t ~t
I. Lands LC. Stanojevic S. Oral non•s1eroi<bl IJ)ti-innammatory
ditions, 400 to 800 mg may be given every 6 hours as
necessary. For fever reduction, an initial dose of
ttm1 dw:rafly (tlf' cy\.OC f1btMi!.. Available in The Cochrane Da-
tabase ofS)')-lc:n\llhc: Rcv1c~ ls.sot 4. Chichester; John Wiky;
~ Z>lc<t Norw~ 6r""'1: bJmot.n. lbup<o>r: lb..oc """°"'NZ: Kl'l
~ f....- hJc>stj; ....... """*11 Me-one:
H.ida<he; Pan;f<n; PMipp.: A<j,;l Bru~f; OcWen: OolM'( hs;>C:
N"°""""'5ion
2007 (ecccsscd 07111/07). Gtn.ebx; ld)t Med::ot Midot - _ . . Pol.: Apro!enc llolrnett; Dftp Re-
400 mg may be followed by 400 mg every 4 to 6 hours 2. Kon.st.In MW. Ibuprofen lhcnpy for cystic fibrosis lung di1e:m: htif; Dof&il: bo!fr< !bu~ lblm: b4lOf. ~ l'Uo'erc l'llrden Mi:<e·
or I00 to 200 mg every 4 hours as necessary. Regard- revisited.c.,,., Opilr P,1/m Med 20(.)S; 14: S67-7l. not Ped<a: Pott.: Anad>it Ar.en; Barcx: ll<vlen: C.lbnJrc Ooloc)'t Oolc>-
ITlllt: Oolorminj: Fa.pc; F..-.b..c Fenpoc; fnr.dor: l:>vpo>cf; Jurilcnf: Kifet<
less ofindication, infusion time must he no less than 30 3. fC'flnel PO. ct ol. Use ofhigh·dose ibupfofcn in o pe<li1nric cystic Lldt<fen: Moment 11otrint; Nolofene: N~rc N'4'flklnf: Nurolen:
fibrosis center. J Cyst Fibros 2007; 6: I 53-8. Oz..,ol; Pede.: -~ Pl\Jooftnt: Secto6n< Solurcrc Solvum: Spicl;rcn;
minutes and a dose of3.2 g daily should not be exceed- 4. Bush A. D:1vin J, Non! 10 no11·steroidal an1i-innamrna1ory 1hcr- Sporfcn: Triutmi: Tlirene: Zafen: Zip·A·Dol; Rus.: Aldosprzy
ed. Ibuprofen is also given parenlerally for the treat- 3py for inO:unm~tory lung dista.\C in cystic r. bf'~si~ (01 lta$1 :u (llAbAoc"'°"); 61.rana (6)1>aH>): Dol11c CA<>'n<T): Faspic (<l><c""): lbalgin
ment of patent duetus arteriosus in prel'erm infants; for the moment). J Ptdlo1r 2001~ JSJ: 228-30. (11G;w ...); lbufen (116NeH): Mig (M•r); N...-oren (Hyp*'): l'.:dca
nu.c>); S~flex (Cc-Ma*-'.e..:t, S.A(r.: Adle!\: Ad~: ll<'t>ges<: S.tapro·
details of doses, see below. Pain. Findiniis from a long·tcnn study' in 585 pa1icn1s (mean le<>: &vfeti: lbo9'tn: llugesic lbule.et: lbum•<t: lbumtdj. lnzo: Norllam Tf;
tWmftn: Pcdea: Ran'cn: Si11gopor~; S.fen: b.I~ Nuro!er'C Zorert Spo;.n:
Ibuprofen is applied topically as a 5% cream, foam, age of 64 ye:irs) wilh knee pain suggeSled thal oral and topical
Ad'JI! ~Y Analgeito: All'asdn: Alg'd-fl: Aloge11a: Alticrt: Apiro-
gel, or spray solution; a 100/o gel is also available. It is
ibuprofen had an equivalenl analgesic effec1although1he former
was associa1cd with more minor ad,·erse effec1s; there was no '""°',...tialn: flab)pnit eexr.:w:C.lmalliert Dad.>set o.i,y. o;k;x: t>cc.
trt Oo:bufent; Dolorac: Ooriv<I\ EIPOI""' F>e1opar< F """"in.
f,,,...,,..,
also used topically as a dressing containing difference in lhe rate of major adverse eftects. fiedosor1' Ftenatmmt Gelobulen <Alofencx Ge:op.i: lb<bo..x: bl.N!Nld
All cross- references refer lo entries in Volume A
 lbuprofe'lllndometacin. 69
Preparatio ns cause precipilalloo of indometacin. Vosuol incompotibility has
Proprietary Preparations (details are given in Volum< Bl been reponed bctwttn indomctacin sodium injection and tolazo-
Spain: Nlil~t. line hydrochloride..' 7.5 and IO'/o £lucos< in~tion. calcium glu·
con3le. dobu1aminc. dopamine. cimclidinc,.. genumicin suJfate.
~vonoxacin,) aud tobramycin sulfotc.' A pl I below 6 may ac-
count fol' lhe YiSua) illOOCllfl"tibiJity Ofindometaein sodium and
lmidazole Salicylate (i!NN) ~-··or lhese dmgs.
lmiOuole. Saficylate d': lmidazolo Salicylas: Salcilato de imldazol. l. M•rquardl ED. Vi~uu1 compa1ibililyo(1oklzoline hydroch1ori«
lrnidalole compounded with ~ficytic acd with. "'ariou.s rncdicct1ons d\ninc s1mul.:ncd Y-sitc injcction.AmJ
Hosp Phann 19<JQ; 47: 1802- l . ·
illMl1A3)(llla ~T
2. lshisaka DY.'' e1I. Vt~ u ;.I eomp:nibili1y of mdomethacin sodiurn
C10H1GN20l 206.2.
CAS - 36364-49-5.
= 1rihydratc whh drugs .:h·en to neonates by continuous inrusion.
An1J HospPJ,,,,.,., 1991 ; 48: 2442-3.
ATC - N028Al6. 3. Sahsmo.n CL.« ol. Compatibility of lcvonoxacin wi1h 34 nw:di-
ATC Vet - QN028Al6. c.ations dunn.c s1mula1td Y-sitc tH,tminis1ralion. "'"' J Henl1h-S)-s1
UNU - 4JVD4XOIM). Phurm 1999; 56: 14!'$-90.
4. l"hompson OF'. Hdlla NR. lncom)»libilit)' of ioj«tablc in·
d('lmcthacin wilh gemarr.icin 1ul(a1c or cobt:unycin sulfate. Am J
ll<>s/J Pharm 1992: 49: &36-l!.
Stability. A reconstituted solution of indomet3cin sodium
500 micTo<~'Tllmsiml.. was st.able for I4 days when stored at 2° to
6° in either the manufacturer"s original glass vial or in a polypro-
pylcoe syrinae. 1
I. Walker SE. 11 al. Scabilily or rtconstitut~ indomr:1h1cin sodium
lrihydroitc in orisinal vials 3nd polyprop)'titne syrin:cs. Am J
lltolth..S.rst Pltnrm 1998; 55: 1S4.o.$.

Adverse Effects and Treatment

As for NSA!Ds in general, p.100.
Profile Adverse effects are more frequent with indomeuicin
lmidazole salicyfalc is a sali~-ytic: •Cid derivativo (sec Aspirin. than with many other NSAlDs, the most common be-
p.21) U>at has been uS<.>d in lhe 1r.:aln1t:nl offc'"" and inflamma-
1ory uspiratory-irael and otorl1inolaryngeal disorders. hnidazole ing gastrointestinal disturbances, headache, vertigo,
salicylate has been given in oral doses or up io 2.25 g daily in dizziness, and lightheadedness. Gaslrointestinal perfo-
divided do5es. It has also been given as a~ suppository and ration, ulcenuion, and bleeding may also occur; rarely,
has been applied topically as a 5% get for the relief or muscular intestinal stricrures have been reported. Other adverse
and rheuma1ic pain.
effeclS include depression, drowsiness, tinnitus, confu-
Prep arations sion, insomnia.psychiatric disturbances, S)ncope, con-
Proprietary Preparations (~ails are eiven in ~lume BJ vulsions, coma. peripheral neuropathy, blurred vision,
ltol.: Sdczen,
corneal deposits and other ocular effects, oedema and
weight gain, hyperrension, haematuria, rashes, pruri-
rus, urticaria, stoma1itis, alopecia, and hypersensitivity
!ndometadn (BAN. rlNNJ reactions. Lcucopenia, purpura, 1hrombocytopeuia,
Jndometacna: lndometac.inas: :ndcmetac~ lndomttacinuri'l; Jn. apl3s1ic anaemia, haemolytic anaemia, agranulocyto-
dometa~ lndometasiini: lndomet.asin: lndomethacin (IJSAN~ sis. epistaxi.s, hyperglycaemia. hypoaldosteronism and
( 1-(4·Chlorob<!r\zoyl)-S-methoxy-2-mcthylindol-3-yl)acetic acid. hyperkalaemia, and vaginal bleeding have been report-
ViH.AOMeT31JSllH ed. TI1ere have also been repo11S of hepatitis, jaundice,
C.,H ,6CINO, = 357.8. and renal failure. Hypersensitivity reactions may also
CAS - 53·86-1.
ATC - COIE603: MOIA801 : MOlAl'.13: SOl6COI.
occur in aspirin-sensi1ive patients. Rectal irritation and
ATC Vt< - QCOIE603: QMOIA601: QM02AA23:
bleeding have been reported occasionally in patients
QSOIBCOI. who have received indomeiacin suppositories.
UNI/ - XXE ICET956. Adverse effects associated with the use of indomctacin
inje<:tion in prema1ure neonates may also include
haemorrhagic, Jenal, gash·oimcstinal, metabolic, and
coagulation disorders; pulmonaty hypertension, intrac-
ranial bleeding, fluid retention, and exacerbation of in-
fection may also occur.
Effects on the blood. There were 1~6t reports of 1dvcrsc re-
actions to indome1ac:in reported 10 1he UK CSM between June
1964 and January 1973. Th= included 157 re1)()fts ofblooddi.s-
orde!$ (25 fatal) including thrombocy1opc11ia (35; 5 farat), aplas-
tic anaemia ( 17; no fatotities). and •ifanuloc)10Si.s or leuoopenia
(21 , 3 fatal).' Subscquenlly, the First Repon from the Interna-
Pharmacopoeias. In Chi11.. £111: (see p.vii). /111.• Jp11. US, and tional Agranulocytosis and Aplastic Anemia S1udy conlinncd a
Viet. significant relationship be1ween 1be use of indomelacin and
Ph. Eur. 6.8 (hlomet.acin). A while or yellow, crystalline pow- agranulocytosis and apl:ristic anaemia.~ Neutropenio has t1lso
der. Practically insoluble in water; sparingly soluble in alcol1ol. b<:<!•1 noted in a pn:mat\lre infant with patent ducrus artcriosus
Protect from lighL after use ofindomctacin.'
lbuproxam (1:NN) USP 33 (lndometnacn). A pale yellow to )"'llow·tan, c1ystatlinc
powder ha,.i11g 1101 more d>an a slight odour. It <xhibils polymor- Although use ofindometacin in 20 women being lttated for pre-
lbuproxatru'n. 4·1sobut)lnydratropohydro><arrrc acid. mature labour did not affect maternal protltt0mbin or activated
phism. Praclicully insoluble in water; soluble I In 50 of alcohol, pc111ial tlu'0111boplastin 1imc, mat<mal blccdina time during thcr-
i116)Tlpo!<CaM I in 30 of chlorofonn, and I in 40 of rlher. Protect from light npy wn.s increased." HO\'•·"C'\-"CI') nn cases '.>f l\conAtal i11travcntrieu·
C 1lH,,N02 = 221.3. Stability. lndomelacin is unstable in alkaline solution. lar h.1emMrt1age or maternal postpartum haemorrllage were
CAS 53648-05-8. SCUl.
ATC - MOIAE13. lndometacin Sodium (e,W/.\•f'IM9 I. Cuthbert MF..4.dvcrst rncl1on1 co non.11~roidal ::in1irhcu1nalit
drugs. Om Mf!d Res 011111 JQ74: ?: ~10.
ATC Ve1 - QMOIAEIJ. lndometacina sO<foca: lndomCtacine Soclique: lndome-.hacin Soc!i· 1. ~ lm.crnacional A3rtmuloc)10Sis and Aplastic Anemia Study.
UNI/ - 03LDl6096Z um (U.IANJ: lndomethac"' Sodium Tnliydrate: Natri r.dometaci- Ri$ks of •p.1nul0t)'l01is 1tnd ap1astic anemia: a rirsl rt'f>'."C. of
nvm. Sodium 1-(4-<Norobe:\Zoyl)-5-metho><y· 2-mcthylondole-3. their relation to d1 U'1 U!C' with spcc·ia1 rcfcttnec 10 1n1l~c::s1 cs.
acetate. trihydrate. JAMA 1986; 254: 1749-57.
3. Ben~tsson 8-0S.. ~' ol. h1dorne1hacin..usocia1td ncutropcnia
HaTpHH VlllAOMCTaW.H with sublcquenl Gr11""--nep1ivc scpsi~ in a preccmt anfant: c.a~
c,,H,~CINNa0,.3H20 = 433.8. or coincidence? J Ptrinarol 2006: 26: 181-3.
CAS - 74252-25-8. .t. I unt CC. ~t "'· Tht tfftet o( indomethac:in 1oc<1lysi.s on maltfml
UNll - OIMX38MlGG. coogulittion s 1:111u. Olwt1 Gmrtol 1994; 84: 820-~.
Phannacopoeias. In US. Efre<ts on cerebral blood now. See P~tent Ducrus Arteriosus
USP 33 (lndomethacn Sodivm). P!'C>l<ci from ligh1. under Uses and AdminiStrMion, below.
Incompatibility. lndomccaci11 sodium inje(tion is reconslituted Etfeas on the eyes. Severe and inc>=ible re1in0pa1hy. pre-
Profile wi~1 preserYatiYl:·liee sodium cllloridc for injection 0.9% or pre- sumably due t0 loog·t<nn in:;:eslion ofbigjl doses of in.domciocin
lbuproxam is an NSAID (p.100) d1at has Ix-en used topically in servative-ti-cc water for injection. Preparations containing glu- occurred in a 33-year-old man.1 A summary of previous htcra·
musculoskclctol.joint. and soft-tissue disorders. cose should nOI be used; m:onsiitution at a pH below 6 may nuc reports of indonietacin-induced ocular effects indicated th al
TilC symbol t denotes a prepar11tion no longer actively marketed
10· Analgesics Anti-inflammatory Drugs and Antipyretics
indomclacin was rctinotoxic:, although to what dcgrcc was unccr- topenia or coagulation defects should not be give'n in - ta. Low concentrations have been distributed into
iain. For reference to effec.ts on the optic nerve associated with dometacin and those receiving indometacin should be breast milk. The tenninal plasma half-life has been re-
indometacin. sec p. I01.
I. Grahzm C~ Stach RK. Jndomcthacin rc'tinopathy: c.uc rcpon
monitored during treatment for signs of bleeding. Elec- ported to range from 2.6 to I I.2 hours in adults. 1be
ood rc>i<w. Br J Oplr1/rolmol l988; 71: 04-8. trolytes and renal function should also be monitored terminal half-li fe in neonates has been reported to be
Effeccs on the gastrointestinal tract. Nausea, vomiting. and if anuria or marked oliguria is evident at the time between 12 and 28 hours (see also below). lndomet-
dyspepsia, gastrointestinal lesions, and serious reactions inchxl- of a sclleduled second or third dose, it should be cJe. acin is metabolised in the liver to its glucuronide con-
ing ga51r0ir1tcstinal bleeding, ulcerauon, and perforation bn~ layed until renal function has returned to nonnal. jugate and to desmethylindomethacin, desbenzoylin-
occumd in patients receiving indomeiacin. Although it is well domethacin, desmethyl-desbcnzoylindomethacin, nod
es1ablished that NSAIDs =produce adverse effects on the up-
Falsc-negalive results in the dexamethasone suppres-
pa gastrointestinal tract, indomeiacin and other NSA!Os can sion test have been reported in patients taking indomet- to their glucuronides. Some indometacin undergoes N-
also affect the large intcstines. 1 Giving indomctacin tO prererm acin. deacylation. lndometacin and its conjugates undergo
neonates increases lhe nsk of small bowel perforlltion and nccr-
Breast feeding. Convulsions in a one-week old breast-fed
cnterohcpa1ic circulation. Excretion of indometacin
otising entcrocolitis.1-4 Risk seems lo be increased in veiy-low- and its metaboliles is mainly in the urine with lesser
infant appeared to be associated with mateln31 ingestion of in-
bitth-wcight or extremely premal\Jrc infants. amounts appearing in the faeces.
domctacin;1 the child had normal motor and menial development
I. Oren R. l.igumsky M. lndomtth»ein--induced colonic ukcra1ion at the age of I year and seizures had not rccwrcd.
and bJccding. A11n Phar1noco1her 1994; 28 : 883-S. 0 References.
2. Ciros(eld JL. et of. Increased risk o( n«roh11ng enterocolitis it> lndometacin has been detec1ed in breast milk, but some l. Moise KJ, et ol. Pbc:ent11I transfer or indomcthaein in the human
premature infants with patent d uctus ancnosus treated with in· worlcenU and tho BNF 59 cons.icier that the amount is too small pregnancy. Am J Obsr<1 Gyo«ol 1990; 162: S49-54.
domdhocin. Ann SU"g 1996; 224: :;so-1. tO be hamiful 10 a breast-fed infan1. The American Academy of 2. Mannila A. t.t ol Plasma 1nd cerebrospiR1I fluid c;ogcentrations
3. Shaner NA, 11 al. lndornttMcin·as.sociated bowel perforations: Pediatrics• also 54a1es that indomctacin is usually compatible of indonicth1cin itl chHd:ren after intn1vcnou.s adminissration. J
a "udy of pou;blc rill< factors.J P..tio1' Su-v 1999; 34: 442-4. C/ln Phormoco/2007; 47: 94-100.
4. Fuj.ii AM. Neonatal necrouz.ini cneerocolitis with intcstiMI pcr- with breast feeding despite acknowledging the above case report
foru ion in cx\reincty premature infants rccei\'ing early in· of convulsions. Howt\'tr, licensed product infonnation rccom· Half-life. 1bc plasma half-life of indomelxin in premarure in-
dometh:>cin 1rea1men1 for peccnl ducru:s arteriOS:t.l$. J Pninotol mend< 1ha1 indomeac:in should not be used in nursin& mo1hcrs. funts can be variable but a~ to be inveiscly proportional to
2002; 22: 53~0. I. Eeg..Olofsson 0. " nf. Convulsions in a breast·fed inf;11n1 after post-natal age and weight. One popula1ioo model suggests lhal
Effects on the joints. For references to concern that NSA!Ds mattrna.I indomcthacin. Umcet 1978: ii: 21S. for an inf.ant of 1.17 kg, half-life would be 22.3 holl11' at a post·
2. Seavlac·BaiJWtcon t . Alltrd G. DiWibutlon or indomcthocin natal age of 8 days, but 16.1 hours at 25 days (and only
such as indomctacin may accdenuc lhe rate of cartilage destruc- in human milk and estimation or ill milk 10 plasma ra1io in \'ilro.
tion in paticnlS with osteoorthritis, see Elfcas on Bone, under Br J Clm Pha,.mocol 1993; 36: 413-1 6 11.2 hours if also receiving digoxin).1
NSAIDs,p.100. 3. Lcbedevs TH. et ol. Excretion o(indofnefhacin in breast milk. Br I. Wica 08. (!t ul. Poputation pharmacokinctie:s of inttavc:nou:s io-.
JC/in PIK1rmocol 1991: 32: 7SJ-4. domclh:icin in neonates v.-ith symptomatic 1'3lent ductus artcrio-
Effect:s on the kidneys. Acute renal failure, 1 nephrolic syn- 4 . Amf'rican Academy of Pc:di3tric.s. The trtnJ(cr of drup and olh· sul. C'//nPhar~11>u 1991; 4': 550-7.
drome.1 and renal papillary necrosis' have been reported in pa- er chemiuls in10 human milk. Pediotnc1 2001: JOI: 776-49. 2. Smyth JM, ~I al. Jot.ravenous indomcticin in prcttnn infants
tiems givai indometacin. There have been suggestions \bat mis- [Rcti"'d M•y 2010) C01TccUon. ibid.; 1019. AIJIO ovailablc .., with symptomatic patc:nt d uctus ancriosus: 1 popubtJOn phanna·
oprostol might reduce the risk of indometacin-induccd renal ht t p:f/a • p pol icy.11ppubl i c.1 tions. org/ccilcon1ent/fu IJ/ co kindic study. Br J Clin Phnrmacol 2004; SS: 249-58.
tOxicity.•.s ped;a1rics'/.3bJOBlln76 (accessed 0711 1/07)
Renal impainnent has also occurred in neonates given indomet· The elderly. After a srudy1ofthe phannacolcinelics ofindomc1- Uses and Administration
acin intravenously for patent ductus arteriosus. Ahbough ran, acin in the elderly it was suggested that the mainlenancc dose of lndometacin, an indole acetic acid derivative, is an
and usually reversible, the effect may be serious in neonates with indometacin in elderly parienlS ~Id be reduced by 25%. The NSAID (p. J03). It is usod in musculoskeletal and joint
pre-existing renal disorders.• Serious or fatal renal toxicity has total clearance of indomctacin in elderly subjects had been re-
been reported in neonates exposed to indometacin due to mater- duced when compared wi1h thal in young subjects; lhis was
disorders including ankylosing spondylitis, osteoar-
nal insesiion.' The renal effects of prenatal indomctacin may be thought to be due to reduced hepatic metabolism in the cldc:rly. thritis, rheumatoid arthritis, and acute gout, and in peri-
prolonged.1 I. Obett>auer R, #I of. Pharmacokinr1ics orindorncth;,,cin in the eld· articu lar disorders such as bursitis and tendinitis. It
J. Chan X. Fata• ren1I failure due 10 indomcthac:in. Lo11c«t 1987; i i : crly. Clin Phormocok;ntt 1993; 24 : 42&-34. may also be used in inflammation, pain, and oedema
340. Pregnancy. See Premarure Labour under Uses and Adminisva- following orthopaedic procedures, in mild to moderate
l . BoUJcin I, el al, lndomcth1dn and the ncphrntic syndrome. Am•
lnr<rn Med 1987; 106: 776-7.
lion, below. pain in conditions such as dysmenorrhoea, and it has
J. Mitchell H, ~I of. lndomclhac:in·indu«d renal papillary MCtOJis been used in the management of postoperative pain as
in juvenile chronic arthrittS. Lonca1 1982; ii: SS8-9. Interactions an adjunct to opioids, and in the treatment of fever. In-
4. Weir MR, et of. Minimization or 1ndomtlhac.in-induced rcduc-- For interactions associated with NSA!Ds, see p. l 03.
tion in renal fi.anetion by misoprostol. J CUn Plturmacol 1991; dometacin is also used as die sodium salt to close pat-
31: 729-3S. Anti-inflammatory doses of aspirin decrease indomct- ent ductus arteriosus in premarure infants (see below).
S. Woni F, ~' ol TM effect of misoprostol Of) indomcth1cin-in-
duc<d renal dysfunction in wcll-compensa1<d citrllosis. J Hepa- aein blood concentrntions by about 20%. Diflunisal do. 1lle usual initial oral dose in chronic musculoskeletal
rol J99S; 13: 1-7. creases the renal clearance and increases p lasma con- and joint disorders is 25 mg two or three times daily
6. Cuzzolin L. '-' ol. NSAIO-ind\Jccd ncphro1oxicity from the fc1us centrations of indometacin. Use of diOunisal with
to th< <:hild. Drug Sqf•IJ' 2001; 24: 9-1&. increased, if required, by 25 to 50 mg at weekly inter-
7. Yan d« Heijden BJ, ct of. Persistent anuria, neon11al dea1h, and indometaein has also resulted in fatal gastrointestinal vals to 150 to 200 mg daily. To alleviate night pain and
renal n1icrocys1ic lesions after prenatal expos1.1re to indomcth· haemorrhage, and the two should not be used together.
>Cin. AmJ Obs/Cl Gynttol 1994; 17 1: 617-23. morning stiffilcss, up to 100 mg of the total daily dose
I. Butler-O'Hara M, o•Angio CT. Risk of pc.rsistcnt renal insuffi- Plasma concentrations of indometacin are likely 10 be may be given orally, or rectally as a suppository, on rc-
ciency in prc ma1ure infantS followin& the prenatal u~ of in- increased in patients rt:«iving probenecid. liring. Alternatively, lhe total daily dose may be given
dometl'l acin for suppression of prcterm laOOr. J P~inotol 2002;
11: S41-6. Antibact erials. tndometacin has been reported to increase rectally as I 00 mg in the morning and at nig)JL The to-
Effects on the liver. Cholesrasi< occurrcd in a S2-year-old plasina concentr.11ions of aminoglycosfdn. tal daily combined oral nnd rectal dose should not ex-
woman seven! days after st3J'ting indomcuicin; 1 hver function Antlpsycho tics. Severe drowsiness aod confusion have been ceed 200 mg. Jn acute gout the daily dose is 150 to
values returned 10 nonnal once indometacin wa.< stopped. reponed in patients given haloperidol with indomelacin.1 200 mg in divided doses until all symptoms and signs
I. C2ppell MS, ~I of Jndomc1hacin-as50ei1led cho1esta1i1. J Cl/11 I. Bird HA, r1 ol. Drowsiness doc to hak>pcridol/indnmc1hacin in
Gos1r0<>11uo/ 1988;tO: 44S-7. combina1ion. /.o1t<:tl 1983; I: 830-J. subside; in dysmenorrhoea up to 75 mg daily has been
Hypersensitivity. Hypersensitivity react.ions including acute Bo ne modulating drugs. lndomctacin has been reported to
suggested. Modified-release preparations of indomet-
utluna have been reported after use of indomctacin supposito- increase the bioovailability of tiludronore, see p.1218. acin are avai lable for use once or twice daily. For doses
ries,1 eye drops,2 or capsules' by patients who were aspirin-sen· in children, see below.
Dcsmopressin. 1bc cffccl of dcsmopressin may be enhanced
sitivc ur had a history of asthma. by indometacin. lndomctacin is used as 0. 1% eye drops to prevent mi-
1. Timrcrman J. A fata1 aahm3tic auac.k following adminl$uation
of an indomelh1cin nipposilory.J Fot'f111ic Med J971; 18: 30-2. Digoxin. ln addition to incre:ising digoxin serum coricentr:l.Jions osis during cataract surgery; the usual dose is 2
2. Sheehan GJ, rt of. Acute uthma a.Hock due 10 ophduilmic in- (sec p.1390), combination of digoxin with indomet.3Cin has been drops, repeated after 2 hours, on the day before sw-gery,
dometh>cin. Ann Int,,.., MN 1989; 1J1 : 337-8. reported to redllcc the half-life of the laner in premature neorni1es then 2 drops 3 hours before and 2 drops 1 hour before
J. John.~on NM. et of Jndcme1hacin·induced asthma In 1.Spirin..scn-
>ilivc palicnu. BM.I 1977, l: 1291. (see Half-life under Phannacokinctics, below). surgery. To prevent cystoid macula r oedema, 1 drop
Parasympathomim etlcs. Licensed product infonnation for may then be instilled postoperatively 4 times daily for
Precautions accrylcholinc chloride ophthalmic preparations has stated thal 15 days, decreasing to 3 times daily thereafter; treat-
As for NSAIDs in general, p. l02. there ha\'e been reports that a~l)1cho/ine and carbochol have
been incffcclivc when used in patients treated with topical (oph- ment should be continued until infl ammatory signs
lndometacin should be used with caution in patients thalmic) NSA!Os. have disappeared. A 0.5% eye drop is also available for
with epi lepsy, parkinsonism, or psychiatric disorders. the prevention of miosis and inflanunation associated
Dizziness may affect the performance of skilled tasks Pharmacokinetics with cataract surgery. lndometacin eye drops are also
such as driving. Patients on long-term indometacin lndometacin is readily absorbed from the gastrointesti- used in other inflammatory eye disorders; the usual
therapy should be examined regularly for adverse ef- nal tract in adults; peak plasma conocntrdtioos occur dose is I drop of the 0.1% strength 4 to 6 times daily
fects, and the BNF 59 particularly recommends period- about 2 hours after ~ dose. Absorption may be slowed until symptoms are resolved.
ic blood and ophthalmic examinations. Rectal use by food or by aluminium- or magnesium-contain ing Meglumine inctometacin and indomelacin famesil,
should be avoided in patients with proctitis and haem- anlaeids. In premature neonates, absorption of oral in- a lipid so l uble ester o f in dometacin
orrhoids. domctacin is poor and incomplete. 111e bioavailability (C 34 H40CIN04 ~ 562.1), have also been given for
In addition indometacin should not be given to neo- ofrectal suppositories in adults has been reported to be painful and inflammatory conditions. A complex ofin-
nates with untreated infection, with significant renal comparable with or slightly less than the bioavailabili- dometacin and L-arginine, known as indoarginine, has
impainncnt, or with necrotising cnterocolitis. Infants ty with oral dosage fo1ms. also been used.
who are bleeding (especially gastrointes1inal bleeding Jndometacin is about 99"/o bound to plasma proteins. It Administntion in children. Althougll indomelacin is not li-
or intracranial haemorrhage) or who have thrombocy- is distributed into synovial fluid, the CNS, and placen- censed in the UK for tlic tru1mcnt of rheumatic diseases such
All cross-references refer 10 entries in Volume A
 lndometacin 71
""juvonilc idiopolhic )r1lm1is in children. the BNFC }()()9 sug- when all primary 0<1tcomes s1.:h as death, cetcbt'll palsy, cogni· age or1hc neonntc and the followin! ~have b..-.:n ~ui;sc:sted
gest< au 01111 6ooe ofO.S to I mg1kg twic• daily in lhOS" oged I tive delay. ~nd severe intrnvcntricular hacmorrh:ige '4crc consid· based up<>n lhe age al lh< first dose:
month to 18 years; higher doses may be used under specialist crcd; however, "·hen ouicomcs W<:re oonsidercd individually, • less than 48 hours old: 200 microgt11ms/ka ini1i3lly followed
supco"Vision there was a significant rcduc:lion in intravc11uicular haemorrhage by two forther ~of 100 micrograms/kg caeh
lndom~acin is also used in the lrc::llm"111 or p•lenl duclus arte- in boys when compared -..ith girls. The a111hors oonsidcrcd the • 2 10 7 days old: thuc dos"5 of 200 micro~'l1lms/l;g each
riosus in 1••m•lurc i11fa111s: sec below roo further details includ- results 10 be a co11sequCllCCofan unra,ourable effect ofi ndomcl- • over 7 days old: 200 mic<Q!rams.lkg initially followed by two
ini1 llui.es. acin in :;iris ratl1cr than any positive effects in boys. Any INC fitnhcr doses of'.!50 microgramYl<g each
difference in effect between the ~cs rem:tins 10 be C(lnfinned.
Bartter's syndrome . The treatment ofBamer's syndrome can IC. 48 hours 3ftcr this course or therapy the duc1us re-mains open
ollen be difficult (sec p.1S15). Blocking the kinin-pcostaglandin lndomclac:in docs nol arpcnr 10 prel'Cllt lhe progression of exist· or re-opens, a second course may be US<d. but if this produces no
axis with a cyclo-oxygcnase inhibitor such as indomeucin im· ing haemon1lagc." response (which mny be the case in 25% of in fonts lreated~9)
proves hypokalacm1a end olher cl inical features (including I. Me:nl LR. ''al Ramdomiud 1ndo1nc1hatin uiil (ot prcvcnlion surgciy may be ncces.<ary.
o rinuawntncul~r hl:morthagc in very low birth weiahl in(nn1s.
growth retardution) in children with 1hc syndrome.'·5 J Podiotr 198S: 107, Q)7-43. lndomctacin has been givcu orally where the injec1ion is una\'ail-
I. Lilllcwood JM,t'I nl. Trt-atmt":ntof childhood 8Atncr'ssyndrom' 2. Rtnnic JM. r1 of. Early admini.scration or indometh:»ein 10 pre· ablc, but absorption of oral indomctacin is poor and iucomplete
wflh ii1. . to11)Cthocin. Lonca 1976; ii: 795. 1cm1;nronis, Arch Dn ChUd 1986: 61: 233 S. ln premature neonates.
c.
2. Sridcl Cl (I/, rr~·pubertal powlh in lht tiyperprostoglandin E J. Bad:i. HS. r:l ol. tndomcthaC'in r«lu-.:(1 thc risk~ or SC\~O: intra·
A decreased need IOI' surgic31 closure and reduced recurrences
'l''~"""' P•fi/(flr N•phrol 1995: 9: nJ.-8. vtocricul:ir hem orrhage.JP~io/r 1989; 115: 63 1-7.
; , Crti1 JC. Falk MC. l n d o m ~1h:ic1n for ttn:il im1>3irmcn1 in oeo.. 4. Menl t N. c1of l..ow..dnsc 1ndome1h:icin and prt\•cntion ofintr.· were seen in neonates in vthom standard intravenous indomct·
ont;:I 0"'1l(:r"S syndrome. lm1C'~ 1996~ :M7: S~O. ;:•~i~~r~;~~~~~8~: • mullic:cnter rundomizcd irial. Pediat· acin therapy was then followed br maintenance thcl1!py(inlr.l,'C·
4, Mounmi CC, cl ol. Oant<r syndrome in 1 neonate: early ln:.11· nous indomctacin 200 m1croi:rams.lkg daily for an additional 5
menl wi;b indome1hacin. Pedlntf' Nrphml 2000: 14: J43-~. S. Volpe JJ. Brain inJury caused by antrav~ntricula r hcmouhaae: is days). 10 Prolonged therapy using high doses of up 10 I mlllkg as
S. Vaisbicl: MH. a ul. Barner ~)'ndromc: benc'fllS and side cfr'cc\1 indom~th~cin the sil\ICr bullet (or prevention? P~Jia1rh:1 1994:
93: 673 7. a sioglc dose every 12 ho~ has also been usctl with some SUC·
CJf long-term lrc:atment. Ptdiatr Ntphrol 2004; 19; SSS-63.
6. Mcnt LR. ,; ol Ncurodevc1opmemal OUk:Omc al 36 mo.n1hs' cess in a few infants who ha'~ nOI responded to Standard regi·
Diabetes insipic!us. lndonK'IAcin and other prostaglandin syn· me::ns." Similar beneficial findiOgs were reportcd11 in infants
::'r~::r::,~';:~~~! ~~~c1~~:u::~~e;J=~9;~
1
tlietase inhibitors have been repoi1ed to decrc:uc urine \'Oh.nne in given prolonge d low- dose indometaci n thera py
all types of ncphrogenic diabetes insipidus (p.2380). 98: 714-18 (100 miaograms/kg daily for6 days). An addi1ional llenefi1wa~
1. Mcnl LR. tt ol. Out::om ~ of children in the 1ndonltlhlcin intra·
Rtforcnces. vcntriculi>r hcmorrh:agt' procntion 1ti:i1. PNittt,ics 2000: 10S: a lower incid<ooe of adverse cffect.s; rcwcr infants had a rise in
I Rosen Cit. ~f al. l ndom~hocin for ncphro1cnlc diabt-lcs insirid· •SS-91. serum crcatininc or urea conccntration:i;. HO\vc:vcr, 01 systematic
ui in a four·wcck·old inrant Clin Pho'•' 1986~ S: 2$4-6. '· Vohr BR. et trl. Sct.:>ol..ar: OUICOITU::s of W.Ty low binh \\"Cilhl revicw13 has .<uggcsted that such regimen~ arc no more effective
?. Libber S. elu/. Treu1n~ nt o(ncphmgcnic diobt tc~ insipic,h1s wilh infan1s in the indomttNc1n it\lrt\i:nuitular hemorrhage prc.,"Cn· 1han the sh<lf'ler Standard regin}(:ns, ond fo1•td an increased ml her
pnn1a¥):.ndin synthesis inhibirors. J P~dio11' 1986; 108: 305-11. cion 1rial Abslr.\Cl: Pedi111ri<'• 2003; JJJ: 874. full '·ers;on
J. A!lcn H M. n al. Jndomc1hocin in 1hc 1rca1mcne or li1hium·in· 1han decreased incidence ofadverse effects (including a !rend 10-
~~~i~~;~~iOaf,publica11ions.or;lcgj/concent/foll/1 1 1 /4/t340
dixcd ncphro3cnic dinbctc.-S insipidus. Arch lntrrn M#d 1989: 1"3rds increased risk of necrotising en1erocolitis"'). Prolonged
~tmcnl with indonicl3Cin could not be recoinmcndcd. 1} Pro-
~;!~;:;,~~·,!!~,~-~~1~.::~~~nfi~0,!;£~;j ~~"/Jo~~
149: tD:Hi. 9
.;. Manina El. tt ol. Luhium·illduccd nephrogcnic diabc1cs iusip· · phylaclic treaunenc or treatntont ofasymp1oma1ic ductus v.1th in-
idus ln:;ited wit.h indo1ncd1acin. Somh /tf~J 1993; 86: 971-3. 34,: t966-72. domctacin his heen hied in pr<matute infants, and there is good
5. J-jnhler T, rt ul lndc.wnclhacin 1 r~1mc 1ll in a1)1photerkin 8 in· I0. Fowlie PW. Oaivis PG. Prophylactic indomclhacin for prehmn
cJu1.:-.:d n cph~<nic dlatk1cs insipidus. Clln lmwug I~; 72: infan\.s: a sys;1em:a1ic rt-view and mcta-ainalysas. .4.rrh D;s Child evidence to suggest that this is dfteli"c in reducing the risk of
i69 71. Ftwl IJ<<>•IOlul £d2003; 88: F464-H66. symptomatic patent ductus aneriosus and in1raventricuhir hacnt-
6. Lim SS, K.j cllt.u·;mdC. Emc~cncye ren1 ni ent of lithium-induc:cd It. M tnl LR. e/ nl. Pttvcn1ioo of intrn\lcntrieular hemorTha!'C' by orrltage (see above) in such patients;'·"·" l!O\<~'~" prophylactic
d1Jbctcs insipidus wilh no:is1cro1d1I im1i.inOAmmatory drugs. ind<"mtthtcin in mile pn1c::rm infnrns. J Pt•diatr lO<M: 1-&5: 1rcabnen1 has not been shown to signifieMtly reduce the risk of
Rtn Fail 1997; 19: t83-3. 832-1, sho11.1enn pulmonarycomplicatiotts such as bronchopttlmon:uy
12. Ohlsson A. ~'of. Malt/(cm1lt differences in indomtlhacln e(·
Martgriint neoplasms. In eoonmon with some other NSAIDs (.:cu in prctcrm inf:tnls. J Ped;.a,, 200S; 147: $~2. dysplasia. Sysiema1ic reviews"·" have also found no C\'idcncc
(Stt p.104) ii has been s11ggested that indome"1cin might possess 1l M<'nl LR. ~t al. Low·dosc indotn<'lhacin therapy ;ind u:tcnsion of either benefit or har.n in neurological de\-clopmenl or other
some antineq>las1ic aetivi1y.' Some NSAIDs such os indomet- of i:n1avtnlricultl1' l~1n~g.e: :s muJciccnter randomized trial. lon~er tem1 outcomes.
acin moy also be or value for the diOi?tential diagnosis and the J Pdiarr 199-1; 124: 9~1-~ . ~other NSA IDs have also been tried in the troa1mcni ofpal·
man3gemen1 ofneoplastic fever, o.< they 3J>PC'lr to be more effec- Patent du<t us arte riosus. In the ftlal circulation the duorus e:nt duc:tus arteriosus. A rcc.~nt system3tie review" fow\d that
tive in reducioa this type of fever 1hon against fever associated artcriosm connects tht pulmonary artery and the descending aor- ibuprofen was as effective as indotnctacin. and also reduood lbe
with infcc1ionS? lndomcrocin has also be•-n lnCd for lhe trcot- ta. After bmh, various mechanisn1s, including a fall in prosiag- risk or nccro1ising enlerocolitis and tnmsicnl renoI impainnenl
ment offever and flu· like symptoms associated with in1erleukin- landin oonc:cntration, trigger its closure but in some infants the Given its lower risk of adverse effects, the authors suggested lba1
~ therapy althoU"JI there has been ooncx:rn over exacerbation or duct1is ortcriosus fails 10 close, a condition known as p<.Tsistcnt ibuprofen is the dmg of choice; ho\VC\'<I'. data on longer tenn
~1al 10.xici1y (see NSAIOs. wldct ln1<rac1ions, p.807). pa1ei11 duclus aitcriosus. This condition may be found in infants ouioomes arc needed before any recommendations regarding the
I. Mertens WC, e1 ul. Effra oftncbnethucin plus r:J.nitidine in ad- with congenital hea11 dclecis but is more commonly SttD in pre- use of indonietacin or ibuprofen cM be made. Ibuprofen is also
,.~,d ntt!lanomn pu1icn1t on hi;.'·dose intcrleukin-2. IA1K,, marure neonates, cspc:cially those wiih respiratory distr= $)'0- eOcctive \\·hen used prophylac1ically: howe>•cr, ther~ h3ve bee11
1992: 340: 397-~ . drome. ropo11s of pulmonary hypcncnsion with s"ch use and ibuprofen
~. En~rull P. ~'al. J\ nti!)yretic effect or indomcth1'cin in malii·
1w.1 lymphoon•. lkro Med Srond 1986; 219: SO!-S. • Some infantS ni•y be asymptomatic or have only slight .clini- is nor rccoinmC'ndcd.''
~I symptoms and no immediate inic.r\'cntioil is required. ln Oral therapy wi1h ibuprofen bas also been 11ied. 1 ~.19
Neonatal incraventrlcular hae morrhage. lndometacin has many cases spon~1 neous closur< will occur after several
boen tried prophylac1ically to prevent the dcvelopm<nt of in1ra- months. or else surgical ligation may be performed if clinical
1. ~-~~~~;.,~:,'.':.'C~nCPf!::n~:~,~ r;!Jj~c111c111 of~1cnt due·
ventricular haernon'hagc in neon3tes al rigk {see p.1157). SevernI ~. Anonymous. Delayfd cfosur:: o( 1he du~tu, . Lonee/ 1983: ii:
symp4oms persist.
1nechanisms hove been proposed for its possible aaion including 4)6.
• In some infants a patent ductus ancrlOSUS is ~cssary for 3. HNOn LP. C2mpbell UE'. Fur1.1o~1t1wit foe- pr("\.<:1ltio1l of in<Wh1d·
1-.d11c1ion of cerebral llow as a rcsuh or vosocons~, rcduc· ily in i:~(lm~1hacin-tn:<1 1 cd infun11 with patent ductus artcrio·
1ion of oxygen ITee-radical dam•a•. and occeleraled marura1ion mnintnining some oxygenation or the blood. for c.xamplc in
pulmonary aiteiy atn:sia or transposition of lite gmll aru:rics. ~u).. ;..,·3il:ablt in The Ca-.:hr:mc 0:?1:ilu$C of Svsccmatic Re-
of blood vessels around the .cntriclcs. Enrly s1udics1·1 ofthe use views: luut .3. C'hiclw11er: John Wilty: 1001 (accessed
These infants require trcalment with a prustaglandin such as 0711 1/071.
of indomet:Jcin for prevention of intravcntricular hae:monhosc
lllpnmodil or dir>OproStone to maintain patency oflhc duclus 4. Silo,·.: ED. PturmacotC\gic::il m:1.1lip\lla.ti<'1l oflhc ducws :1.rteria·
produced conllicling results. A subsequent 13rgc multiccnlrc
aneriosus 11u1il ~utgcry can be p.:rfonned 10 com:ct the mal- sus. .4rr/J Dir Chiltl 19&6: 61' 827- 9.
Sludy' (lhe lndomethocin lntravcnlricular Haemorrhage Preven- 5. 0o.r$t Rf. G1:rsony WM. 111'" pharmU1:olog1i..~l lrc•tnK"ftl o( P•H·
tion Trial. llHP) suggested 1ha1 indon1ctacin could reduce the in- fonna1ion.
c:nl du c tu1nr1erio~us: 2 :c:\•iew 0(1hc c\' i dcl'lc~. D'"ZS 1989: 38:
cidence and severity of intraventricular ha~hage, especially • Infants with hacmodynamieally significant duc1us aitetiosus, 249-66.
for the more severe fonns. Neonates with •~bVth·weight of 600 signs of hcan failure, and who require ventila1ion should un- 6. A1.:hct N. r~ tt:ut c.luctus ancrio;u1 in the newborn. An:1r Dis
10 I 2SO g were given ind ornetacin in a dose o f dergo l..:3b11en1 to close the patent clucrus ancriosus. C"11d I?93: 69: 529-32.
1. Cl)tT13" RI. Reccnnine11cbti0N (or 1he po.srnatal use of in··
100 111ictogramslkg intravenously al 6 lo 12 hours aficr delivery l niti~I monagemcnt involves fluid restnctioo, diuretics, concc·
domcd.adn: an analysis of four Upclf'll~ •r~tmcnl stratcg.ics. J
and then every 24 hours for 2 additional doses. 11lCJ'C w.is. how· 1ion or anaemio.. anti suppon of respira1ioo~ C'1/oro1'1io;;ide and p.,q,,,,, 1996: 128: l>Ol-7.
ever. concern~ that an unusuaHy large number of ncon;itcs with .firrosemitk ore diuretics commonly used. Th.re has been con· S. Vnn O\"ftmc:i1c: B. ct ti/. EQrty versus b•~ indomc1h:.dn lN:":lt·
severe intraventricular ha..--mon'hage i!• ~1e control group migtil ccn1 thal fur05Cllliclc migtt delay closure in infants with 1<:spir-.i· men1 for pa1c11t duc1us on.:riosus in prcmattKe inf3n1s "'i1h res.·
1ory dislr"'<S syndrome. 2 A systematic ...,,;e,,.J concluded that pint.torydisuus 1yndro1ne. J Petliotr2001: 13~: 20$- 11. .
h•ve biased 1hc findings. 9. Gersony WM. ,., nl Erfi.•c1s o f i ndometh~m m pttmnture Ill•
A concern 11,ith the use of indometacin is the possibiliry lhot ii 1his did 1101 scc1111obcll~ case, and 1ha1 the diuretic n1igh1reduce (2nts with ~1w1 ductus ancriosu1: r~suhs or :i na'1oml coll:ib-
may produce ccreb111I ischaentia due 10 its vasocons1rictor aaion adverse renal etlCcls of indometacin: however. II~ cvidaice for nr:ui"c slud)'. J Pl'dl..,,,,. 19$3: 102: S9S-906.
and 1heufore increase the risk of dn"t'lopn~n1al hnndicaps- Fol- this w•s limited and i1 was felt tl1at thc1c was not cnuugh evi- 10. Humm..:nnan <:. Anmburo MJ. Prolol'lscd lndomc1hacin lhcr.i-
low-up at 3 ycors! OI 4 '.~ years,' and II 8 years of age in the dence 10 s11ppo1t 1he use of furo,.emide in inf!lllts he>tcd with fp':;;;};:
r9~~·~~ ~~:~~m:ntd o( potent Jue1us :trtrriosus.
infants included in the llHP study reponcd no·~ effects on indomcuu.:in. 11 Sperandio M. r-t ct!. EffC\.,i\"elltSS and sic.ti! effects ofa_n escalat-
cognitive or motor developmcnL HowC\.'Cf. another large multi· If 1n1111I trea1men1 fai!s 10 co111rol sympl0tns after 24 to 48 hours ing. stcpwiic approac.h to indome1haci" 1rc:11rne111 for $)1TI.lpl0-
cen1res1udy9 (lhe Trial ofl ndomcthacin Propbyl:ixis in Pretcnns, then indometucin is generally gi•en to promote closure of the macic patent ducws "'114.'fiosus 1n pr<mtuurl! infanls below 33
duct us. ,,._..Ille benefits oftre3ltnenl with indomdacin as soon as \\uk$ of ~\!$ti:ilion. Pt-cfi111rH:1 200~: 11 6: 136~ ~. .
Tll'I') i11 extremely-low-bir1h-wcigh1 infants (less lhan 1000 ~) 11. Rennie JM, Cooke HWI. Prokwlgcd tow dose mdoou:1h:mn for
found 1ha1 allhouglt i11doine1ocin !'educed the incicJcncc of SCV\.'fe symptoms become app:ircnt, rather than delaying 1rc-.itme11t until pcr$i$U'Pt duetus ~rtcr1 1.>suJ of pre:t.laturity. ,,rch Dis CMld
h'1Cmorrl1age, it did nol •ml)rove survival without ~tsory signs of oongcstr.-e failure develop, ho\'e bcm debated.'' Early 1991: 66: SW.
impaim}(:nt al 18 months. A s11bseq11ent systematic rtvte\\''° also 1rea1rnen1 may sismficantly roduce the 111orbidities arisiOB from 13. Ht'n'<r.a <.". t:t c!I. Profon~cd "e~us shon t..'"OutM: o( indometh:acin
concluded th31indon~l3Cin prophylaxis did no1 improve swviv- a persistent 1iaten1 ductus aneriosus. 7 Howe,-cr, dtlaying treat· for the crea1mtn ('f paiem duc11.1s ancr~ in preccnn infants.
Available u\ TMCochraoc O~nabasc~• fSyStcm<tti\: Rtvicws; b·
31 frtt of ncuroscnsory diS3bility although, •gain, the incidonce m<nt until the end of1hc firSI week of lifo can allow for sponta- sue 2. Chkhestn: John Wiley: 2007 (acc,ued 07/11/07).
of severe in1ravcn1ric11lar hacmarrhage was !'educed. neous closure •nd a\"Oid the n<ed of exposing infants to lhe toxic 14. Fowhc PW. Davis PG Prophylac1ic lntrt\ Cn-nuJ ·mdnrr~Jhacin
effects or indomelacin.1
Funher analysis of the data from the llHP Slttdy has suggested
1ho1 indon1Cbcin might reduce intr3,~n1ricular haemorrhage in lndoinctacin probably leads to •'lu>ure or lho ductus tllfUllgh in-
~~.ri~ir:•il~i~~ec~~ ~~~~~~b~~~:$::.!~~~~~i~~~:::
sue;. Chichescer: John Wiley: 2002 (acccu cd 07/t J/07l.
boys Inn have linle effect in girls;" verbal see<es at ages 3 to 8 h1bi1ion or pt\lstaglandin S)1l1hc:sis. II is sh-en as the sodium salt 15. Cooke: L. et ed. lndon'lcthacin f'l)r asymptoma1ic pau:::At duc't~
yeurs were also higher in !hose boys treat.!<! wilh iudom~laein in 1hn:c inln!\-<.'10US doses a1 12-10 24-hoor intervals; each dose o.rteriosus in prc1cm1 inrantl Au1lablt 1n illt Cochrane 0:11ta·-
when com pa~ with n control group ofboys treated with saline; should be infused over 20 to 30 minutes. lndometacin sodium b3.sc of Syst.:matic Reviews: ls.sue I. Cllichcstcr: John Wiley:
no dilferenccs in S\."Ol'C$ were nutcd in indonlClacin·ttt•l•d &iris injection is reconstituted with preserva1 i,~licc sodium chloride 2003 (occcncd 07/1 1/07).
16. Ohluon A. ct til. Ibuprofen (N tht 1rnuncn1 of patelll ductus
and ~heir comrol iroup. Re-anulysis of data from the T!Pr 0.9'/o for injection or water for injection; glucose solutions arttrtOSul in pr~tcnn andtor low binh \\Ti&hl l~ranu. AV1ilabte
Sludy°' in ex1mncly-low-birth-wcigh1 neonates sug;es1ed a sho11ld not be used (Ste lnco111pa1ibili1y, above). The dose of in- in The Coc:tvanc Oa ltlbt>~c of S)stcmtntc Rc\litw1~ h.suc -t
weak gender dill'ercnce in th< effect of indometacin t~1nerit donic1ucin sodium (expressed as indo111c1acin) dcrcnd.• upon lhe C'h1d1u1<r John WHcy: 2010 \>ct6...S 16'0&/10),
 72 Analgesics Anti-inflammatory Drugs and Antipyret1cs
11. Shah SS. Ohlsson A. lbuprof<n for Ille preven1ion of patenl due- sepsis, pneumonia, and onset or reactivation of tuber-
tus artcriosus in prclcrm and/or low birth weigh1 infants. A\'ail-
ablt m The CochraM OatabaltC of Sy$tcm111ic: Reviews~ Issue t. culosis (see Infection, below), particularly in patients
Chichester: John Wiley: 2006 (•cccssed 07111/07). with underlying conditions predisposing them to infec-
18. Heyman E. ct t1I. Closure ofpatct11 duct\IS arteriosus \'•ilh oral
ibuprofen suspension in prem:aturt newborns: a pit~ study. Al'>- tions; in some cases death has resulted. TNF inhibitors
strac:1: P~Jl"1rl''I 2003; 1ll: I l70. Full vcuion: should not be given to patients with severe infection,
hup://pcdi111ics.1appublic1tionJ.org/cgi/rcprin&/l I2/5/c354 .pdf
(accc,.cd 07/11/07) including active tuberculosis, abscesses, and opportun·
19. Chcrir A. ti ul. Ra1\domiz.ed pilot study com1>aring oral ibupro- istic infections, and should be stopped ifthcsc develop.
fen wilh introvcnous ibuprorcn in very low binh weight infants Patients should be evaluated for latent and active tuber-
with pa1cnt ductus ancnosus. Ab!ltract: Ptdiolrics 2008; 122:
1361- 2. Full vcriion: hup://pcdi1Lrics.aeppublications.org/cgi/ culosis before beginning therapy; if evidence of latent
reprint!l22/6/ol256 {accessed 16109109) tuberculosis is found, the risks and benefits of treat-
Polyhydramnlos. lndometacin may be of benefit in the man· ment should be considered carefully and chemoproph-
agement or polyhydraninios (an excessive accumulation of am- ylaxis should be started before giving a 1NF inhibitor.
ni('lllt fluid)."' Polyhydramnios is a feature of the neonatal vari-
ant ofBamcr'uyndromc (sec also above). They should also be used with care in those witl1 chron-
I. Cebrol D, ct of. Trcalmcnl ofs)inplOmatic polyhydramnios with ic infections, a history of recurrent infections, or with
indom<lhacin. E•r J ObJ111 Gyntc0/ R•prod Biol 1996: 66: underlying conditions that may predispose to infec.
11-15.
2. Abhyar.k:ar S~ Sah•i VS. lndomc1hacin lhc~py 1n hydr.amnios. J Lions. Patients with listulising Crohn 's disease with
/'osrgrud M•d 2000; 46: 176-8. suppurative fistulas should not be given infliximab un-
) . Kriplm1 A, <I ol. lndomcthocin tlotr11py in die trc1tmcnt of Poly·
hydr2mnios due co p!accnt1I chorioangioma. J Ob.sittt G.vno«:ol til possible infection sources such as abscesses have
Rn 1001: 27: 245- S. been ruled out. Patients should be instructed to seek
Premature labour. The mOSI common approach to poslpoo- medical advice ifsymptoms suggestive of tuberculosis
ing pnon1ture labour (p.2166) with d~ has historically been (such as persistent cough, weight loss, or low grade fe-
"ith a selective Ilea, a&<>nist Howe-, llS pros1agbndins have a ver) occur. Patients should be monitored for signs of
role in uterine contraction and cetYical ripening and dil1tatioo, infection after stopping treatment: for adalimumab,
proslag)andin synthelase inhibi1ors such as indometacin have
also been used. Comparotivcsludies12 have shown lbat indomet- golimumab, and infliximab, which all have long half-
acin and ritodrine me equally effective in inhibiting uterine con- lives, monitoring should continue for 5 (adalimumab
tractions and delaying delivery 1n patients in prcterm labour who and golimumab) or 6 (infliximab) months; because of
have inract ,,,_branos and in whoon tile: gestational age is less its relatively shorter half-life, the elimination of etaner-
than or equal to 34 weeks. ln one study an initial o<al loading
dose of indometacin SO mg was given, followed by 25 to SO mg cept may be quicker.
orally every 4 hours unlil contractions slOppcd and then by a There have been rare reports of severe hepatic reac.
maintenance dose of25 mg every 4 to 6 hours. In the other com· tions such as acute liver failure, jaundice, hepatitis, and
parative study' indometacin was given as a 100-mg rectal sup- cholestasis with infliximab; some cases have been fatal
pository followed by 25 mg orally every 4 hours for 48 houtS; if
regular u1erinc contractions persisted I to 2 hours aflcr the initial or required transplantation. Patients with signs or
suppository, an additional 100-mg supposi1ory was given before symptoms of hepatotoxicity should be evaluated and
beginning oral therapy. Terbut.aline was given for maintenance infliximab should be stopped in those patients with
lhcrapy. jaundice or marked elevations in liver enzyme values.
Unfortunately intJometacin can constrict the ductus artcriosus,3» lnfliximab (BAN. rlNNJ Jnfliximab and other TNF inhibitors have also been as-
which may lead to pulmonary hypertension? and has also been
associated with bronchopulmonruy dysplasia,6 rcduu:d volume cA2; CenTNf; lnfliksimab; lnniksimabr. lnOiximaburn. lmm..t· sociated with the reactivation of hepatitis Bin chronic
of amniotic fluid (oligohydra11mios)M and possible remJ dam- noglobu'n G (human-mouse monoclonal cA2 heavy chain anti· caniers, which has resulted in fatalities in some cases.
age (see EtfeclS on the Kidneys, above) in the rerus. Another hunwo tumor necrosis faaor). disulfide with human.mouse Patients al risk of hepatitis B infection should be
complication is that prenatal indomct.acin exposure may increase monoclonal <Al l'ght chain. dmer: screened before starting treatment; it is recommended
both the incidence and severity of patent ducrus a11eriosus in l-'JHCjwll1KCHMa6 that ca.11iers treated with a TNF inhibitor are closely
premature infants,7.1 as shown by the increased need for post- CAS-170277· 3/ . J.
natal indometacin therapy and swgical ligation in such infanlS. monitored during, and for several months after stop-
However, there is evidence to suggest that lherc is no significant ATC - L04AB02. ping, treatment.
increase in the risk of neonatal complications in infaru exposed ATC Vet - QL04A602.
UNI/ - B72HH48FW.
Blood dyscrasias, including leucopcnia, thrombocyto-
ro indometaein tooolysis when comfl"red with control grours of penia, pancytopenia, and aplastic anaemia, have been
infanlS who ~ived either no treAlment or tooolysis "11h drug$
Oilier than indometacin.'·'° Adverse Effects, Treatm ent., an d Precau- reported rarely with TNF inhibitors; in some cases the
The cvid<ncc for any overall bentfir ofindomeucin in delaying tions outcome was fatal. They should be used with caution
tahour is equivocal, 11 ·1l and ii is gencnilly rcserved as a sccond-
Acute infusion reactions during or within I to 2 hours in patients with a history of blood dyscrasias.
line tocolytic or for use with an intnvcnous IOCOl)tic when an Rare, and sometimes fatal,cases of interstitial lung dis-
_ additive effect is required. of infusion are common with infiiximab, and other
I. MOt11ks WJ. ~'al. Etrrca.cy ind safety of indomahacin vt1'SUS TNF inhibitors, particularly with the first or second ease including pulmonary fibrosis and pneumonitis
ri1odrine m the mana,emen.t of prclerm l:abot: a nndomlud dose. S}mptoms include fever, chills, pruritus, urticar- have been reported with lNF inhibitors.
study. ObJtn Gyn«Ol 1919: 7~: 567- n .
2. Bc:sinier RE. d ol. Randomil.Cd comp1n1h-c er;. I of 1ndometh· ia, dyspnoea, chest pain, and hypertension or hypoten- lnfliximab and otherTNF inhibitors are also associated
or
acin and ri1octrine for the lons-•c-rm '1talment preterm labor. sion_Mild reactions may respond to a reduced rate of with an increased incidence of malignancies including
AmJOb81<1Gyn<CtJI 1991: 164: 911- J. lymphomas and leukaemias (sec also Carcinogrnicity,
3. Mo;K KJ. ti ol. lndome1.hac1n in lhe uauncnt o( prcmahne: la· infusion or a temporary interruption. If reactions are
bor: effects on the f<tal due1us 1r1criosu1. N Engl J M•d 1988; more severe, therapy should be stopped. Pretreatment below), a!though occu11enccs are rare. Some groups of
Jt9: 327-31. patients treated with TNF inhibitors may already have
~. Hall3k M. ~' oJ. lndomethacin for PfCCc.rn' labor: fcul to.'<;cily in with paracetamol, corticosteroids, and antihistamines
a ditysotic 1win gestation. 00.t.r GynKOl 1991; 78: 911- 13. may be considered. TNF inhibitors should only be giv- an increased background risk of developing malignan-
5. Vcnnillion ST. ti ttl. The effect or indome1hacin lOCOIY!iS on cies, regardless of drug treatment Care has been advo-
fetal ductus artcrfosus GOns1rKtion with ldvancins ,esuitional en where facilities for resuscitation are available. De-
age. AmJ Obsw Gyn«ol 1991; 177: 25~1 . layed reactions have occurred 3 to 12 days after inflix- cated in patients with a history of malignancy.
6. Eronen M. ~1 of. Increased incidence ofbr0t1chopulmonary dys-
pla.sia aft.er 11ntcna1al administration of indomcthacin 10 prc.vc:nl imab treatment; symptoms include myalgia, artlualgia, Anaphylactic reactions have been reported rarely with
prct<rm l•bor. J /'ediatr 1994; 124: 78l-& . fever, and rash. Similar delayed reactions may also be TNF inhibitors. lnfliximab should be avoided in pa-
7. Norton ME. et of. Nconatol cornpliC""ollions ofter the admin1s1ra.
\iro °.!j~domechacin for prc1c:rm labor. N Engl J Mt1d 1993: 329:
seen when infliximab has been restarted after an ex- tients with a history of hypersensitivity to the drug or
2 tended period without treatment (see below). other murinc proteins.
8. Hammerman C. ct al. Jndomethacin 1ocolysls lncreascs post-na-
lal patent ductus arteriosus severity. Abs1roc1: Pt:dlorrtcs 1998: Other, common, adverse effects include nausea and TNF inhibitors have been associated in rare cases with
102: 1202-3.
full vtrsion: h11p://pcdia1rics.11ppublica1ions.or;/csi/con1enl/
vomiting, abdominal pain, diarrhoea, fatigue, dii:zi. seizures and clinical or radiological worsening of de-
fulVI0215/c56 (accessed Oi/11/07) ness, headache, and back pain. Antibodies to inflixi· myelinating disorders such as multiple sclerosis or op-
9. Vc:nnilfion ST, Nc""·m11n RB. Recent indornc1h1cin 1ocolysi.s is mab (human antichimcric antibodies) may develop, tic neuritis; care is tequired in prescribing it to patients
not associated whh nconaul complicalions In prclcnn lnfantJ.
AmJO/Jdl<tGyneeo/ 1999; 181: 1083- 6. and are associated with an increased incidence of hy· with such disorders or symptoms suggestive of their
10. Loe SM, et al. Auc.ssing lhc ncon111J ufery of indomdh1rin persensitivity reactions. Antinuclear antibodies and onset.
1ocolysis: a systern~nic re\'iew with mcta-an1lys is. Ob1111 G)'r'IU.
col 200S; 106: 173 9. anti-double-stranded-DNA antibodies have also devel- Worsening and, in some cases, new-onset heart failure
11 . Maconcs GA. Robinson CA. Is then jus1ifiCRlion for using in· oped with TNF inhibitor therapy. A lupus-like syn· has been reported with TNF inhibitors (see Effects on
domethacin in pretcrm labor? An arntlysis or ncontLll risks t.nd
bentlits. Am J ObJ1e1 Gy11eco/ 1991: 177: 819- 24. drorne has occurred rarely; treatment should be the Heart, below). In the UK. infliximab is contra-indi-
or
12. Pan1cr KR, Pl al. "fM e1Tect indomct.haoin tocofys:i• in pre· stopped if it develops. cated in patients with moderate to severe heart failure
1crm l:Jbout on perinatal ou'tcomc; 1 r1ndomiscd placebo-con-
trolled irial. Br J 00.rei G.1Y>Occol l999; 106: 467- 73. Infections are corrunon in patients treated with inflixi- (NYRA class Ill or IV); however, US licensed product
13. Macones GA, rt ol. lbe conlrovcrsy sunounding indomethacin mab or olher drugs that inhibit TNF, and most often information advises that doses up to 5 mg/kg may be
for tocolysis. AmJ Obst•' GyMc'Ol 2001, 184: 264-7: .
affect the upper respiratory tract and the urinary tract. used in such patients. It should be used with caution in
Preparations
8P 2010: ~ W...les: lndomoOOn Su;:lpoMcr'.o:s.
TNF inhibitors have also been associated rarely with patients with mild heart failure (NYHA class 1 or TI).
USP 33: t>done".hoOn c.p..Aes: ~h>M Ex\-ose C.C.- the development of serious opportLUlistic infections, All patients with heart failure should be closely moni-
All cross-references refer to entries in Volume A
 lnfliximab 73
tored and infliximab stopped in ihose who develop 1•
2. 6oog.>r1t T, tttN. Anli.. TNf :mtihody 1h.t:r:iip)• mtunl:iit.oid :iir- lcal improvement in patients given inOiximab S mg/kg or
thri1is und 1he rtSk of serious infections and mahari~i~: ~ys­ 10 mg.'l<g when compared wilh placcbo;5 in addition, those given
new or worsening symptoms of heart failure. Similar tem:HiC' rcv1~· •nd rncta-oit'lalysis of HIJ'C ha1 mful effects in nu-
domiied controlled tri:ils. )AM.• 1006; l?S: ?215-&$. lhe higher d05c had an increased risk of death or hospitalisation
oec::immendations are given for the TNF inhibitors due to worsening heart failure.
Co1rccdon. /bid.: 1482.
adalimuniab. etanercept. and golimumab alchough UK ; . Di.xon \V, Sihm1n A. Is dt:-Jc an u.ioci11icn belwccn znti·TNF I. K\von HJ, t!t of. Case ttp0n.So(hc111n. 01ilurt' crter t~py "ith a
licensed infonnation for etanercept only advises cau- monocl<1na1 amibody therapy in rhtum~toid nnhrilii :and ri1k of lumor necrosis factor antqonist Ann lntcm Med 200~; J38:
maliinanc.:y <ind serious infcct~n7 Cocnmenfary on the 1naa. 807-11.
tion in patients with heart failure. an=ilysis by Bonsar1t. ct 11. Ar11t,-,,tJ Ra Thcr 2006; 8: 1I I. .!. J:icob~on LTH, cl ol. Trc.temcnl wi1h tumor necrt1s~ factor
... Gcboltk P, Cl al. TumCk.lr ntcrOSiJ rxcor blockers do n(l1 in- brockc-rs is associ;ucd ~·iLh 1 lower incidence of first cardiO\tJ..
0 General references. tra$(: overall tumour risk in piUieots w;th rheu1na1oid arthriiu;.,
cul~ tvcn1s in p:nicnu wi1h rhcuJM:toid <1rthri1is. J RltertMatol
I. Hansen RA. el al Scn"us ndvcr$t C\ cnts wilh inflixin>3b; anil· buc may be associated with l\n inerc;M d risk or lymphomas. Ami 1005:31: 1213-1&.
ysi-!' ursponumcously ~ttcd ad\. erst C\'Cnls. ('/in GtttlrtX!IUCr• Rhcu,,, Dis 200S: 64: 699-703. :;, Cunis JR. t't al. Ilcarl r11ilure: among youn&tr rhcum:itoid Arthri-
ol Hq"'1ol Z007: 5: 729•lS. 5. SclQiochi s. ~'al. Tumor necrosis factor c. •n~s.onisi use and tis and Ctohn 's p.:11icnts exposed to TNF-u a.n10.1onisu. Rhc11111a-
2. lt'clusc LLA. « ol. Review and cs.pttt opinion on pl'C'\oention cancer in paucn\S. with rheumaloid arthritis. Artlt,fti1 Rhet1111 ro/og,i· 10t/Ol'd) 2007: 46: 1688-93.
and tre:nmcni of inni~imab-relatcd infosion reactions. Br J Der- 2006; S.f: 2757- 64 Correc.1ion. ibid.; 31 ;.4,
4. l.isuna J. tt nl. Does tumor necrosi~ f1a0t o inhibilion promote
"'"'ol 2008: I 59: 527-36. 6. Ai;kli111 J.ttal. Canecrr~ in pa1iems wi1h rhcumaioid arthritis or prevent hc:an &ilwe in i»;ticnts with fh(Umatoid arrhritis? Ar-
3. 2.abana Y. ~t ol. lnnix.imtb s;fety profile and1ong•tcnn applica·
~~:~~~ :~;~ ~~~~:i.=~i=r:~~~ r:,c~~:11~:::r~~= ·~~!
1
1ltrl1/1Rht11ut2008: 58: 667-71.
h1hl)' in tnfla01mitory bowt"I distak' ~year experience in clin-
2009: 60: 3180-9. S. Chung ES. <t al. Randon1;<ed. douhle-bHnd, pl•«bo-conorollcd.
tcal practice. Alimeut P!wrmOCD/ Thcr20l0~ 31: SS3-60. pilot trial of inOiximab, a chintcdc monoclonal :mibody 10 tu·
1. DiaRC:Ol'IC l, ttt al. lnflixim3'b and newly diagnosed neopl;.s.ia in
Carcinogenicity. Maligiiancics, csp::cially lymphomas, have Crohn's disease: .. ntultie:cnttt matched pair i::1udy. Gut 2006; mor nccrooii f'aclor-oi in PQticnts wilh modmtc·(O-.scvcrc hart
been seen in pa1icn1s rrcarcd wilh TNF inhibitO<S for rheumatoid SS: 22&-33. failure: rcsuhs or the AntJ..TNF Thcr3py A_gain$1 Conscaive
arthririsand Crohn's diseasc; 1however, the suggestion ofa caus· $. Wolfe F. Mid1aud K. Lyn1~ in rht1unatoKI orthrilis: the tr· Heart foilure lATrACH) 1riat. Circ11fa1ion 2003; 107: 3133-10.
al relationship is concroversial. A mera-analysis2 in 2006 idenli· rca of n..elho1rc.x.:1tc and unti-lumor nttro~is rac1or lherapy in Effects on the lungs. lnOiximab treatment has been associated
I&..512 pati~nas. A,.,lld1i1 Rheum 2004; SO: 1740-S I.
lied :4 published reports of malignancies in 3493 study paticnls with a fatal cxacerbarion of previously 8$ymptomatic fibrosing
wilh rheuinatoid arth:ritis who had received at least one dose of a
9
· ~:r:~,i£; ~"~:i~~=~~hc~m~?!:~:'j'~f~,~~rl~o~~~ alvoolitis in 3 p•uienrs with chronic rheumatoid anhritis;1 all 3
TNF inhibilor (1dalimumabor inRiximab) aIona "ilh 2 castS in Av1il~blc .al: hnp://www.hc-sc.gc.ca/dh_p-mps/1h format~ patients wetc also taking azaihioprinc and prednisolone. There
1.512 control potienlS; further. unpublished, ca= were also hpll>-dJpsolpdrl.,«1<117rem;cade_3_hpc<p<-cn;.pdf(xeessed was no C\~dence of iniCcrion or other underlying causes for the
29108/081 declia~ in respiratory function.
round using FDA data to gj\'C 29 malisnoncics in lhe treatment 10. Mickey AC. tt al. llcpatOS(llcnic T cell lymphoo\8 usoc:iated
aroups and 3 in 01e control groups. Based on these figures, !here wi1h infliximab ust- in youna, palirn1s creotcd for inf\amm.atory I. Oster AJK, et ol. fatal f'X*Ccrbfltion oftbc-urnatoid arthritis asso--
w11s a 3.3·fold increase in the risk of malignancy in patients bow.: I diicut. J Ptthn,,. G011rtHmt1YJ( Ntnr 2007; 44: 26S-1. ciat(d r1brosing ah·eolhis in pa1icn1s gh·e-n inni.ximab. BMJ
receiving lNF inhibitors when compared with con1rols. These 11 Abboll, UK. Oir(Ct he1llhc.trc r.ofcuionnl communie:acion on 2004; 329: 1266.
resulls ha\-e, however. been criricisedl on several poims includ· :~rtJu~i~~;~~!~~~~1~ij{;~~1~~~~nJauli;, ~Q~S).ll treated Effects o n the skin. Patients \\ith rhewnatoid art1Ti1ls receiv·
in~ the diJficulty in applying !hem to current praclice hecause Availabl~ at: hup:l/www.mhra.gov.uk/Safetyi11rotm11ion/ ing TNF inhibitor 1herapy are more likely lo develop adverse
ctan<:reept "'11S not included in the anal)'!>is, and, in paniculor, the Safell"W'lllminasolcr1sandrcca.lls/$afcc)'Wamings1mdmcssapei;fo skin reactions tl1a11 1hose who arc not.' Of 289 patients taking
unexpectedly low raie (If malignancies in the conttol groups.
Other slUdics in pa1ien1~ "1d1 rheumatoid ar1hritis"' end Crohn 's
::i::~th~~~~;~~~;:ji!i:~~~O~;t'O,';(~::~~!Jdt;~~~)i TNF inhibirors (inftiximab, etanercept, adalimum3b, and lener-
cept). 72 (2S%1 reported 128 detmatological events including
11. FUA Information for hcalthc3re professt0nals: tumor necrosis
disease' h3\'C generally conchlded thar the overall risk of malig- f1ttur (ThF) block~rs (marketed .ili RemiClde.. Enbrel. Humira, skin infec1ions, eczema. drug·reloted eruprions, and nialignon-
nancie.~ is nor significantly increased in pcitienl.S taking TNF in- C;mzia. Ind SU1!p<>ni) (issued 4th Au&ul<. 2009). ~ic~ such as actinic kerofosis; of the 289 patients not taking 'INF
hihimrs when compared wilh palieni.s who have not taken these Available at: hUp:llwww.fda .gov/l)rugstUrugSafe1y/ inhibi1ors, 37 ( 13%) reported dennatol<>sical events.
drugs. Some smdies'-' in pai;.,.ts 'vith rheumatoid arthritis have, PosrmtrkctDru~Sarctyl11form11io11rorPii.1icnts:mdPro~·idcrsl
OrugSa fe&y In formationfor Hc Ill he: are PTo fcssi on:al•I Jn another review.1 cUlaneous adverse c:fTeciS were seen in 35 out
however, shown a possible inc=sed risk of lymphoma with u<m l 74474.htm (accesS<d 261t0/09J of l SO patients receiving lNF inhibitors (adalimumab, etaa>er-
TNF inhibitor trealment, bul cau1ion in interpreting these rC$Ults ccpt, or inniximab) for rllcuma1ic disorders; cases included der-
was recommended as 1hey were based on a small number ot'cas· Delayed reactions. Ten of37 pa1ients with Crohn's disease re·
matitis hcrpetiformis :ind lcucocytocloSlic vasculitis :ilthougb cc·
cs; in addition, the background risk ofl}mphoma is increased in treated wilh in fliximab after a 2· to 4-ycar period without treat·
rnent had delayed hypersensitivity reactions, of wl1ieh 6 "-ere zemalous and skin inl'cctions were more common or infCClious.
meumatoid anhritis rcg;irdlcss of treatment. Pethaps unexpectedly, psorias$-like lesions were seen in 8 pa-
Rare cases orhepatoSplcnic T-<:ell lymphoma ba\-e been ll<!Cn in
or
considered serious. None the patiallS had had infusion-relalcd
or
tients. 6 of whom had no bi.story psoriasis; similar effects have
adverse effects with 1heir original inf\iximab therapy. Adverse
adolescents and young adulls given inflix.imab for the 1reatment also been noted in 01her patients with rhcumato;d a1thritis3 or
of Cl'ohn 's disease. In July 2006, the manufacturer was aware of rcactioos dC\-elopcd in 9 oftl1e 23 patients orieinally lreated "'ilh
Crolm's discaseH (see also below).
a discontinued liquid fonnulation, •nJ in I or1hc 14 patients who
6 cases of rhis type oflymphoma in S adolcsccni.s aged 12 to I9
previously received the mari<etc-d formulation, leading to sp<...:u- or
Rare cases serious skin reactions hl\'C been associated with
years and one 31-ycar-old adult;9 4 of 1he 6 cases oocurrcd in TNF mhibitor treatment6 Since approv:il in 1998, the FDA hos
l3tion tha1 the fonnula1ion may have been a contnlluting factor.
males. The tre;itrnent dll!1ltion rtngcd from I or 2 infusions to received 15 C3SCS ofcrythemo mulrifonnc, S cas•s of Stevens·
over 4 years or1herapy; in all cases. patients were also laking or Effects on blood lipids. A 3S-year-old man with psoriatic at· .lohnson syndrorne, and I case oftoxicepiderm31 necrolysis as-
had taken azathioprine or 6-mciaptopurine. lllis type orJyni- tlvitis and psoriuis de\-eloped markedly elcvalcd lri&JY""ride sociated \\;lb in0ixilll3b: C<ISCS for etanercept, approved in the
phoma is aggressive and S of1he abo,·e palients died. A causal levels a11d a mildly incruscd total cholesterol level aRcr a single
infusion ofin0iximab;1 previous Jc,;ts lml shown a mild hyper·
or
same year, included 13 repons el)1hema multifonne, and 4
relationship was not clearly established altboug)l it could neither reports each of StC\IO'ls·Johoson syndrome and Joxic; cpidcnnal
be excluded. Funhcr casts have since been rcported. 10 Hepac- trigl.vceridaomia for which he had rccei~ no treatment. No fur. necrolysis. For adolimumab. "'hich was morkcrcd lalc in 2002.
osplenic T-c.:ll lymphoma has also been associated with adali- thcr doses of innixitnab were given and his triglyceride levels tbcrc have been 4 cases of crythema muhiforme and 2 of Sle·
mumab. Jn July 200&, 01e manufucturer was aware nf3coses;11 subsequently improved. Yens-Johnson S}'1dromc.
of these. 2 had OCQJIT"d in young men also laking azathioprine I. An&oniou C. e1 al. Elc vitcd lnglycmdt and t:holesierol lcvc>ls In August 2009. the FDA' rcponed 1ha1 it had reviewed 69 cases
01' 6-mercap!opurine for inRa111111a101y oowel diseas.:. (Details of aflr:t intra..,cnous antjrumour nccrosi1 ractcw..g lhciapy in 3 pa·
ticnt wi1h ~tic ;.r1hritis 1.111d pJOri:ms ,·u1,pris. BrJ lkrmutof ofnew-onset psori:i.<is. including J>U$tular( 17 C11ses) and palmo·
the Jhird case were not provided). plantar{l 5 cases) psoriasis, in all poticnJS receiving TNF inhibi·
2007: IS6: 1090-1.
Cone<: ms about the risk ofcancer in children a1ld adolescents re- tor therapy for auto-immune and rheinnatic disorders other than
ceiving TNF inhibirors prom(lled die FDA ' 2 to review all cases Effects on the CNS. Aseplic meni11gitis dc~'eloped in a pc11ien1
pSOriosis and psoriatic anhritis; or these, 2 cases \\-ere ofchildren
of cancer in children taking >dalimumab, e:anerccpt, or inOixi- or
after his fifth injection inOiximab for rheumatoid anhrilis. 1 and 12 had resulted in hospi131L<ation. The time JO onset of pso-
mab. (Ccnolizumab and golimumab were nol included in the re· Similar symptoms also occurred after a sixrh injection riasis ranged from weeks t<> years ~ fter srarting TNF inhibi1or
view as neither were licensed for use in children and were mini- Two palienrs with infbmmlltory bowel disease dc,-eloped acute rherapy; symproms improved in the majority of parients after
mally used during lhe review period.) Jn Auaust 2009, their molor ncuropathy wilh multiple conduc1ion blocks after inflixi- stopping 1he drug. None of the cases had reported pre-existing
findings were reported. Foity eight cases ofmalignancies in chil- n111b treatment; both patients imp<oved ancr infliximab was psoriasis.
or
dren and adolescents were identified; thesC, about holf were stoppcd.l Similor adverse effects were reponcd in 2 further pa· F« upons of drug-induced lupus or lupus-like syndr(lfne OS>O-
lymphomas, including Hodgkin's and non-Hodgkin's lympho- 1ieni.s:l ooe \vas laking etanercepl for rileunutoid arthritis and the cioled with TNF inhibitors. sec Lupus, below.
mas. 01her reported mali2Jl•ncics i11eludcd leukaemia. melano- other infliximab for an!..-ylosing spondytitis. Three cases of bi lat· 1. Fl<ndric M. et al. DctnlAtOk>&ia1 conditions during 1~F-o.·
ma, and solid organ cancers; malii;nnncics that are rare in chil· era! 0p1ie neuropothy assocfated with inOixiniab theropy have Mocking.Cherapy in p:nii:nls with rhC'umuoKI ~rthrilis: a pros.pee·
dren such as leiomyosarc:oma, hepatic malignancies, and renal also been reported.' 01hcr neuropathies have been associated 1ivc study. '411hritij Ru TJicr 200S; 1: R666-R616.
cell carcinoma were also reponed. About 88% of d~ 48 pa1ien1S with "TNF inhibitor trea1men1, .including Guillain·Barn! syn· 2. Lee H·H, n al. Cuu.mcous sidc-cfl'ccl.$ in ~i-tnlS v. i1h rheumatic
were also taking or her immunosuppressants such as uathaoprine drome.> disuses dwinc applic:nion or tumour necrosis fx1or·u antngo·
and mcthotrexa1e. There "ere 11 faialilics rcpo1ted, comprising I. Matone H, ~' ul. JnOlxi1n.Xt--i11duced 3SCplit mctuniihs. Lanc,, n;sl$. BrJ 0..-o/2007: 156: 486-91.
2001: 358: 1784. 3. Detcurc 0. ~t nl Psoria\iic lesions indnctd by ~nutumour necro--
9 cases ofhepatosplenic T-cell lymphonia, I orT-cell lympho- sil f:1c1or-u 1rcalntcnt: two c:ssc:>. 9,. J Dt:rmmol lOC>i: 151:
~- Sinaer 0(', '' al. Acute neur.lhy wi1h 111uhip1e conductton
ma. and I of sepsis ofter :achieving mnission of !he lymphoma. blocks ~ncr TNFG monoclonal amibody 1hcrapy. Neurology S-06-7.
The FDA considered !liar there is an increased risk of malignan- 2004: 6J: 175~. 4. V(~M MM."' nJ. t•soriuirorm etup<ion indutcd by infliximab.
cy with TNF inhibitors although they "'o:n: unoble to characterise 3. Rithet C, cl al. Neurop;ilhy rt-SoC'Ql.bli"I CIOP in palicnts rtteiv. Ano Phw·11uu'<#ht:r 2004; 38: S4-7.
the Slren~Jh or1his ao:;ociltliOn due to factors such as the relalive- ins 1urnor necrosis r:.c10,..n b1('1oCkeu Ntm'Oiogy 2005: 6..&: S. Conklin LS, l!I al. Rash induced by an1i-1unmr nee:msis fa«or
t468-70. Jgcnts in :m adolC$cenl with Ct0hn°1 disease. Nm Rev Casfr«n-
ly rorc occurreJk.-e of thc,;e canccrs.1hc limited number of paedi· mol H•patol lOJO: 7: 174-7.
011 ic patients on TNF inhibi1or thernpy, and Jhc possible role of 4. len TUS5ch.:r MPM. ~,al. Sil:ucnl anterior 1oxic ophc ncun,lp3·
lhy and the Ult or inflixirnub. OMJ 2003; Jl6: 579. 6. FDA. TumC1r ntttosi11 r11~li.>r alpha (TNF-ol a11Wgonis1s. JnOtxt-
concurrent lnununosuppressa111s. mab (min'kcted G.S Rc1nic;ide). etanc:rttp( (marketed u l!nbre"1),
5. Stetbgen J-P. TUJlK)f nrcrcsls rac1or-o ant::t;onisu: and ncuropa·
In a second analysis the FDA" reviewed 147 reporu of leukae- ~d :.tdalimunub (nurkc1cd as Humira). Snlou.s skin reactions.
thy. M""cl• N.,... 2008; 37: 2S 1 -9~.
mia associated with TNF inhibitors in all patient$, including FD.f o...,Sof1n·N<>••slm_,2001: I: IS-:lO.
Effec:ts on the heart. llie FDA h;is reponed 1 oo 47 p:llicn1s Avo1L;ible ,,. huP:t1www.fda.sov/dow·nl~c.s/Oru;Sl.'lfcty/
adull.S. Ofthese, rhe mos1 fi<qucntly reponcd were acule mycloid Dru&Sar•l)'Newskuer/ucm t09 169 (accessed 2&'07/10)
who developed he:irt railurc during long·term theropy wilh TNF
leukaemia (44 cues). chronic lymphocytic Jeukaen1ia (31), and 7. FDA. 1nrnrm2r1on for lteahhcarc prnfessiONts: 1umot necrosis
antibodies (ctan~ and infli>Jniab) for nnhri1ic conditions or
chronic myeloid leuknemio (23). Aboul 61 % ofthe patients were
Crohn ·s disease. Of these, 38 developed ncw·onscl h<:art foilun:.
r.. c1or (~f) blockm (m:u*tted 111 RcmiQdc. Enbre-l, Humint.
also rcceiw1g other inmmnosuppressanu. There were 30 fatali· Cimzio, •nd s;1nponi) (i»1i<d 4rh Au;usr, 2009).
19 h•ving documented risk 13ctots for hean failure, und 9 had Av1ih1 bit a1: bup•// v. •·w.rda .gov/Orugs/OragSafctyl
ries rcroned; of these. 26 were due IO leukaemia. The average
exaccrllolion of existing heart rullurc. llic modian lime 10 r~w­ Po.stmarke 1OrugSafcl)' Inform11tionror P:n icn1sand Providers/
rime to onset orlcuk<icmia was wilhin 1he lirs1 2 years of TNF
onsct hcut r•ilure was 3.S anonrhs. However, studies2.. invc~li· OrugSnfc1 ylnform11ionrorHc•thcnrc P rofessionals/
rnhihitor thorapy. Based on rhe available d>I•, the FDA conclud· ucml7J474.htn>(•cccssed ~7/10/09)
gating a possible association betv.~ TNF inhibirors 3nd the de·
ed that tl1ere is a po<Sible associotion between TNF inhibitor
therapy and Jeuk:oemia.
YC!opment ofhcart failure luivc been equivocal and further inws· or
Infection. 111ere luave been sp011tanCOOS reportS onset or re-
_\igatioo is warranted. activation of tul>errulo.fl.• in patienis treated with in0ixin1ab, in-
I. Brown SL. ti ol. T~nncr necrosis factor an11gonist d~•PY ind
lymphoma dt\•tlopmtnl: lwcnty-six cJ.ses rcpoc1cd to lhe food Preliminary inYCS1iga1ions on rhe use of innix.imab in 1he treat- cluding ca.cs or' miliary. ruberculosis and unusulll exrrnpuhno·
:i.nd Drug. Adtnir1tS1ration.Anhrit1's Rheum 2002: 46: llSl-8. ment of modcnne to seYCre he3rt failwt failed to show any clin · nary dii;ca..._ •The UK CSM norcd in Febnr.uy 2001 rhat there
The symbol t denores a prepamion no longer actively marketed
74 Analgesics Anti-inflammatory Drugs and Antipyretics
had been 28 such reports worldwide. The US manufacturcrssu~ Abatacept. Use ofthe TNF inhibitoretancrccpt with at>.1accp1 when signs and symptoms of the disease recur (but see
sequenlly reported2 (in October 2001) that other scriou.1 oppor- has resuhcd in an increase in lhe incidence of scr10us adverse below). UK licensed product infonnation does not rcc-
tunistic infcc1ions, including histoplasmosis. listerlosis, and effects including serious infections; in addition, there W11S no in- onunend further doses in patients who are unrespon·
pnwmocystosis had occwnd, and had led to some deaths; the crea.« in clinical benefit.' Combinations of abatacept with TN!'
number ofrqx><ted cases ofrubcreulosis had risen to 84. F1uiher inhibitors are not reoommcndcd by UK licensed product infor- sive after the first 2 doses; in the USA, a patient is not
opportunoslic infections also continued to be reponed; FDA daia mation. considered to be unresponsive until 3 doses have been
up to August 2002 included reports of ca11<lidiosis, coccidioul- I. Wtinblau M. e; al. Selecti\·e costimulaliOn modulation u.sin& given. A similar regimen is used in patients with fistu-
onrycosls, nocardiosis, aspergil/osis, and infections due to non- abat:tecl'l in patic.nl$ with 11c11ve thtumacoid a.r1hritis white re·
lising Crohn 's disease although ther.ipy should not be
tuberc<Jlous mycobacteria.3 Hea.lth Canada rcponed' in October ccivina ctancrccpt: a randomi-5ed c;linititl triul. A,,,, RhcMRI Di~
2004 that it had received 188 and 109 reports of infections asso- 2007; 66: 228-34. cons idered ineffective until after the third dose of inf-
ciated with inOiximab and etancrcept respectively, front January Anakinra. The inci~ of serious infections, injcaion site re- liximab. US product infonnation suggests that doses of
2000 to May 2004. Of these, 10and2 reports were of tuberculo- actions. and ncutropenia is increased when anakmra is given up to I0 mg/kg may be used in patients who relapse
sis associated with in01ximab and ctancrcepl respecti\'ely. The with the TNF inhibitor etanercept. 1In addition, the combination after an initial response. lnfliximab is also used in the
FDA also received 25 reports of rube!culosis associated with did not provide any further clinical benefit when compared with treatment of moderate to severe, active ulccralive col-
ctanercept between November 1998 and Mardi 2002.' More re- c1ancrcep1 alone. Similar finding$ may be e-'<pected ifanakinra is
cently, a review" ofliteroture published up to June 2007 rep0r1ed given with other TNF inhibilors. itis (see Inflammalory Bowel Disease, below) in pa-
281 cases ofinvasi'-e fungal infections associoted with 1NF in- I. 0cnuvC5C MC, er al, Combin11ion 1hcr1py with ttaoc:rccpl and tients unresponsive to convenLional therapy; the rec-
hibitors. Of these, 226 w ere associated with inOiximab, 44 with ~k11ira in the lf<:atmcnl of ~licnts -...ilh rheumatoid an.hri1fs ommended dose is 5 mglkg given as a regimen similar
elaocrccp~ end I I with adalimumab. The most prc,'alent infec- who h:tve bttn tte~r(d unsucCC»fully w•lh me.1ho1rcx11e. Ar11Jr/.
1& RM11•12004; scr. t412- 19. Lo that used for Crohn's disease (see above). Therapy
tions were histoplasmosis (84 cases), candidiasis (64), and as-
petgillosis (64). Although the majority of patients also bad a his- should not be considered ineffective until after the third
tory of treatment with immunosuppressants including Pharmacokine t.ics dose of infliximab.
corticosteroids, the inhibition of1NF may affect normal immune lnfliximab shows linear pharmacokinetics. It is distrib- In the treatment of ankylosingspondylitis (see Spond-
responses and predispose patients to opportunistic infections. uted mainly in the vascular compartment and, after sin-
Delay in diagnosis and ll'Clltmcnt of invasive ~I infections gle doses, has a terminal elimination half-life of 8 to yloarthropathies, below}, UK licensed product infor-
hM resulted in fatalities; paticn1s should be dascly monitored for mation recommends lhat intliximab should only be
signs and symptoms of systemic fuugol infection during and af- 9.S days. After repeated doses, infliximab has been de- used in patients with severe disease who have had an
ter treatmt:nt with mF inhibitors. Empirical antifungal therapy tected in serum for at least 8 weeks. inadequate response to conventional treatment; how-
may be considen:d in those though! to be at risk of endemic fun- ever, in the USA it may be used in early treatment The
gal infections.'' ORefcrcnces.
Ncstorov I. Clinical pharm.acokineiics of tumor nt.'<.IOSjs (act«
Guideli11C$9 have been issued by the British Thoracic Society to I. antagonists. initial dose is S mg/kg, repeated at 2 and 6 weeks and
J Rlttumorol 2005; 74 (suppl): 13-18. then every 6 to 8 weeks; if there is no response after 2
quantify the risks ofrcactivatK>n oftuben:uklsis withTNF inhib- 2. Kto1z U, e1'11. Cliniul phvm;coki11ctics and us..: or ;nn;Ji:daib.
ito<s and to advise on the treatment of such infection in patients C/;n Phor..,ocokl•<t 2001; 46: 64S-60. doses no funher treatment should be given.
being assessed for mF inhibitor therapy. Other guidelines••. Infliximab is also used in the treatment of active and
have also been issued based on a review of the literature ond cur· Uses a nd Adm inistra tion
reot national recommendations. progressive psor iatlc a r th ritis (see Spondyloa r-
lnfliximab is a chi'!'leric monoclonal antibody to TNF thropathies, below); in lite UK, its use is limilcd to pa-
For the mention of leprosy associaled with infliximab therapy,
sec under Uses and Administration, below. a, a pro-inflammatory mediator. Elevated levels of tients who have had an inadequate response to standard
1. CSMIMCA lnOiximab (Remic:adc) and tubcrcuJosi$. C11rrt111 TNF have been found in the affected tissues and fluids DMARD but, as before, US licensed product informa-
Prob/1.,1100t; 27: 7. of patients with rheumatoid arthritis, ankylosing tion allows earlier use. In the USA, it may be given
2. Sch1ible TF (Ccntocor. Jnc.]. Imporcant drua ...,...min& (issued spondylitis, and psoriatic arthritis, and Crohn ·s disease
5\h Ociober.200t). with or without mcthocrexate; however, UK product
Available at: hllp://www. fd1.gov/downl...WS•rcl)'IM<dW01<1~ and ulcerative colitis. Elevated TNF levels are also information only recommends use without methotrex-
S3.fctylnform11ion/SofctyAlcr1sfor-Hum:t.nMtd1call>roduc:ts/ found in psoriatic plaques. l nfliximab is described as a
ucml74242 (a<c.eSJed 28/07110) ate in tl10se patients who are intolerant of or have con-
J. \Valli~ RS, tt ol. Oranulomatous infectious diseases associa~ biological disease-modifying antirheumatic drug tra-indications to such treatment. It is given in a single
•ilh lum0< nccrosis fac1or 1a111onisu. Clin /,~feet Dis 2004; 38: (OM.ARD).
126 1-S. Corrc:clion. ibid.; 39: 12$4-S. dose of 5 mglkg, repeated at 2 and 6 weeks and then
lnfliximab is given by i ntrav~nous infusion over a usu-
.. ~~!~~~~r::it.~~~i::i~:':!~1o~i~t~,~~~.:.c::er~~~;'!~
2004; 14( 4): 2-3. Also availoble ao: al period of not less than 2 hours; shorter infusion times
every 8 weeks thereafter. Guidance issued by NICE in
the UK recommends thal treatment with infliximab is
ht1p://www.hc-sc.cc.<aldhp-mpslalt form11slhplb-d&1>solpclr/ have been used in some patients with rheumatoid ar- stopped after 12 weeks in !hose who show an inade-
mcdcflYc•rft·bc:ti_vl4r>l ..ng.pclf (•tCcsscd 29/0SIOS)
5. Mohon AK. ti ol. Tuberculosis following the ust of ct.anerccpl, thritis (see below for further details). quate response.
a 1umor necrosis f11c1or inhibitor. Clin lnfttl DU 2004; 39! Infliximab is used with methotrexate in 1he manage-
29S-9. lofliximab is used in the treatment of moderate to se-
6. Tsiod.ras s. ti al. Fungal infccl10t"ls complicating tumor nccroiis ment of moderate to severe, active r heumatoid ar- vere plaque psoriasis (below). Its use is usually limited
factor o blocbde thcrAp)'. A/ft)IO Clin Pmc 200R; 8:3: IBl-94, thritis (below) In the UK it is licensed for use in pa- to patients in whom other treatments are not suitable.
1. FOA. lnfoon;1tion for he•hhcare profc-s.sionals: Cimz.ia (cenoli·
zumab pcgol), Enb«I (cl>n<rcq>I). Hu1nir> (•dolimumob), and tients who have had an inadequate response to standard lnfliximab is given in a dose of 5 mg/kg, repeated at 2
Rcmic:ade (inniximob) (issued 41h S<p<embcr, 2008). DMARDs although, in severe progressive cases, it and 6 weeks, then every 8 weeks thereafter. Treatment
Avai lab le a1: hnp:/lw~w. fd1 . s.ov/D ru 1~10r u g$::1fc1t/
Postmarkc1DrugSafo1yJnformationrorP:111icnuandProvidt.rs/ may be used in patients not previously treated with should be stopped after 14 weeks (4 doses) in patients
ucm l 2• 185.hlm (accessed 27110/09) me1hotrexate or other DMARDs; in the USA it may be who show no response.
8. Smhh JA . Kauffm•n CA. Endemic fvngal infcc1ions in paticn1s used for treating early rheumatoid arthritis. lnfliximab
receiving lurnour ntC"rosis factor-o inhibitor thtrapy. Drugs If the signs and symptoms of rheumatoid arthritis or
2009; 69: 1403-15. is given in a dose of 3 mg/kg, repeated at 2 and 6
9. British Thoracic Society Standards of Care Commiuec. BTS weeks, then every 8 weeks thereafter. For the first 3 Crohn 's disease recur infliximab may be readminis-
rceomme.ndation.s ror assessing ri5k and for mamting Myco· tered ifwitbin 16 weeks ofthe last infusion. Read min-
bac-crrium tubcrC'ulosis infc(tion •nd dtsease in pa11cn11 due 10 doses infliximab should be infused for at least 2 hours;
sun anti-TNF·a lrtatmcnl. Thorax 2005: 60: 800- S. Also however, UK licensed product irtfom1ation suggests istration after a drug-free interval of more than I 6
available at: http://www.bril·lhoracic.org.uk/Pon alslO/ weeks may be associated with an increased risk of de.
Clinin ~%201 n fo rm a t ion/A n1i%20TN FV.20Trt.:ument/ that subsequent infusion times may be reduced to a
Gu1dclinn/an1i1nf treatmem.pdfCacttsscd 13/06/08) minimum period of I hour in those who tolerate the Jayed hypersensitivity (sec Delayed Reactions, above)
10 Pcrlmvucr A, ct 07. Tuberculos:is and tumour nccroiis factor.._ and consequently is not recommended. Recommenda-
inhibilor therapy::. rtpon of lhrtt CO$tS in p.;atients with psoria- ini tia l infusions. A clin ical response is usually
tions regarding the read ministration of infliximab for
~~~~~:~B~~~~~~~~ ~~/~~i8f.(utic &uidetincs for achieved within 12 weeks of starting treatment Pa-
tients with an inadequate response during this period or other indications (other than those detailed above) have
Lupus- In Juno 2009, the Australian Adverse Drug React.ions who later relapse may benefit by increasing lhe dose: not been established. Limited data from rcadmin istra-
Advisory Comminee (ADRAC)' stated that 36 out of87 reports tion with a single dose of infliximab in psoriasis after
ofdrug-induced lupus erythematosus or lupus-like syndrome re- in tlte UK, a maximum dose of 7.5 mg/kg every 8 an inteival of20 weeks suggest reduced efficacy and a
ceived since 2003 were a!>SOCia1ed with lNF inhibitor ther~py. weeks (with increases made in steps of 1.5 mg/kg) is
Of these, 21 ~ports were associated with inOiximab, 10 with reoommended whereas, in the USA, a maximum dose higher incidence of mild to moderate infusion reac-
adalimum:ib, and 5 with ctancrccpt. of I 0 mg/kg is allowed. Altcrnatively, a dose of tions when compared with the initial regimen.
I. A1.h·etK Orvg Rc.-actions Advisory Co1nmiuce (AORAC). Drug·
incfvctd lupus t>rythcm3tosus: an tl'Mfli"I asso(iation with TNF 3 mg/kg may be given as often as every 4 weeks in For details of infliximab use in children, see below.
i.nhibitor:s. Aflsl Ad,'Ct'$t Dntg R~ncr 811112009; 28: 10-1 1. Al!OO such putients. Continuing lherapy in those who show Administration in children. Jnnixhnah is licensed for use in
av111lahle ao: h11p:llAAvw.1p.go•.. ulldr/,.drbl•odr0906.pdf (ac- no response within the first 12 weeks of treatment or
ccss<d 27110109) modcnuc to severe.. active Oohn "s disease in children aged 6
after dose adjustment should be carefully reconsidered: years and over who have not responded to coovcntional therapy,
Interact.io ns in the UK NICE recommends that infliximab be with- or who have contra-indication for or are intolcr•nt of such treat-
Live vaccines should not be given with infliximab or drawn if there is no adequate response within 6 months ments; doses arc the some as those used in adults (sec above). UK
licensed product in!Onnation suggests that the d05ll¥e interval
other drogs that inhibit Tl'.rF as the effect of such d111gs of starting treatment. may be adjusted 10 maintain any benefits: however. funhcr treat-
on vaccine efficacy or the 1isk of infection transmission Patients with moderate to severe, active Crohn's dis· ment is unlikely to be ofuse in patients nol responding within the
is unknown. The use ofTNF inhibitors with the imer- ease (see Inflammatory Bowel Disease, below) unre- first 10 \YCeks.
leukin-1 receptor antagonist anakinra may increase the sponsive to conventional ueatment may be given a sin- Although unlicensed for such use in the UK. inOiximab has also
risk of serious infections and neutropen ia; such combi- gle infliximab dose of 5 mg/kg. This may be followed been used in children with lislulising Croltn's disease; the
nations are not recommended. A simi lar interaction has by a maintenance regimen of additional infusions of BNFC 20/0111 rocommcnds that those •!cd 6 to 18 years may
be treated with the same dosage regimen that is used for this in-
been seen with TNF inhibitors and the co-stimulation 5 mg/kg at 2 and 6 weeks after the initial infusion and dication in adults (sec above). JnOiximab ha. also been tried in
blocker abatacepL then every 8 "eeks, or the drug may be rcadminislered the treatment of severe, refractory ulccn1tive colitis.
All cro~s-rcfe:rcnccs rerer to entries in Volume A
 lnfliximab/lsonixin 75
Asthma. lNF inhibi1ors such as innix imah have been inve~i­ pa1ien1s gi\'CO inniximob for rheumatoid arthrilis ha\'c also hcen :\. Nl<.:F.. Ernncrcept and infliximnb for the tr~J IM('lll of adult~~' ith
galed in lhe lfeatmenr of refrnc1ory asthma (p. 1220). •.! There is dcscribcd: 1 reversal ( l)'J'? I) reae<ions occumod iu bolh when in- psC'lriatic arthritis: ·rcchnology Appr3is;il Guidance 104 t issu~d
Some evidence lh31only a minority Of palienlS will r"'llOlld tC' fliximab was Slflppcd. .fu1y 2006). Available aic h11p ://www.nicc.<1fV·Uk/nici:n1edi~/pdll
1:>. I04suid•nce.pd f t•cct11scd OJ/t 1/08)
such therapy. and lhal lhc bener.1s and risks must therefore be I. Foiber WR.~' ol. Trcaunent orrecurrcn1 crythem:i nodosum lcp· 6. Rou S. et al. Successful treatment o( ICvtrc psorfotic nn h rit 1 ~
carefully assessed.' rMurn with intli'JCim1b /¥ Engl J Mui 2006: 355: 739. wich inmximab in on 11-yc:»r·Clld child ¥Ufrtr1n.. from linc--.tt p.l;O.
I. &in EM, ct ol. T11c cf(tcu. o( 11 monoclonal :antibody d irect.rd 2. Scoll.ard OM. ct t1I ~Hlopm«11 of leprosy and type I leprosy ri1sis :tlong Ii MS of Blaschko. Br J Dtrnra1u/ 2007; 157: I91-2.
against rumor necrosls ractON• In osdnm. Am J Respir Crit COIT rcaetions 1Atr 1rc1tment with intli"-imab: a report or 2 casts. 1. McLeod C. "' ol. NHS Htahh Ted\nolo;)• Auc"1nent Pro·
M.0 2006: t74: 753-62. C/i., Inf«/ o;, 2006: 43: e 19-e.."2. 1nmrne. Adalimum.ab. et:1.nercf'pl and u1Jli\im.;ab (or tht UH\-
~. Briglulin! C. ct ol. Tatg.,1ns TNF-•lpho: a novcl lhcr.>peutic ap- Psoriasis. lnniximab is used in lhe ~tmcnt of moderate 10 se- mcn1 of a1tk)'IO$.ing s.pcondyhlii: I l.)'SCcrnlllc rcvi~ and CCO·
pmadi f(J< lsthm•. J All~ Clm ''"""""" 2008; I ? I: S-10. vere plaque psoriasis (p.1723). 14 However, TNF inhib1ton have nomic: evalua1ion (issued Au:,ust 2007). Avai lable al:
hup ://"''""'"'~.hta.ac . uk/ fullmonolMon I 12S.pdf (:»ccu,e:d
lnfiammatot')' bowel disease. lnOtximab is used in adults for been associated wilh \'IJrious adverse effects on the skin, see Ef· 3 1110/081
die treatment of Crohn's diseasc 1•12 and ulcerdlivc coli1is'-r;-n fects on lhe Skin, above. a.. NICE. !\d2llmumg;b. c1anmep And inOi.ximab for ::mkylosing
(p.1846); it has also bet:n u;ed in children in the treatment of in- I. 9enoi1 s. ~I ol. Trci1rneri1 or re:calcitranl pustular psonas1.s wiih ~ndylitis: Technology Appraisal Guidance 143 (issued M:Jy
llammalory buwel disease. •WI panicularly Crohn ·s disease. inOhamab: e!Tccth'c reduction of chcmokine c:xpress•on. Br J 2008). Available al: http:/fww"-.llicc.ora. uk/nicemtdialpdf/
Jn the lfeatmcnl ofCrohn'sdisease, guidance issued in the UK by O..ro101012004: ISO: 1009-t2. TA 143Gu idancc.pdf{acccncd Jl/IO/OR1
l . Oo1tlieb AB.~' of. lnOiximab jnduction 1hentpy (or patients wi1h 9. B:uaHakos X. Br:»un J. Anti·TNF..o. 1hc,.,py with in.mxim.ab in
NICE recommends that inniximab is used in patients with severe spondyl oarth ri tide~. E."tX!N Rt·v Clln /111m11nol 2010: 6: 9-19.
severe plaque-type psot'iasis: a rondomiicd, double-blind. pl1ce-
disease when treatment with i1nmunomodulators and corticoster- b<J.con11olled trio I. J Am Acod Dmllalol 2004; 51: 534-42.
oids has failed or is not lolenned, and when surgery is inappro- Uveitis. lnOiximab has been lried 1' 11 wi1h some success in the
3. Reich K. tf tJI. EX PRESS s1udy invcsli~.alors.. lnni.xi1n•b induc-.
priate.2'~ 1ion and main1enoncc lherapy for modcratc-lo·uvcrc psorfasi); o u-eabnent of uvcitis (p. 1653) including 1ha1 associated wilh Be-
phau Ill, muhicentre, double-blind trial. i.An('«t 2005, 366: h~t's syndJ"Ome (p.1637). Uveitis Clln Dlsu dc,oelop as a compli-
In the treatment of ulcerative coli1is, guidanee issued by NICE
1367-74. cation of olher inOammatory disorders such as rhcumaloid ar-
recommends again$1 the use of in0ixin1ab in subacu1e manifes- 4. Reich K, f:I ol Improvement in qU1tli1y of lilt wilh inni:t:im1b ~cri1is; 1rc.tune111 wilh inniximab may improve ocular symptoms
tations of moderately lo severely ac1ivc disease (defined as that 1nduc1ion and main1cnancc thernpy in patients wl1h m~cr.ue~J.O.. in addi1ion lo iis elfeel on the primary disorder.
which would normally be managed in an outpatient setting, and SC\'~ft psoriisis: a randomized comrolled trial. Br .I Dcn"ornl
does not ~equirc hospitalisation or the consideration of urgcnl 2006; t54: 1161-8. t. Murphy CC. et of. T•mor rlCCl'Ol<i• f•CI<>< olrh• blodoldc widt
Snuth CH. et ol. lnni:cin-.eb ror SC:\'etc, trcatmcnc.tu1stan1 pso- infli.:<imab for refractory uvci1is and $Cleril1J. Oph1holrnol"!(v
s..-gical intervcnlion).:n Jn the trealmcnl of acute exacerbations 2004: JI\ : 3S2~.
ofseverely acti•e ulcerative colitis, NICE guidance recommends riasis: 1 prosp«JiYC, open.label study. Br J DerowJo/ 2006: 155: 2. Bodaghi 8. Cl al. Therapeutic UJC or 1nni~imab in light thrt:oll-
160-9.
use ofinOixiniab only in pe1icnu in whom ciclosporin is contl'll- 6.. MC'ntcr A. ~' ol• •Ii r:mdomizcd comparison of coatinuws \'S. in· ifi~&r~:!~1:!°:J::~v~::;~~ Z!:c~~· safety. and fon·
indicated or clinically inappropria1e; ocherwise, it shoo Id only be 1mnineru innixirmb ~intenan« rtgim~ over I yu.r Jn the 3. Braun J.~1 oL Dcettased incid<'nce: ofantttior uvti1i1 in patients
<JScd for such lrc.tunent in lhe con1ext of clinical snxlies.1• lte:IU'Mt:nl of modt.ralr-to-sc"·erc: pbquc psoriau1. J .A111 A('Ot/ '\\-Ith anky1osing spondylihs uc:awj with lhc 1n1i--tufn0f" necrosis
I. Prc$t'nl DH, ti of. fnOb:imab f« rhe treatmtflt of fi.srulas in pa- Dmua>o/2006:56: 31.<l-IS. factor agenu inflix.im.ab and ctantrttpt. Arthrilis Rl~rlll'I 2005:
1icn1s \\'fth Crohn's disease. /ii Engl J Med 1999; 340: 7. Pou1alhon N, et ol. A follow-up study in 28 palicn1s created whh 51: 2441-~t.
1398-t40S. 1n0i.drnnb for s.?verc recakilrant psoria.si.s: evidence for err.c.cy 4. Richards JC. cl ol. lnntxim~b for ju\''Cnilc idiopnthic a.rthritis-
2. Rutgccns P. ~'al. Efficacx and safety of rt rrealmcn1 "ilh anti- and Mah incidence of biological 3utoimmunily. Br .I l>,rmt11ol associat~d uveius. Cli11 Erpcr/m~ffl Ophlf)(1/mof 20(1S: 33:
tumor necrosis fac1or :intibody (infliximab) 10 maintain remis- 2007; 156: 32~36. 461-&.
s-ion in Crohn•s disuse. Grumucml'rolOJD' 1999; U7: 761-9. 8. NICE. lnnixim:ib for the 1.rea1mcnt of aduhs whh psoriasis.: S. Lindstedt E.\V, el ol. Anti-TNF-u 1hcrap)' for sis:ht threatening
3. Hanouer SB• ., al. ACCCNT I S<udy Group. Main1enane< in(· l"echnology Appraisal Guidance 134 (iuucd January 2008). uvcitis. Br J Opl11halmol 200S: ¥9: 533-6.
liximab for C'rohn's disease: the ACCENT l r::111domisc:d trial. Ava il able al: hup://www.nice.otg.uk/ nicc medla/pd (I 6. Saurcnmann RK, t-1ul. Tumour nccr~is r}lctor 3lph.a inhibi1orS
/,,mr_,,r 2tJQ2; 359: IS4 l-9. T/1 13 4Guidonec.pd((acccsse<l 22i08/08) in the 1rca1ment of childhood u\'eitis. Rll,wm<11ology (Oxford)
4. Ru13ceru P, tt al. Comparison of scheduled and episodic 1reat- 2006; 45: 982-9.
1ncn1 stnncgics ofinOis.imobin Croh!'l's disease. Gostroeutqrof· Rheumatoid arthritis. TNF inhibitors pl3y an increasingly 7. Kahn P. ct al. Favorable rcspouK to hiith·dll~ inlliximab fur
og;i-1004: 126: •02- 13. imponan1 role in the management of rheuma1oid anhritis; they refractory childhood uveitis. OphlhoJmoJi>g.1• 2006; 113: 860-4.
S. Sands BE. d t1l. Jnniximab maintenance thcmpy for fis1ulizing lend to be reserved for patients who are unresponsive to 1nore 8. Guignard S. eta/. Efficacy of tumour necrosis (actor b locktrs. io
Crohn's diS<?a•<. N Ent,IJ Mccl 2004; 350: 8"!6-·8S.
6. Panaccionc R. tt of. Ctn.tdian Association of G;utrocntcrolOjy conventional disease-mod ifying antirhcumolic drugs ~!:~~~f::~:~<l~~:;!niRl,'~!~1Di,'2~~'65:di~~~~palhy: a
Clinical Practice Guide-l~nn~ the use or inOiximab in Crohn's (DMARDs). although some favour use earlier in managcmcnL 9. Tyn.j31i P~ el ul. lnniiimab and ttanttcepl in rhe lrt'a1menr of
disease. Cnn J Ca1/IW1Jltrol ~004: 18: S03-S. Some references'" to the u:;e ofinOiximab in rh.:umatoid arthri- =~",,",,ci~t,~z1toc,j~~if~~?o~uvcnilc: idiopathic :u-
Also availlblc at: bup:J/www.C3g-acg_orgfuploadslguidelinW
lnniximab%20Suidclinc"'202004.pd( (.cces=! 13/06/08)
tis (p.12) and juvenile idiopalhic arthritis (p.11). 10. Ardoin SP. et ol. lnniximab 10 ttta\ chronic noninfttbous uvd-
7. Siddiqui MAA. Scon U . 1nmximab: a. revi""" of its use in I. M1inl R. n al, ATT'IV>CT SlUdy Group. lnR1x imeb (d11mCl'ie tis in childnm: ret.rOSpc:C:hvc: COK tcnts l'ilh btg-lenn folio\"·
Crohn's disease and rhevm11oid uthrilis. Drwg$ 2005; 65: 1r1ti-cumour necrosis (actor 1Jpha 111onoclor.al ancibody) versus up. ARr J Ophtl>olmol 2007; t«: CC<t-9
2179-2208. ContttiOC\. ibid. 2006; 66: 13S9. plKCbo i.n rheum:uoid ~nhrilis patients rccciv1na concomitant JI . Pipi I.One N. ti ol. lnfli~imab for t.hC' trc:atmcnl ofNcuro-~1 ·s
8 . Ru1,tcru P. ~' ol. Revirw anicte: innixim:ib therapy for innam~ mc1ho1rnat~ : :. randomi~ phase Ill 1rial 1A1ttt' 1999+ l~: disc:a$C: ;a ca~ wries ;and r-e\·ic" or lhc lilc::rature. Arthritis
r:~~!~\'!JI: ~~:~\"en years on. AUment Plrormacol 1932-9. R""""' 200S: 59: lt>S-90.
2. L..ipsky J>E. ti al. Anti·Tumor Neuosis FtclOr Trial in Rheum1- 12. Y3mada Y. ~1 ol. Comperison of inniximab versus cidosporin
9. Ru1ttens P. ti nl Scheduled mainlt:nanct 1re:1tmtnl with innix- to1d Art1vi1i1 with Concomi1an1 Tl-.c:rapy Sl~y Croup. lnnixi· during 1hc initi:ill 6-monlh 1rcotmcnt p:riod m Reh9et d is~~c. Br
~7c~~:1!:~~:ii:.:S~~(~~~~~e;i~~~~G~~~~~~1~~:£:Z:~ mab and mcthotrex2tc in 1hc trcatmtnt of rhc:um11oid ru1hri1is. N J Ophlhalnm/2010; 94: 284-8.
t'nJll J Me</2000; 343: IS94-1602.
2006; 63: 433-42. Vasculitic syndrome s. For a preliminary report on the use of
Maini RN, ti al. Ami· Tu mor Nccr0$i$ hclor Tdal in Rheuma-
10. LCm1nn M, flt e1J. Oroupe d'E1udc Therapeutique des A ffection~ toid l\rlhri1is ,,..;,h Concomi1an1 Th~ropy Scudy Oroup. Sust•incd inniximab in Takayasu's orteritis, sec p.1 653. lnOiximab has also
JnOamma1oil'U du Tube Di ~tsli( (GETAID). lnOixinrnb plus improven11m1 ov('r <wo ye3rs in physical func tion, struc1ura l been investigaled in lhe man3gcmtnl of Kawasaki disease
az:uhioprinc: for stcroid dcpe11der11 Croh r~ 's dis~sc pa ti ~1u1: a
0
d1maoe., "Jld iigns and sy111p1oms Mlona: p:itic:ms wi1h t11eu1na- (p.2435) in palienlS who are unrespunsi•c lo s1a11dard n·eat-
~~i~o'Q~c!f.111c:ebo·controlled trial. Ge1s1ro~n1~1vlugy '1006;
1 4 1oid 011hri1is tre:ued with in 0ixim:1b :lnd mtlho1rexa1e. Ar1/11#is
Rht!um 2004~ !\O: 105 1-65.
ment.1-'
J. Bums JC. ~I al. tnni:Ull13b trc::itntcnl for rcfratt('lry Kaw:isoki
U. <Xterman MT. Llcluen~c in GR. lnOiximab in fiscuUzina 4. Qoinn MA. t! ol. Vtty catl)' 1rea1n1c-nl with 111tliximab in .3ddi-
Crohn's ducuc:. Oo:11roc111t•rol Clhr No,.1'1 Am 2006; 35: syndru111<. J P~i<1tr 2oos. I4G: 662-1.
79s-820. 1ion 10 mcthOtK.."tatc in early. poor·prornosii rheurn11oid anhritis 2. Saji T. Keminotsu Y. Sntli~im:ib for K;1was:ak.i syndrome. J Pctli-
t2. E4ehe:vtn MJ. ~t al. Optimizine the use of tumour nttrosiJ fac:· reduces m•gnetic rcson:ancc imagln; evidence of syno\itis :n<I alJ' 2006: 149: 426.
'°' inhibitors in Crohn •s disease: e pr;ic:iic:al 1ppoach. Dntt.J dam3a;e. ¥i-it.h su:5t»ifled benerit after inni.xi1nth w11MmW1I: rt·
sufu: from a twelve-month randomiud, Juuble-bhnd. ph11tt:bo-
3. O'Connor MJ. Saulsbury FT. lncompktc and 01ypic;1.I Kawa~lc.i
20 IO; 70: I09-20. disea.sc in a young inra~1 · aco,.uc,. rcc:1k:i1nn1 disn.sc ruponsiYC
13 Probtn CS. tr ol. lnfliximab in modtn:tely !'le:'\c~ &lucocorti· con1rolled tri1t Arthr;1;s Rlt<u., 2005: 52: 27-3S. to infliximab. a;,,
P~diu1r (PlllluJ 2007; 46: 34S-S.
coid rt':S4Sllm. u1ccr;cive coliiis: a randomised controlled trill S. Voulpri PV. ~' "'· lnOi~imab lhtrapy in cst~blisMd rtic:um2101d 4. Bums JC~ ~' of. lnfli'umab 1re:ntnt'nl of intrJvcnous immu-
Gv1 2003; S2: 1191-1002. 1nhrills: an obsavational ,.udy. A•iJ .lkd?OOS: 118: Sl$-:?O. nog.lobulin-resis.tanl Kl""'"IRld dtKH~. J P.:JiOlr 200$: ISJ:
14. Rulll,cctlt P, a al. 1r10lxim~b foe induction and n\Oltntc:n:>nc:c 6. Chen y.r. ~I ol. NHS Huld1 TccbnOlotl)' A>S<'S)m<ft( f>ru. 83~.
&t"amme. A S)'Sttrnati:c: r<vie.w oflhc cfftCli'\•eness orad.,limum-
~~62!''6.fC~,~~~nt.'~:,;~·,~~; t547~~·J-t~a 200 $; 153: ah. eaanl!rCt"pt and inOixim:ib for the1re11men1 ol't11eumaat>id ar· Preparations
JS. Lawsoo MM, t:I ul. Tumour necrosis factor *lpho blcw:k:ina, 1hritis in aduhs, and an ~conomic e:valuauon or their cost·
agcnlS for induction of remission in ulcerative: eo1ilis. AvoiitQ.ble dfccli..,cnus (issued No'\•embc:r 2006). Av.,ilable 01: hup:// Proprietary Preparadont (dc1ails ar< given in Volume B)
in The Cochmne OttAb:>sc of Sysccmalic_Rc"icws; ls.sue 3 www.h<uc.uk/fullmonclmon I042.pdf (•«'<sscd 31/t 0/08) Rcmoude: Auruio: lltrnrcode: lklc.: Rerni::ilde;
Ari:~ Remicad<: Austtol.:
Chiehe>l<r: John Wiley; 2006 (accessed 13/WOS). Broz.: Remicadt: Canad.: ~c: Chile: Rerric.ade: Cz..: ~Ide;
1. Ruperto N. et ol. Paedi:itric Rheurnatolo:y lntc:niational Trial~ D~nm.: Rel'Y'icadc: Rn.: Remlud'e; Fr.: Rerr~ade: Ger.: Remirtde: Gr.:
16. Abcm FN, Lich1cns1c:it1 OR. lnOi>.imab in ulccro1ivc coli1is. Orca11is31io11. Pediatric Rhcum:nulo¥y C:vll~horali\.e Sludy
Gtr.<1t0tut~'OI Clln Norlh Am 2006; JS: 821-36.
17. Oisbcn JP,'1to/. Systematic review: fnOixim.lb therapy inul«:r-
Group. A randomized, pl:>ec:bo+con1rollcd lriol or inOiximob plU$
m.:1hotrexa1e for the 1r..,.;i1mcn1 of polyanicul;ir-·coursc ju\'enile
~~::'1~~:,7r!T"~dh'a7.:u~~:.:~7::; =~~=~;
otive colitis. Allmcut Pharmncol 17u:r :!007; 25: 19-)7. sio: Remicade; Me.x.: Re•"icade: Neth.: R~mic:adc'. Norw.: Remicade; NZ:
rheumatoid anhri1is. ArthrMs Rhaum 2007: SG: 3096-3106. Remicadc; Philipp.: Remicade; Pol..: Remic.ade: Port.: Reniiadc, Rus.:
18. Boldosuno R, or ol. lnni.\im>b (REMICAOE) <hcrapy in che 8. NICe. Adalirnun13b, ecantrcepc and inObc.imab (o1 the tr<almem
treatment or
pcdiotr'ic Crohn's d isc~se. A m J Gn1tro~Ulel'OI Remic.:tde (Pc:,....11(~: S.Afr.: Rtvt41e.x: Singapore.: RE1nicad-!: Spain:
of rheumatoid anhri1js: Technology Approistil Guidance 130 (is· Rem>cade'. Swed.: l'\cmocacl<: Switz.: ~ Thai.: Re<l'iczdc: Turk.:
2003; 98: 833-8. sued Octoher 2007). Avait:ihlc:- at: l1up;//www nite:.org.uk/
19. Hyams J, 11 ttl. REACH Stud)' Group. Induction and mnintt· Ronic.:ide. UK: Fluroc•do: USA: P..m<ade: Vtnei.: Rcm<adc.
niec1nedia/pdflrA 130guidon..-..pdf(•«,,..<d OJ/I I/OS)
nancc inniximab 1hcr.1py for the trca1mcnt (I( mod<:r•CC:•IO...SC•
VtfC Crohn~s d1U:Ut m children. Go~tr<;Wmuo/ogy 1001; Ill: Sarcoidosis. For n menlion of possible benelil frocn inOiximab
863-73. in =idosis, sec p.1650.
20. de: Ridder L.. N al lnm,im:ab use in children :t.nd odolc:sc.cnu l sonixin (<l'IN)
"'1th 1nOAmnw1tory howel disuse. J Ptdiu1r Gas1'0#n1rrol ,.,.,,,,. Spondyloart:hropathies. References'~ 10 1hc use of innixi· 15Cnixine: lsonCOro. lsorol<nim 2-H;Jdroxy#-(2.6-dimclh)'iphe-
2007: ·~: 3-14. mab in the trentment of ank)1osing spondylitis and psoria1ic ar·
21. Vertt G. «t ol lnOh.1m;,:b thcnipy in cllildrcn ~nd 3dotcsccnts ~ot.narrcc!e
wHh 1nfb1n1n::uory howcl disa~ Dntgs 2001; 61: 1703-23. 1hri11s (p.14). In the UK, NICE considers 1hat TNF inhibi1o..s
ill30k"1~..CHt1
or
22. NICl!. Ouid:incc M the USC inOixtmab for CroJ1n·s disc:tis1:: should be reserved for severe active diS<:aSC unrcsponsi,·e to at
C,.H ,.N102 "' H2.3.
Technology Approinl Guidance 40 (iuutd April 2002). least 2 s1ruxlard drug treatmc111s; in both indica1ions, etanerccpl
Avai lable IL: h1tp;//www. n icc.org..uklnice:mcdi1/pdf/ or adalimumab are prefcrr.:d to infliximab.~-' CAS - 57021 ·61 · I
NiccCROllNS40GUIOANCE.pdf (acc<md 13/06/08) UN/I - 8YX6£7MSQE.
23. NICE. l110ix1inab for subacu1c ma ni f~smtions of ulcera1ive col· I. 8rand1 J, t•t '"· lnflixi1nab in llx 1n:111mcnt of active and severe
his: Tcchnoloay Appraisal Guidance 140 (issued April 2008). ankylosin& spondylitis. Clin E.tµ R/1(11motol 2002; 20 (suppl 28):
SI06-S11 0.
~:f!~~~a~c.~l~~:~;;~·~~~j~i·uklnice nlcdia/pd rJ 2. Brand1 J, t i ol. Successful shoN «tl'1n 1rc11mc:n1of severe undif·
24. NIC£. lnfli~im1b ror act.11e e~acerbati ons or\llccr:uh•c CCIIit is: foren tiatcd spondyloanhropalhy wilh the t1nti·tu1nor necrosis
Tcchriolo~y Apprnisal Guidance 161 (issocd December 2008,. factor-a lpba monoclonal anlibody intliximab. J Rll~mnmol
2002: 29: 118-22.
~~ ~ 6~f!u~a~~c.~'"~:=:~':;;~~~0~1.uk/nicc:mcdia/pd I J. Collantc:-s·EstC¥cz. E.. et ol. lnniximab in rtfnclory spondyloar·
1hrop3thies: a muhice:1Hrc 38 week open 1ludy. Aun Rlr~um Dis,.
Leprosy. lnniximab has been <JScd1 i111he trca1n1e11t of recurrent :!003: 62: l239-40.
type 2 (erythema nodosum leprosum) lepr:i reactions (p.188). 4. Robinson OM. Kea1ine CM. lnnixi1nJb~ in anlo.ylosina 1if1<Jndyli-
Howc,•cr. 2 cases of rapidly progressive lqn05y developing in 1is. D<ugllOOS: 65: 1283-91.

~ symbol t denotes a preparation no longer aeuvely marketed

76 Analgesics Anti-inflammatory Drugs and Antipyret1cs
Profile Profile Analysis indicated that the number of reports for topical ketopro-
Jsonixin is an NSAID (p. 100) that has been used in the manage· Kciobemidooe is an opioid analgesic (p.JOS). It has be<n givco fen was disproportionately high in relation to irs usa~.
mcnt ofpain and inflammation associated with mtL..:uloskeletal as the hydrochloride orally, by injection, or rectally, somotimcs I. Mimhieu L, et al. Contact ind pho1ocontact allcrty lO ltt:1opro--
and joint disorders. 11 has been used in doses of 400 mg two to with an antispasmodic. ren: the Bclgi1n experience. C.of'ltnct Dermot1tu 2004: SO:
23&-4t.
four times daily orally or by reclal suppository. It has also been O Refcre1ic:es. 2. HindsCn M, ~ol. Pboloallcrg.ic con11adcrma1itis Crom ketopro-
applied topically as a 25% cream. t. Al·Shulb1ji A, Tokics L The phermacokinctics of kc1ob<m1· fen in southern s..-.-edcn. Con/DC/ fNrMotltis 2006; 54: 150-7.
done jn cri,ietUy ill patients. Br J Clln PltornllJCol 2002 S4: 3. Oi.u ~ tt al Grc.11cr allcrgcnicity of topical kccoprofcn in con-
Pre parations S&H. tact dmn:atitis cunlirmcd bv us.c; C.Omoct £h,.mo1/1iJ 2006; S4:
Proprietary Preparations (details arc given in Volume B} 2. JylJj L. et of. Comp1>riJon of I.he analaC'sic dTteacy of kctobcrrti· 23H3. -
done and morphine ror man3gcmenl of posloperativt pain in
Spain: Ni>Q'1' childrm: a randomiud, conrrolltd study. Acta A11oeMl1e.,iol Hypersensitivity. Life-tlueatening asthma, urticaria, and an-
S<a1Kl2004; 48: 1256-9. gioedcma developed in 2 aspirin-sensitive patients aJ\er taking
Multi-ingredient: Spain: N°'>f'
P reparat ions ketoprofcn SO mg orally. 1 Cardiac and respiratOl)I amst occurred
in an asthmatic patient shortly after raking keloprofcn. 1 Life-
Propriet;iry Prepar:atlons (detoils are given in Volume 8) threatening asthma has also occumd after topical applicarion of
~= K<todui: Norw.:~. Ket~ s-d.: K~ l(.etogan ketoprofcn.1
Kebuzo ne (riNN)
Hulri-in&red'iene Oen= Ketog•n: Norw.:~ Swed.: Kctog61\ Delayed slcin hypersensitivity wu seen in a patient who used a
Kebuzona; Kebuzone Kebuzooum; Ketophe<l)'lbutazone. '4-(3- topical gel cooraining kctoprofcn.• The rcae1ion recurred on rc-
0><obut)i)-l.2-ciphenytpyrazolicfine. 35-dione. challcngc to kctoprofcn gel but not to a similar gel containing
Ke6y3oH diclofenac. The authors of!he report noted that the UK CSM had
Ketoprofen (8AN. USAN.-rlNNJ received 1S rcpons of skin reactions to ketoprofen 8cl. including
=
C,,H 1,N10 1 322.4. two each ofdermatitis and urticaria.
CAS - 853-34·9. Ketoprofeerf: Ketoprofb-c K.etoprofenas: Ketoprolene; Ketopro- See also EtreclS oo the Skin, above.
ATC - MO IAA06 reno; Ketoprofen.rn: RP-19583. (RS)·2·(3·Benz01lphe11)i)propi- I. Fril.h P. 6 ol. Li(c-lhrutcnina Hlhma. urticaria. 3nd •naiottdc~
onoc acid. m11ft:e.r kctoprofen. lancet 19i8: ii: S47-8.
ATC Vet - QMOIM06. 2. Schrt'Uder G. Kctoprofcn: pos.siblc 'diosyncralic. acute bronchos-
Keronpo4>e1<
UNll - 4VD83UL6Y6.
=
C 16H,.01 254. 3.
p:um. Mtd J A•SI 1990; I S2: 332-3.
3. Kuhiwabara K, Naka.mUl"I H. Antl.gaic.·induccd a.slhma caused
CAS - 12071-15-4 (ketopro(en): 57469-78-0 (keropro- by 2.0% kcloprofcn 1dhe$l~ a@_ents. but not by 0.3% agcnts. /11·
(en 1).-sme): 57495-14-4 (ke1oprofen sodium). run Med2001; 40: 124.
4. Oh VMS. Kctoprofm g•I Ind delaye4 hypcr..,nsitivity dermati-
ATC - MOIAE.03; M02MIO. ,;._ BMJ 1994; 30': Sil.
ATC Vet - QMOIAE.03; QM02AAIO.
Myasthenia gravis. A cholincrgic crisis was precipitated by a
UN/I - 90Y4QC304K.
single oral dose ofkctoprofcn SO mg in a patient with well-con·
trolled myasthcnia gravis. 1 The patient had pn:viously noted a
sirnil1t but milder reaction with aspirin, but not -.i1h paraceta·
mol
1. McOowcil IFW, McConnell JB. Cholincra.ic cris is in myastheni1
g.avis prcclpi11ocd by lmopror•n. BMJ 19SS; 191: 1094.
Pancreatitis. Panen:atitis has been associated with ketoprofen
Profile use. 1.2
Kebu2one, a phenylbulazooe derivative, is an NSAID (p.J 00). II 1. Cobb TK. Pierce JR. Aculc pancrC3titi.$ associ1\td wilh ketopro·
Phatmacopoeiu. In Chin., Eur. (see p.vii),Jpn. and US, fen. South MedJ 1992; 85: 430-1.
has been given ll>r musculoskeletal,joint, and soft-tissue disor- 2. M~C o. ~ al. Pancrtathe 1igue ea kt.ioprorcne. Go11r<x!n tuol
Ph. Eur. 6.8 (Ketoproretl). A white or almost white, crystalline
ders in oral doses ofup to 1.S g daily in divided doses. Kebuzone C/l•Bio/200 1; 2S: 721 -2.
powder. M.p. 94° to 97°. Practically insoluble in w.iler; freely
has also been given as the sodium salt by intramuscular injection Photosensitivity. Ketoprofen causes photosensitivity
soluble in alcohol, in acetone, and in dichloromcthane.
in doses equivalent 10 I g ofbase once or twice daily. USP 33 (Ketoprofen). Store in airtiahr containers. · reactions 1.l ond cross-scnsirivity to other drugs, notably the li-
bratcs beufibnite, ciprofibrate, and fenofibrare, has also beal re-
Porphyria. Kebuzone is considered to be unsafe in pa1ien1S with ported. The cross reactions were anributed to the bcnzoyl ketone
porphyria because it has been shown to be porphyrinogenic: in Dexketoprofen Trometamol {BA1'bl>t <L'INM)
structure that the drugs bavc in common.
onin'IO/J or in--vil ro systems. (S}(+)-Dexi<ctoprofen Trometamol; Dcxketoprolene Trorr.!ta- Sec also 'EITeclS on tbe Skin (above).
Pre parations mot Dex~toprofeno trometamol; Dexkeioproferun Trometa- I. Baiflcrl H. et al, Pl\otoscnsi1ivity to kctoprofen: mechanisms
molim. Ind ph1tmacocpidcmiologiul dau. Dr111 Sa/tty 2000i 22:
Proprietary Preparations (dciails are given in Volume Ill Aet<a<eTon~ TpOMcTaMOA );~9.
Austria: Kr.Wont. C..: Kewont. 2 Vtync O. et nl. Bilan de l•tnquCtc nationale sur lcs cfTets fndC.·
CAS - 21161-81-5 (dcxkctopro[en). sirablts cuuin~ s du k~loprof~nt &el cnrcgis l r~• enlrc le
H uld·lnirecflenc Aun:rlo: Rhtuint:SSef"; CL: Ke°.azor• Cc:lnl>ositumt. ATC - MOIAE.17. 01109/1996 el le 31/08/2000. Tltoropi< 2002; 57: 5~.
ATC Vet - QMOIAE.17.
Renal Impairment. The elimination half-life and unbound
plasma concentntioos ofdexketoprofon are increased in patients
Ketobe mido ne H yd rochlor id e {BANlll. liNN'.4) 0 CH3 with renal impeinncnt given racemic kctoprofenY this appears
to be maioly attributable to impaired renal c!earanC1C of the acyl·
<:etobemidone, chlomydrate de; Cetawmidone Hydrochloride;
~COOH glueutooide conjusates in a stcreoselcctive fashion, with subse-
Cetobemidon1h)>drtxhloridum; Hidrodonxo de cetobemidona:
Ketobemidon-~hk>rid; Kctobemidonhrdroldorid; Ke-
tobemidoni Hydroch!oridlm; Ketobem donhydrol<loridi; Ke-
lobenVdono hidroc~rida$. I 0(4-m-Hydroxyp~.enyf- 1 -methyl.-4-
uu (duketopri)fen)
quent hydrolysis of the unstable conjugate back ro the aglycone
producing increased plasma-kctoprofcn concentrations.'" 1bc
authors of one study suggcstcd3 that dosage adjustmeolS of ra·
cemic ketoprofen were indicated only for patients with moder·
ately severe renal failure (ereatinine clearance of less than
p1peridyl)p<O!)<ln- I-onc hydrochloride. 20 ml.Jminute).
KeTo6CM1o1A0><a f 'W'""""P'IA For advice on the close of dexkctoprofcn in patients with renal
C,~H21N01,HCI = 283.8. Adve r se Effect s, Tre atme nt, and Precau- irnpainnenl see under Uses and Administntion. below. See also
tions Adverse Elf.as and Precaulioos, abo\'C.
CAS - 469-79-4 (ketobemidone); 5965-49-1 (ketobemi- I. Hayball PJ, ''al. The inOuencc or renal fu-nc1ion on the cnanti·
done hydrochloride). As for NSAIDs in general. p. l 00. osclccci\lt: ph.armacokinctic.~and phannacoclyn1mics ofketopn:>--
ATC - N02A801. When ketoprofen is given intramuscularly there may fcn in p<1tients wilh rhcurMtoid 3r1hritis. Br J Cliu Phormocol
t993; 36: t8S-93.
ATC Vet - QN02AB01. be pain al the injection site and occasionally tissue 2. G111bb NG, '101. Stereoocl«Uvc pharmacokinc1ies ofk<1op<ofen
UNll - U9U6LTV801<. damage. Topical preparations containing keloprofen and k.ctoprofcn glucuron;dc in cnd·s1:igc rcnol discsc: evidence
may cause application site reactions. Ketoprofen sup- for 1 'rulilc cycle' of elimination. Br J CUn Phor111ocol 1999i 48:
494-500.
positories may cause local irritation; rectal use should 3. Skcilh KJ, d al. The inOucncc of renal function on the phamu·
be avoided in patients with a history of proctitis or cokinctic:s or um:h.:angcd and ac;yl·ctucuroconjugalcd ketoprofcn
enantiomers tt\cr SO and JOO mg r1cemic k~oprofc.n. Br J Cl/Ir
haemorrhoids. Ketoprofen should be used with caution Phormocol 1996; 42: 163-9.
in patients with renal or hepatic impainnent; it should
not be used in those with severe renal impairment. Interactions
Dex.Jcetoprofen should be avoided in patients with For interactions associated with NSAIDs, sec p.103.
moderate to severe renal or severe hepatic impainnent, Probenecid delays the excretion ofketoprofen and de-
and in those with severe heart failure. creases its extent of protein binding resulting in in-
Effects on the skin. Conl3Cl o.nd photoallerg_ic dermatitis have creased plasma-ketoprofcn concentrations. Not unex-
(ketobemidone) ~n seen after topical use of ketoprofcn. '" A rc1rnspec1ive pectedly, a similar interaction may be seen with
study' found that of the 139 cases ofcallaCI reactions to topiC31 dcxketoprofcn and probcnecid.
NSAIDs reported to the Spanish Phannacovigilance System be-
P ham>acopoeia.s. Jn Eur. (sec p.vii).
tween 1996 and 2001, 84 inYOlved ketoprofen (16 11llergy; 68 Pharmacokin etics
Ph. Eur. 6.8 (Ketobemidonc Hydr<XNo!ide). While or almost photoallergy). Totals for other NSAJDs included piroxicam (21}.
white, crys~illine powder. Freely soluble in waler; soluble in al- etofenamatc (10). piketoprofcn (5), salicylatcs (4), fepradinol Ketoprofen is readily absorbed. from the gastrointesti-
oollol; very slightly soluble in dicbloromcthane. A 1% solurion (3), diclofenac (3). indorneucin (2), phcnylbulaZ.One (2), benzy. nal «ract; peak plasma concentrations occur about 0.5
in water has a pH of 4.S lo S.S. damine (2), accclofcnac (I), naproxen (I). and mabuprofcn (I). to 2 hours after an oral dose. When kctoprofen is given
All cross-references refer to entries in Volume A
 KebuzoneiKetorolac Trometamol 77
with food, the bioavailabilitv is not altered but the rate cally, they are applied 2 to 4 times daily for up to I0 Ketorolac Trometamol (BANM. r1rJN1v1)
of abso1µtion is slowed. K~toprofen is well absorbed days.
l(etorolaal«itrometamoli; Kc?torolac vorneta"l'lol: Ketoro1ac
from the intramuscular and rectal routes; only a small Dexketopro.fen is given orally as the trometamol salt.
Tromethz.rnine ~SAN); Ketoro!aco tron1e1amol; Kctorolacum
amount of percutaneous abso1ption occurs after lopical Doses are expressed in tenns of the base; dexketopro- Trometam::>~~ Ke:oro!acum trometamolum: Ketorolak Trometa-
application. Ketoprofen is 99% bound to plasma pro- fen trometamol 36.9 mg is equivalent to about 25 mg rnot Ketorolak 2 trometamolem; Ketorolal-.1rornet~mot Ketorco·
teins and substantial concentrations of drug are found of dex.ketoprofen. Usual doses are J2.5 mg every 4 to i~k-u".lmetamol: RS-37619.()(1.3 1-3: RS·37619 (Ketorolac). (±)·
in the synovial fluid. The elimination half-life in plas- 6 hours or 25 mg every 8 hours; tl1e 1otal daily dose 5-~nzo}'f-2.3-diltdro· IH -pyn-oJiz;n.,. 1.carboxyficac:O com.
ma is about 1.5 to 4 hours. Ketoprofen is metabol ised · should not exceed 75 mg. Elderly patients should be pouM with 2-amino-2·(~i'drox)meth}of)·l.3·propanediol ( I ; I).
mainly by conjugation with glucuronic acid. and is ex- started on a total daily dose not exceeding 50 mg. Dose KeTop0t.aK Tpo~Taw.O/\
creted mainly in the urine. C 1-tH 2'\N ,.0 6 = 376.4.
reductions are also necessary in patients w ith hepatic or
CAS - 141 OJ.06 -3 (k~toroloc): 7-l 103-07-4 (keioroloc
Ketoprofen possesses a chiral centre. It is usually given renal impainneut, see below. It is usually recommend-
~ rotneromoJ).
as the rncemale bul its phannaco]ogical actions appear ed that NSAIDs are taken with or after food to reduce ATC - NoOI ABi 5: 50 I BC05
to be due largely to the S-enantiomer, dexketoprofen. any adverse gastrointestinal effects; however, licensed ATC Vet - QMOIAB l5: Q5016C05.
TI1e pharmacokinetics of ketoprofen appear to show product infonnation for dexketoprofen states that ab- UNil - 4£V£5946BQ.
little stereoselectivity (but see 'under Renal Impair- sorption is delayed if the drug is taken with food and
ment, above). · therefore recommends that in acute pain dexketopro-
o References. fen should be given at least 30 minutes before food.
) . Oebruyf\e D. ct al. Clinic:>.I ph:trmacC1kinctiC$ o f kctopro fcn af· Ketoprofen has also been used as the lysin e and as the
tcr sin.tk introvenous admimstr:itioo :>.~a 0011.1~ or infosion. Clin
Pllomncokiner 1987; 12: 214-2 1. sodium salt.
:!. FJo u\lot B. '°'
al. Pharmncokinctics of h-coprofco in m~m t.ifler
0 Reviews.
rcpeattd ~ rC'u tan c:ous administration. Ar:neimit1<'lfnrsc/11mg
1989; 39: 8 12-15. .
I. Mauldin D, el al. Preclinical and clinicnl development of dcxke· (ke1oroluc)
3. J:on ~li F. Bu?cks OR. ~ linical 1>h.:1.nna.cokinc1ics ofketoprofcn IOprofen. Drugs 1996: 52: ~4-46.
::rnd its cn3nt1omc:s. Clm PJ1orn111cokii1tf 1990; 19: 197-217.
~. Cicissling~rC.. t:! fll. Phannocokint lic..- t--ifl:ttoprofen en.-ntionl- 2. Moore RA. B:nden J. Systematic l"C'\•iew of dexkctoprofcn in
crs aflcr different dos<es o f 1he raccmatc. 8r J CN11 Ph<11'lt1(l('Q/ :JCUh!:rnd chronic pain. BMC: Clin Plwrmacol 2008: 8: 11 . Pharmacopoeias. Jn £111: (seep. '~i) and US.
199l: 40: 73-5. A\'ailablc at: hllp:/i www.biomcdc;entr::il.com/content/pdfi Ph. Eur. 6.8 (Ketoro!ac Tromet2mol). A white or almos1 white,
5. Barbar:oj MJ. e1 ttl. Pharm!ieokin.ecits of dc.-<ketoprofen lromet- 1472-6904·8·1 J.pdf(•cccssc:d rn09/09) CJYSUllline powder. Freely soluble in wa1er and in methyl alco-
amol i11 healthy volunteers arier single and repeated oral doses. hol: slightly sohille in alcohol; prnc1ically insoluble in dichlo-
J CJiu Pharmocol 1998; 38: ,l3$.-40S. Administration in hepatic or renal impairment. No spe-
cific dosage recommendations for raeemic ketoprofe11 in patients romerhane. A 1% solution in '""ater has a pH of5.1 to6. 7. Protcci
6. Kokl.:i H. r1 11/. Pharmocokin..:tics of ke1oprofcn syrup in t'mall fromligh1.
children. J CJ;n Phnrmocol 2000; 40: 354-9. . wilh hepatic or renal impainnent are given by UK licensed prod-
7. B~rbauoj M-J. Cl ul. Clinical pha rmacokin~tic:s of d!!xkt:lopru- uct information, although the drug is concra-indicatcd in severe USP 33 (KetOl'dac Tromemamine). A while to off-white, crys-
(en. Cfin Pliam1<1c-0J:i11fl 2001 ~ 40: 245- 62. renal impainnenl and it is advised that the dose be kept as low a.s (alline powder. F!'eely soluble in '''ater and in methyl alcohol;
l:>. Kokki H. et al Ph:1.r1nacokinetics or" inuavenous 3nd rectal ke- possible and rena1 function be monitored in more modcrntc renal sligbtly soluble in alcohol in dchydra1ed alcohol. and In tetrnhy-
toprofm in y<Hmg children. Ciin Ph'1rmur-oll.i11e1 2003: :12: drofuran; practic:illy insoluble in acetone. in acetouiu·ile, in butyl
373. . 9, . impairment (bul see also Renal lmpainnent, above). In !he USA.
9. Valles J. tt1 ul. Clinical pharmacokineti<:s of paremer.sl·dcxkcto• however. it has been rec.:ommendt:d 1ha1 patients with hepatic iin- alcohol, in dichk·romethane, in d io);an, in ethyl ace~te, in hex-
proteo trometamol in heahhy subje.ClS. Mc,;ht><ls Find Exp Clbr p ainneni ;md a scrum albumin concentration of less· than ane, and in toluene. pH of a I% solution in water is between 5.7
Phunmitol 2006: 28 (suppJ A}: 7-12 . 3.5 g/dL should be given a maximum inilial daily dose of and 6.7. Store in ai11ight conl3ineis at a tempe"'1lurc of25°, ex-
10. Valtcs J. ct (I/, Single 3nd repcotcd dose ph:>rm3cokint1ics of JOO mg orally. Patients wi1h mild renal impainnent should be cursions pcnnilled beiween I 5° and 30°. Protect from light.
de:'\ke1oprofen nomciemol in young :md elderly subjecl.~. Mt'th 4

Qd,· Fi11d E.,·p C/itt Pharmaco/2006: 28 {suppl A): 13- 19 . given a maximum daily dose of 150 mg and those with more se-
vere imrainncnt (GFR less than 25 111L'minu1e per 1.73 m' or Adverse Effects and Treatment
end-stage renal impainnem) should not exceed a maximum dailv As for NSAIDs in general, p. l 00.
Uses a!ld Administration dose of I00 mg. ·
Ketoprofen, a propionic acid de1ivative, is an NSAID Concern over the high incidence of reported adverse
UK licensed product information for dexketopmfen recommends
(p.103). lts anti-inflammatory prope11ies may be weak- effects with ketorolac trometamol has led to its with-
a ocduccd initial daily dose of 50 mg orally in pa1ien1S with mild
er than ~1ose of some other NSAIDs. Ketoprofen is a to moderate hepatic or mild renal imrainnenL Dcxkctoprofen drawal in some countries while in others its pennitted
racemic mixture; in animal studies the S-(+) enanti· should no! be used in pa1icn1S with severe hepatic or moderate to dosage and maximum duration of treatment have been
omer, dexketoprofen , has about twice the analgesic ac- severe renal iinpainnent. reduced.
tivity ofketoprofen by weight. Preparations Adverse effects reported include gastrointestinal dis-
Ketoprofen is used in musculoskeletal and joint d isor- BP 20 I 0: K•tc;><cle n upsvle> Keioprofen Gel: turbances including gastrointestinal bleeding (espe-
ders suc:1 as ankylosing spondylitis, osicoa1thritis, and USP n: K"'oprofen EX\ef>ded·Release Cap"'les. cially in the elderly), perforation, and peptic ulceration.
rheumatoid arthritis, and in peri-articular disorders Proprietary Prepan1tions (details are gi"en in Volume B) Hypersensitivity reactions such as anaphylaxis, rash,
such as bursitis and tendinitis. It is also iised in dys- Arg.: EnW)....,,: Htlcn1t On.dst: $alicren1 K: Austl'OI.: Orvcis: Oruvai::: bronchospasm. laryngeal oedema, and hypotension
~ustrio: Ketos.p~y: Pf'ofcnid: Prontokc.>tt Belg.: S--Rofend fastum: Rnfe·
menon'hoea. postoperative pain. in painful and inflam- nid; Broz.: Artn:'enil. An.-irid: Al't•'O:>il; Bi-Ptofcr.id; Cepl'of..en: flatnacioe·; have also occrnTed. Other adverse effects repo11ed in-
K~cpt: Prof'!l-.,:d: Canad.: Apo·Keto: Novo.Ketot: Rho<ist: O.ife: Scnit clude drowsiness, dizziness, headache, mental and sen-
matorv condilions such as acute iaout or soft-tissue di s- Cirus: De*..eto: Dokrl<etazon: Dolofar. Fasti..mt: Ao~o~ Profenid: Re-
orderS, and to reduce fever. DeiZketoprofen is used in Jater.e: Taff.ex: Cz.: Bi-Profctoidt: Dexo·<et: fastu'l'I: Kepi.at t:'.etesse; Keto~ sory changes, psychotic reacti ons, sweating, dry
the treatment of mild to moderate pain such as muscu- tenet: Ketoi\il~ ?rofe•·"d: Proo~oflex: Prontoke:f; Toprec:f; Oenm.: Oto- mouth, thirst. fever, con vulsions, myalgia, aseptic
fet'( On.1d1s: Fin.: E"la..."l\)\rn: Ketes.se: Keto; Ketctne.x: Ketoi'in; Ot\Jdis; Zor.:
loskeletal pain, dysmen01Thoea, or dental pain. fr.: Bi-Profanict Keturn: Pt·ofen!:t TopCer\2; Topl'ec; Ger.: Afheum1.n Oo- meningitis, hypeitension, dyspnoea, puhnona1y oede-
k>rmin rit. Kctoprofe;'l Ef~on mit Ketoprol'.en: Gabrileo;: O:udist. PhatOO! ma, bradycardia, chest pain, palpitations, fluid reten-
In the treatment of rheumatic disorders a usual oral dai- S:hmerr. Spondylon: S)'mp<I; T~>I Mo~i l·Gel m~ ketoprofent; Gr.:
ly dose of ketoprofct1 is 100 to200 mg in 2 to4divided Drilstirel: Fa1-bovi!: Kctodlir: Me.'\i!tt Nosatcl: Onlv~~ Pl'Ofinject: Sdu-Kct: tion, increases in blood urea and creatinine, acute renal
Totifen; Viaxat Voten: Hong Kong: ~·Ketc-E: Fast.um: Mohrus: Orudis: failure, oedema. hyponatraemia, hyperkolaem ia, uii-
doses; modified-release formulations taken once daily
may also be used. Some licensed product infonnation ~~~i~~;5,~:·~~!~t~::rn.: ~~~~~~!~1~~~n~~t~~~:: n~ry frequency or retention, nephrotic syndrome, flank
··os: Lv:ur.arn: MolaPan'( Na~n.tm: Nuo.-c!: Ovuril?i; Profe<:cm: Profeni<t. pain with or without haematuria, pnrpura, thrombocy-
suggests initial ora l doses of75 mg three times daily or ?rofka: Prona~gts. Pro:o<erc RemaP4 o. Rerna.tcf; Rheto01.m: Svpt"'c1fcrict Jrl.:
50 mg four times da ily increased as needed to a maxi- fa.s111TI: Kerat Oruc:fat: Orv~~: On.......ail fsrotl: Orwailf: Proicnid ' t,ol.: topenia, epistaxis, i11hibi1ion of platelet aggregation, in-
1\1<.ei.: ArtJ'OSi:C~: Desketo: Doig,~: Enantyum: Ei.ik.etos: fa'Stl.l"n: Rexen: creased bleeding time, postoperative wound haemor-
mum of 300 mg daily in divided doses. Ketoprofen lbifen: lsofenal: K...~it. Ket2rtri1..rn: Ketesse: Kctodol; Keiofarrn.: Ketoptus:
may also be given rectally as suppositories in a dose of Ketosetect: l.asO<b"tf<)( Lason:! CM: Lio,oodot Meprofenf: Ol<i; <lnJds: Re· rhage, haematoma, flushing or pallor, and pancreatitis.
wrcfent: Top."ekt:Jpn: Mollrus: M oloysfa: Apo-Keio: mturn; KelenTecll: Severe skin reactions including Stevens-Johnson syn-
100 mg at night or 100 mg twice daily. It is recom- Ker.hance11: Kenofen: KetoCerc K~ tcx.opt: Orvdis: Mex.: Atkf:t t. ..cv-thri; Cl:-
mended that the total dai ly combined oral and .rectal Profcnoct Bbi>t: Efokcot: K-Prof"'1; Ke1"'1e><; ()Jci JA: Orvdi~ Paiosil:: Prole. drome and Lyell's syndrome have been repo11ed. Liver
dose should not exceed 200 mg. The usual oral dose
n1d: Stadi..Jm; Neth.; En/IJ'ltyorn; O ru;Ss. Orvvail: Oscorel: Rilies: Stadium: function changes may occur; hepatitis and liver fai lure
Norw.: 01'l•dis; Zen: NZ: O·udist: On.Wt Philipp.: Fzstum.: Ketofen; Ke-
for the treatment of other painful conditions including to•op: O"udis: Udz.:iper.j: Pol.: S.-Ptolen<l; Dex<k: Fas:"'" Fi:llrolen; Ket· have been reported. There may be pain at the site of
co.at Ktlopn:nn; Y..etopronit Ketores: Ketosprav: Profer.id: Refastin:; Utrafas- injection.
dysmenorrhoea is 25 to 50 mg every 6 to 8 hours. For t~ Port.: Anrofcnet: D?!\ogixt: Enant)'vm: Fastum: Kc-plat: Kctesse;
details Oll the use ofketoprofen in.patients with hepatic Kctofenet: Profu1"'1; Quwajf-: Rus.: Artro$i!en (Ap1JX>3n~H~ 8ysV\..ll"02el The most frequently reported adverse effects ofketoro-
(&.,cTpyMrtAb}. De)"(llgir; (AtKC-3'1.IV.M) ; hs~um (<Da(T~·M): febc"of.d lac intranasal spray were mild and transient local reac-
or renal impaini1ent. see below. {~Ct:>o$>CA): Fl~f'l'l.a>< (Q.\'laMat<C~ Flexen (CDM:i.ceH); Ket.on.al (l<eronat..):
Ketoprofen may be given by deep intramuscular injec- O ki (0'-•); S.A(r.: Fav.um: J(e;oP.am; Myprof..imt: Ontv.bt~ s;ngopore: tions such as nasal discomfort or irritation.
Apo-Keto: Fa!.tu."I'( KcfeoTech: r.'.erliancer: Kctotopt: Oruvail; Provaiif:
tion into the gluteal muscle for acute exacerbations of Spoin: Ado!qu1i·: A.rte-mat: Enangel; Ena1tyum: Ewa;::M,: fastum: Ketesgel: Ketorolac eye drops may produce transient stinging
musculoskeletal, joint, peri-articular, and soft-tissue Keu~s~e. Ketosolant: O rud£ Pyt1.aft Qui..-a:am. Quirget Sweet: Ketoflex; and other minor symptoms of ocular irritation. As with
O<Wos; Po'ode<!f: Soduro: Zen: Switz.: fastum: Ket"""; Thoi.: rastum: Ka· some other NSAIDs used in the eye. ketorolac has
disorders, and in the management of pain after ortho- proftn: lo.'i1a... On.1v~i1t: Pro'ent::t Rhumafen: Ro(epain: Vcsmn; Turk.:
paedic surgery. Doses of 50 to J00 mg may be given AJ.,..e!es; Bi-P.'Ofe:r.::t, fa.njel Keles-se; i"~to; Ketofent. Profeo1d:: UK: Axorid: been implicated in repo11s of corneal toxicity (see Ef-
K~rdk Ketccid: Ketovai!; la"'3fen; 0:-udis; Oruvcil: Powerge~ Tiloket: Ukr.:
every 4 hours, up lo a maximum dose of'.100 mg in 24 Oex4'.lg·n (Ae1"1ca,,,r1-1tt): f -Ge: {<D--f eAb): Fa!.tum (<l>acry""'}; Keton;;J fects on the Eyes, p.4 7).
hours for up to 3 days. In some countries, ketoprofen (Ke'°""'.); USA: 0"-"<•it· Vtnez" Dclo.'?ll><: l(elfen; Ke:o: K<!'/do\ Li<':d<· Incidence of adverse effects. Adverse eftects reported with
ton: 0:-oleno: ?cindol; Profenid; Proleroif.
has also been given intravenously in similar doses. ketorolac are mainly those common 10 all NSAIDs with gastroin·
Mulri··i ngredient: Gr.: ?rdenil Co•x: MeK.: S~E!tral: Oolo Bedoyec- testinnl reac1ions being. che most frequent followed by baemato-
Ketoprofen may be applied as a 2.5% gel for local pain to: Re.Jmophan At:<!.
Jogical. renat hYJ>CrSensiti"ity. and then neUJ\1logical reactions.
relief. Doses vary slightly berween preparations: typi- Ffom 1990 to 1993. 97 r\!ac1ions with a f;ual outcome were re-

The symbol t denotes a preparation no longer actively marketed

78 Analgesics Anti-inflammatory Drugs and Antipyretics
ported worldwide.' The causes or death were: gastrointestinal · Drowsiness and dizziness may affect the perfonnance ble; oral use is limited to 7 days. In the USA it is rec-
bleeding or pcrfora1io11 (47 cases); renal inipainncnl or insuffi- of skilled tasks such as driving. ommended that lhe maximum combined duration of
ciency (20); anaphylaxis or asrhma (7); haemorrhagic reactions use of parenteral and oral ketorolac should not exceed
(4); and unexplained or miscellaneous c-•u.~cs ( 19). Concern over Breast feeding. The conccnuation ofkctorolac distribu1ed into
lhc safety or kelOrolae has led 10 adverse reactions being moni- breast mill< is very low and a study 1 considered1ha11hc 1moun1 5 days.
tored clo5ely and to Ille implementation or rcslriotions on <lose ingeslcd by lhc infant would probably be too small to be harmful. • In the UK the recommended initial dose by the
and duration oflre31.mcnl (sec Uses and Administration, below). The American Academy ofPodiatrics2 also stales lhal lhcrc have parenteral route is I 0 mg of ketorolac trometamol
A postmarketing surveillance study> examined the risks or been no reports ofany clinical etrecton the infant associated with
parcn1eral ketorolac in 9900 paticnlS given 10272 courses or the use ofkctoroltc by breast..f"ceding mothers, and that therefore followed by I 0 to 30 mg every 4 lo 6 hours as re-
ketorolac. The results indicated a dosc>rcsponsc relationship it may be considered to be usually companble with breast feed- quired, although ketorolac may be gi\ien as often as
with average daily kctorolac dose ror bolh ga.<tmintestinal bleed- in&. SimjJatly. the BNF 59 considers the amount to be too snail every 2 hours in the initial postoperative period if re-
ing and operative site bleeding. the ex~cd major ri5ks, and an IO be harmful IO brcaSl-fed infanlS. Howc--cr, both UK and US quired. The total maximum daily dose is 90 mg
association between gastroinlcSlinal bleeding and therapy for licensed !lfodllci information recouunend that kctorolac: should (60 mg in the elderly, patients with mild renal im-
over Sdays. The risk of serious gastroin1estinal bleeding and~ be avoided in mothers who are breast feeding.
crativc site bleeding was higher for elderly patients (liccoscd 1. Wischnik A, 11111. The c:xcre1ion ofketorofac tromtthamine into pairment, and in !hose weighing less than 50 kg). In-
product inforrnalion recommends thal lhe elderly should not re- breut milk after muhiplc oral dosing. Eur J Clin Pha,macol travenous injections should be given over at least 15
ceive daily parenteral doses greater than 60 mg). Ahhough the 1989; 36: S2H. seconds. During transfer from parentera l to oral ther-
overall associations bctwc~n ketorolac use and both gastroinlCS· 2. er Amcricim Ac3dc::my or Pediatrics. The transfer of drugs and oth·
chcmic.t'lls in10 human milk. Pediatrics 2001: 10K: 776-89. apy the combined daily dose for all forms ofketoro-
tinal blec-ding and operative site bleeding arc small, the risk be- (llcllrcd May 20 10) Correction. ibid.; 1029. Al•o uv•il•bl• ui: lac trometamol should not exceed 90 mg (60 mg in
comes clinically importanl as doses increase, in elderly palients, http ://aa ppo Ii c y.a a ppu b Ii cations .org!c gitcont en11ru II/
and, for gastrointes1inal bleeding only, when used for longer than pedi11rics%lb IOS/3n76 (accessed 07111/07) the elderly, patients with mild renal impairment, and
sdays. in those weighing less ihan 50 kg) of which no more
US product information has consequen1ly emphasised that Interactio ns than 40 mg should be given orally.
ketorolac is a potent NSAID and is indicated only for the short- For interactions associated with NSAIDs, see p.103. • Regimens in use in the USA include a single intra-
tcrm management Of moderate lO SC'°Cfe pain and not for minor
or cluonic painful conditions; its use canies many risks and re- Ketorolac should not be given to patients already re- muscular dose of 60 mg or a single intravenous dose
lated adverse effeas can be serious especially when used ina~ ceiving anticoagulanlS or to those who will require pro- of 30 mg, or a multiple-dose regimen comprising
proprialcly. After examining data from the above study the EU phylactic anticoagulant therapy, including low-dose 30 mg every 6 hours intramuscularly or intravenous-
Committee for Propricwy Mechcinal Products adopted the opin- heparin. The risk of ketorolac-associated bleeding is ly, up to a maximum of J 20 mg daily. These doses
ion that ketorolac had a narrow thcRpcutic margin but that it was also increased by other NSAIDs or aspirin and by pen- should be halved in the elderly, those with renal im-
indicated for Ille short-term management or moderale 10 severe
aclJle postoperativ~ pain. tox ify lline and use together should be avoided. pairment, and those weighing less than 50 kg.
Further rerermces 10 ketorolac's adverse effects are given bc- Probenecid increase.~ the half-life and plasma concen- • The recommended oral dose in the UK is I 0 mg
low.;..12 trations of ketorolac and the two drogs should not be every 4 to 6 hours (every 6 to 8 hours in the elderly)
l . CSMIMCA. Kc1orolac: new rcstric.1ions on dose and duration of given together. to a maximum of 40 mg daily for a maximum dura-
treatmcnl. Currem Proh/1tm1 1993: J9: S-6.
2. Strom BL, tf al. Parenteral kctorol3c end risk of gas1roin1cslinal Parasympathomimetics. Liceosed producl infonnation for lion of 7 days.
Md operative si1c bleeding; a pos1mu kc1ing surveillance study. acetylchnline chloride ophthalmic preparations Stales !hat there
JAMA 1996; 2H: 376-82. • In the USA the recommended oral dose is 20 mg
have been reporlS that ocetylcholine and c01·bochol have been (10 mg in the elderly, the rcnally impaired, and those ·
3. ~!~~~=~A~~·r~~:!~!,,~~·, ~f:~~~~9.1ssocia1ed with ineffective o.11en usod in patients treated with topical (nphthal·
weighing under 50 kg), followed by I 0 mg every 4
4. Boras-Ubtt LA. Brackett NC. Kt1orolac-induced acute renal mic) NSAIDs.
f1 ilu~.AmJ Mtd 1992: 91: 4S0-2. Corre<:llon ;bid.; 93: 117. to 6 hours to a maximum of 40 mg daily.
j. Schoch PH. ~/of. Acute 1c:na1 f1ilurc in an elderly womm fol-
lowing inrra.muscut~r kt1otol1c administration. Amt P~o­ Pharmacokinetics For doses in children see Administration in Children,
tbu 1992; 26: 123l-6. Ketorolac trome1amol is absorbed after intramuscular below.
6. Gocu. CM, n al. Anaphytaccold tucllon following kct.orolac
lrometh~.mine adminislrtiion. An,, Phor1t1oco1h«r 199?: 26: or oral doses. At physiological pH ketorolac nometa- In the USA, ketorolac trometamol is also approved for
1237-8. mol dissociates to form an anionic ketorolac molecule 1heshort-tenn management of moderate to moderately
7. Randi ML. ~' al. Hicm-olytic urtc:mic syndrome during 1reat-
ment with keto..olx tromeu1mot BMJ 1993; JCHi: 186. which is less hydrophil ic than the trometamol salt. severe acute pain as an intranasal spray. It is recom-
8. Fong J. Gora ML. Ren"iblc rcn•t io.~ufficicncy foll~v.:i ng Peak plasma concentrations of kctorolac occur within mended that die maximum duration of use either alone
ketorolac l11erapy•.ifnn PhartnU(.O//lf/r 1993~ 27: 510-l2.
9. Col'Clli RL. Gcrickc KR. Rcn1l insuffidcncy tssociet~ with in· about 30 to 60 minutes; absorption after intramuscular or with other ketorolac preparations should not exceed
tramusc-ufar adm inistration of kciorof~c 1rome1hamine. Ann injection may be slowet than that after oral ~oscs in 5 days; it should not be used at the same time as other
Pharmacother 1993; 17: IOSS- 7. some individuals. Ketorolac is over 99% bound to
10. Buck ML, Nor\..•ood VP, Kctoroluc-induccd ac.ute ren.31 (3ilure kctorolac preparations. The recommended dose is
in a previously hc-ahhy :idolcsccnt Ptdiot,.ks 1996; 98: 294-6. plasma proteins. II docs not readily penetrate the 15.75 mg in each nostril every 6 to 8 hours to a total
11. Feldman HI, et of. Parcn1cral kc1orolac: the risk for acute renal blood-brain barrier. Ketorolac crosses the placenta and maximum daily dose of 126 mg. In patients aged 65
failure. Ann lnttrn Med 1997; 126: 193-9.
J2. Reinhart DJ, et al. Minimisina the adverse dfcct.s ofke1orolac. small amounlS of drug are distributed into breast milk. years or older, and those weighing less than 50 kg, the
Dmg Saf<ty 2000; 22: 487-97. TI1e terminal plasma half-life is about 4 to 6 hours, but recommended dose is 15.75 mg in one nostril every 6
is about 6 to 7 hours in the elderly and 9 to I0 hours in to 8 hours to a total maximum daily dose of 63 mg.
Precautions patients with renal dysfunction. The major metabolic
As for NSAIDs in general, p. I 02. Ketorolac trometamol is used as 0.5% eye drops 10 re-
pathway is glucuronic acid conjugation; !here is some lieve ocular itching associated wim seasonal allergic
In light of the concern over ilS toxicity, licensed prod- para-hydroxylation. About 90"/o of a dose is excreted conjunctivitis. Ketorolac tromctamol eye drops 0.5%
uct information for kelorolac recommends that it in urine as unchanged drug and conjugated and hy- have also been used for the topical treatment ofcystoid
should not be used during pregnancy or labour, nor giv- droxylated metabolites, the remainder is c:xcrc:tcd in macular oedema and for the prevention and reduction
en to mothers who are breast feeding (but see below). the faeces. ofinflammation associated with ocular surgery. In die
Ketorolac is contra-indicated in paticnrs with a history 0 References. USA, 0.4 or 0.45% eye drops are also available for
of hypersensitivity to aspirin or other NSAIDs, a histo- I. Kaurrman RE.'' ol, Enan1iomcr-selcc1ivc pharmacoldne1ks and postoperative ocular inflammation.
ry of asthma, nasa l polyps, bronchospasm, or an- melabolism orkctorolac in children. Clin Phtwniac."I Th~r 1999;
gioedema, a histo1y of pcpti¢ ulceration or gastrointes- 6S: 382- 8. 0 Reviews.
2. Jlamunen K, Cl al. Stercosc l cc1iv~ pharmacokinetics ort.:ecorolac I. OillisJC. Brogden RN. Kctorolac: u reappraisal oriu pha.rmaco·
tinal bleeding, in patients with moderate or severe renal in children, adolescents and adults. A~to Anoe.flllt.fiol Scond d)11amic and phann3cokinetic propcr1ics and 1hcrapcutic use i11
impairment, and in those with hypovolaemia or dehy- 1999: 43: 1041- 6. piin management. Drugs 1997; 53: 139-88.
3. 0$ida RM. e1 ul. AJc-Ji.ratiticd phamtaookinciic.s of Sic:torolae 2. Di Man3 A, er al. Ketorol:ic for pacdi11ric postoperative pain: :1
dration. Ketorolac should not be given to patients with tromethlminc in pediatric surgietil ]Xtlien1s. A11t>$1h At141g 1002: review. Mill~n."' Anestuiol 2000; 66: l49·56.
coagulation or haemorrhagic disorders or those with 94; 266- 70. 3. Arora s. et al. Myth; parenteral kctorolac provides more crrec-
confinned or suspected ccrebrovascular bleeding. It is 4. McAlctrSD. 11 ul. Phannacokinctics and sefcty ofkctcwolac fol· tivc analgesia thon 01111 iboprofen. CJEM2001; 9: 3~2.
lowing sinsle in1ral\UIJ and inlnmuscuJar adminis1r111ion in • • Schechter BA. KetoroJsc 1romclh3mine 0.4% IS a lrc1tmcn1 ror
contra-indicated as a prophylactic analgesic before sur- h..l1hyvoluntccrs. J Ci;., Phannocol 2007; 47: 13- 18. allergic conjuclivitis (sic). £.sfHrl Opin Dnts; >.lt'Jtlb To.d«J
gery and for intraoperative use because of its inhibitory 2008; 4: !07-l I.
Uses and Administration S. Sinha VR. ~'al. Kctorolac tromcthamine formulations: an over·
effects on platelets; il should also not be given postop- ,;cw. Expert Opin Drug o.li• 2009; 6: 961- 7S.
eratively to !hose who have undergone procedures wilh Ketorolac, a pyrrolizine carboxylic acid derivative Administration in chadren. Kctorolac tromcwnol may be
a high risk of haemorrhage. structurally related to indometacin (p.69), is an NSAID used for lhc short-term managemenl o( moderate to severe post·
The total daily dose ofketorolac should be reduced in (p. 103). It is used mainly as an analgesic. operative pain in children. In the USA, children aged between 2
the elderly and in patients weighing less than 50 kg. It Ketorolac is used intramuscularly, intravenously, or 10 16 ~may be given a single intramuscular d0$e of l mg/kg
or kelorolae trornetamol up lo a maxim urn of 30 mg or a single
is rccorumcndcd that p<1tien1s with mild renal impair- orally as the Lrometamol salt in the short-tenn manage- intravenous dose of 500 micrograms/kg up lo a maximum of
ment should receive a reduced dose of kctorolac and ment of moderate to severe postoperative pain. How- IS mg. In the UK, parenteral ketorolac is only licensed for those
undergo close monitoring of renal function. Ketorolac ever, it should be noted that because of concerns over aged 16 and ove.r; dose.• are :IS for odulL• (sec above). However,
should be used with caution in hea1t failure, hepatic im- the high incidence of reported adverse effects with the BNFC 2009 suggests that children a!lcd 6 months to 16 years
painnenl, and conditions leading to reduction in blood ketorolac irs dosage and maximum duration ofuse are may be given an initial intravenous injccrion or 0.5 to I mg/kg
(maximum or t5 mg), followed by 0.5 mg/kg (maximum or
volume or in renal blood flow. Ketorolac should be restricted. The recommended maximum duration for IS mg) CVCI)' 6 hours as required, to a maximum daily dose of
withdta'Wll if clinical symptoms of hepatotoxicity de- parenteral d1erapy is 2 days in die UK, and patients 60mg. ·
velop. should be transferred to oral therapy as soon as possi- Oral kctorolac is not licensed for use in children.
All cross-references refer to entries in Volume A
 Ketorolac Trometamol/Leflunomide 79
Administration in re<1al impairment. Ketorolac is cootto- TI1e active metaboliteofleflunomidc, A-771726, has a nomode therapy ran!!ed from 2 months to 2 yc.'lrs :ind the reaction
indicatcd in patients witl1moderote10 severe renal impairment: half-life of abol1t 2 weeks. Consequently, the adverse ob:lted alier stopping leflunomide.
for sua1es1c:d do<es in le.<.< advonccd renal impainnent. sec u~ I. Bonnel RA. Gr.iham OJ. rtt1phrrol ncuropa11hy in p11ie.ms ttcat-
and Adinmisb"ation~ ahov..!.
effects ofleflunomide may continue even after therapy cd ,.,,·ith lcf1 unnmidc. C/111 Pl:ar11u1col T1Ntr 2004; 75; 500-S.
has been stopped. When severe reactions occur, a drug !. Martin K. et ol. Ncur<'p•uhy assoc:11rcc1 with lcnunomidc: a uu
Preparations washout procedure (see below) may be required. ~ics. Ann Rh~um Dis 2005; 64: 649-SO.
USP 33: r-etoro'..: "'r~ I~; Ke1crot.c 7rome!Nmtt lab- ;_ McWcr C. el al. Peripheral ncurop1thy in paticnls with s-y.ucmic
ltl<. l..cOunomide should not be given to immunocompro- rhcum11ic d1scu.~s trcattd with lenu,.ornide. An11 Rlumm Dis
Proprietary Preparations (details are given in Volume Bl mised patients or to patients with severe infections •. he- :oos: ~: 179$-1 800.
4. Advt:l'$c: Drug Rcxlioos Advisory Comminec (AO RAC). UOu-
flrg.: kJ..'u; eloodol Dohen: Kelle Ke"™"'t KCt'attr. Kc<o1>h>"'" patic or moderate to severe renal impairment, severe nomidc and pa~hcrat ncuropathy. Aust Adtters~ IHui React
~ ~at Slnalgico: Tdodot T<nloc!ct Unicalm; Aurtral.: Acol~•;
hypoproleinacmia, or bone-manow dysplasia. Patients 8111120<16; 25: 18-19 Also nailable at: http:l/www.1,p.:o\·.au!

f.ac: Oloc; Dolgenat Findedolj: Neut -em;

Tcnctot Au.nrio: ACtJla1·: Belz.: AaAut: Ta."ldyt: Brc:t.: Acu!ar: C~
Oeoclf: T~ T~-sesic; Conod" AoJtr T<ndct Chll•: k..JIJf; Brod·
a..-..,. Syndot Otnm.:
,..cvi.1~ Tor.oot fin.: Aahr: Toradol: Fr.: /:oc.Rr. Ger" Aoilor: Gr.: Acu·
tar: ie,..dol: H°"g Kcnc: A..'\JI••~ Keto: Tor.oot Ind;,,, CoOaloc; Ketaror.
with a history of tuberculosis should be carefully mon-
itored because of the possibility of reactivation of the
•dr!ORdrb!..dr<>6' O.pd( (•tt<SS•d 13106/03)
S. Health Unada, LcOunomide and peripheral neuropathy. Can
,ltfvc,·sc Rcm.·1 Ncu'I 2010; ?0 (2): 1-2. Also av"Hible at: htip:r/
ww,\.h(·SC.!lC.celdhp·mpS1a1t_rorma1s/pdf/mcdeffJhullctin/
Ketb: Ket<><tt:ips; Ketone Torct>e lndon.: Dol.c F¥J»ln Kelop~n: 1..>c-
infection. Intra-uterine devices should be used with <>m-bcci_•20nl-eng.pd((ae<cssed 07~S/10)
caution during immunosuppressive treatment as tl1cre
~.nt~,;~=:~:.t 1~1~~Ai1.:~~t. is an increased risk of infection. Live vaccines should
Effects on the skin. A 58-year-old woman developed lup~s
erythematosus I month after Startin~ leflunomide 20 ms daily
Ital; A::vlar. Uxidot Tor..Oct Molaysio: Acl.larf: K<tlllC>lt lt(ot?: l(n.
dot M • "-' AWaren; ....neloct. Ai'.crrd: AliOOtt: Apo\oke. Brunoc:ot Cel- be avoided for the same reason. Blood pressure should for treatment ofSj6gren's syndro111e. 11ie rash r=lvcd within 4
f>x 03<.et Doi.le: Oolcopl&r. Oclb\ Oo1cY.orf: Drotr.etok Ein':-<n>t Est· be monitored regularly during therapy. weeks of stopping lcflunornidc but recurred on 2 sepunate ucca·
ope« - Flndolf: Fonloc: GelGola ~ Gltcima: Godek ll>hti: sions when she took the d111& again.
l<o~ Kcndot Ke<>dolit Kcprak; La<dot l..>cornin. l.an<faco: Le""""" In the UK, licensed product infonnation recommends I. Gcnsburger 0. tf ol. lupus erythcmato.-;us wi11l lclluno1rudc:. in-
Lolt.r.t-: IA<ol«'. Kr/idol: O""""'r: Pt..<ndot -ICX Rapix: Roi~:
lhac liver enzyme values should be checked before bc- cJuc1ion or reactivation? Ann Rham Dfs 200.S; 64: I Sl-S.
=~~!1.~=~r~~.=.~=}r~~i~ giMing therapy and at fortnightly in!Cl'Vals during the Ove rdose. Unintentional overdoses witl1 leflunomidc have
~=~~~~~=~at:~~~=~
Rus" AdOlo< (/\n""°p) Doloc ~•): Ketalgin (KOT-~ ""'""°"'
first 6 months of treatment; US product information
recommends monthly monitoring for the first 6
been reponcd in 2 patients. In one ease, no adverse cf!ects were
seen in • 40-:;ear-old woman who had mistakenly taken both ft
(l<n_,.): Keloi'trol (KnoQpo..~ Keldac: (Ke>""3><); Kllorol (i(o'Topo.): 100-tng and• 20-ong tablet daily for 28 clays;1 in another case, a
S.Afr" Atui..·: Se<Jor.-: Tor1-0ot Slniopon: Atuiar: To1·adol: Sporn: At· months. Subsequent monitoring should be carried out 70-yct>r-old onan who took 100 mg weekly, in addition IO 20 mg
u¥. Afgl<•y: Oro.I; Tonumt. Tor;>dot Swe<l.: Tol'adot Sw;tL: AW.¥-; at 6- to 8-weck intervals. Dosage should be reduced if daily, for over 2 )'Cal$ was found to have interstitial ncpluitis
Tora-Oot Thai.: MAN. Turi<.: k<l4r: UK: "'<•.tar: b-adot Ul<r.: Ke<'"'°"
(Ko>iHOt~ K.ttoion& (K<"T°"OHr). Nov....1 (-•er~ USA: Acvlar: moderate elevations ofliver enzyme values occur (see which improved after lcflunomidc was stopped.' In both cases,
Acuvat Spree;~ Vonez.: Acubft.
Doble Keloc: ~I t: Kelorolt, Administration in Hepatic lmpaim1ent, bcl!)w); for the I 00-mg dose was meant to be taken for 2 or 3 days only as a
Nctolac Ocudot PoenkeraL loadingd~
Mult:i-insredient: Mu.:Gamm•dol: ~ ~~-
persistent or more severe elevations leflunomide
1. K1m1li s. el al. An unusual overdose of lcOunomidt In a plticnt
should be stopped and washout procedures begun. with rhcumaioid arthnti<. .4nn Phomwn>tlt.-r 2004; 38: 1320- l.
Monitoring ofliver enzymes should be continued after 2. J·byd&r AA, d ol. Chronit overdose of k:Ounomidc inducing in-
slopping therapy until they rerum to within the normal ltrstitial nephritis. Nephrol Dial Transplant 2004; 19: l3l~S.
Leflunomide (SAN. tr.>AN. rlNN) range. Blood counts should also be checked at the same Pregnancy. Leflunomide is contra·indieated during pregJJancy
HWA-486; Lcfivnomict Leftvnomida; Le8.-iomide: Leftunorr:ici; lime as liver enzyme values. as its ac1ive onetaboli1e has been sliown 10 be teratogienic in m1i-
Le~vnomidt.m: RS-3"162 1: SU-101. u.a,.·Tr.$.io:o·S·meth)·I+
mals. Pre~ancy ~hould therefore be excluded before be&tnnin&
0 References. therapy, and liecnsed prod\lel o.nfonnation states that rcliftbleeoo-
isoxazolec.aoboxy·p-toluidide.
t, Alcorn N, ~'al. ~ncfi1°risk assessment or lcflunomide: tm ::p- ttKeption should be used in women of child·bearins potential
/\e<jlf.)'HOM"A J\raisat or Jicnunomidc in rtieum:ttoid arthn1is 10 years after li- (UK product info1mation also recommaids reliable contracep-
C11H9rlNP1 270.2. = c:~nsintt- Drng So/~1)' 2009; 32: 1123-34. tion in men !teated with le011nomide). Women wishing to be-
CAS - 75706-! 2-6. Effects on che lungs. Up to Oa:<.'Cmbcr 2006. the AUSU'alian come p~nl should wait for 2 years alkr stopping therapy, or
ATC - L04AA 13. Adverse Drug Reactions Advisory Committee (AORAC) had if this is infeasible, o washout pr0<:edurc (sec below) should be
ATC Vet - QL04AA 13. received 142 reports of respiratory symptoms wid1 leflunomidc performed and o waiting period of 6 weeks be observed from the
use since ils introduction in 2000. 1 Of these. 22 rcpons men- time plasma concentrations of the metabolite fall below
IJNll - Glc2GK9U4W
tioned at least one of the following serious reactions: pneumoni- 20 nano3romslml before attempting conception. A washout
tis (8), interstitial lung disease (9), lung infiluation (4), or puhno- procedure with a waiting period of at least 3 months is recom-
~ in men who wish 10 father children. Women who be-
nary fibrosis (3); it was considered that all these were likely 10
represent interstitial lung disease. Fo..- patients died, but relative come pregnant dwing thernw should also undergo a washout
causality was difficult to assign as me1hotre~te was also given procedure.
in many cases, howe,cr, several patients had been on melhocrcx- \¥ashout procedure. If sa-ious ad\"USe cffccu occur <!uring
atc long-term without any problems. It was recommended that leflu11ontide therapy. licensed product information recommends
tho pulmonlll)' status of patiellts should lie considered before that a drug wllliltout procedure is performed. TI1is may also be
staning le011nomide and moni10<ed during treatment; if symp- considered if o patient becomes pregnant while toking lefluno-
toms such as cough or dyspnoea develop"! worsen, lenunom1dc midc. or if it is necessary to swap to onother disease-modifying
may need to be stopped. AORAC sobsequcntly reported2 that in antitbeuonotie drug sucl1as111cd1otrc.•ole.
Pharmacopoeias. In F.111: (se~ p.\'ii) and US
June 2009 the number of reports of respiratory symptoms witb For the washout procedure. either 8 g of colestyrnmine is iivm
Ph . Eur. 6.8 (Lc~ide). A white or almost "11i1e powder. It
lcnunomide had increased 10 196. Of these. 153 repons men- Miiiy 3 t11nes daily or 50 g of activated charcoal is given orally
exhibits polymorphism. Practically insoluble in water; freely sol-
tioned use with mcthotrc.otc including 23 of the 39 reports of ur via• nas<.>gastric tube 4 times daily. Thcnpy is nonnally con·
uble i11 methyl ~lcohol: sparingly soluble in di<:hloromedianc.
interstitial lung disease. tinucd for I I clays. but should be repeated until plasma concen-
Protect from light.
USP 33 (~nomide). White IO almost white powder. P"!"li- The risk of interstitial Jung disease with lcflunomide has also trations of the primary metabolite A-771726 arc below
cally illS(lluble in water: freely soluble in acetone, in occ1oni1tile, been assessed using data from a lar&e cohort study.> This study 20 nanogramslml. verified by two separate tc.\ts at least 14 days
in olcoho~ in chlorofonn, in ethyl ocetJJtc. in isopropyl alcohol, found that, overall, there was a t\\ofold increa<e in the ri~k of apart.
011d in methyl alcoool. Store at a temperature not exceed ins 30°. intcrSlitial lung disease in patients treated with leflunomide com-
pared with those ..1io did not rcceil'e lcflunomide. However, Interactions
subgroup analysis showed that this increase v.115 limiled 10 tl1ose lncrt:'.ised adverse effects may occur if leflunomide is
Adve!"se Effects, Treatment and Precautions patients with a history of mctliotrexate use or interstitial lung dis-
Common adverse effects seen wi th lefl11nomideare hy- ease; in thme with no previous methotrexate use or no history of given with ocher hepalotoxic or myelosuppressive
penension, gastrointestinal disturbunces (particularly inlcrs1itial lung disetist, thett was no increased risk u.i1h JeOuno· drugs: these effects may also be seen when len11no-
dianiioea), weight loss, lleadache, dizziness, leucope- miclc. See also under lntcractiorts, below. mide treatment is followed by such drugs without a
nia, asthenia, paraesthesia,joint dison.lers and synovi- I. Ado;crsc D«.if Rcaccions Advisory Comrni1lec (/\ DRAC}. Lcflu· drug washout procedure (above). The risks of com-
nomide and 1ntc151itiJI luAg disuse. ·""" AJ'.Wsc Dmg React
tis, upper respiratory-tract infections, alopecia, ecze- 81J/l 2006: 25: 22-3. Also a'·:aiJ1blc •-= hnp:liW\l.•w.tg.a.gov.aut
bined use with other disease-mod.ifying antimeumatic
ma, and dry skin. Hypersensitivity reactions may occur adrhadrbluclr0611.pd f (at·o.-s•<~ I~) drug:;, particularly in the Jong tem1, have not been stud-
2. Ad\(T'SC Dn.ig Rn<;tions Adv1t-ory Committee tADRAC). Is ii ied and such use is not advised in the UK; however, US
and a few cases of S1cvcns-Jolmson syndrome, ery- lcOunomide lung? ~fast Adwtrsr Drug RMCt Bu!l 2009~ 28: 15.
thema muhiforme. toxic epidem1al necrolysis, or vas- Also :1w11bble at http:/lwww.rs... s,ov.au/~dr.'aadrbfud.r0908.pd( licensed product infonnalion recommends that iflong-
culitis have been reponed. Hepa loloxicity has oc- (accessed 23!10109) term combined use is necessary, liver enzyme values
3. Suissa S. e1 nl. LcOunomJdc use and ihe risk of intc1sti111t lung and blood counts should be monitored monthly, for the
cu1Tcd. It is usually mild and reversible but rare cases t!iscasc in l'hcumato1d •nhriiis. Ar1/witi.f Rhttum 2006; 5':
of severe, sometimes fatal, liver disease, including 14.3~-9. first 6 months, rachcr than evety 6 to 8 weeks (see Ad-
acute hepatic necrosis. have been seen pa11icularly in Effects on the nervous syst~. Pcripbcnil ncuropa1by has verse Effects, Treatment, and Precautions, above).
the first 6 months of therapy. Other adverse effects that been associated with lcOunomidc use.'" Up to October 2006, the See above for precautions about use with Iive vaccines.
have been reported include anx iety, peripheral ncurop- Ausltalian Adve<sc Drug Reactions Advisory Comminee had re-
Anticoagulant.. r:or reference to the effect of lcOunomidc on
athy, hypokalacmia, and mild hyperlipidaemia. There ceived 659 ttpons of adverse reactions associated with lcfluno·
the acLivity of wc1fari11, see under lnunWI05Uppressants, p. I569.
mide, 30ofwhich mentioned ncuropathy or periphenl neW'Opa·
have been rare reports of pancytopenia, agranulocyto- lhy;' lcflunomide was the sole suspeelcd drug in 24 of these Me thotrexate. Lcfiunomide therapy has been rarely associat-
sis, and thrombocytopenia; these effect~ arc more com- cases. Recovcry"'"S llOled •fter dru~ withdrawal in 6 patients, of ed wid1 pancytopcnia. Of the 18 e<oses (ntedian age 65.S yenrs)
mon when letlunomide is given with other myelosup- whom 3 underwcnl washout procedures; however. IS patients rcpooted in one series, 14 patients were nlso rceeivingmcthotrex-
pressive drugs (sec Interactions, below). There have had not recovered 01 thc time of the reports and there was no in- ate the111py. 11he pancytopcnia was typically severe Md required
formation oo the remaining cases. More recently, up to October bospitalisa1ion; 5 patients had died, 4 of whom w<:l'e also taking
been oocasional reports of pancreatitis, interstitial lung 2009, Health Cana~ 1 had roccivcd 26 rcportS of peripheral ncu- methotrcxate. Time to onset of pancytopenia ranged fiom 11
disease, and severe infections, including fatal sepsis. ropothy symptoms associoted with leOunomide. Of these, 9 re- ~ys to 4 yi:ars. The au1hou concluded tbot the risk of pancyto-
Renal fai lure has also been reported. ports had spec1fic:d periphcral ncuropathy; the duration of leflu· pcnia during lcflunotnide treatment appeared to increase when
The symbol t denotes a prcparntion no longer actively ntarketed
80 Analgesics Anti-inflammatory Drugs and Antipyretics
used with mcthotrexaic. and emphasised the impon.mceofongo- Rheumatoid arthritis. References'" to the •!Se ofleflunomide Profile
ing monitonng ofblood counts. in mcwnatoid anbritis (p.12). Le\'aCCl)'lmcthadol, a diphcnylh<pt.ane derivative, is a lon~ct­
l..cflunomide lhcnpy with or without mcthoim<atc has also been I SU1n:d V. et a l. Trca1mcn1 or active rheuma1oid lilnhtitjs with ing opioid analgesic (p.108); it is a derivative or methadone
rarely associated with inten:1i1ial lung di.<ease including intersti- lcOunomidc compared wi1h pl;ac:tbo :ind mec~trexa1c . A1Th Jn- (p.88). II was used as the hydrochloride in the management of
tial pneumonitis (s~ above). Up 10 M•rch 2006, the Centre for '"''Med 1999; 159: 2$42-SO. opioid dependence. However, the proorrh}1hmic effects led to its
Adv<ne Reactions Monitoring in New Zeal•nd1 had received 7 Prakash A. Jarvis 8 . Ldlunomidt; I review of its UK 1n Kll'f'C ";1hdrowal in the EU and the USA.
rh<um•tuid anhriois. Drugs 1999; SS: 1137-64.
reporu of poeumonitis associated with leflunomide in patients ;, Emery P, ti of. A comparison of the: effi~ty and saf~y of le Ou·
who were also taking mcthotrcxate. Of these, 4 had taken mcth- nomidt and mt1hottcxalc for the trcat1ntm of rheumatoid trthri·
otrcxatc (which is also associated wiU1 pncumonitis) ror more tis. RIH!umutolO/fJ' (Oxford) 2000: 39: 6SS~.
than I year. Respiratory symptoms developed 12 10 36 weeks 4. McCatty OW, •I al. L.cOunomidc in lrt1Ltncn1 o( rheumatoid ar· Levomethadone Hydrochloride (11NNMJ ©
after statting lctlunomide therapy; S paticn1s recovered, I died. t~ritis. U.ncct 2002; 359: II SS.
S. MiceJi.. Rkh:>rd C, Oougados M. LcOunomtde for the 1rc1tmcn1 Hodroc:orvro de levomet.adona: Levomet.tdonhidroldorid: Lev-
and anOlher iinproved but had some persisting respiratory im- or rMumatoid anhri1ls. Er.prrl Opm PhormoC'Ol /Jtr 2003; 4: ometadonhyd-oldorid: l~dOOlhydroldoridi: ~t<ldo­
painnent. 987-97. no hid~chlorida.s; lbomelhadone, ch'orhydrate de. l.el.cmeth-
l'or advice on a drug washout procedure, ~c nbovc. 6. Maddison P. c1 ol. LeOunomidc in rhcum3toid 11nhritis: rccom-. adon·h)'drochlorict le.iomethadoni hydrochloridum: (-)-Metha-
I. Chin J, r1 ul. LcnvnomidCWH50Ciatcd ranc'1lopcni1 with 0r mcndation.s 1hrou:.h a procns of comensus. Rheumotoltlf.'' (Q_'f•
wi1houl rnclhotrex:»:1e:. Aj1n PhormocotlH!r 2004; 38: 1206-11. ford) 2005; 44: 2~ Corre<tiun. Ibid.; 569. done Hydrochbide. (- )-6-0iroethylamino-1.1-<fophcnyiheptan-
2. Savagt R. Lcflunomidt and pnC'umoni1is. Pfha·;bn Updnt, 7. Silverman £. ~1 ol. Long-term open-label preliminary sc·udy of 3-one ~Nortde.
2006; 27: 7-9. lhc saftty and efficacy of k 01.1no1nidt in patienlS '"-lth polyon ic· r
/\e30'4CT3Ao+<a ><Al)OXAOP" A
ular~ ju\'cnilc rhcum1\loid uihrids. Arthntis Rhe..1m 2005;
52: $54-62. C21H21NO.HCI = 315.9.
Pharmacokinetics 8. Silvemdn E. ~'al. LcOunomidc in Ju"enilc Rhw m~ toid Arthri· CAS - 125-58-6 (levomethodone); 5967-7 3.7 (levometh-
After oral doses lefluuoniide undergoes first-pass me- tis (JRA) lnvcsllgo1or Group. Lc:flunomide or mt:thotrexate for odone hydrochlor1de).
tabolism in the liver and gut wall to A-771726 (terillu- juvenile rhoumatoid enhritis. N £,,g/J M•d200S; 352: 16S~
nomide), which is responsible for the majority oftbe in Spondyloarthropathies. References'-' to the use of k:fluno-
mide in ankylosing spondylitis and psoriatic arthritis (p.14).
vivo activity. The bioa"ailability of lellwiomide after
I. Cuch.i.cov;ch M, Soto L LeOunomidc decreases joini trosion.s
oral doses ranges fiom 82 to 95%. Peak plasma con- and induc.q r~p;1rativc. changu ii\ a patient with psoriatic anhri•
centrations of the active metabolite may occur from 1 tis. AnnRMumDiJ 2602; 6 f : 942-3.
2. Kolf\l.•uscr JP, et ol. Treatment of Psoriatic A rthriti~ Study
to 24 hours after a dose. Group. Efficacy and saifcty of te:nunomidc in the uuunent uf
A-771726 is more than 99% bound to plasma proteins, pSoriatic arthritis 1.nd psoriasis: ;1 multin11iooal, double-blind,
randomized. pl:.cebo..controUcd ctinint tri1I. Arfhritis Rhrum
mainly albumin. It is further metabolised; about 43% 2004; SU: 1939-50.
of a dose is eliminated in the urine, mainly as glucuro- 3. Haibcl H, ti ol. Six mon1hs open label tri11 of leRunomidc tn
nides, and 48% is eliminated in the faeces via rhe bile. aclivc ankylosin&spondyhtis. Ann Rheum Dlt 2005; 64: 124-6.
4, van Ocndereo JC, 11 ol. Double blind, randomised, plactbo con-
A -77 J 726 has an elimination half-life of about 2 u·ollcd study oflcnu:nomide in che 1rca1mcm ofa((ive ankylosing
>?Ondylitis. Ann RO.um Dis 200$; 64: 1761~ .
weeks, which is thought to be mainly due to enterohe- S. Schmin J. Woul G. Psori11sis-1n.hri1;s-Langztit·ther3pic 1.we•·
(levomeihodone)
patic recycling. Colestyramine or activated charcoal er Pahcnttn mit LcOunomid J /)tMh CHr-.1c1ol Gt., 200S: 2:
are able to interrupt recycling and can therefore accel- 763-6. Pharmaco poeia.s. Jn Eur. (sec p.,·ii),
erate <hug elimination.
6. Nash P, ti ol. 1..-cOunomide imprO\CS psoriasis in pa1icn1s with Ph. Eur. 6.8 (l~ Hydi'OCl-bide). A while or al-
psori:11ic arthritis: 1.n in-depth analysis of da1a from the TOPAS most white, c'Y1>tallinc powder. Soluble in water; freely solu ble
Studies in animals suggest that lellunomide or its me- Sludy. IN.ri1101nlnK' 2006: ?12: 238-49.
in alcohol. Pl'Otect from liSl>t.
tabol ites are distributed into breast milk. Pre parations Profile
0 References. USP 33: L"'\.norridc Tobie:• Lcvomethadonc is an opioid analgesic (p.105). II is the active
1. Rozman B. Clinical pharmacokinelics or lcOunomiJc. Clin Proprietary Prepararions (detoils arc given in Volume 8) isomer orracemic methadone (p.116) and is used similarly, as the
f>horMOcok;n.12002; '41 : 42 t-30. Art" 1'.ioncen: At>va: Fifal'VO>; h'IM1oa·1to; l.dw. Mol•prl: Aunra/.: hydrochloride, in the 1reatmen1ofscverepafoand in the onanaie-
2. ShiJ. cit». Popula1ion ph:innacokineticso(lhcK1i .. c me1.aboli1e .......,.,,.,"'-Aunna: ArM: 8t lf.1 tv..r. Bnn.: kw.I: Conod.: Atr."¥. ment of opioid dependence..
of tcflunomide in pcdiatrii.: )Ubj«u with polyaniculu course ju- Otrtr. NM; Ar'tnmod: t.entJ0"0.\1:: CL: Anva:. De.nm.: Arava: F;n.: An--'1:
venile rheumatoid uthrilis. J Pltonnarot incl Ph11rmorody11 Fr~ Arl'f"i\ G•r.: lv<P4: Gr.: AllNC. Honr Kong: An1..·a. Hunc,: Na\.-a: Preparations
100$; 32: 419- 39. India: ArM: Larat; Le!umide: flunolot lndon.: ..,,.,., lrl.: _.,.,.._ 1...,.t
NM< ltol: ~ Malaysia: ,,,,_ Mex.: /Viv>: Nech.:""- Non." P·r oprietary Preparat ions tdctAils arc givro in Vohtmc B)
J. Chin v." of. Population phann1cokinetics and association be·
l'nNa. NZ: N~o; Phflil>lt-: Ara-..; Pol.: Aravo: Port.:~ Ru..: A...,. Ger.:L-~
tween A 77 1726 plasma concentration) and disuse 1c1ivi1y
(Apa&.o): S.A(r4 Amo: .SinJ0$>0N!: Aiava: Spain: krq; S~ ~
measures follow in; administratH>n ol"lcOunomidc 10 people v.;th SwitL: ~·'< Thal.: IVl,.rr. Turi<.: l'noro. UK: IV~lr; U/v4"""" (Apw):
rheumatoid anhfllis.. Br J Cli11 Pharmacol 2005; 60: 2S1~. USA; Arava: Venn .: Anva.

Uses and Administration Levorphanol Tartrate (BAMl,rrNNMJ

Lcflunomide has immunosuppressant and antiprolifer- Lc-iorphan Tartl'ate: Levorp"iaool Bll.artratc: le~ Tar·
Levacetylmethadol (rN>I! trale de; Lt'llOrphanoli TartT<1$: Mcthorphinan Tartrate: Tartrlito
ative properties. It is used as a disease-modifying
iCl-Acefytmethadol: lAAM (levocetylmethadol or lcv.>cet)i- de !evorfanol. (-)-9a-Melhytrnorphin1111-3-ol hyCrogcn tartrate
anlirhcumatic drug (DMARD) in the 1rca1ment of ac- methadol hydrocl-bide); lAM: Levacetilmetadol; levacet)i· d·hydrate.
tive rheumaloid anhritis (below). It is also used in the m"1.adol; Levac!ty'.rnClhadol: Levacetyf,.,..,thadckJm: Lcvase- /\eao1'4'aHON1 Taprpn
treatment of active psoriatic arthritis (see Spondyloar- tyyfmetadolt LC\'Ol'llelhadyt Acetate (USA~ 1-Methadyt Acetate. c,,H21NO.C,H,o,.2H,O :: '113.5
thropathies, below) and has been investigated in the (-)-<1-0irnetJ¥armo- I -clhyl-2.2.<fiphenylpentyf acet>te. CAS - 77-07-6 (levorphor.ol}; I 15-72-4 (anhydrous lev- ·
management of various solid neoplasms. /\eUUCTW\MeT3AOh orphonol tortra te); 5985-38-6 (levorphonol to11rote d;hy-
Because of the long half-life of the principal metabo- CnH11N02 = 353.5. drote).
lite, a loading dose oflellunomidc is required to reach CAS - I 477-40-3 (levomclhodyl): 34433-66-4 (le- UNI/ - 04WQU6 T9Q/.
W><etylmethodol).
steady-state concentrations relatively rapidly. Therapy ATC - N076C03.
should start with an oral loading dose of I00 mg once ATC Vee - QN076C03.
daily for 3 days. However, in practice, the loading dose UNll - R38637Y991.
may be omitted in those patients at an increased risk or
adverse effects, particularly haematological or hcpalic
effects. The maintenance dose is 10 lo 20 mg once dai-
ly for rheumatoid arth1itis and 20 mg once daily for
psoriatic arthtitis. Dose adjustments may be necessary
in patients who develop abnormal liver enzyme values.
see below. The therapeutic effect usually starts after 4 (lcvorpho.iol)
to 6 weeks of therapy and further improvements may
occur for up to 6 months. Pharmacopoe ias. In US.
Adminirtr ation in hepatic impairment. Ldlunomide is US P 33 (l.~hanol Tanrate). A practically white, odourless,
con!ra-indicnted in patients wit.h hepatic impainnenl. Pa1icn1s aystallinc powder. Soluble I in 50ofwalcr and I in 120 ofalco-
who dc-.·clop moderate elevations of liver ellZ)mo values (de- hol; insoluble in chlorofonn and in ether. Store 31 a temperature
Levacetylmethadol Hydroc hloride (1INN.V.J of25°, excursions ptnnined between 15° and 30".
fined as 111lnsominnse levels 2 to 3 tin>C$ the nonnal upper limit)
while receiving lcOunomidc tteatmcnt s.hould have their dose re- Hodrodoruro de levace~tneladol; lAAM (levacety'methadol o~
Profile
duced to 10 mg daily; if OOCC$S'1ty, monitoring or liver CtlZ)·mc levacctylmethadol ">'drocNoride): levacetyt~dol Chlomy-
Lcvorph:inol t:arttatc, a phcnanthrcne derivative, is a potent opi-
valuu should also be pcrfonncd at weekly intCl'·nls. If moderate dratc de: l.ev2Cei)4methadol1 Hydroctbidum; LCYOmethadyt
oid analgesic (p.105) used in the rnanagcmentofmoderale tose-
elevations pcrsjSt or if severe elevations occur. leflunomide Acetate H)'(hxhloride (USAN): MK-790. {-}(3S.6S}6-(01meth- "ere pain. The analgesic effect usually begins about 10 to 60
should be slopped and washout procedur.:s s1Ar1od (sec above). ylamino)-4.1.<fiphenyl-3-heptanol acet2te h)-drodlloride. minutes after oral doses and lasts up to about 8 hours. A usual
Inflammatory bowel disea.se. t..ctlunomidc has been tried, /\eaauenw.eTaAOlla f '1AflOX!>O~ initial oral dC>se o flevorphanol tartralc is 2 mg repeated in 6 to 8
with some success, in the management of Crohn's di~aset CuH1,N01.HCI 390.0. = hours if nccessruy; the dose may be increllscd 10 3 mg cvay 6 to
(p.1846). CAS - 43033-72-3. 8 hours, adjusted aooording to response. ·nie maximwn initial
1. Praj11pa1i ON, tt ul. L<Oune»nidc uc:umcnr of Crohn's dise..lsc ATC - N076C03. daily dose in non-opioid tolerant patients should not exceed
potticnts inrolennt 10 s1andard immunonlodulalor 1 ~npy. J Clin ATC Vet - QN076C03. 12 mg. Elderly or debilitated palientSmay n:quirc lower doses;
Go11rocn1erol 2003: l7: 12.s-g. UNll - 854CW5KG52. initial doses should be reduced by 50% or more.
All cross-references refer 10 entries in Volume A
 Levacetylme:hadoVLumiracox1b 81
Levorµhanol tartn11t has also l:>«n given by incramuscular, su)>.
cutaneous, or slow innvtnous injeccion for pain relief and for
prem<dieacion. HO

~"-0
O References.
1. Prommtr E. Lt\:Ofph<\nol: the fOrJOUtfl opioid. Suppon ("°"
Car>ecr 2007: IS: 2S9-<'4.
?reparations

Cl~/
CJSP 33: L~ Tarvat., lnie<liO<l: le'""""""°'
Tonnie T.oiotl
Proprietary Preparation.s (d~tnils arc given in ~lumt 8) (loTcprofen)
USA: Lcvv·Drom:>r.inf
Phannacopoeias. In Jpn.
(Ionozoloc) Profile
Licofe lone (rfNNJ Loxoprofen sodium is an NSAIO (p.100) used in painful and in·
Licofelor.a: Licofelone: licotelQ:"lUIT'( HL-3000. (6·(4-0:lcrophc- Profile Oammatory conditions. It is given as rhc dihydrate although dos·
ny!)·2.2-dimemyl-7-phenyl-2.3-d;l'l)'dro-I H-pyrroli2in-S-)'1Jacetic Lorul>.OIAC c:<lcium is an NSAIO (p.100). It has been given orally cs ore expressed in tenns of lhc anhydrous salt. Anhydrous loxo-
•nd rectally in the lreatmcnl of pain, innainmac.ion, and muscu· profen sodium 10 mg IS <quivalcnc 10 about 11.3 mg Of
acid.
lO<keletal and joinl disorders. loxoprofcn sodium dibydrate.
fwt•*""""
C!lHnClN02 = 379 9. Preparations
For the man•geinenl or pain and inflammation 8$SOCiaCod with
musculoskelctal •nd joint disorders, or operative proc:cdures. a
CAS - 156897-06·2 Proprietary Preparations (details arc gi\'Cll tn Volume fl) usual oral dose: equivalent 10 60 mg of the: anhydrous fonn has
UN/I - PST6&YS22Y. Austrio: tm...nf: W..; Arr.int. Port.: Atrlont. been tiV'Cll chree times daily. II has also been applied copically as
a poultice COlltllining Che equi"alenl oflOO m11 ofchc anhydrous
f0r1n or as a 1% gel.
Lornoxicam (SAN. USAN i<NNJ Preparations
Chlorotenoxicam; Chlorteno><ic.lm: CTX; lomoksikam: Lor· Proprietary Preparations (details arc giveo in Volume 8)
Ari.: O xeno: 8raz.: LOM>f'Wt /pm Lobu; loxonin: Mex.: lmconft
rd<sir<.am; Lomoxicar:ium; Lomcooanum: Lornoxikan'< Ro-13·
9297; TS.110. 6-Chloro-4-llydrox)'·2-rr.eth)'~N-2-P>'fidyl-2H­
PhUipp" Loxcrint; T~ol.: lco<orin: Vencz" Lox°""'
th=o[l.J-e][l.2}thiazine·3<artloxamde 1.1.<fiolOde.
J\opHCM<CH'<iM Lumiracoxib (BAN. CJWI. r.NNJ
Cl C,1H10CIN10•S2 = 371.S. Cox-189; Lumiracoxobum. 2-{[(2·CNoto-6-nuorophenyljami·
CAS - 7037•-39-9.
no]-5-~l)acetic acoci.
ATC - MOIACOS.
ATC Vet - QMOIACOS. /\y....paK0!<0<6
Profile UNI/ - EP.09 I 26G7A c I )HI 3CIFN01 = 293. 7.
CAS - 220~91-20-8.
Licofclone is an NSAID (p. I00) stared ro Ix boch a cyclo-oxyge· ATC - MOl ...H06
nase and lipo>'"Y!lenase inh1bi1or. Ir bas been invcstigalcd for ~1e
ATC Vet - QMOIAH06
lrearmenc of osteoorthriris. UNI! - Y9 / T9204HU.
0 References.
I. Kulk:imi SK. Singh Vf'. Licofclone-a r>1n-cl amit1uic: and anti-
inflammatory 1:cn1. Cm·r Top Me!d Chem ~007: 7: 2S I 63.
2. Fischer I..., ti ol. The molec:ul.ar mechanism of the inhibition by
Jieoftlone of the h1osynlhesis of S-lipnx)'gcnase prottucas.. 9,. J
Pltm'llwC'Ol 2001; 152,; 471-30.
3. Rl)'08Vf.J JP, ~t al. Canadian Lkorclun~ Slud)' Group. Proieai'"e
dfccls of licofclooe, a S·tipoxYJ.tn.a5e 11nd cyclo-oxygenase in- Profile
hibitor, versus naproxcn on carhl:1ge loss in knc~ oSLcoanlvtlis· Lumoxicam, •11 oxiea1n dcri\'ativc. is an NSAID Cp.100). It is
1 first mulliceotre clinical tr1JI us-ing qu;)ntilali\'t MRJ. Arm
Rhnm• Dis 2009; 68: 938-47. used in musculosk.eletal andjoinl disorders such as osceoanhri(is
and rheumacoid arthritis; ii is also used in lhc crcaunem of o<her
painful conditions including postoperative pain.
In the ll'Cttmem of osteoarthritis and rhcuniotoid arthritis lomox-
lithium Salicylate icam isgiV'Cll in on initial oral dailydoseof 12 tng in two or three Adverse Effects, Treatment, and Precautions
Lithium SahC)1ocutrc Saldato de litio. di"ided doses; if necessary the daily dose may be increased to a As f0<NSAIOs in geuer•l. p.100.
maximuin of 16 mg. Hypenensiriviiy re3clions ineluchng anaphybxis and angiocde-
J\!4TUfl Ca11HUHAa-
Lomoxicorn is given in oral dose.~ of S to 16 mg daily for 1he 1111 have occurred in palicntS fC."C'CiY(ng tuniiratoxib; it should be
C 7H~l 1Q l = 144.1. trc:umcnr of pain; similar dosi:s may be given by intravenous or stopped al the first signs of hypersensitivity.
CAS - 552-38-5. intrnmuscular injection. Lumiracoxib usr, particularly at high doses, may cause seven:
UNll - 9 JF I SP6QIN.
0 References. liver 1oxieiry (sec Effects on the Liver, below) and its use is con·
I. BalfourJA,ct,t/. l.omoMam:3r~viewo( ilspl'l::irm ocologyaM
cra-indicared in paiicnts wich heparic disease:. II should also nm
1benpe111i~ po1enth1I in tht rnana~cnt of p21inru1 ond inOarn· be used in those with a history of drug-induced increases in
tnalorycondi1ions. Drtrgs 1996: SI: 639'--S7. crans:imincse v•lues gealer lhan 3 times Che upper limit of nor-
2. Skjodt NM. Oa\'ii:s NM. Clinica,1 pharmo:K'Okim:1ic1 of lornox.i- m11I (ULN) <>r in those caking Oilier drugs lu>OWl> to cause clini·
ca_m: a short h~lf-l i fc oxic~m. Cf;,, Phorn,ntoklnct 1998'~ 34: <.11ly signifi<:onl hepalotoxi<:iry. All patients should have baseline
421-8. li""r function tests hcfore sta11in11 lumiracoxib trcalmcnt; UiMC
Friuien') I., a al. Smdio a lungo •ermine wdftc.acia c sicurezza in whom cransaminases Mc 1nore than l.S ci111es cbe U1N should
l(."f'apcutic.a di kxno:dcam ncll 'anritc mnnatoic!e. Miucn·a Matt
2002: 93: 3 I $-20. noc sian treatment. Liver function tests should b<: repealed
4. Thitnthong S. t't al. Tr\:;alm~nc of p;iin afitr spin;,I wrgtry in lht monchly anJ lumiraw.~ib should be slopped in lhose paticncs
Profile wich an increase in llansaminascs greater lhan 3 rimes ~1c LILN;
Lithium s:ilicyl~lc is a salicylic acid derivative (see Aspirin, recovery room by smale dose tomo:<.icam: a randomized.. double
lllind. placebl>con1roncd 1riu.I. J Metf ...b1oc Tito, 2004: 81: in chose wilh 1111 incrcasc grcarcr 1hnn 2 times the ULN, liver
p.21) cha! has been usod in rl>eumatic diso1'de1s, bul its use cannot 650-5. function tests should be repeated in 7 days. Pauencs should be
be recommended hccatl<C of the phArmacological cJTecc of Che S. Zh~o H. t·r ol. Applie:ltion of lomo~ic.::im 10 plticnt-conttollcd advised co repon any symptoms suggescive ofliver toxicity such
lithium ion. an1lgesi1 i11 P"-lients unckrgoi~ 1bdo1ntnal surgcrici. Cl:/11 Akd as an0<exia, nausea, vomiting, abdominol pain, fatigue, dark
Homoeopathy. Lilliium salicylatc has been 1ised in homoeo- S<I J 200.S: 20: 59-62.
urine, and jaundice.
palhic medicines. Preparations Lwniracoxib sl100ld n<>l be u.<cd m pati<:nCs wich ischaemic heart
Preparations Proprietary Preparations \dc~ils ire ;ivcn in VOiume 8) disease, cerebrovaseular disease. or peripheral arteiial diseale- It
Proprietary Prepar«tions (derails •re given in Volume BJ Ari, H)IX!<lol' X•fo: Aurtrio: Mol¢ Loma<f: Xefo: Chilo: At•bdt. should be used wiU1 caution in paticnrs wich significant risk fac-
Cr.: X.lo: Detim: Xeloc G<r.: T<los: Gr.: X.lo: Hung.: Xef<x lrl.: Xcfo; tors for cardiovascular disease such 3S hypertension, hyperlipi·
Homoeopathic f<" Gt>Nlcs !!<>rophann IY.> 2•f. lsrool: Xclo: ltol.: No>con: la&'ioo'; Jpn: lo'<O!Tt Pol.: Xelo: Port.: A<I·
d:iemia, and diaberes mcllilu:J.
btl: Clo.<pomn: Ru1.: Xeloam (Kce¢o<llM); S.Afr.: x.1o< Spoin: Ac>btt
Sosporoo' Swod" Xelo; Switz.: X.,fo: Thol.: x.fot: Turi<.: Xtlo: Viv.: Lumiraco><ib is also C(llllm·indicaled in patients wich inlla1run3-
Xeio<im (Kc~). l'enoz.: Aabel. 1ory bowel disease. moderace to severe heart failure (NYHA
Lonazolac Calcium (IN'lMJ class II ro IV), Md nroderacc 10 severe renal impairment associ-
ac.'ll with • Cl1:lllininc clearance of less chan SO niUminuu:. Cau-
Ulat lonazolacum; Lonatsolaal<kikalsi..-n lonazolac C.lcique: tionis recomm<nded when using lumiracoxib in dehydrated pa·
Lona.zolico c.ikico: Lonazolacum Calocun'< Lonuolald<atcium loxoprofen Sodium itNll'>IJ
tiencs.; it may be advisable 10 n:hydran: patients before giving
Calcium 3-(1<hlorophenyt)-1-ph~-'l-ylacetate. CS-600 (loxoprofen); Loxo;iroteoe Sodiq;e: Loxoprofeno s6di- luniiraeoxib.
K.w.w<~ l'IOHa3C>lla• co: Nlvii lo><op.ofenum. Sodium (±)-p-[(2-oxocyclopentyl)me· Effects on the cardiovascular system. 1liere have been
c,.H;,CaCl2N<O, = 663.6. lhyl:Jiy<htropale cihydrate.
<~ abouc the adv MC cardi0\'3scular effecrs ofselccti•c cy·
CAS - 53808./!8-1 (lonozoloc): 75821-71-5 (I011ozoloc HaTpt<ii llot«:onpo+e" dO-OJ<ygcnaS<.~2 (COX·2) inhibitors after lhc worldwide with·
calcium). c,)H1101Na.2H20 = 304.3. drawal or rofeeoxib (see p.125). The catdiovascular safety oflu·
ATC - MOIA809. CAS - 68767·14· 6 (lo;copro(en): 80382-23-6 (loxopro- miraco~ib has been assessed in the Therapeutic Arthritis
ATC Yet - QMOIA809. ;en sodium d1hydrote). Research and Gasuoincesrinal Event Trial (TARGET)' which in-
The symbol t denotes a preparation no longer actively marketed The symbol ®denotes a substa11ce whose use may be restricted in ccnain sports (see p. vii)
 82 Analgesics Anti-inflammatory Drugs and Antipyretics
volved over 18 000 palicn!S with osLeoanhrilis. Lumiracox ib dose of I00 mg daily that is recommended in the UK and other 3. Rordorf CM, ct"'· ClinicnJ phormocok>gy or lumiraoosib: a se-
400 mg daily (2 to 4 times the recommended dose) was com- European oounlries. (H igher maximum daily doses have been Ii· lc:cLive cycl0-0xygenase.2 inhibitor. Clln Phormoctt4'it1e.t 2005;
pared against either naproxen l g daily. or ibuprofen 2.4 g daily; censi:d in other countries; in Australia, die licensed maximum . 44: 124 7-66.
4. Sch1lilzc:r TJ. c1al. L.umincoxib in the trellmcnl of oslc~nhr i­
low-do5c aspirin ( l 00 mg dajJy or Jess) was also allowed where dose was 400 mg daily for some conditions.) At that time in the tis. rheumatoid Jrt hrit.i~ and acute postoperative dental pain: re.
indicated. After a planned treaiment duration of I year. !he inci- UK. new prescribing rco;trictions on the use oflumiracoxib in OS· .suits of three dosc-ruponsc studies. Cun- J.ftd Res Opm 2005;
dence of myocardial infarction, Sltokc, or cardiovascular dealh tcoanhriris were issued (sec Adverse E!rccts and Prccau1ions, 21: lSl~l.
widt lumiracoxib was found to be similar to tl1at for ibuprofen or above) while its safety continued to be reviewed by European S. Bcrcnb.,um f? ¢1 <11. Efficacy of lvmi'1tcoxib in osleoanhdtis: a
.naproxcn. More events were noted in the lumin!COX.ib versus regulatory aulhorities. After a review in Ocrober 2007. 1he review of nine studk.s. J /1t1 Mtd R~1 200.S; ll: 21-41 .
naproxen subgroup than in the lumiracoxib versus ibuprofen MHRA reitcnted its earlier prcsaibing resuictions for luminl· 6. Sheldon E,., al. Efficacy and 1olenb1li1Y of lumirac:oxib in the
tr<alme111 of osteoarthritis of lht kt>ee: I I )·wed<. randomized,
group; however, this difference was nee sratistically significant coxib and swed lhe issue ofhepatotoxicity would continue to be doubk·blind comparison wit!> celtco>ib ind ploeebo. Oin Th•r
and the authors considered thllt the hi&her number of Jl"Tients monitored. They also advUed \hat, worldwide~ umil !hcn. lhere 2005; 17: 64-77.
,.;th a history ofvascular risk in the lumiracoxib VCISUS naproxen had been 19 cues ofsevere liver re.1Ctions, inchldiog 13 oflivcr 7. fleisclunmn R.. tt ol. Lumir»t.'OJub is effective- 1n d.c trca.tmenl
subgroupeould explain lhis fmdmg. In addition, it was noted that failure, 2 deaths, and 3 liver transplants suspected to be possibly of osieoanhrilis: or1hc k.nrc; • prospcctiw randomized 13-~"Cck
lhe incidence of bean ranun: was less licqucnt with Jumiracoxib related 10 use oflumiracoxib.' At about the same rime, lumira- study versus placebo and cclecoxib. Clln Rh<umo1ol 2006; 25:
42-SJ.
although, again, lhis was not significant.; however, blood pres- coxib was withdrawn from the Canadian marlcet after Health
sure changes from baseline were significantly less likely with Ju- Canada noted 4 cases of severe hepalotoxicity, includinf 2 in Preparat ions
m iracoxib lhan with ibuprofen or naproxen. Canada, associated with lbe l 00..mg dose of lumiracoxib. Sub· Proprietary Preparations (delails an: given in Volume 8)
More recently, a mcta-aMlysis2 by the maoufa~turer (which in· sequently, in Nov<'111ber 2007, the MHRA suspended the product Att·' Prexige:Auruol.: Prex"'-<f; Aurtrio: l'rc><ii:et. Broz.: Prcxige; Chile:
eluded the above study along wilh other published and unpub- licence for lumiracoxib after a further review of worldwide safe- l'rcl<;ge: Fin.: Pno<~ej: Gr.: frtxocel: Pmcigr. Hunr.: p,.,.;gol; lndon. :
Prexiget: N Z: Prexigo; Po rt.: fttxocett: Hiroat; Swed.: Prcl<igcj; Turi<.:
lished clillical studies oflumiracoxib in the treatment ofosteoar· ty dalll showed an increased number of serious liver reactions Prexig r. U K; f're<igef.
tluitis and rheumatoid arthriiis) has also found no evidence that wilh the IOO·ms dose which, in some cases, occWTed wilh short·
the risk of thrombotic events with lumiracoxib is significantly term use.6 In addition, the EMEA7 has recommended its with·
increased when compared with placebo, with naproxen ( I g dai· drawal in the EU.
ly). or with the NSAJDs diclofenac (ISO mg daily). ibuprofen I. Australian Therapc.u1ic Coods Administration. Urgent adv tee ro· Lysine A spirin
(2.4 g daily), celccoxib (up to 400 mg daily). and rofecoxib prdir'lg management o( patients 1akillg Jumiraco:11:ib (Prexige) AceUs.alici!ato de lisina: Aspirin D.·Lysint!; Lysiiniasetyytiafisyiaatti:
(2S mg daily) as a youp. (issued I Jlh Auausl, 2007). Available 11: http://www.11:".iov au/ l~t: lysine Ac~oeytale: c..-lystt Acetytsali-
1lcJ1s/ptex11t.htm (acccnc:d 081t 1/07)
For further dciails on lhe relative risk of cardiovascular throm· ?. Adverse Onie Rooctioos Adv;.c,y Committte (ADRAC). Wi<h· q!a1e; Lysn;rn~
bolic e-'Cllts with NSAJDs, see p.100. draWll of lumaraco.xib in Australia. Ansl AthTrJ~ ~ RNtel llHJMH•AaMp'<H
For discussion and advice on the use ofselective COX-2 inhibi· Bu/12008; 27: 6-7. Also •Vlilable at;
hnp;//www.1&1 hcallb.gov.awadrludtblaadnl804.pdf (a«tiscd
C 1sH12N20& 326.3. =
rors in patients with cardiovascular or cerebrovascular disease. l?/07/08)
CAS - 62952-06-1 .
see under ~lecoxib, p.3S. 3. MHR.A. New (inlttim} rtstnctioos on prescrip(ion of lumiracnx· UN/I- 2JJ2?4Jl45.
I. Farkouh M£, et of, Com~ri.on of lurrnraco>1.lb wilh n:iproxen ib, followin1 concerns ovet liver safety (issued 24th Augu)t.
aod ibuprofen in cht: Ther1peutic Arthritis Rescatth and Gas· 2007).
trointcstinat Event Trial (TARGET), card1ova.scular outcomu: Available at: htlp://www.mhra.gov.uk/Safctyinform•tion/
randomised controlled trial. lan«l2004; 364: 67S- 84. Sa (c1yw 1rn in;sa lcrtsandrecatls/Safetywarn i ngsandm cssa
. 2. Matchaba P, Cl()/, Cardiovncular u rc1y of lum ir~coxi b: a me.ta• gcsfom1edicincs.'CON2032098 (• ccesscd 2911l8108) H1N ~COOH
::1nalysis of all randomiz.ed C()(llrolled trial~> I v.•c:ck and up 10 I 4. MURA. l..umir1coxib and li,..er adverSe rt3ctions (i$$ucd 16th
year in duraliOn Of p3litnlS whh OSICOUTthrhis 111nd rheuma1oid Oclobcr, 2007).
arthtilis. CUn Ther200S; 27: 1196- 1214. NH2
Available 11: http:i/www.mhra.gov.uk/Safctyinforml\ion/
Effects on tne gastrointestinal tract. It is generally accept· Sa fe1ywarn in g.stl ensandreca lls/Saf ctywarn ings11ndmcssa
gcsfomcdicincs/CON203283 l (accessed 29/08/08) Pharmacopoeias. Jn Fi:
ed that the inhibition of cyclo-oxygcnase-1 (COX-I) plays a role
5. He1lth Canada. Withdrawal of marke1 authorisation for Prexage.
in the adverse gastrointestinal etrcctS ofthe NSAlDs, and that the (issocd 41h Oclobcr, 2007). Available at: Adverse Effects, Treatment, and Precautions
selective inhibition of the other isofonn, COX-2, by NSAIDs h11.p:J/wwwhc:-sc.ac.ca/1hc-a$c/mcdla/ advisorics·•visl2007/ As for Aspirin, p.21. Anaphylactic shoclc hu bceo reported in
such as lumiracaxib may cause less gaSITOtoxicity than that seen 2007_t41_e.html (accessed 30tl0ilJ7) patients gh'CD lysine aspirin by injection.
with the non-selective inhibition of the traditional NSAIDs. 6. MHRA l..umiracoxib (Prcxigc): $Uspcnsion of mutcccini 1u-
thoriA1ions (issuc:<I 19th November, 2007). Lysine aspirin, like aspirin, should not generally be gi""'1 IO chi!·
However, licensed product information his sraied that upper gas. drc:n bccauseoflhc risk ofRcye's syndrome.
trointcstinal ulcuarion and bleeds, in some cases fatal, have oc- Av11fablc at: hnp:J/www.mhra.gov.uk/S:11fetyinform1tion/
Safe1ywnnin1s.alcns1ndrcca11s1Safdyw::uning:nndmcua Hypersensitivity. For a suggC$1ion lhat inhaled Of in1ranasal
curred willt h.miracoxib trealment, consequently it should be gcsrormtdteines/CON2033073 <•=-d 29/08.'118)
used with caution in patients at rislc of such events. 7. EMEA . .European Medicines Agency recommends "'ithdrawal lysine: aspirin miglll be more suitable than aspirin for the diagno-
Resul!S from controlled studies confirm that NSAIDs selective of the market1na 1ulhorisatict1.S for lumiracoxib-eontaining med"' sis of sensitivity to NSAlDs, sec under Hyperscnsirivity on p.22.
for COX-2 are associated with a lower incidence of serious gas- icines (issutd 131h llc<cmbcr, 2007). Interactions
trointestinal cffCCIS. A srudy1 in palienls with osteoarthritis tak· Available t\t hup://www.cmca.curopa.eu/pdfs/humanlprcn/pr/
PR_Lumir11ooxib_57930107cn.pdf(ac.,...cd 17/07/08) For interactions associated with aspirin, sec p.24.
ing lumiracoxib at supraiherapeutic doses (400 mg daily) con-
cluded that there was a lower incidcnce of dcftni<e or probable Interaction s Uses and Administration
For ioteraaions associated with NSAIDs in general, sec p.103. l.ysinc aspirin has analgesic. anti-inllamma1ory, and antipyretic
uppc< gastroinlestinal ulcer complications (bleeding, perfora1ion,
or obstruction) aner 12 months or
trealment when compared Lumiracoxib may cause liver toxicity and eonsequenily it should actions similar to those of aspirin (p.24). When given, lysine 35·
not be u.oWOd with 01hcrdn1gs known to cause clinically sii;nificant pirin dissociates into lysine and aspirin; aspirin is ~1en hydro-
with non-selective NSAIDS (ibuprofen 2.4 g daily or naproxen
hepototoxici1y. lysed to salicylic acid. Lysine aspirin 900 mg is equivolcnt to
1 g daily). The incidence of endoscopicaUy-<letected ulcers was
also less with lumiracoxib than with non-selective NSAIDs. about SOO mg ofaspirin.
The11: is the pussibility tliat lumiracoxib may dccrcasc the clear-
However, the ~ of low-<lose aspirin appeared 10 nultify any ance of drugs that are cylOChromc P450 CYP2C9 subslntes and Lysine aspirin is used in the treatment of pain, fever, and rheu·
procccrive gastrointestinal effect oflumiracoxib. caution is advised when it is given with CYP2C9 substrates that matic disorde.s. It is given in oral doses equivalent to 0.5 to I g
have a nanow therapeutic index such as pbenytoin and warfarin. of aspirin, repealed every 4 to 8 hours as needed up to a maxi-
An analysis1 of pooled da11 from IS pre-hcensing studies in pa·
mum of3 g ofaspirin daily (2 g daily in the elderly) fQr pain and
ticnts with rheumatoid arthritis or osteoartbritis has also conellJO. Pharmacokinet ics fever. The dose for rheumatic dis<lnl<n is equivalent to 3 to 6 g
cd that the risk of upper ~nu:stinal ulcers and ulcer compli- Lumiracoxib tS absorbed liom the gastrointesainal troct after oral of aspirin daily in 3 or 4 divided ~ Lysine aspirin is also
cations is less with lumirac:altib lhan with noo-sclective NSA!Ds use and peak plasma coocentrations OCQlr in about 2 hows. Pro- gi"en intramuscularly or intravenously in similar doses; lhe max-
(diclofenac, naproxen, and ibuprofen). tein bindin& is 11 lcasl 98'.4. Luniracoxib un<k'l'gocs extensive imum daily parenteral dose is equivalent to4 aofaspirin for very
I. Schnitzer TJ, ~'al. Comparison of lumiro.coxib with naproun hepatic metabolism; several enzymes appear lo be involved in-
and ibuprofm in the Thcrapcu1ic A11hricis R.esarc.h end Oas~ severe paio and to 6 g ofaspirin for rheurnalic disorders.
trointestinal Event Trial (TARGET), reduction in ulcer compli· cludini: &lucuronosyl1r:1nsferase and cytochrome P4SO isoen- Lysine aspirin is also used with metoclopramide in the treahncnt
cations: r.mdomiscd controlled iriat La,,C'f:f 2004; 3 64: 665-74. zyrncs. The main oxidative palhway is media1ed by the CYP2C9 of migraine.
2. H3wkey CJ, et a l, Gaslroinlestinal 1olert1bilily of lumiracoxib in i~oenzyme; however, this does oot appear to be the major palh·
Lysine aspirin has a)so be<n used in lhe manai;cmcn1 of chrom·
patients w ith os1cnarthrili1 and rheumatoid arthritis. Clin Gos· way. Three major mctaboliles have been identified: 4' -hydroxy·
rroenterol Htpoto f 2006; 4: 57-66. bocmbolic disorders.
lumiracoxlb, S-carboxy·lurniracoxib, and 4'-hydroxy-S-car·
Effects on t he kidneys. Limited evidence of the renal toxicity boxy-lumiracoxib. 1llc 4'-hydroxy metabolite is active as a C)'C· Headache. Some references to lhc use of lysine aspirin, often
of the selective cyclo-oxygcnase-2 (COX-2) inhibitors such os lo-oxygennse-2 (COX-2) iohibicor although it is less polenl than with metoclopramidc, in the treatment of migraine.
lurniracoxib suggests that these NSATDs appear to have effects lumiracoxib. The plasma half· life of lumiracoxib is aboln 4 I. Trclt·Han.sen P. et of. The clTcctivcnr:ss of combined o.-aJ tysinc
oo raial function similar to those oflhe non-selective NSAIDs hours. Sligbtlymoreofa dose isexcre<ed in the11rine (S4%) 1han accty1salicy1atc and mctoc:Jopramidc compared with oral $U- .
in the faeces (about 43%); only about 5% of a dose is excreted matriptan for migraine. Lonut 1995; 346: 923-6.
(sec p.102). ?. Diener HC. Efficacy md safely of in1rave.nous acc1ylsalicylic
unchanged. acid lysinate compared to subcu11ncou1 sumatriplan and
Effects on the liver. In August 2007, the regulatory authority
in Austrolia withdrew lurnncoxib from the market after repons OReferences. parenteral pbccbo in the acute ltntmcnt o( milfliM. A double.
blind, double-dummy, randomiud, mul1ict0tt<, poralkl group
ofbepalotoxicity. 12 In the 6 months since mari:eling, there had I. Se:on <l 11 oL Ptwmac:okinetics oflumirxoxib in pl11ma and srudy. C<phnJotgta 1999; 19: 581-8.
been 8 n:porlS of serious ldYette livet reactions resulting in 2 synovi1I Ouicl. Clin Phamocokinct 2004; 43: 467-71. l. Tfch-HaNCn. P. The dfcctivcncsi of COftlbincd oral lysine ace-
deaths and 2 traosplantations. There was some concern that pre- Uses and Administration 1ylsa.licyla1c and mdocle>pn:midc (M11priv") m 1hc lrcaame.nt of
liccnsing clinical study da11 ~ to suggest th al those patients Lumiracoxib is an NSAlD (p.103) reported to be a selective in· mia,rainc auac.ks.: companson with pltccbo and oral sumatriptan.
who developed elevated liver IUncrion tests while on lumir.lcox- F11nct Neufo/2000; J S(suppl )): 196-101.
bibitorofcyclo-oxy11cnasc-2 (COX-2)- It has been wiihdrawn in
ib would recover once the dru& was slopped; however, in the 8 many countries after reports of hepatotoxicity. Lumiracoxib h~~ Nasal polyps. Two long-term controlled Sllldies1 suggested that
Australian cases, some patients did not improve because of lhe been used in the rreaonen1of osteoarthritis of the knee ~nd hip in 1opical (endonasal) lysine aspirin may be cffeC1ive in preventing
severity of the hepatic damage. an oral dose of 100 mg once daily. Higher doses of up to 400 mg · 1herecurre.uce ofnasal polypsaftcrSUJgical removal (scep.1646)
In response to the Australian data, the MHRA in lhe UK reported daily have also been used but may be associated wi1h an in- in both aspirin-tolerant and aspirin-sensitive patients. This effect
that it had received 16 rq:torts of suspected adverse rcaclions 10 creased risk ofhepatolox.icity (see Effects on 1he Liver, above). may be ottributed to the non-specific anti-infiamma1ory proper-
Jurniracoxib;3 of these, one was a case ofhepatotoxicity in which ties of lysine aspirin. Although no adverse effects were reported
the patient recovered after the dn1g was withdrawn. Worldwide, OReferences. in this study, hyperscnsicivity reactions have been seen after use
the MHRA was aware of l l rcpons of serious hcpatotoxicity in· I. 1,y.. na·Williomson KA. Curran MP. Lumi,;..oxib. Dmu 2004; ofsalicylalcs in tht: presence of nasal polyps (see Hypersensi1iv·
6 4: 2237-46.
cludiog 9 cases of liver failure, 2 death., and 3 liver transplants ity under Adverse Effcas of Aspirin, p.22).
2. Bannwanh B, Bc1cnbaum F. Clinie:al pharmacoloq of tumira·
suspecled to be at least possibly relalcd 10 lumiracoxib use. 1llc coxib. a $CCOl'ld-generaijon cyclooxygena5e 2 sclcc11ve inhibitor. In another Sludy2 intranasal lysine aspirin did not show signifi·
dose used in most of 1he cases was higher than the maximum Expert Opln ,,,_, Dnti' 2005; 14: S21-33. cant clinical benefit in preventing the rceurrcncc of nasal polyps
All cross-references refer 10 entries in Volume A
 Lysine Aspirin/Mefenamic Acid 83
wh~n con1pared with placebo. However. significant improve-
mein at a microscopic leve) was noted. ·
Miefenamic Acid (SAN. usAN.1iNNJ

x~JvCH3
l. Nuccrn E. <?I al. EOi.:c.."ts of lysine-:icctylsa!icyfo1e (LAS) lfC'11· Acidc mefCnamtq-..ie: Acidc mefeoci.rnico: Addum mefenamicum:
menl in n.asal po l yposis~ iwo con1rot1ed long lenn pros.pec1ive Cl-~73: CN-35355; INF-3355: Kwas mefenamow1: Kyselina
follow up studies. Tltom.\' 2000; S.S (S'U!>PI 2): S?S- 78. mef~namov?.; Mefenaamlhappo: Mefenamik Asit; Mefenam;nsav:
2. Parikh AA. Scadding GK. lntronasal lysioe-aspirin in as.pirin·
scn:si1i·1c: n3~1 polypo~is: a controlled trial. laryng<>S('(l/)f' 200S:
1)5: 138$-90.
Preparations
v,JJ Cl
Mefenamo rug$t s: Mefenamsyra. N-(2.3-Xytyl)anthranilic acid.
Me<i>eHaMOS<1R KlltCAOTa
C 1 ~H 1 5N0 2 := 24 1.3.

Pharmacopoeias. In BP{l'el). CAS - 61 -68-7.

Proprietary Preparations (details ate givell in Volume B)
SP(Vet) 20 I 0 (Medofenamic Acid). A white or almost white, ATC - MOIP.(01.
Arg_. Asprir.a: Dccitr;ot Ye-:.wpirin; Belg.: kpegic: Cprdegic; C:z.: ~
ATC 'let - Q.MOIAGOI.
~°t.~~~o~;,t*~1~'b,f.';~t''t.~~~~~=~t:~~~ crystalline powder. Practically insoluble in water; slightly solu-
ble in alcohol and in chlorofonn; sparingly soluble in e1her; sol· UNil - 367589Pj2C.
Hung.: Aspefiic Kor.:leg;c: Kor<f.<enj: ltol.: Aspegic: Asp<lolj: Cardirene:
Flect•dcl: Me<.: CO<aspir; Kardegic: N•th.: Aspeg<:: Cardegict: Pol.: uble in dimethylfomiamicle and in IM sodium hydroxide.
Lc.spalt: Port..: Asp~ic: lr~sprin: thlraspir: Kardegtc: L~spin: Tiplact;
Spain: ASLt: lnyes?'"•n: Switz.: A!cacyl iostarrtar.ce; Aspeg:c Y~rdegic
Turk. : J.lo.spegic: Venez.: Asalist. Medofenarnate Sodium (SAN!v\ U5AN. rlNNMJ
Multi·ingredient: &lg.: Migpriv:· Otile: Oolotol 12; Cz.: Migprivt: F1n.: Medofer.a.-nate de Sodium Meclofen;.1nato s6dico: Nallii
M:gprf.r, Fr.: Aspegic Codeinet. M:gpriv; Gr.: Egrtyt P1 ~ Hung.: Migpriv. Medofer.arna~
kol.: Migpl'i\.-; ~ptim; Mex.: Af'rtjg_ram; Neth.: 11igra6n; Norw.: Mig-
prWf, Pol.: M;gpriv. Sw<td.: M;gpriv. Switz.: l'igi>-iv. UK: M;gramax. HaTP"'H MeAAo<jleHaMaT
C,.H:oCl2NNa02.H20 = 336. 1.
CAS - 6385-0Z·O. Pharmacopoeias. In Chin., Eur. (seep.\'ii), Jpn, and US.
Magnesium Salicylate UNll - 94NJ8 I 8U2W. Ph. Eur. 6.8 (Mefenamic Acid). A white to iilmost white, micro-
Pharrnacopoeias. In US. crystalline powdu. It exhibits polymorphism. Practically insolu-
SaJicitato magnesico. ble in water; sligJ1tly soluble in alcohol and in dichloromethane;
USP 33 (Medofenam21e Sodil.ITl). A white to creamy white,
Mar""" CGAv.uW\3.T odourless to almost odourless, crystalline powder. Freely soluble dissolves in diluic solutions of alkali hydroxides.
C,.H ,0 Mg0.,4H iO 370.6. = in water, lhe solution sometimes being somewhat turbid due to
partial hydrolysis and absorption of carbon dioxide; the solution
USP 33 (Mefenarnic Acid). A white to off-white. c1)'Stalline
powder. Practically insoluble in water; slightly soluble in alcohol
CAS - 1891 7-89-0 (anhydrous magnesium salicylate):
I 8917-95-8 (magnesium solicylole teuahydrale). is clear above pH I 5. Slightly soluble in chlorofonn; practically and in methyl alcohol; sparingly soluble in chlorofonn; soluble
UNI/ - 4 I 7Z8CY7UX (magnesium soficylote): insoluble in ether; soluble in meth)'I alcohol. Store in ainight in solutions ofalkali hydroxides. Store in ainight containers. Pro·
JQ69D454NI (anhydrous magnesium solicyla te). containers. Protect from light. tect from Iight.
Adverse Effects, Treatment, and Precautions
As forNSAIDs in general, p. 100.
Adverse Effects, Treatment, and Precau-
tions
HO~;} Incidence of adverse effects. 111e commonest adverse effect As for NSA!Ds in general, p. I 00.

0-
0 o· in 2500 palienls given ineclofenamate sodium was gastrointesli·
Mg2• nal disnirbance. 1 Diarrhoea occurred in I 1.2% of patients in dou- Treatment should be stopped if diarrhoea and rashes
ble-blind studies and 32.8% of patients in long-term srudies (up occur. Other effects reported include drowsiness, and
OH ·o to 3 years). Ulcers were detected in 22 patients during therapy eftects on the blood such as thrombocytopenia, o~ca­
0 and rashes occurred in 4% of patients. Transient increases in se-
sionally haemolytic anaemia, and rarely aplaslic anae-
rum aminotransferases and BUN occurred in some patients.
Pharmacopoeias. In Chin. and US. I . Preslon SN. Safety of sodium mcdo(cnamatc (Mcclomenn1).
mia. Convulsions may occur on overdosage.
USP 33 (MagriesAim Salic;fate). A white. odourless, effiorescen1, Cm.,·17,erRes 1978; 23 (•uppl 4$): SI07-Sll2. Mefenamic acid is contra-indicated in patients with in-
crystalline powder. Soluble in water and in alcohol; slightly sol- Effects on the blood. Case rcpons of agranulocytosis 1 and flainmatory bowel disease. Licensed produ.i:t infonna-
uble in ether; freely soluble in methyl alcohol. Store in airtight thrombocytopcnia2 associated wi;h mcdofenamate 1herapy. tion recommends that blood counts and liver and renal
containers.
I. Wishner AJ. Milbum PB. Meclofcnamate sodium-induced function should be monitored during long·te.rm \hera-
::igr:mulocyto~is and suppres~ion of C l)' thropoic~is. J Am Acod
Adverse Effects, Treatment, and Precautions
Dcn11atol 198S: 13: 1052-3.
py. Drowsiness may affect the perfonnance of skilk:d
As for Aspirin, p.21 . Magnesium salicylate should also be used tasks.
2. Rodrigu~t J. Thrombocy1opcnia associated with medofena1mne.
with cau:ion in renal impainneot because of the risk of hyper·
Drug 1111~/I (Jin Phmw 1981 ~ JS: 999. Mefcnamic acid may give a false positive in some tests
magnesaemia.
l11e use of aspirin and olhcr acetylated salicylates is generally Interactions for the -presence of bile in the urine.
not recommended for children because of the r isk of Reye's syn- For interactions associated with NSA!Ds, seep. l 03.
Breast feeding. No adverse eftec1s have been seen in breast-
drome, unless specifically indicated. Some licensed producl in- P harmacokinetics fed infants \Vhose mothers were given mefenamic acid, and the
fonnation extends this precaution to magnesium salicyla1e. Meclofenamalc s(ldium is readily absorbed when gi\'en orally. American Academy of Pediatrics considers' that it is therefore
Interactions Peak plasma concentrations occur about 0.5 to 2 hours after in- usually compatible with breast feeding. TI1e BNF 59 also consid-
For int~ractions associated "ith salicy!ales, see Aspirin, p.24. gestion. Meclofenamate is over 99% bound to plasma proteins. ers that the amount of mefenamic acid d istributed into breast
TI1e plasma elimination half-life of mcclofcnamate sodium is milk is 100 small to be hannful to o breast-fed infanL An early
Uses and Administration a!xiut 2 to 4 hours. It is Jll<'laboliscd by oxidation, hydJ'Oxylation, study~ confinns that the distribution of mefcnamie acid into
M'1gnesium salicylate has analgesic, anti-inflammatory. and dehalogenation, 4\nd conjugation with glucuronic acid and ex· breast milk is minimal. However, licensed product information
anlipyrelic actions similar to those of aspirin (see p.24). AJ1hy- creted in wine mainly as glucuronide conjugates of the melab<>- contra-indicates the use of mcfcnamic acid in nursing mothers.
drous magnesium salicylate I g is equiV"dlent to about 1.2 g of lites. Aboul W to 30% is recovered in the faeces. Oneoflhe me· I. American Acaclc:my o f Pedi:llriC$. The transfer of drugs and olh·
aspirin. (! is used in the creanm:nt of pain and fever and has b~en t"bolites. a 3-hydroxymelhyl compound, is reported to be active er chemicals ir.10 hum;in milk. Pcditw•ics 2001; 108: 776-89.
used in tbe management of inflammatory conditions such as os- although to a Je~ser extent than the parent dfUg. tRetired May W IO) Correction. ibid.; 1029. Also :lvai13blc at:
hup ://aappolicy.3a ppu blication s.org/cgi/conrent/fu I If
teoarthritis, rheumatoid arthritis. and other arUui1ides. Usual oral
O References. pcdi"l riC$~0Jb108/3/776 (>CC<$S<d 08/11/07)
doses of magnesium salicylate, expressed in tenns of anhydrous 2. Buc hanan ltA . n al. The breast milk excn;tion of mcfcnamic ac-
magnesium salicylate, are about 300 to 600 mg every 4 hours for I . Koup JR. ttl ol. A single :ind muhiplt: do ~c phannaco kinctic and id. Cmr Ther Res 1968; 10: 592-6.
pain or fever. me1abolism sludy of mtclofenamatc sodium. Bint>honn D""g
Dispt>s 1990: II: 1- 15. Effects on the blood. References to haematological reactions
Preparations in patients taking mefenamic acid including haemolytic anae-
Uses and Administration
USP 33: M"gncsium Satiqilatc Ta.b!cts. Mcclofcnamic acid, an anthranilic acid derivative similar lo mia.1 teucopenia,2 neutropcnia,1 and agranulocytosis.'1
Proprietary Preparations (details a1~ gi\len in Volume B) mefcnamie acid (below), is an NSAID (p. I03). It is given orally I. Scou GL. "' nl. Autoimmune hacmolyti<: ilnnemia nnd mtfenam-
ic acid thcrnpy. BMJ 1968; 3: 534 ....s.
as the sodium salt in musculoskeletal and joint d isorders such as
~~n~~~~gt~~ac~~·5::'~a~~~~~~i~=t: osteoarthritis and riteumatoid arthritis, in mild m tnocleratl! pain.
2. Bums A. Young RE. Me(en~mic ;icid induced leucopenia in the
elderly. lonceJ 193~; ii: 46.
M"s<ulor S.c.lache FonnAa: MST: Novasalt Nupril Bact<ad>et. and in d ysmeno1Thoea and menorrhagla. 3. U<l1lda SI. Frctsto1tc S. M~rcnamic ai:Kf~induced nnnropcnia

~~~r~t~"~;.,<i~~1i~~.t:'.."s~ ~~ ~~;;'c~~f?~
1 Doses of meclofenamale sodium are expressed in tcnns of the and ren::il foi lwe in elderly fema les wilh hypothyroidism. f'oll•
equivalent arnount of meclofenamic acid. Meclofemunic acid srnd Moo J 1 9~0; (06: 557-9.
ESt: Durob<lc fone: Extra Svoogth Doan$ PM: Mobigesr.t: P•ln•id 81\F 4. Murai K. et Pl. Trea1inent of drug-ioduced agranulocytosis with
S.d: 11£1ic! Fo.-m.Aa: Tetra.f";ag. I 00 mg is equivalent to abou1 113 .S mg of mcclofenamate sodi- ;;ranulocytc:•co:cu1y Slimulacing foct (lr. Lancet 1989; ii: 55.
um. In arthritic conditions it is given in doses equivalent to 200
to 4-00 mg daily; daily doses are usually given in 3 or 4 d ivided Effects on the gastrointestinal tract. Reversible steatar-
doses. For rcliefofmild to moderate pain doses are 50to JOO mg rhoea has occurred 1 with mefenamic a<;jd; it may also provoke
Meclofenamic Acid (8J\N. U'..i'.N. rlNNJ every 4 to 6 hours; the daily dose should not exceed 400 mg. The colitis in patients without a history of this condition.1
dose in tbe treatment of d)'l'menorrhoea and menorrhagia i-' l. M:irks J S, Gleesoo M H. Stc:a1orrhoca coinplicaling lherapy with
Acide Med ofenamique; · Acido meclofenamico; Acidum 1ncfcnamic acid. OMJ 1975: 4: 442.
I 00 mg three limes daily for up to 6 days during menstnmtion.
MeclofeNmi<:vm; 0-583; INF-1668. N·(2,6-Didlloro·m· 2. Ravi S, rt ul. Colitis causod by non-01<roidal ami-infl•mmAlory
1o~·l)an1hranilic acid. Meciofc.namicacid has been given as a rectal supposito1)' and is druss. Posigrad M•d J 1986: 62: 773-6.
also used in vecerinary medicine.
MeK11.0<f>eHaM0Ba.R KHCAOTa Effects on the kidneys. Nonoliguric renal failure has occurred
Preparations in elderly parienls who had had diarrhoea and vomiting while
C,.H 11 Cl2N02 = 296.i .
USP 33: Meclofenamate Sodium Cops.Jc!. laking mefenamic acid and had contioued to take the drug. It is
CAS - 644-6}.-l.
nonnally recommended that mefcnamic aci<l be stopped in the
ATC - MOIAG04: M0 2AAl8. Proprietary Preparations (details are given in Volume B)
event of d ianh<l<!a and it was suggested that in these patients the
ATC Vet- QMOIA(;04; Q.M02AAl8. Cftile: MedOfOen: Gr.: Medome"" ltol.: l eM:k>lor: Mo.....ens.
gastrointestinal toxicity had led to fl uid and electrolyte depletion,
UNll - 4815W4ZWD. thus predisposing these patients to mefenamic acid's ncphrotox·
The symbol t denotes a prcpara1ion no longer actively 01arkeled
 84 Analgesics Anti-inflammatory D rugs and Antipyret ics
icicy.' There has been a subsequent report=of nonoliguric renal longer than 7 days unless they are receiving mefenamic acid for prescription evenr monitoring study has also analysed events re-
failure in elderl)• palienlS given mefenamic acid for musculoskel- Still's disease. However, the BNPC 1009 only recommends poncd with meloxicam use.' In a cohort ofl9 087 patienlS who
e1al pain. mcfcnamic acid for acute pain. including dysmenorrhoea and had recehred meloxicam some time between December 1-996
I. Taha A, "''''· Non-oliguric r~naJ f:Ulurc durlni 1rc211mc-n1 with menorrhagia, in those aged 12 yeais and over who m"y be given and March 1997. 203 patients had had 252 events considered to
mtfenamic .itid in eld-:rly patients: ~ continuing probkm. BMJ !he usual aduh dose (sec above). be suspected adverse reactions. The majority of n:adions were
198S: 291: 661-2. not serious or were labelled adverse effeclS of meloxicam. Rare,
2. G rant OJ, MacConnachic .'\M . Mcfcnamic acid is more d;.ngc-1- Preparations serious suspected adverse reactions included 2 reports oflhrom·
o us 1han m0$1. BMJ 1995: 311 : 392. BP 20 I 0: Melenam<; Ac<! C.psuies: Melenam;c Aod Table:s. bocytopcnia and I each ofi nteistitial nephrilis and idiosyncratic
Effects on the sl<in. Bullous p:mphigoid, 1ogether \vith USP 33: M¢1e,,..,.,;c Add Uils•4'?s. liver abnonnality. The most frequent gastrcintcstinal event was
haemolytic anaemia and dian·hoea, 1 and fixed drug cruplions!...,. Proprietary Preparations (de1ails are g iven in Volume B) dyspepsia; other more serious gastrointestinal events occurring
have been associated "ith the use of mefenamic acid. Addition- Arg.: Ponstil; Austral.: Mertct : Poostan: Aus-trio: Polrkemed: Broz.: during meloxicam exposure included upper gastrointestinal
ally, Stevens-Johnson syndrome. together with choleslatic hepa· f'onsdril: Ponsun: Chile: A<lesna: l>Jgex: Al&<femin: Oclc;nt. Fl.pat Sotadol: bleeding (33 reports) and peptic ulcer (19 reports). However, it
TdnSton: Templadol: fin.: Pcnstan: F'" fbns:yl: Ger.: P,.-l<emedt. PONlaJi;
tilis and haemoly1ic onaemia, in one patient has been anributed Gr.: Acinic: Aidol: Algopress: CatrnO; Ocmo~un: Pado:Td; ~nt.a.: PonstN1; was considered that !he incidence of gastrointeslinal disturbance
to mefenamic acid.s It is generally recommended lhal mcfcnam· Vodan; Hong Kong: Gynogesic Halritanf: Hornnt. Med<ap: Mef•j: Mo- was low in the abs!:ncc of g-•slrointcstinal risk factors. Adverse
ic acid should be withdrawn if skin reaciions develop. famict. MeCeo: Mefenac: Mefencid, Mefic: Metsyn: Nam;c; Na.pan:: P.iMox; drog reactions reported during the first year of marketing of mel·
I. Shepherd AN. ('I ul. Mefem'lmic ac i ~- int.luced bullous pemphi~­
Pekasot. fbngcsic: Pons;s; Ponstan: Pontacidt: Seinlic Uni-Fenan"tc: Hung.: oxicam to the Swedish Medical Products Agency suggested a
o;d. PvSlg rod M ed J t986: 62: 67-8. fbnmel: Indio: Dysmen 500. Ponrun lndon.: Anac's;>ec Asom; As""'t similar safety profile 10 other NSAJDs.1 Of the 15 reports, 6 were
Benostatx Ccta1mC. Corstanal: Datan: Dogesic: Dolfcna t, Oolos: D»stant.
2. Wilson CL Oner A. Fixed drug eruption associated with Femisic Fensllc Gi'Oa.--omirt Upisun: Lk.ostan: Meaa."'lt: Meiast: Me:Ena:t ~­ for gastrointestinal distwbances and 5 invoh•ed skin reactions.
me:fenamic ::icid. BMJ 1986; 293: 1243. f1n1er: Mcflx: Mer. n: Molasic: N ichonan: Opist~: Pehastan; Por.aJar: Pon· I. CS}>.i/MCA. Meloxicam (Mobic): gastrointestinal and skin reac-
3. Lone CC. el nl. Fi:'\ed drug eruption to mefenamie acid: a repon cof~ Pon6ex: Ponsa.m:C Pons1an: Ponstclax; St.ana!in; S.unzat: Stelpoot. tions . Citrrtm hob/ems 1998; 24: 13.
of three cases. Br J Dernm:ol 199 :? ~ 126: 409-1 1. "feam1c: Topgesic Tropistan: lrl.: ,......elite: Pcnalgi:; Pon..-n<.-1: Pomtarr. Ital.:
4. R.sllis E. · Dalmatian dog'- like skin emp1ion (lwocases of muhi- l ysalgo; Malaysia: Bearem;c: Meroc: Nan-«; Napan: fbn<ttn: f\ontalon: Sc· 2 . Martin RM, e/ al. T11c incidence of adverse. cvenls and risk foe-
roeOJI fixed drug eruption induced l>)• mcfcnamic ~cid) . J Eur fmic Mex.: Artriden: Na"Tlilen: Fbostiln: NZ: R:inst.v\: Philipp.: Acidan; 1ors (or upper gastroin1estinal disorders associated wi1h mc:loxi-
..4cad Dtrmt110/ Vuuereol 2005; 19: 75.l-S. Al igec; Algifort: Analcid; Ana!min: Af>roS'l.31t. Ar.Jiran: At.more: Se1(00ane; cam use among.st 19 087 patients in general practice in Eng.land:
Calibt~t; Oolfena!: Oolmetinet: Dohten: Es.c.~rf': Eurostan; Finox: c ohort study. Br JC/in Phormacol 2000; 50: 35-42.
5. Ch;m JCN, ~' nl. A ('a$e Qf S1ei.:tn$-John,$On syndrome, ehQles-
laatic hc:p11.titis and hilemolytic anaernia associated with use of r,omcfen: G.ro.n: Gisien; H'•pe<>< lnflasoc lsagesoc: lmn: Kr•mor< uli't<t 3. Anonymous. Mcloxicam safety similat to other NSAIDs. WHO·
met'Cnamic acid. Dmg Safe!')• 1991; 230-4. '= Ma1fen: Mecid A;, Medianon: 1'1.efart 1"'1efenax Mefril: Met.aflam; MFE: Ne·
ostan; Penomor. Ponscr; Ponstan; Pont~ser: Ra:ge<: Remi<etn; Revalan;
D111g lnfor11101ion 1998; I:?: 147.
Overdosage. Mcfenamic acid overdose has been associated Sclmac: SenO;wnt. Spegic: Stangcsic: ~ Totag<!'k: Tyn0<1an; Vamge· Effects on the gastrointestinal tract. ii is generally accept·
with CNS toxicity, especially with convulsions.' Coma'~ has sic.f: Vandifen; Zanovic: ZapAnc Zestan: Pol.: Mefacit Port.: Poostan: ed 1ha1 inhibilion of cyclo-oxygenase- J (COX· I) plays a role in
also been reported. ~~~~:;i~~~~=~~~nf;~1:!f:~e~!~~;:? the adverse gastrointestinal effects ofNSAIDs, and that selective
J. Court H, Vola ns GN. Poisoning after o'·erdosc with non-s1croi- basant: Mefeoacide; Mefenamin: Mefenamin.acid: Melu1t; Mephadolor; inhibition of the other isofonn, COX-2, by NSAIDs such os
dol anli-infla mm:iroty dtugs. Adw:rse Drug Reoc1Acu1e Poison• Ponstln: Spitolg;ne; Thai.: Amgan; Anagic C'*f. Conam<: o;smen; Dol(en; meloxicam may cause less gastrotoxic.ity th3n that seen with the
ing Re v 1984; 3: l-21. Dol!'cinalt: fastar.; f emer.: Femic: Fenam~ Fennic G cindin: Gynoge sic: noo•selec1ive inhibi1ion oftrnditional NSAIDs. However, there
2. Gi'is.<jnger H. e1 al. Coma in mcfen<lmic ttcid poisoning. L<mce1 loq>~irt Manic MJromic; M<l.Saf.!fl l1L-dtarc Mednil : Mefa: Mefa.'Tled: r"1e·
famic: Mefen; Melenac: Mefenan: Mefnasic: MCNWric.: Nalgcsin; N.amic: has been linle convincing evidence that the risk of severe gas-
1982; ii: 384. trointestinal events is lower with meloxicam than wilh otl1cr
3. Hcndricksc MT. Mcfciuimic acid overdose mimicking brainstcm Nt..tfemic: Pacamic Painnox Panamic: Pefamir. Pon:tt.tp: Pondr"'dysmm
stroke. /,.an«e/ 1988; ii: 101 9. Por.gesic;s: Ponnesia; Ponstar:,; PontalQni Pt-onamic Prcman: P1f"r..i:rk: Se<rric: NSAIDs at equi-cffective doses. ' Two large muhicentre
~st.tnt Turi<: Poomn: Roladol; Rola.- . UK: Ponstar, USA: Pon<tet Ven· studics2; have reported a lower incidence of gastrointestina l ad-
Pancreat itis. A report of pancreatitis assoc iated wilh ex.: fbnstan. verse effects with meloxicam rhan with ron-selec1ive cyclo-
mefenamic acid., · Mutti ..ingrediant: India: Cydomeff: Oysmen; ~men Forte: Meft~I oxygenase inhibitors (diclofeoac2 or piroxi::am') bu! in one of
1. van Waltavcn AA, el al. P:merc:itilis caused by mcfcnamic 3cjd. forte: Spa.smonil forte: Spasrnonil Plus: Tnnfib MF: Ze-Spa~ Thai.: A rr these' the dose of meloxicam give.n also appeared to be less ef-
Cnn Med Assoc) 1982; 126: 894. puz.z: [);femk: MaimCO<: Ukr.: Mep.'>enillum (Me¢E>.ar)t. No-Spasmo (Ho-
Cm1Ma}. fective than the reference drug. A more recent systematic
Porphyria. Mcfe11amic acid is considered to be unsafe in pa- rcvicv.-A also found a lower risk ofseriow gastrointestinal loxic-
rients wilh porphyria although there is conllicting experimental ity with melox icam 7.5 mg daily when compared with d i·
cvidenoe ofporphyrinogenicity. clofcnac (100 or 150 mg daily). naproxe.n (SOO mg twice daily).
Meloxicam (BAN. us.~N. rlNN) or piroxicam (20 mg daily); however, when given al a <lose of
Melol<s;J.aamr. Meloksikam; Meloxicam: Me!oxicamum: Me~ 15 mg daily, lhe risk of toxicity wilh meloxicam was sii,'llificant·
Interactions ly lower only when CQmpared with piroxicam.
For interactions associated with NSAIDs, see p.103. oxikam; UH-AC-62: UH-AC-62XX. 4-Hydroxy-2-methyl·N·(S-
meth)'f·2·thiazoly1)·2H- I.2-benzothiazine-3-carboxamide I.I ·di· Individual case rcpo11s of gaslrointestinal toxicity with meloxi-
oxide. cam included one of ischaemic colitis associated wilh high-dose
Pharmacokinetics (l 5 mg daily) meloxicam lrcatment.5
MeAoKc~t<aM
. Mefenamic acid is absorbed !Tom the gastrointestinal I. Anonymous. Mcloxicam-a safer NSAJD? Drug Ther Bull
C 11 H 1JNJO,S 2 = 351.4.
1ract. Peak plasma concentrations occur about 2 lo 4 CAS - 71 I 25-38-7.
1998: 36: 62-4.
hours after ingestion. TI1e plasma elimination half-life 2. Hawkey C. er of, Gastrointcstin31 tolerabili1yof meloxicatn tom-
ATC - M OIAC06. p11ted to diclofenac in ostcoanhritis pa1icnts. Br J Rheuma1ol
is reported to be aboul 2 10 4 hours. Mefenamic acid is ATC Ver - QMOJAC06. 1998; 37: 937-45.
more 1han 90% bound to plasma proteins. It is distrib- UNll - VG2QF83CGL. 3. Dequeket J, et of. lmprovemen1 in gas1rointc::n in;1l 1olcr.1bility of
uted into breast milk. Mefenamic acid is metabolised the sclc-ctivc cycloo xygenase (C0X)·2 inhibitor, mcloxic<lm,
comp:ircd with piroxicam: results of 1he 5afcty and efficacy
by the cytochrome P450 isoenzyme.. CY P2C9 to 3-hy- large..scale evaluation of COX·inhibiting tbc:rapies (SELECT)
droxymethyl mefenamic acid, which may then be oxi- trial in ~h::oarthr it is. Dr J Rl1tumatol J998~ 37: 946-5 1.
dised to 3-carboxymefenamic acid. Over 50% of a 4. Singh G. e1 al. Risk of serious upper g3stroin1es1inal and cardio-
vasc.ul11r thrombocinb<>lic complications witll mcloxit:s.m. Am J
dose may be recovered in the urine, as unchanged drug Mcd2004; 117: 100-106.
or, mainly, as conjugates ofmefenamic acid and its me- S. Garcia B. ct of. Jschacmic coli1is i n i paticJlt laking mcloxicam.
tabolites. Lancet 200 I; 357: 690.
Precautions
Uses and Administration As for NSAIOs in general, p.1 02.
Mefenamic acid, an anthranilic acid derivative, is an Phar macopoeias. Jn Chin., Ew: (seep.vii), and US. Mclox..icam should be a\'oided in severe hepatic impainnent.. in
NSAID (p. 103), although its anti-inflammatory prop- Ph. Eur. 6.8 (Me!oxicam). A pale yellow powder. It exhibits pol· bleeding disorders, and in pa1ients with rcr..1 failure unless re-
ymorphism. Practically insoluble in water; very slightly soluble ceiving dialysis. Rectal use should be avoid:d in patients with a
erties are considered to be minor. history of proctitis, haemorrhoids, or reclal bleeding.
in alcohol; soluble in dimelhylfonnainide. Protect from light A
ll is used in mild lo modernte pain including headache, pale yellow powder. Practically insoluble in water; very slightly Renal impairment. llie phannacokinctic~ of mcloxieam were
dental pain, postoperative and postpartum pain, and soluble in alcohol and in methyl alcohol; slightly soluble in ace· not substantially altered in patients \.Vith a creatiniue clearance
dysmenorrhoca, in musculoskeletai and joint disorders tone; soluble in dimelhylformamidc. (CC) of 41 lo 60 mUminutc compared with those wi1h nonnal
such as osteoarthritis and rheumatoid arthritis, and in USP 33 (Mcloxicam). A pale yellow powder. Praclically insolu· renal function.' In those with a CC of20 to40 mlJminute, total
ble in water; very slightly soluble in alcohol an<l in methyl alco- plasma-mcloxicam com..-ent.rations were Jower but mcloxicam
menorrhagia. hol; slightly soluble in acetone; soluble in dimelhylfonnami<le. free fraclions were higher. Such free mcloxicam conccnb"ations
In the UK, the usual oral dose is 500 mg three times Adverse Effects and Treatment were similar 10 the other groups. On the basis of these results, it
daily. US licensed product infonnation recommends As for NSAIDs in general, p. I 00. was suggested that ii was not necessary to reduce IJlCIOx icam
an initial dose of 500 mg followed by 250 mg every 6 doses in patients with a CC grealer lhan 20 mUminute.
Incidence of adverse effects. B<:tween Sep1ember 1996,
hours as needed. In addition, in the USA, when when meloxicam was first marketed in the UK, and mid-June I. Boulton-Jones JM, et ol. Melo:c:ic:am pharm1cokintlics i n ren31
impairment. Br J Clin Pharmocol 1997: 43: 35-40.
mefcnamic acid is used in the treatment of mild to 1998 the UK CSM had received a tolal of 773 repons of J339
moderate pain in adults and adolescents aged 14 years suspected adverse reactions for meloxican1. 1 Of all !he reactions Interactions
and over, it is also recommended that it should not be 41% were gastrointestinal and of these 18% involved g;ostroin- for interactions 3ssociated with NSAIDs, seep. I 03.
tes1inal perforation, ulceration and/or bleeding; the mean age of
given for longer than 7 days at a time. the parienlS involved was 64 years. Although most patienls re-
Colestyramine increases the clear.ince and decreases the half-life
For doses ofmefcnamic acid ir. children, see below. of meloxicam.
covered after willidrawal of meloxicam and/or treatmenr_ 5 died.
Mefenemate sodium has also been used. A total of 193 reacrions involved the skin, the most common be· Pharmacokinetics
ing pruritus, rash, and urticaria. There were also reports of an- Meloxicam is well absorbed after oral or recbl doses and peak
Administration in children. Jn the UK, licensed product in- gjoedema (2S). photosensitivity (12), and bullous dcnnatoscs, plasma concentralions occur within 6 hours. It is 99'% bound lo
formation states that mefenamic acid may be used in children for including erythema multifonne and Slcveiis-Johnson syndrome plasma proteins. Meloxicam has a plasma-elimination half-life
the treatment ofStill's disease (see .Juvenile Idiopathic Arthritis, (S). No patients died from skin reactions and most recovered af- of about 20 hours. h is extensively metabolised, mainly by oxi·
p.11) and lever. and fordysmenorrhoea in older children; a sug- ter mcloxicam was withdra\\11. Otber frequently reported reac- dation lo its major metabolite, 5'-carboxymeloxicam. In vilr o
gested oral dose in those over 6 months of age is 2S mg/kg daily tions were neurological (mostly headache). cardiovascular studies suggesl Iha! the C)1ochrome P450 isoenzyme CYP2C9
in divided doses. Treatment in chilaen should be given for no (oedema and palpitations), di22iness, Oushing, and fa1igue. A plays an important role in the metabolism of meloxic-.am with

All cross-references refer 10 entries in Volume A

 Meloxicam/Meptazinol Hydrochloride 85
CYP3A4 involved10 a lesserdegre.e. Meloxic.am. in the fonn of Sil.ion: Tcnaioo: Zixt ; Cz.: A nt.r·cnc:t h1!':1cn~ Du~ic:.ctm;: Enaros: Galoxr- ing. Meptazinol is claimed to have a low incidence of
mclnbolites. is excreted in similat amounts in the urine and in the
faei.:.es~ less than So/o of a dose is excreted unchanged. The vof-
';:r~~~~ri~~l:~~~~.::~n~~~~:~:.~: =~;NG~;
Mdox: Nobe-::: Gr.: Arsttl'(: Ar lliit«. A1Jzy,ci(;;;n: &-o.s.ira!: Docti:ion: &.-am·
respirato1y depression; nonetheless, UK licensed prod-
uct infonnation states that it should not be used in pa-
ume of distribution is i11creased in renal failure. d; f31-mclox: Fido>:: Fiumidon: 1attoaxicam: latc.n: lconat ln!OCT1el; Loxitan:
Mecabx: l"'ttdo.«am; Melice: Mt?k>c.alm: Meloc'".; Melocox Metod1m: t.,..r.::. tients with acute respiratory depression. There have
(• References. oprot, Metorem; Me:Orilit: Melote<; Mek>t~ Mo!o><: Meloxeron; Meloxil:
I. Narjts H. e111/. Pha1macokinetics and 1oler.1bili1y of meloxi::oam
been occasional repo11s of psychiatric disorders such as
Mclcxit.O:"; Mei:,,s; Meomel: Movatec. M:ro.•axin: Moxalid; Notpel: Parrial:
:tf!cr i.n. administration. Br J Ctin Plumiwro/ 1996~41 : l 35-9. F!~pof\.S; Re-:tilox; Rei;molet: Rc~theon Sa~rrorc Sar,iflairt S131'1'nC:!· hallucinations, confusion, and depression. As meptazi-
, Tilr<:k 0. et ;1/, Cl i ni c~l pharmacokineties or mcloxicam. Ar;11e- ox: Supercad: Tl'ar-santor: Tro,x*f\'. Va.toxi:"'( V~m. Zametrixat Zereli:i: nol has both antagonist and agonist prope11ies its ef-
imi1tcdjor:u :lumg 1997; 47: 253-S. Hong Kong: AnlJX': Melcam: Melfbin: ~ .,..){: Mo!>ic: Hung. ~ Bett:Jjn:
·'· Oavje-s NM, Skjod1 NM. Clinical phOlnn.acokinetics of mcloxi- Umelox; Mdodyn: Melogen; M<!iox: Melo><••• f1Q.fa6~ l"lo>cicam: Nol'.a· fects may be only pattially reversed by naloxone, but
c:.im: a cyclooxygenasc-2 preferential no1LUcroidal anli-inOam- men: Indio: Md-OD. Mel~ Mefs1ari': Jndan.: Artrilox: Carr.<.ioc: Fl<lm· use of the latter is still recommended in overdosage.
ll\:ltory drug. Clin P/t(lrmocokinf!/ J9~~ 36: 11S-26. oxi: FIMic:<»<: L0><i!: Lox~nk: Mee~~ Mcloxn Mevilcx: Mexpharm: MobiRex:
4. Meinckt I. T6rc:k D. Population phannacokin~ic am11ysi:> or
MOVl-Cox: MOV"ix:: MO>Cl m: Mcx.ic: Nv!ox; Ostelo>e Rclox: Rem;,carn; Meptazinol has the potential to precipitate withdrawal
P.hen'v.CO')( Velcox: X-Cam;; ltl.: /.VC:IQ&er ~ Mekam: Mcbiic; Mobicam: Mo·
mclo:cicam in rhe:uina1oid arthritis patients. Br J C/;n Plwrmacol
bit«an; Mo-.io>': ltaf.: LM•'OI; M otic: Jpn: Mobic: Malaysia: Arrox; Mel· symptoms if given to patients who are physically de-
2003; !6: 32-8. . 00: Melartin. M~oc.am Melo>: Mct:ic Rafrt.-e; Mex..· Atli!.mid; Anflatox1-; pendent on opioids.
5. 8urgos·Vnrg3s R••bt nl. Phsrmacokinc1ic5 of mcloxicam in ('ll'l· A~e: AuriCAnl; Coxylan: Oolo::~m : Exel: Rexiver: Flexot: lexpram:
tiems \\ilh juvenilc rl1cumatoid :inhritis. J Clln Ph(J1'nrot:ol 2004: Loxamt U:i~ch: LQ)(1best: Ma\1VVO: MaxoOam: Meflen: l"'lelirttw'yl: Meli· Abuse. See uodo:r Oepend<!llce and Withdrawal, above.
44 : 86~-72 . can: MeloS?.era!: Menltixjt Mobit.o>e P1\)me¢JOI'\ Reosan: Retollam; Neth.:
Ma.:.alis: Movie.ox; Norw.: Mcbic: NZ: Mobie; Philipp.: Be.xxam; Caxlm"t Effects on the respiratory system. Mepia;jnol is said 10
Renal impairment. For reforence to 1hc pharmacokinetics of Me1lam: M e!ar..: Mek"om: M~ofbrn: M~ Meloxin: MOOc: l"iox.ert Neox..· have a relatively low po1en1ial for respiratory depression and in
meloxicam in rena1·impainnent see under Prccautionsi above. iCKr< Ncwsicam; Rafree: Pol.: A~: Aspicao~: Lormed; Melcbax: Mdok-
sam; Melo!.tsiat: Me.lotev. Melo>t1c: l"lelo:xilek: Meloxi$tad: Movalis: Port.:
healthy subjects ""s reported 10 produce substanti:llly less respi-
Uses arid Administration Dortcx: Lador~ Marlex; Mc!por; l1ovalis: Ziloxi::ant: Rus.: Amclotex ratory depression than morphine or pentazocine at usual analge·
Mcloxicam, on oxicam derivative, is an NSAID (p. I03). It is re- (~Teo<c); ArVozan (Aprpo3!1H), lem (/'....,): Matao..n (Man ,>eH): Mel- sic doses.1 However, respiratory depression does occur in anaes-
ported 10 be a selective inhibitor ofcyclo-oxygenase-2 (COX-2). ollam {Me~M): Melo!t.an (MeM)Kiri)t: Mel0>< {MeA.Ol<c): Mesipoi thetised patients given meptazinol2 and the efl'Ccts on respiration
Meloxicam is used in the management of rheumatqid arthritis. (MecwnciA): 1.,;r;<»< (M"'P"CKC~ l"iov•lis (Mo..,..c): M<>-osir, (Mooocl<H}: may be similar to those of morphine-'" or pethidine."' Compen·
Ma.;ix {Mos11xc.}; S.Afr.: Arthrocox; ~ P.exocam; l oxillam: M-Cun;
fol' the sti.:irt·tcnn symptomatic treatment of aeule exacerbntions Mclllam: MOO>c Singoport: i".-e:CX: l'IOOic: Spain: Jo.llviodol: MWAll!; PA· s;itory mecha11i'i!P$ m~y come int9 ploy ofter repe;il\Xl do~ Qf
of osteoarthritis, and for the symptomatic treatment of nnkylos- rocin: Uticox: Swed.: Mobic; Swla..: MOOOC.ox:: Thai.: Mek.am: Mebbic: mcptazinol but 1he inh'3venous use of mepta1jnol during anaes-
ing spondylitis. It may also be used in the treatment ofjuvenile Melox: t-:.'Obic: Turk.: Exe:i: Mcksur.; ~ox. Melu1jin: Mes"-vn; Mabie: MO"'ie: thesia should be Yicwed with as much caution as wilh any ocher
idiopathic urthriti~... Romacox; Runomex; Ze:Oxi'n; UK: Mabie: Ukr.: Me-!bcc (1'1P.tfx.!K); M~Jok· opioid.6
sam {MellOt<C~M): Melox.ic (Mt:llOKCl-11<}; Reu:-r.oxicam (PeMOKCHt<aM):
In 1hc treumcnl of rheumatoid arthritis and ankylosing spondyli- USA: Mot»::: Venez.: ~lox; Ca1rnox-j': M&o:xt M~ona~ Melovax; Respiratory arre.<t occurred after an overdose of 5() nieptazinol
tis, melo>.icam is given in a usual oral do~ of IS mg daily as a Mobic: Mowint: Taur.amn. 200-mg 1able1s and a quarter ofa bottleofwhisky.7 Full recovcl)'
single dose. Those with an increased risk of adverse reactions Multi-ingredient Arg.: ~x Ae:y,; Flexidol Relax: Mcxtran Flex; Tcnar- eventually followed supportive measures ahhough spontaneous
should be s1a11ed on 7.5 mg daily. A dose of7.5 mg daily is rec- on Flex Indio: Melodct: Mtx.: Dokxilm PM.; Dolocattgen: Ootsat: Flex- r~spiration was not re..eslablishcd by naloxone intravenously to a
ommended for long-tenn treatnient in die elderly. In the 1rea1- ""°it: Nu,.o·S: Retollam f. cumulative total dose of I0 mg.
ment of acute exacerbations of osteoarthritis the usual oral daily 1. ,lordan C . ('' ul. A compnrison o f the r~ sp ir3tory effects of
dose of mcloxicam is 7.5 mg. increased if necessary to a !naxi· mcplazi1101, pC't1taz.od ne and morphine. 81· J A11nes1/1 J979; 51:
mum of 15 ms daily given as a single dose. 491-502.
For dosage details in children, sec below. Meptazinol Hydrochloride 2. Hnrdy PAJ. f\·1C:JH3';inol :rnd r~spir.uory depression. lo11ct1 1983;
ii: S76.
Meloxlcam may be given by rectal suppository in doses similar (BilNM. USAN. rlNNM) 3. Fr:l\C1' RAS. ct ¢/. An"lgcsio-induecd respiratory dtpn:ssion:
to those used or-•lly. comp:itisonof meptaz.inol ond morphine in the postopcra1ivc pc·
For 1hc dose of meloxicnni in putiems with renal impainnent, sec H drocbn..o de mepla2ino!; ll-228 11 (meptazinol): Meptaiino!, Tiod. Br J Anae:t/1 1989: 63: 260--5.
be.low. Chlomyd<ate de: Mepiazinoli Hydrochlo1idum: Wy-228 1 I 4. Vcrborgh C. C'nmu F. Post-·surJ_ical pain relief wi1h zero-order
(meptazinol). 3-(3-Ethyl- I-methyfpemydroazepi:.-3-yl)phenol inlr~vcnous inf.asions of' mepun;inol and morphine: a douhle ·
Administration in children. In the USA, meloxicam is used blind ph1ccbo·controllcd evaluation or their effects on vcntila-
hydrochloricie. 1ion. Eur JC/in PhtmnuC()/ 1990~ 38: 437~2 .
in the crcatmcnt ofjuvenile idiopa1hic arthritis in children 3ged
~ years and over. The recommended oral dose is Menl33io!H0 Nl f •ApoXAC>p4<A 5. Wilkin$01l DJ. c:I al. f\'lcptazinof-:i cnuse ofrespiratory dcp1es·
125 micrograms/kg once daily, up to a maximum of 7.5 mg dai· s ion in g.ener:il anaes1he.sia. Br J ...f1u1el·th 1985; 57: 1077-8~.
C 1;Hi;NO.HC! = 269.8.
ly. In the UK, licensed product infonnation slates ~lat mcloxicam 6. Lee A. Orumrruud GB. Vcn1ilatory cfitc1s of 1nept.a2inol t111d
CAS - 5 4340-58-8 (m eptozinol); 59263-76·2 (meptozi- p<:~hidine in :ir.acs1he1iscd patients. Br J Anoes1h 1987: 59:
should nor be used in children aged w1dcr 16 years. However, (he nol hydrochioride): 31154 .5 9. 1 (±>meptazi~ot hydrochlo- 1127-33.
BNFC 2f.09has suggested die following oral doses, according to ? . Davisoil AG,~, :JI. Mep1az.inol O\•erdosc 1)(oducing near fo1af rcs-
ride).
body-weight. for the relief of pain and inflammation in juvenile pir:nory depres.-<ion. Hum Toxic'Ol 1987; 6: 331.
idiopad1ic at11uilis and 01her musculoskeletal disorder.> in tliose ATC - N02AX 05.
aged 12 to 18 year.> who are inloferant ofother NS.'\ IDs: ATC Vet - QN02AX05.
Interactions
• less than 50 kg: 7.5 nig, once daily UNI/ - T62FQ1ZCPA. For interactions associated with opioid analgesics, see
• over 50 k~: 15 mg once d3ily
p.107.
Admini!tration in rena! impairment. Meloxicam is nor·
m.ally contra·indicated in patients '"i1h severe renal impainncnt
Plasma concemrations of meptazinol 111ay be increased
However in d ialysed patients. me1oxicam may be given fr> a by ritonavir and use together should be avoided (see
dose oi75 mg daily orally or rectally as supposito1ics. No dose also p. I 07}.
reduction is requil'ed in those wi1h mild to modernte l'enal impair·
ment (cn:atinine clearance of grca1er than 25 mllmin). Pharmacokinetics
Muscu!oskeletaJ and joint disorders. Meloxicam is used in After oral doses of meptazinol peak plasma concentra-
lhc 1rca1rncnt of os!coarthrilis (p.11), rheumatoid arthritis (p. J2) tions have occurred within 0.5 to 2 hours, but bioavail-
iucluding juvenile idiopathic arthritis (p. I I), and ankylosing (meptozinol)
spo11dylitis (see Spondyloa11hropathies. p.14). However, in lhc ability is low since it undergoes extensive first-pass
UK. th!:! use of meloxicam and other selective cyclo-oxyg.enase· melabolism. Systemic availability is improved after
2 (COX-~) inhibilors is limited 10 those patients wilh good cardi- Pharmacopoeias. In Bi: rectal doses. Peak plasma concentrations have oc-
ovascular he3hh and at high risk of developing serious gas1roi11- BP 20 I 0 (Meptazinol Hydrociiooide). A white or almost while
powder. Very soluble in water and iu methyl alcohol; freely sol- curred 30 minutes afier rectal or intramuscular use.
tes1inal problems if given a non-sdectivc NSAID (see p.101). Plas1na protein binding has averaged only about 27%.
uble in alcohol; vel)' slightly soluble in ac.e1one; dissolves in di-
References. Elim ination half: Jives of about 2 hours have been re-
lute solutions of 3fkali hydroxides. Store rit a temperahue not ex-
J, l~mmd ~M. <f al. EfliC3C)' and snfoty o f mcloxicnm in patienls
wi1h rheumatoid ~nhric is . J Rl1eJmuflol J99?; 24: 282-90.
ceeding 25°. ported. Meptazinol is extensively metabolised in the
1. Yocum 0. t!I nl. s~rcty and efficacy or
meloxic-am in 1he lrc3t- liver and is excreted mainly in the urine as the glucuro-
menl of osteo:mhritis: a 12-wcck, double-blind. multipk-d1,.1:-;e. Dependence and Withdrawal nide co1tjugate. Less than 10% of a dose has been re-
1>lacelxl-~ <mtrolled triat The Mclo~icam Os1col\nhri1is ln\'CSli·
antors.An-h lnfC"m M~d2000~ 160: :294i-54. As for Opioid Analgesics, p. I05. covered from the faeces. Meptazinol crosses tbe pla-
•1. Cl)mbc B. e1 al. Compari$Gn of iinramu~ular ;rnd oral rnitlo.xi- centa.
c3m in rheumatoid ur1hri1is pa1ien1s. lnjlnmm Res 2001~ 50 (sup-
0 Jn ass">'Sing the dependence potential of inepla:zinol, a WHO
pl II: 510-516. expert comminee1 noted in 198'J thal abrupt dimmtinualion of <> Referen.:es.
4. F'leist:hm:.lnll R. "' ol. Mdoxic:nn. £.\·J)f!rt Opin Plmrmocotlu:r chronic mep1azinol use precipilated only slig)1t wi01drawal signs
t . Frank Iin RA. eJ al. S1udics on the mc1abotisin of mcp.lazinol, a
2002; 3: ISOl-12. in animals and that meptaz.inol did not suppress opioid with· n(:w ;malgcsic (rug. Br J Clin Plwm1acol I9i6; 3: 497 .. 502.
Veterinary use. For 1he suggestion ~lat meloxicam shoul<l be drawal sigi1s and symptoms in humans dependent on morphine. 2. Fl'anklin RA, \'/ ed. Studi!s on 1hc abscirprioo and disp0sitlon of
1<<;ed a.< an altcmative 10 diclofcnac in canle in So111h Asia (to Abuse had 1101 beeu reported. They considered that the likelihood mcpHIZinol follo\\'ing. r<!clal udministr:.uion. Br J Clin Pl:armocol
reduce toxicity to vultures who may consume their carcasses)~ of abuse was moderate and that intemalional conlrol was not 1977; 4: 163-7.
see under Precau1io11s of Diclofenac, p.47 warranled at that time. }, l):l\'ies (.i. et n/. l'h:lnnacokinctics o r mt:ptatillOI in nl:lO follow·
I. WHO. WHO ex.pen comminec on drug dependence: 1wentr· ing repealed inlr\lmust:ular adminislf~tion . f ur J C/in Pharmo·
Preparations : fifth re-port. WHO T1:t:h Rep St'r 775 1989. Also available at: ml 1982: 23: 535-8.
hup:f/libdoc.wf10. im/rrsl\VHO. TRS_775.pdf coccessed 26i0&08J ~ . Norbury HM. i•t al. Pharm::icokinelics of the new ;~na l g~i(!,
BP 2010: Meloxicam Tab'ets:
USP 31, ~~IO>OCvn 0"<11 ~nsion: Me~o.,ca1n Tablets. mc:pt:l2inol. nftu oral ;&f'l4' inu-;p,;~n9u$ :ic;lministr:11ion to volun-
1ects. Eur J Cliu Plwmut<.'(1/ 1 983~ 25: 71-80.
Proprietary Prepvations (decails are given in Volume B) Adverse Effects, Treatment, and Precau- S. Murray GR. e1 cl. The sys1einic :t"Vailabili!y ufmc!'p1azinoS in man
Arg.: Sronax: Domioa001: f ie>cidol: C!eX'lun"I; l ox:itenk Me:.orac: Melo)O(lf:
M~rapira:n t: Mextra.,: M -o~llt: M1-olo:x: Mabie: Te'at'oidt Tenaron: Aus·
tions after oral nnd rectal dos1:s. Eu r J Cliu PJwrmocol 19S9; 36:
279-82.
trot.: Mobc: Mova!is: Mox:i::am: Austria: Mc!odynt. Meloxistadf': MetOS¥1: As for Opioid Analgesics in general, p. I 06.
Movaas: Belg.: Docmebxi: Mobic:: Braz..: Al'Maflf: Arl.ri!etj: Biofl3c: Dia. The elderly. A lower clearance and longer elimination half-life
tect: DonT1tlox; Flamatec; l~ox: Le~ tonaflamf: Loxa.'Yl: LOY.iflan: Me- Gastrointestinal adverse effects are commonly report- have been reported for mep1azi11ol in elderly patients, but dosage
bc.o1<t: l""'1it!onan'f: Mek>NXt: Melote:c: Meloxig.i-an: Meloxi1: Mev.vnox: Mo- ed with mepfazinol and include abdominal pain, con-
vKoxf: C"b.r.itec: MCIJOXJC.am: Canad.: Mabie.ox: Chile: Anposel: Ecax: reduclion was not considered wammccd on phannacokinetic
Hyflex: ISO< Meic: Melodot M: xarr Mexilal: Mibloc FT: Mjonam: Mobex:: stipation, dyspepsia, diarrhoea, and nausea and vom it- grounds. Mean ha11:1ivcs in elderly and young subjects were
The symbol j denotes a preparation no longer actively m:lrketed
86
3.39 and 1.94 hours, respectively after single oral doses 1 and 2.93 Methadone causes pain at injection sites; subcutaneous
and 2.06 hours, respectively after in11'3venous doses.' injection causes local tissue irritation and induration.
I. Norbury HM. et ol. Phannacokinctjes of mcptazinol aRcr singJc
and muhiple oral adminislration to elderly patients. Eur J Clin Effects on the cardiovascular system. Methadone prolongs
Amidine Hydrochloride: Amido.oe Hrdrochloride: Hidroclonxo
Plrormocol 1984; 17: 223-6. the QT interval and has rarely been associated with torsade de
2. Murray GR.. et al. Pharmacokinetics of meptuinol aft.er de amidina: Hidroclorvro de metadona: Metadon Hidroldorur: pointes. In a retrospective case series, 1 17 patients on high-dose
paremeral administration in lhc cld::rly. Eur J Clin Phormaco/ Metadon·hidroklaid; Ketadonhydroklorid: Metadonihydroklori- methadone (mean daily dose of 397 mg) deV.loped torsadc de
1987;31: 733-a. di: Metadono hidrochloridas: Metadonu chlorowodorek: Metha- pointes; of these, 14 had potential risk factors for arrhythmia and
H epatic impairment. Oral bioo,·ailability of mepiazinol ap- don hydrochlorid: Methadone. chlorhydrate de: (±)-Methadone 6 had had their dose increase<! within the last month. In another
pcare<l to be enhanced in patients witl1 liver disease. After a sin- Hydrochlo<ide: Methadoni hydrocliloridum: Phenadone. (±)-6- study2 torsade de poinles developed in 5 patients laking metha-
gle oral dose of mcptazinol mean peak plasma concentrations Dimethylamioo-4.4-diphenylheptan· 3-one hydrochloride. done (mean daily dose 268 mg); however, they all had other con·
were 184 nanogramsfmL. 131 nanogramsfmL, and r
MeT3AOHa V.AP0XAOP"A
tributing risk factors. Other studies'-• did not find instances of
53 nanogramslmL in cirrholic pationts, patienls with non-cir- rorsade de pointes and the increase in QT int:rval was considered
C2,H21NO.HCI = 345.9. clinically insignificant; in one study;~ the mean daily dose of
rhotic liver disease, and palienlS wi1h normal liver function, re-
spectively, although there was no evidence of accumulation after
CAS - 76-99-3 (methadone); 297-88-1 (.:i:methodone): methadone was l ro mg and some patients also had risk faclors
chronic dosing. ' There were no significant differences in plasma I 095-90-5 (methadone hydrochloride): I 25-56-4 (±meth- for arrhythmia
clearance after an intravenous dose. Reduced oral doses of adone hydrochloride). For a repon of QT interval prolongotion in an in fan I born to a
meprazinol might be advisable in cirrhotic patients. ATC - N07BC02. mother on maintenance methadone therapy fo r op ioid addiction,
1. Birnie GQ c1 o/. Enhanced or31 bio11vailobili1y of mcptnzinol in ATC Ver - QN07BC02. see Pregnancy, below.
cirrhosis. C111 1987; 28: 248-$4. UNJI - 2298099358. In a small case-controlled study of sudden cardiac dealhs,' the
Pregnancy. In women given an intramuscular injection of'l 00 prevalence of underlying cardiac disease or structural aboonnal-
to 150 mg during labour, meptazinol was found 10 cross the pla- ities was lower in the 22 cases with evidence ofthe.rctpeutic meth-
centa readily bu! was rapidly eliminated from the neonate.' This adone levels when compared with the I 06 cases without evi-
dence Of !Jlet!Ji!QO!le U~. TJie ~ulh9r~ CQll!;igered that the low
contrasted with pelhidine which was known to be excrc1ed l'cry
slowly from neonates. As in the adu'.t, elimination ofmeptaz.inol prevalence of cardiac risk factors in the methadone group sug-
by the neonate appeared to take place mainly by conjugalion gested a role for methadone itself in the pathogenesis of sudden
with glucuronic acid.2 A half-life of3.4 bours, similar to that in death in this group.
aduils, has been reported in the neonate,! in conlr.iSI to '22.7 hours I. Krantz MJ. et of. Torsade de poinles. associtted with vcry.Jiigh-
dose methadone. Ann Intern .Med2002~ 131·: 501,.......
for pethidine in neonates.
2. Sric.herling C, et al. Me1hadonc-induccd lorsadc de ;>ointes 1ach-
Disposition ofmeptazinol appears not 10 be sigi1ilicantly affecte<l y<:ordias. Swiss Mc4 Wkly 2005; 135: 282-S.
by pregnancy. Mean half-lives of 1.36 and 1.68 hows were re- 3 . Martell BA. el al. 'The imp<1.cl of me\hadone induction on cardiac
ported in pregnant and non-pregnant women, respectively,' com- conduction in opiate users. A11n Intern Med2003; 139: 154-S.
pared witl1 2.06 hows in men. (methadone) 4 , Cruciani R..o\, e1 al. Measurement of QTc i'l patients recch•ing
chronic melhDdone therapy. J Pain Symp10111 Mtmoge 2005; 29:
I. Franklin RA. v ol. Preliminary st1.1dies on 1he disposilton of 385-91.
mcp1azinol in the neonate. Br J CUn Pharmacol 198 1; 12: Street names. The following terms bave been used as 'street 5. C hugh SS, e1 al. A communiry.based cvaJuidon ofsudden dca1h
88-90. associated wi1h 1herapcutic levels of mcfoadone. Am J Med
names' (see P-'~) or slang names for various forrns ofmctha·
2. DowcJI PS. ti of. Routes of mept.:uinol conjugation in the ne- done: 2008; 12 1: 66-7 1.
onate. Dr J Clin Phormato/ 1982; 14: 748-9.
Amidone; Balloons: Breeze; Burdock; Buzz bomb; Dollies; Effects on the endocrine system. Hypoadrenalism has been
3. Jackson MBA. Robson PJ. Prelimimry clinical and pharmacok· Dolls; Done; Doses; Fizzics; Juice; Jungle juice; Junk; Meta;
inetic experiences in th1: newbom w~c:n mepu1zinol i£ compared found in chronic methadone addicts. f incings consistent with
with pelhidinc as 3n obstetric an3lgesic. Pru1grod Med J 19Sl;
Mud; Phy; Phyamps; Tootsie roll. deficient ACTH production and subsequent secondary bypoad-
59 (suppl I): 47-51 . P harmaco poeias. In Chin.. Eur. (sec p.vii), and US. renalism have been reported 1 although1herc is also e\·idcncc2 of
4. Murray GR. ti of. The disposition of mcptazinol after sing.le and P h. Eur. 6.8 (Methadone Hydrcx:hloiide). A while or almost methadone-induced primary adrenal cortiC<!I hypofunction.
multipS( intr:>venous adminisuatjon to pregnant and non·preg~ white, cryslalline powder. Soluble in water; freely soluble in al- Hyperprolactinaemia and galactorrhoea have also been report-
n41nt women. Eur J Cliu Pho,.macof 1989: 36: 273-7.
cohol. Protect from light. ed.l See also Effects on Sexual Fuoction. below.
USP 33 (Methadone Hydrochloride). Odourless colourless l . Dack.is CA, ti of. Methadone induced hypo.adrcnalism. Umcl!f
Uses and Administration cryslals or while crysralline powder. Soluble in water; freely sol- 1982; ii: t 167.
Mcptazinol is a mixed opioid agonist and antagonist uble in alcohol and in chloroform; prac1ically insoluble in ether 2. Pullan PT, f'f ol. Methadonc·induccd hypciadrenalistn. L.:1nce1
and in glycerol. pH ofa 1% solulion in water is between 4.5 and 1983: i: 714.
with partial opioid agonist activity at the µ 1 opioid re- 3. Bennett J. Whale R . Gabc1orrhoca may b( a~sociated '"''ith mc\h.
6.5. Store in airtight containers al a remperarure of 25°, excur·
ceptor (see p. l 08); it also has cholinergic activity. sions pellllilted between 15° and 30°. Protect from light.
•done use. BMJ 2006; 332: I07 I.
Mcptazinol is µsed in the treatment of moderate lo se- Effects on the nervo us syste m . Chojeic movements oc-
vere pain. It has a shorter duralion of action than mor- Incompatibility. TI1ere appears to be adequate evidence thal curred in a 25-year-old man on long-tenn methadone mainte-
stable solutions containing methadone hydrochloride and hy- nance lreatment of 45 to 60 mg daily for diamorphine addiction.1
phine. droxybenzoate esrers can be fonnulated bur the risk of precipita- Similar adverse effects were seen in a 4 !-year-old woman taking
Mcptazinol hydrochloride is given orally or by intra- tion exiSls if syrup preserved wi1h hydroxybenzoa1es is used to 5 mg methadone four times daily for compl!X regional pain syn-
muscular or intravenous injection; doses are expressed extemporaneously prepare a methadone mixrure 1 mgfmL to the drome.2 In both cases, symp1oms resol"ed when methadone was
DTF forrnula. 1 An oral fonnulation ofmethadone hydrochloride
in terms of the base. Mep lazinol hydrochloride S mglmL containing methyl hydroxyber120ate 0.1 % as prcserva·
stopped.
115.6 mg is equivalent to about I00 mg of meptazinol. I. Wasserman S. Yahr MD. Oloteic movements induced by the U $(
live rather 01an chloroform has been reported stable for at least 4 or methadone. Art:h Neural 1980; 37: 727-8.
For the short-tenn treatment of moderate pain meptazi- months at room temperarure.2 2. Clark JD. EIHou J. A c:asc of a methadon(·illductd mov(mcot
nol is given in an oral dose of 200 mg eveiy 3 to 6 I. PSGB lob Ra1wr P/80/I I980. disorder. ClinJ Poin 2001: 17: 375-7.
hours, as requiredc The intramuscular dose is 75 to 2. Ching MS, et al. St01bility of methadone mixture with methyl hy·
droxyben.7.oale as a preser.·~uive. Amt J Nosp Phornr 1989; J9: Effects on the respiratory system. Sleep apnoea has been
100 mg given eveiy 2 to 4 hours, as required; for ob- 159-61. reported 1.2 in palients on Slable me1hado110 maintenance treat-
stetric pain a dose of2 mg/kg (I00 to 150 mg) may be ment.
used. Meptazinol is also given by slow intravenous in- De pendence and Withdrawal I. Tcichtahl H, e1 ol. Slccp·disordered breathing in s1abk mctha·
done programme patients: a pilot study. Addiction 2001; 96:
jection in doses of 50 to I00 rr.g eveiy 2 to 4 hours, as As for Opioid Analgesics, p. I05. 395-403.
required. Methadone withdrawal symptoms arc similar to, but 2. Wang D, ti nl. Ccnlral sleep apnea in stable 1nethadone mainte-
nance trt'atmcnt pa1icn1s. Ches1 200$: 128: ; 348-56.
Administration. EPIOVRAl ROUTE. Epidural meptazinol more prolonged than, those produced by morphine or
Effects on sexual function. Sexual pcrfom1ance was im-
90 mg for poslopcralive pain was r-!ported lo be superior 10 an diamorphine. 111ey develop more slowly and do not paired in 29 male diamorphine addiclS r<cei,•ing methadone
intramuscular dose of 90 mg. 1 However, in a nor her srudy2 a usually appear until 3 to 4 days after the last dose. maintenance therapy. 1 TI1e funclion of secondary sex organs was
30-mg dose was ineffective and aS1oeiated wilh an unaccepl· markedly suppressed when compared wi~1 unrreated diamor-
able incidence of adverse effects. A 60-mg dose was also
Methadone is used for substitution therapy in the man-
agement of opioid dependence (see Uses and Admin- phine addicts or conlrols and serum-testost:rone concenlrntions
found to be ineffective because ofiis short duration ofaction.> were 43% lower in those on methadone. However, in a more re-
UK licensed product inforrnalion states that U1e injectable fonnu- istration, below) including neonatal abstinence syn· cent study2 in 92 opioid addiclS also receivi1g med1adone main-
Jation is not suilllblc for epidural or intrathecal use. drome (see Administration in Children, below). tenance, rates of sexual dysfunction (eroctil!, libido, and orgasm
I . Vcrborgh c. el al. Meptazinol for postoperative pain relief in dysfunction) were found to be simi lar to that of the general pop-
man: cQmparison of (lUradural ar:d im 3dministr.uion. Br J Adverse Effects and Treatm ent ularion. Rates of dysfunction between palients just started on
AnccS1ii 1987; 5?: 1134-9. methadone aod those on methadone for at least 60 days were not
2. fr111cis RI, Lockh:irt AS. Epidural mep1azinol. A11uestl11:.sio
As for Opioid Analgesics in general, p.106. sigiiilicantly different allhough new patients generally had lower
1986; 41: 88-9. Methadone has a more prolonged effect than morphine rates. Mean plasma concentnui on~ of testosterone and prolactin
3 . Birks RJS, MarSh DRG Epidural mtptazinol.Anae-.sthesio 1986: and readily accumulates with repeated doses. It may were within normal ranges and a lthougJ1 8 individuals had low
41: 883. teSlosterone concentrations, only I case of dysfunction was re-
have a· relatively greater respiratory depressant effect
Administration in hepatic impair ment- See under Phar- ported in this group.
than morphine and, although reponed to be less sedal· I. Cice-ro TJ, ~I al. Funt1ion of the male S(X <·rg:ins in heroin ::md
maook.inelics, above for a suggcslion that doses may need to be
reduced in patients with cirrhosis. ing, repeated doses of methadone may result in marked mc1hadonc users. N £ng/J Med 1975; 292: 882-7.
sedation. QT prolongation and torsade de pointes have 2. Brown R, et al. Methadone maintenance arid male sc:rnal dys·
P re parat ions function. J Addict Dis 2005; 24: 91-106.
been reported rarely with methadone use, particularly
BP 20 Io, Meptazinol lnjectioo: Meptazinol Tablets. at doses above JO() mg daily. After gross overdosage Overdosage. Most cases ofmethadone poisoning occur in per-
sons not on maintenance, 14 particularly children or family mem-
Propr ietary Preparations (details arc given in Volume 8) symptoms are similar to those of morphine poisoning. bers of maintenance patients. 2Methadone is highly toxic to any-
Ger.: Mt-ptid: Gr.: Nestan: lrl.: Mep~ic:t UK.: 1'1eptid. Pulmonaiy oedema after ovcrdosage is a common one who is not tolerant to opioids; 50 to I 00 mg can be life·
cause of futalities among addicts. threatening in non-tolerant adults and 10 mg can be fatal in a
All cross-references refer to entries in Volume A
 Methadone Hydrochloride 87
young child.:? Furthem1ore. life~lhrcatcning toxicity from oral 7. Jans.son LM . ('t al. Melhadone maintenance und bteastfoedioti in zyme inducer rifampidn. •·:: Coover$ely. the use ofciprofloxaci11,
doses as ow as 5 mg has been reported in children.'·' the nec.nntul period. Pediotdcs 2008; Ill: 106-·· 14. - which inhibits CYPIA2 and CYP3A4, has resulted in si!!llS of
S. Jansson LM, ~'al. Methadone maintenaoc~ and lonlHCrm l:icta· me!Mdone toxicity.' •
Various groups3·• have found that the risk of dearl1 from metha- tioo. Bre<utfced M~d 2008: 3: 34-7. ..
done toxicity is grea1es1 during the first 2 wee.ks of maintenance 9. Smiaiek JE. er ul. Methadone dcalhs in d1iiJ1cn. JAMA l977: I. Kreek MJ. tH al. Rifa1.npin.,nduced metha<ione ·withdrawal. N
therapy. This has beeo attributed to the difficuhy io determining 238: 2516-17. Engl J Med 1916; 294: 1104-6.
2. Bending MR, Skaccl PO. Rifampicin and methadone wi:hdraw·
a safe and effective >1arting dose of methadone and unreliable Pregnancy. Mc<hadone is not recommended for use in labour .. 1. lemce11971; i: 121 J.
accow1rsof a patient's recent drug use. because ii$ prolonged duration ofaction increases the risk of neo- 3. Rais1rick D. Ci of. Methadone maimenance and tuberculosis
1. Aron()"'-' R. e1 al. ChildhGOd poisoning: an unfortun:itc: conse- nalal rcspir.HOJ)' depression. treatment. DMJ 1996; 313: 92~6 .
qucnct of'mc1hadonc availabifoy. .JAMA 1912; 219: 32 1-4. .1 . Hcrrlin K. ~t ol. Mclhadooc, eiproOoxacin. and adverSe drug tt--
2. Harding.Pink 0. Opioid toxicity: methadone: one person's Neonatal abslinence syndrome and low bir1h-wcight arc imme- actio1lS. Lo,,ctu 2000; 356: 2069- 70.
meintc1.:incedo~ i.i: anotl\cr's poison. UJnctJt 1993; 341: 665-6. diate problems in infants born 10 women receiving melhadone
for the management of opioid addiction; increased still-birth Antidepressants, SSR/s such as fluoxetinet and
3. Zad(lr DA. Sunjic SD. Me1hadOne·rel2tcd dea1hs and monality
ra1¢ durlns induclion into methadone maintenance, New South rates have also been noted. 1"3 Jn the neonatal period moderate to nuvoxamine1•1 may enhance the effects of some opioid analge·
Wales, 1996. Drug .4/rohol Rel' 2002; 2 1: 131-6. sics; such interactions may lead 10 methadone toxicity, S1 John~
severe opioid abstinence syndrome occurred in 75% of infants in
4. Sachdeva OK, Scadnyk JM. Are one or two d<1ng.erous? Opioid
a study,2 as well as reduced head circumference and raised systo- won reduced the plasma-methadone concentration to dose ratios
expOSll'C in toddler$. J Emerg Med 2005: 29: 77..,g4, by 47% in 4 patients on methadone maintenance therapy for opi·
5. Caplehotn JRM, Drummer OH. Monali1y associated with New lic blood prc.~StJtc. At follow-up over 18 months these children
had a higher incidence of otilis media, of reduced head cfrcum- oid addiction; 2 ~aticnts reponed >)'mptomssuggcsti,,e ofa wilh-
South Walli!.s mechadone prt1gr:l1m in 199-4 : live~ lost :u1d saved. drawal syndrome.3
M.OJ.4u$119'.19; 170: 1(04-~. ference, and of abnormal eye findings when compared with
6. Buster MCA, Cf (I/, An increase in overdose mortality during the drug-free contt'Ols. Neurobehavioural abnormalities and lower I. E.ap CB. et ol. fluvoxamme and fluoxetinc do not imer.ict in 1he
firSt Z .vecks after entering or re-entering mclhadon.c trc01tmcn1
same v.oay with lhe metoabofo:m of 1he enantiome.rs of methadone.
scores on mental and motor developmental indices were thought JC/inPsyl:hop.'wn11acol 1997; 17: ll'.>--17.
in Am!l<!rdam. Addiction 2002: 97: 993-1001. to be possible predictors oflater learning and behavioural prob- l. Berl.Schy G. El al. Probable melabolie inu~nction between mcth·
lems. In a later study,' the use of methadone alone duriog prcg· a.done and flu.,oxamine in addict patients. Thcr Drug Mani1
Precautions nancy as pan of a maintenance progrnm was claimed lo increase 1994: 16: 42-5.
As for Opioid Analgesics in general, p.107. tt1c risk of prematurity twofold, of intra-uterine growth retarda· 3. ·Ei<:h·HOchli D. et al. Methadone mainlenance treatment :md St.
Jolm's Won: a C3$C report. Pharmncopsychim1y 2003: 36: 35-7.
tion fourfold, and of microeepru!ly threefold when compared
Methadone should be given with caution to patients at with a nom1al population. In addition, in those mothers who con.. Antiepileptlcs. Opioid withdrawal symptoms have boen re-
risk of developing prolongation of the QT interval in- tinued to abuse other drugs, as well as receive methadone, the ported in patients maintained on mt..1'hadone when they were gfr.
cluding those with cardiac or hepatic disease, with hy- risks oflhcse events were further increased. However, an earlier en carbama.zepi~e, 1 ~ phenobarbltu/,3 orphe1~ytoi11.4> Con\'erse-
pokalaemia or other electrolyte imbalance, or with a or
study! has reported that methadone diamorphine had no spe- ly, methadone-induced rc.~piratory depression developed in a
patient on carbamazcpine, gabapentin, and methadone forneuro-
family history of sudden death. It should also be used cific effect on intra-uterine and postnatal growth.
The relationship between maternal me~1adonc dose and the inci- pathic pain, after carban1azepine w-•S stoppcd.6
with caution in patients who are taking other potential- I. Bell J, et ol. The us~ of serum inctJ1adone levels in p:nie:us re.
dence and severity of neonatal abstinence syndrome is uoclcar.
ly arrhytlunogenic drugs, drugs likely to cause electro- Although a retrospective study6 found a correlation in some ceiving methadone: mttin ten~nce. Clin Plumnocol Thet· 1988; 43:
lyte imbalance, or drugs that inhibit the cytochrome 623-9.
pregnancies. others7·1 did not and there \Vas no evidence of atl 2. Saxon .4.J, et al. Valproic acid. unlike other anliton\.·uJsants, has
P450 isoenzyme CYP3A4 (see under Interactions, be- increased incidence of neonatal withdrawal symptoms even with no cfTce1s on methadone me1aholi!'in: two cases. J Clin Psychia-
low). ECG monitoring is recommended before starting bigh malcmal doses of JOO mg or more daily.8 ''Y 1989; 50: l?S-9. .
A small retrospeccivc study9 comparing the use of methadone '· Lill s.J. W:ln! RIH. Case rcp0n ofbarbitura1e induced enhance·
0

methadone treatment in these patients, with a further ment of me1h:.rlone metabnlism and withdrawal syndrome. Am J
dwing pregnancy for the treatment of chronic pain with use in
test at cose stabilisation. ECG monitoring is also rec- maintenance therapy for opioid addictioo folllld a lower jnci·
Psychiatry 19&1; 141: 1287-8.
4. Fineni PF. Phcnytoin a1ld mcth~done tok:rt1nc;c. N Engl J Med
ommended before and at 7 days after dose titration dence of neonatal abstinence syndrome and better growth pa- 1976; 294: 227.
above 100 mg daily in patients without recognised risk rameters in infunls born to the former group ofm.others; howev- 5. Tong T~ et o/, J>hcnytoin·jnduccd me1h11done wi1hdraw3I. Ann
er, a higher rate of slight prematurity was also found in this group h1tern Med 19El; 94: 349-:>L
factors. 6. Beniiez.Rosari-> MA, c:t al. Methadone·induced respiratory de~
of infants. The authors suggested that lower maternal doses and prcssion :lfter discontinuing carbami\Uf'lille adrn inisnatinn . .I
Administration. Methadone has a Iona half:.life and accumu .. shorter durations of trearment may account for 01e favourable
lat ion may occur wiOi repeated doses, esjiecially iu elderly or de- J'clin S.l·mp1om Monogc 1006; 32: 99-100.
findings~ in addition to better maiemal health, nutrition, and so·
bilitated paliems. An 81 -year-old woman given methadone 5 mg. cio-economic status. AntifungaJs. Use of methadone with fluconazole has been
three times daily orally for 2 days became deeply unconscious repo11cd 1 to increase serum concentrations of methadone al-
Clinical!)'. significant prolongation of the QT interval has been though the authors considered chat for patients being treated for
but awoke inu11ediately when given naloxone 400 micrograms
reported'" in an infant born to a mother taking mctl1adonc 50 ti1g opioid dependen::e the interaction was unlikely to require adjust-
intravenously.1
daily for maintenance therapy; the infant had mild withdrawal ment of the methadone dose. However, respiratory depression
Sudden ccath in JO diamorphine addicis oceuned between 2 and symptoms and follow-up at 2 months of age was normal.
6 days after starting a methadone maintenance programme.1 The has been reported1 after intravenous doses of fluconazole were
t. Blinick G, et al. Melhadooe maintenance, pregnancy, and prog· given to a 60-ycar-old man also taking oral methadone for pain
mean prescribed dose ofmethadone at the time ofdeath had been eny••MMA 1973; 225: 47i-9.
about 60 mg. 111ere was evidence of chronic persistent hepatitis 2. Rosen TS. Johnson HL. Children o( meth~don e·maintained relief in advanc<d g!15tric cancer. Although a randomised placc-
in all cases and liver disease cou'd have reduced methadone mothers: f'ollow·ur. m IS months of age . ./ Pedio1r 1982; 101: IJo-controlled study' found that giving vorico11azole lo patients
clcanince resulting in higher man expected blood concentrations. 192-6. on ml!thadone maintenance therapy for opioid addiction was
3. ~;~~tt ~ ;~~rl'~~~ J. Congenital malformation$. N Engl J Med
Liver function tests and wine testing for the presence of dmgs
before entry into methadone maintenance programmes, :ind low-
38 1 generally safe and well tolerated, the authors recommended
monitoring and possible dose reduction of methadone when the
4. ~rfe 1u~ R~ c.•1 ~/.
Mc1hadonc 1naintenunce program in pregnancy
er st:u1ing doses, might decrC<>sc the likelihood of such deaths. a Swiss per1n:>t:ll center (II): neo1Hll<JI outcome ;ind social re·
in 2 drugs are used together. Similar recommendations are also giv-
Like dt:><tropropoxyphene, 01ethadon~ has membrane slabilisin& sources. Aru1 Obsut Gy11erol Sctmd 2005~ 84: 145-50. en in the licensed product inlOnnation for vorico1tazole.
ac11v1ty md can block nerve conduchon aod it w11s suggcstccP 5. Lifsd1i12 MH, ct nl. Fetal and pOSl1lalal ~rowth of children born I. Cohh MN. et <J. The effee( of fluconazolt on the clinical ph:ir·
1
10 n3.rcol ic..dcpendem womefl. J Pcdi01; 1983; I 02: 686- 9 J. moi1.:okinetics of me1hado11e. Cli11 Phurmocul Thu 1998; 63:
that the s·Jdden deaths were mainly due to aceumulation of meth- 6. Dashe JS et al. Rcla1ionship between maternal melhadonc dos- 655~2.
adone over several days resulting in complications such as cardi· a~e aod neonatal w ithdtawal. Obs1e1 Gynecol 2002; 100: 2. Tarumi Y, (ff al. Methadone and tluconazolc: respira1ory depies·
ac orrh)1hmias or cardiovascular collapse (see Effects on the 1244--9. sion by drug i111erac1ion. J P11ln Symptom Mon(lge 2002: 23:
Cardiovascular System, above). See also Overdosage, above. 7. Berg.hella V, el al. Maternal methadone dose and neonatal with- 14&-53.
draw~(. AmJ Obs1e1G)'ntco/2003; 189: 312-1 7.
for the eifects of hepatic and renal impairment on the disposition 3. Liu P, <U ol. J>t.armacokinelie inleraction bc1wecn voric:onu.ole
8. McCarthr JJ. el al. I Jigb·dose methadone maintcnanoc in preg- <md me:thadclne at ~teady slate in patien1s on rnc1hadon: 1hcrapy.
of methadcmt!, see under Pham1acokinetics, below. nancy: matemo:it and neonatal outcomes. Am J Obste1 Gynecol Amimicrot>Agmts Chttmut/Jer2001: 51: 11~18.
I. Syrnonds P. Methadone and the elderly. BMJ J977; i: 512. 2005: 193: 60<>-IO.
2. Orumr:1er OH, ct ul. Deaths of heroin ~ddic1s staning on a incth· 9. Sharpe: C, Kuschel C. Outcomes of infants born lo mothers re- Antivirals- The potential for interoction between antirctrovirals
ad one 01ain1en:lnce pro;rannne. Umcet 1990; :ns: I 08. ceiving methadone for pain management in pregnancy. Arch Dis and methadone ~.as been revicwed. 1 Available evidence for HfV·
Child Fetal Neonarol Ed 2004; 89: f33-F36. protease inhibitors suggests that atoza11d\:ir> lndinavlr, and, pos·
3. Wu C, ~knry JA. De:.tlh:> ofheruin ~d dic1s startin$!. o n mtthadonc
maintenance, l.01rce1 1990; 335: 424. ... I0. Hussain T. Ewer AK. Ma1emal methadone may cnus.c: arrhyth· sibJy, soquinovir alone have no cffeet on plasma concentrations
mias itl neonates.. Acta PoeJic1r 20-07; 96: 768-9.
Breast feeding, The American Academy of Pediatrics consid- of mctJ1adonc; cmpren<I\'ir·, neljinavir, dtonavir, and ritonavir-
boosted soq11inavir may reduce plasma-methadone concentra-
ers that tbe useofmcthadone in breast-feeding mothers is usually Interactions tions but the effe::t is unlikely to be clinically sig11ificant. Lopina-
compatible wiOi breru;t feeding. 1 The BNF 59 also permits breast For interactions associated with opioid analgesics, see
feeding by 1nothers on methadone mail)tenance although the vir-ritonavir may also reduce methadone concentrations and, al·
dose shc..!d be as low as possible and the infant monitored to p.107. though most studies found the interaction to be insignificant~ one
avoid sedation. Others have suggested that the amount of meth- Methadone is metabolised in the liver mainly via the study rep0rted opioid withdrawal symptoms in some paticn!S.
adone in breast milk is unlikely to have any pharmacological ef- Unpublished data [also referred to in the licensed product infor·
cytochrome P450 isoenzyme CYP3A4; the isoen- mation) on lipra,wvir (boosted with ritonavir) in healthy, opioid-
fect on the infam,2•8 However, there hos been a rep0t1 of the death
zymes CYP2B6, CYP2D6, CYP2C9, CYP2Cl9, and naive subjects soggcst that it may decrease plasma-methadone;
of o 5-week-old breast-fed infant whose mother was on metha-
done 1naintenanee.Y CYP I A2 are also thought to be involved. Consequent· Jicen~cJ producl information for tiprdnavir reco1mnends that p-...s-
ly, use with other drugs that induce or inhibit these tients arc monitcrcd for symptoms of opioid withdrawal.
l. ~/'~~;~~~i~:i~~1~u~~:~<:~i11~~sp~~:,,·;~~s~Oo~~ d~~~ ;1;~~~~~ isoenzymes may result in changes in plasma concen- The NNR!"ls nevirapine and efovirenz have both been reported
(Rc1ir.:d May 2010) Correction. ibid; 1019. Also available at: to reduce plasma-methadone levels and ";01drawal symptoms
h1 t S:> :fl.~ appo I icy ,aa p pub Iic a Iions. org/eg i/con tcnt/fu 11 / trations of methadone and, possibly adverse effects. have occurred when they were given to patients receiving meth·
tx-<11u111cs%3blOS/3n76 (acccsS<d 26i0610S) There is a risk of cardiac events in patients receiving adone. Conversely, delavirdine may incrcast methadone concen-
2. Blin)cl: G. e1 ttl. Meth3.done .issays in pregnant women and prog· methadone who are also taking drugs that affect cardi-
c.ny. Au1 J Obstet Gpnttol 1915; 121: 617- 21. trations although the effect is unlikely to be elinically significant.
l WC1jnar· Horton RE, el al. Methadone distribution and excretion ac conduction or electrolyte balance. Methadone possibly increases plasma concentrations of the
j1110 brea!it milk of clients in a methadone mainten:mce pro· NRTI !idovudin<(scc p.101 1).
gummc. Br J Clin Pltormorol 1991; 44: 543-7. 0 Drugs that acidify or alflillinise the urine may have an effect on I. Bruce: RD, er u.'. Ph:Jnnacokin~1ie drug interae:1ions between opi·
.ii. Geraghty B. et Pl. Meth3done levels in breast milk . J Hum Lari methadone phannacokinclics since body clearance is increased oid agonist thailpy and :'lntirelroviral medica1ions: implications
1997; 13: ~~7-30. at acidic pH and decreased at alkaline pH. 1 <:Hld managell'l(nt for clinical practice. J A.cquir fmm1me Defic
S. M1.:Cm1hy JJ, Poser BL. MethadOJle le\'t:'IS in human rnilk. J I. Nilsson M·I. el al. £:1Tcc1 of urioar)' pH on the disposition of S!'"d" 2006; 41: 563-72.
H11m Laci :woo; 16: 115- 20. meth;i.donc in man. Ew· J Clin PhormOC()/ 1982; 22: 337-42. Gastrointestinal drugs. Histamine H2-antagonisissuch as ci-
6. Oegg £J. f!t (I/. Oislribution of R· and S· methadon~ into human
milk c!uringo multiple. medium to high oral dosing.. Br J Clin Antibacterials, Withdrawal symptoms b3ve been n:ported in metidine (sec p. 108) may enhance the effects of some opioid an-
PharmnrDI 2001 ~ Sl: 681- S. patients maintained on methadone when they were given lhe en .. algesics; such ii~eractions may lead to methadone toxicity.
The symbol i" denotes a preparation no longer actively marketed The symbol ® denotes a substance whose use !)lay be rescricted in cettain spoi1s (seep. vii)
88 Analgesics Anti-inflammatory Drugs and Antipyretics
Grapefruit juice. Grapefmit juice. an inhibitor of the cyto- ln a study ofpatients on methadone maintenance thcrapy2 appar· ly decreased until total withdrawal is achieved. Metha-
chrome P450 isoenzyme CYP3A4, has been shown to modestly en! tenninal half.life of methadone was prolonged from a mean done is usually given orally for the treatment of de-
increase the bioavailability of melt·adone; 1 although no symi>- of I8.8 hours in those with healthy livers to 35.5 hours in patients
loms of methadone toxicity were seen in the studied patients, the with severe chronic Jivet disease. However, plasma concemra- pendence although parenteral routes may be used,
authors commented that such enecli may occur in patients with tions were not increased in such patientS. particularly when ornl therapy is not possible; the doses
reduced opioid tolerance, particularly when s12ning methadone I. Moore RA, e1 ol. Opiate meu.bolism and e>.:cretion. Boillierc:s stated above may be given orally or parenterally. In the
treatment. CU11.4.t1ocsthesiol 1981: 1: 829-SS. UK, oral treatment is commonly given as a mixture
I. Bcnmebarek M, uf. Eff« L( or g,raperruit juice on the phuma-
t!I 2. Nov;ck OM. e1 ol. Methadone disposition in patients with chn:m-
cokinctic.s of the cn3nliorneos of methadone. Clin Pbormacol ic liver disease. C/in ,O},ormocol Ther 198 1; 30: 3S3-6:2. containing I mg/mL of methadone hydrochloride.
Thtr 2004; 76: SS-63.
Pregnancy. Plasma concentrations of methadone were reduced For details of doses in children, see below.
in methadone-maintained pregnant women, probably due to en· For the control of intractable cougk associated with
Pharmacokinetics banced metabolism.'~ II was sugg~sted that the dose of metha· tenninal lung cancer, methadone hydrochloride is usu-
Methadone hydrochloride is readily absorbed from the done might need to be increased in such patients. ally given in the form of a linctus in a dose of I to 2 mg
gastrointestinal tract and after subcutaneous or intra- J. Pond SM, c.1 of. Altered methadone phannacokinctie$ in metha· every 4 to 6 hours, but reduced to twice daily on pro-
muscular injections. It is widely distributed in the tis- done-rnainlaincd pTC"g.nant women. J Phormacol E.t:p Ther 1985;
233: t-6. longed use.
sues, diffuses across the placenta, and is distributed 2. WoJfT K. et al. Changes to methadone clearance during preg.nan~
into breast milk. I! is extensively protein bound. Meth- cy. Eur J CUn Plianuocol 2005; 6t: 763-8.
Administration. Although duration of action after single doses
of methadone is similar to that of morphine, it increases consid-
adone is metabolised in the liver, mainly by N-demeth- Renal impairment. The urinary excre1ion of methadone was erably with multiple dosing of methadone because of the long
ylation and cyclisation, and the metabolites are excret- reduced in renal failure, 1 bul plasma concentrations were within elimination half-life (see under Phannacokinetics, above). The
ed in the bile and urine. Metabolism is mainly the t<"ual range and taecal excretion accounted for the majority minimum effective dose of methadone can be difficult to titrate
catalysed by CYP3A4, although other cytochrome of the dose. Very linle methadone was removed by peritoneal for the individual patienL A fixed J0-mg oral dose widi a flexible
dialysis or haemodialysis. patient-controlled dosage interval has been used in palients with
P4SO isoenzymes also play a role (see Interactions,
1. Kreck MJ, ef a!. Mcth.1donc use in paiienls wilh. chronic renal chronic cancer pain.' Dosage ne>t more frequently than every 4
above). It has a prolonged half-life and is subject to ac- disease. Dnig Alcohol D•JHnd 1980; 5: 197-205. hours during the first 3 to 5 days, followed by a fixed dose every
cumulation. 8 to I2 hours depending on the patient's ro:iuiremcnts, was ad-
Uses an d Admi nistration vised.
o ln reviews of the phannacokinetics of methadonc 1·> particular
reference has been made 10 its long climinalion half-life, accu- Methadone hydrochloride, a diphenyU1eptane deriva- A suggested initial dose for patients who need to swi1ch from
mulation after repealed doses, and wide interiridividual varia- oral morphine to methadone because of poor pain control is one
tive, is an opioid analgesic (p.108) that is mainly aµ- tenth of the total daily dose of morphine, but 001 greater than
tions. opioid agonist. Single doses of methadone have a less I00 mg, given at intervals detennined by dle patien~ typically
Methadone is rapidly absorbed afteroral doses and has high oral marked sedative action than single doses of morphine. every 8 hours. 2
bioavailabiliiy; peak plasma concenlrations have been reported l
to 5 hours after a single tablet. It ucdergocs considerable li>-sue Methadone is a racemic mixture and levomethadone When switching from oral to parenteral use it was suggcstcdl
dis1rihution and protein binding is reponed to be 60 to 90% wilh (p.80) is the active isomer. that the dose ofmethadone should be halved and adjusted I here-
cr 1-acjd glycoprotcin being Che main binding pro1cin in plasma after as necessary.
Methadone hydrochloride is used in the treatment of Evidence of the prolonged effect of methadone was seen when a
Metabolism to the major metabolite 2-ethylidine-l ,5-dimelhyl·
3,3-diphenylpyrrolidine and the minor metabolite 2-cthyl-3,3-
moderate to severe pain; it may be of use for those pa- single intravenous bolus dose of20 mg resLited in postoperative
diphenyl-5-methylpyrrolidine, both of them inactive, occurs in tients who have excitation or exacerbation of pain with an3Jgesia lasting about 25 hours.' An jnitial 2·hour loading intra·
1he li\'er. These metabolites are excreted in 1he faeces and urine morphine. Methadone is also used in the management venous infusion of meUiadone l 0-0 to 200 micrograms/kg per
with ·unchanged methadone. Other nietabolites, including mcth· of opioid dependence. It has a depressant action on the how· to provide rapid analgesia followed by infusion al a lower
adol and normcthadol, have also been described The liver may maintenance rate of I0 to 20 micrograms/kg per hour forconlin·
cough centre and has been used as a cough suppressant uous pain rcJicfbas been used in bum patients.s Methadone has
also serve as a major storage site ofmchanged methadone which
is taken up, bound non-spccificall~ by the liver, and released in terminal illness, although the BNP 59 discourages also been given by continuous subcutaneous infusion for severe
again mainly unchanged. Urinary exx:retion of methadone.is pH· this use because of the risks of accumulation. cancer pain6.' although this route has been associated with local
dependent, the lower the pH the greater lhe clearance. tissue irritation and induration. Epidur•I methadone has bee·n
For pain reHef starting oral doses of methadone hydro- used successfully in d=s of up to 5 mg for analgesia with bupi-
Io addilion to markcc.I intcrindividucil variations lhcrc arc differ· chloride may range from 2.5 to 10 mg given every 6 to vacaine.8·9 Intermittent and continuous epidural infusion of
cnces in tl1e pham1acokinetics of methadone after single or mul-
8 hours or longer and thereafter adjusted as necessary. me1hadone has also been 1.ried 1o in poc.1opcrative analgesia.
tiple doses. Elimination half-lives vary considerably (a range of
15 to 60 hows has been quoted) and may be much longer than Methadone may also be given parenterally. In the UK, A small case series 11 foWld topical methadone powder lo be cf.
the 18 hours reponed following a single dose. Careful adjust· the subcutaneous and intramuscular routes are licensed fective for pain relief of open, cxudative wounds.
ment of dosage is ne~ with repeated doses. I. $3wc J, c1 t1l. Paticnt·C'ontrolled dose regimen of mc1h2donc for
with the intramuscular route being recommended for chronic c,ancer pain. BMJ 1981; 282: 771-3.
Most studies have been in addicts. ?J:15ma c~ntrations have prolonged use; US licensed product infomiation sUites 2. Morley JS. t!I o/. l\·1e1hadonc in pain uncontolled by mol'J)hine.
been found to vary widely during methadone maintenance ther- that the intra venous, intramuscular, and subcutaneous Uincet 1993: 342: t243.
apy ....ith large differences between patients and wide fluctua- l . $3wc J. High·do.sc morphine 3nd methadone in c3ncer pa1ien1.s:
tions in individual patients. Thc~c variations in kinetics have also routes may be used although it gives doses for the in- clinical phannacokinctic cons-idcf.dlions of or3.I 1reatmen1. Clln
Phormacol:.l11cr 1986; IJ: 87-106.
been seen in cancer patients. travenous route only. !nitial dose ranges for parenteral 4. Gourlay GK, el al. Mcth3done produt<'!i prolonged pOStopcra-
I. S!l"'C J. High-dose morphine and mtth:uJon( in C:3noer p.alicnls: routes are similar to those used orally; however, if tive analge!:i.a. BMJ 1982: 284: 630-1.
clinical ph:mnacokinetic: consider:Jltons of oral trcallnen.t. Cli11 transferring between oral and parenteral methadone, 5. Denson DD. e1 ol. Phannacokinetics or <:.ominuous intravenous
Pharmacokinet 1986: 11: 87- 106. infusion or meth3donc in the co.rly post-burn period. J Clin
2. Moore RA. t!t ,,/. Opiate me1aboli.S:'ll and excretion. Bnillier's US product information stales that the initial conver- Phnrmacol 1990; ]0: 70-5.
Clin A11ae.t1ht!siol J981; I: 829- 58. sion dose should be based on the guide that I 0 mg of 6. Matl1ew r. Storey P. Subcul:UICOUS methadQne in 1e1111inally ill
3. Eap CB, et ol. Jn1erindividual v21tiability oflhe c:Jinieal pharma- P"ticnts: manugenble local to>;icity. J P11ir1 SJ•tnplom Mo11oge
cokinclicsof m..:thadone: implica1ions for the treatment of opioid
oral methadone is equivalent to about S mg of 1999; 18: 49-52.
dependence. Clin Phonnacokin~t 2002; 4 I: JI 53-93. parenteral methadone. The analgesic effect of metha- 7. Milk in MK, Morley JS. Sub<'-Ulaneous meth~donc io termin::illy-
ill patients. J Pt1in Symptom Monug~ 2000; 19: 237-8.
4. Ferrari A. t!I al. Methadone-metabolism. pharmacokinetics 3nd done begins about 10 to 20 minutes after parenteral in- 8. On:ngcr B. et ol.' Extradural bupivaeaint ::i.nd mclhadone ror u-
interactions. Pharmocol Res 2004; SO: 551-9. tracorporcal shock·wave li1l1otripsy. Br J Anoes1h 1989; 62:
5. Lugo RA. e1 al. Pharm3cokine1ics of mc1h.adone. J Pt1i11 Pollim jection and about 30 to 60 minutes after oral doses, the
82-6.
Cart I'hormocother 2005~ 19: 13-24. effect of a single dose usually lasting about 4 hours. As 9 . Martin CS, at ol. Extradun.I methadone ::&1'14 bupivaciinc. in la~
Administration. Methadone is OO'lsiderably more lipid-solu- accumulation occurs with repeated doses, the effects bour. Br J A11bes1h 1990; 65: 330-2.
become more prolonged. Consequently, to avoid the 10. J>ric1o·Ah•ttrez P. et "'· Con1inuous epidural infosian of racemic
ble than morphine. A siudy of plasma concentrations and analge- methsdone resul L~ in effecti~ JXlStoperativt at1~ lges.ia and low
sia after intram~ular injection inCicatcd that more rapid and risk of opioid overdose, it is reconunended that in pro- plasma e:onct-ntrations. Can J Ano~sth 2002; 49: 25-31 .
greater relief of pain might be achi,ved if lipid-soluble opioid longed use methadone should not be given more than 11. Gallagher RE. et al. Analgesic crfects of lopical methadone: a
anaigcsics were injccled into lhe deltoid rather than the gluteal repon of four c:ases. ClinJ Poin 2005; 21; 190-2.
muscle; there was oo significant diffe:rcn« in absorption of mor- twice daily.
Administration in children. Methadone is not licensed for
phine from the two sites. 1 Methadone is used as part of the treatment of opioid use in children. HOwever, it has been tried' intravenously in chi I·
Other routes investigated in pharmacokinetic studies include dependence, although prolonged use of methadone it- dren aged 3 10 7 years to prevent postoper.rt.ivc pain; a dose of
continuous intravenous infusion2 and continuous epidural infu- self may result in dependence. Initially, methadone hy- 200 micrograms/kg was given perioperativcly followed poslOJ>-
sion.3 Rectal administr.uion( has also boen studied. eralively by 50 micrograms/kg every I 0 minutes until the patient
drochloride is given in doses sufficient to suppress was both comfortable and adequately alert. Methadone has also
I. Gr:..ibinski PY, e1 ol. Plasma lc\'tls al'ld analgesia following del-
toid and gtutul injections of melhadc>ne 3nd morphine. J C/in signs of opioid withdrawal but avoid toxicity; the been ttied 2 orally for the treatment ofsevere pain in hospilali>-cd
Pllarmocol 1983; 23: 48-SS. BNF 59 and US licensed product information recom- children; daily doses ranged from 200 to 600 microgranisikg for
2. Denson DD. ei al, Pharmacokinetic$ of continuous intra\'cnous up to 6 weeks.
infusion of melh;tdonc in 1hc early pC6l·bum period. J Clin PJwr-
mended a starting dose of JO to 40 mg daily. Subse-
maco/ 1990; 30: 70-5. quent dose adjustments should be made cautiously be- Methadone is used for the management of neonatal abstinence
3. Shir Y, ~t al. Plasmaconce-ntrations of methadone during postop- syndrome (p.I 06). The BNFC 2009 suggests an initial oral dose
cause of the risks of accumulation; the BNP 59
erative patitnt-controlled txlradural .analgtSi3. Br J Anae.\•th of I0-0 micrograms/kg increased by 50 mi<rogramslkg every 6
1990; 65: 204-9. suggests adjusting the dose in steps of up to 10 mg to a hours until symptoms are controlled: once stabilised, ths total
4. Dale 0, et of, Qi03vailabilities of rectal and oral methadone jn maximum weekly increase of 30 mg. Once the dose daily dose is given jn 2 di\'ided doses for maintenance. When
heahhy subjects. Br J Clin Phqrmct 0>f 2004; 58: 156-62. has been stabilised, patients may choose to receive pro- withdrawing methadone, the dose should be reduced over 7 to I0
Hepatic impainnent. Overall hepatic dysfunction docs not longed therapy with a carefully selected methadone days.
seem unduly lo disrupt methadone metabolism' and it has been I. Be°rde CB. et al. Compari~on of morphine and methOOone. for
dose for each individual; most patients in such mainte- prevcncion of ~topera 1ivc pain in J- 10 ?·year-old children. J
suggested2 that maintenance dosage of mC1hadone need not be
ch<laged in stable chronic liver disease, althougll abrupt changes nance ·programmes are stabilised on once-daily doses Pcdiow f991~ 119: 136-4 1.
of60 to 120 mg. Alternatively, detoxification may be 2. Shir Y, el ol. Oral methadone for the 1rca1ment of severe pain in
in hepatic status might result in subgantial alter.itions in metha- hospitalized children: a repo11 of five C:i.ses. Clin J Pain 1998;
done disposition requiring dosage adjustments. appropriate with the dose of methadone being gradual- 14: 350-3.

All cross-references refer to entries in Volume A

 Methadone Hydrochloride/Methyl Salicylate 89
Cancer pain. Methadone is used as an altemative to morphine Profile
in the tre~tmcnt of severe cancer pain (p.5). A bc'.Uer understand- Methyl but~1isalicyJate is a salicylic acid derivalive lhal has heen
ing of its pharmacokinetics and of equianalgesic doses may ad- used similarly lo methyl salicylate (p.89) as a iut>efacient for the 0

~OCH3
drel's early concerns about 1hc risk of cumulative toxicity associ- relief of mnsculoskeletal, joint, and soft-tissue pain.
~tcd with prolonged use. However. its long tenninal half-life
Preparations
1nakes it less suitable for the trcntment of breakthrough pain.
Propr ietary Preparations (dctoilsarc given in Volume B)
Methadone has been given by the oral, rectal. and p.rentcral liol.: Oo4oderm.
routes. UOH
Reference~
I. AyoJltindc OT. Cridge OT. The rcdisco\'cry of mcthadonC' for NOTE. Methyl salicylate and methyl salicylatc liniment have been
c<"!ncer ~in management. MedJ Aust 2000; 173: 536-40.
Methyl Gentisate known previously as oil ofwintergreen. wintergreen. and winter-
2. Bruera E. SwecnC)' C. Me1h;idone use in c3ncer patients wilh Gef'lisato de metilo. 2.5-Diiydr<>A-ybenzok acid methyl ester. green oil. Wintergreen oil has also been kno-..11 as sweetbirch oil.
riin: a review. J Pollio1M~<f2002: S: 127-38. Me-r"1AfCHT~CaT Pharm acopoeias. ln£11r. (see p.vii)../pn, and Viet. Also in US-
3. 3 ruera E. <:I al. Methadone versus morphine os a !irsl-linc s1roag NF.
opiC1id for <:anccr p:;iin: a randomized, double-blind s1udy. J Ciin CeH 80, = 168.1.
Oncol 2004; 22: I SS-92. CA$- 2150- 46-1. Ph. Eur. 6.8 (Methyl Salqiate). A colourless or slightly yellow
4. Moryl N, e1 cl. Methadone in 1h¢ treatment or )»in and 1errni11a1 liquid. Very slightly soluble in water; miscible with a!coho~ and
delirurn (sic) in advanced cancer pa1iCnts. Po/liar Suppor1 Care witli fatty and essential oils. Protect from light.
2005; 3: 311-11. USNF 28 (Methyl Salicylate). It is produced synthetically or is
5. M21nnir.o R, er al. Methadone for canccr-relarcd neuropathic obtained from the leaves of Gaultheria procumbcns (Ericaecae)
p:i.in: a Tcvicw of the lilcrature.J Op;oid Manag 2006; 2: 269-76. (wintergreen] or from the bark of Betu/a lento (Betulaeeae)
6. Nichol!.On AB. Methadon( forca1lcerpain. Availab1e in The: Co-
[sweet or black birch]. The source of the methyl salieylate must
chrane Oatab3SC: of Systematic Reviews: Issue 4. Chiches.ter:
John Wiley; 2007 tDcccsscd 26106/08). be indicated on the label.
A colourl..s, yellowish, or reddish liquid having the characieris- ·
Opioid dependence. TI1c treatment of opioid dependence is lie odour of wintergreen. Slightly soluble i.n waler; soluble in al-
discussed on p. I 05. In the UK, oral liquid preparations of meth- cohol and in glacial ac.etic acid. Store in airtight containers.
adone hydrochloride I mg/ml are widely used for 1his purpose.
It is important to note lhat these preparations are 2.5 ti mes Profile Storage. Certain plastic conrainers, such as those made fi'om
stronger tl1an MeUiadone Linctus (BP 2010), and although some Methyl gentisate has been used topically for the relief of muscu- polystyrene, are unsuitable for liniments or ointments containing
are licensed for analgesia in severe pain, many are licensed for loskeletal and joint pain. It is also used as a skin lightening agent. methyl salicylate.
U1e lreatment of opioid dependence only. Methadone Oral Solu- O Refen:m.:~. Adverse Effects, Treat m ent, and Pre caut ions
tion (I nig/mL) (BP 2010) is available as a ready-to-use solution I. Gaito R, Baldari M. Allergic contact derm~ni 1 is fronl inethyl gen- Salicylate intoxication can occur after ingestion or topical appli-
or O)ay be prepared from Methadone Hydrochloride Oral Con- tisatc in:> bleaching C(c3m. Contact Dernmtili$ 2006; S4: 220-l. cation of methyl salicylate (see Overdosage. below).
centrate. However, rnost oommercia1.IY ,avai1abJe preparations in 2. Scm-Baldrich E, el al. Allergic c-0ntac1 dCrm3titis to methyl
the UK slill follow an earlier formula f6rmerly !isled in the Drug ge11tisate. Comac1 Dermotiris 2009: 60 : 225-6. Overdosage. lngestion of methyl salicyiate poses the U1reat of
TariffFoonulary (DTF): Preparations ~"ere, rapid-onset saJicylate poisoning because of its liquid eoo-
cenn·ated fonn and lipid solubility.1 It is readily absorbed from
Methadone Mixture l mglmL Proprietary Preparatio ns (details arc given in Volu"?~ B) the gas1roiate.~tinal tract and most is rapidly hydrolysed to free
methadone hydrochloride l 0 mg Multi·lngredienc Ital.: Reun'lrCCOl'l salicylate. The s)mptoms, which may appear within 2 hours of
Green S and Tartrazine Solution (BP 1980) O.OZ mL ingestion, are similar 10 1hosc of salicylate poisoning in general
CompoW1d Tanrazine Solution (BP 1980) 0.08 mL . (see Adverse Effects of Aspirin, p.21), ahhough methyl sali-
syrup, unpreserved 5 mL Methyl N icotinate (WiN! cylate is expeete<i to be more toxic because of its lipid solubility.
TI1ere have been repons of fatalities after ingeslion of as linle as
chlorofonn water, double-sh·ength to 10 ml . Methy{e. nicoti,ate de; Mc1hyii Nicotinas: Methylis nicotinas: Me-
4 ml in a child •nd 6 mL in an adult, although the adult lethal
Some connnercially available formsofDTF Methadone Mixture thyl-nikotinat Metilo nikolinotas; Metylnikotinat Mctyyliniroti- dose is estimated to be 30 mL.' Topical Chinese herbal medici-
I mg/mL use a preservative system based on hydroxybenz.oate naani; Ni<otin2to de metilo. Me1hyl pyridine-3-carboxylate. nal preparations may contain methyl salicylatc in variable
esters ra1her tlian chlorofonn; however, syrup presen,ed with hy- MeTW\t-IMKOT1oi1.jaT amounts, and salicylate poisoning has been reponed in a 40-{'ear-
droxybenzoate eslers may be unsuitable for extemporaneous dis- C 7 H;N0 2 = 137.1. old man after a tollll body application ofsuch a preparation.- Sal-
pensing (see Incompatibility, abo,•e). CAS - 93-60·7. icylatc poisoning has also been reported in a woman who had
References. UN/I - 7BIAVIJ9DJN. attempted suicide by ingesting Red Flower Oil, a topical Chinese
I. Ghodse AH. el nl. Comp..1rison of oral prc:p;mtlions of heroin and herbal oil. 3 The authors also noted that some patients took >mall
mc1l1adonc: to s1abilise opiate misus(rs 3$ inpatients. BMJ 1990 ~ amounts of this preparation orally in an attempl to enhance its
300: 719-20. a11al2esic effects.
l. Wolff'K, e1al, Measuring .::ompli:mcc in tl'tclh11done mainleMnce 1. Chan TYK.. Potential dtingcrs from topical prcpar:ttions contJin-
paticnls: use of a phi!nnacologic indicntor to "es1imate:" ntelh<11- ing methyl ~a,l i;..;•late. Hum E:"p Ta.ritol 1996: 15: 747-50.
done plasma levels. Clin Phonnacof Ther 1991 ~ 5-0: 199-207. 2. Bell AJ, Duggin G. Acute mc:lhyl salicylatc toxicit)' COn\pliC3l-
3. Wilson P, ct ol. Meth3dooc maintenance in g!!neral prJetice: pi!- ing herbal ~in 1tca1men1 for psoriasis. Emerg Med (Fremnmle)
ticnl$, workload, and outoomcs. BMJ 1994; 3Ct9: 64 1-4. 2002; 14: 188-90.
~ . F:irrell M, c1 nl. Methadone m3lnten~nce lreaunent in opiate dc- ~. Chan TH, ~, 11/. Severe saticylatc poisonini; associated wilh the
pmden·!e: 3 re\i i ~w. BMJ 1994: 309: 997-1001. inlakc of Ch in ~ medicinal oil (' Red Flower Oil'). A11st NZ J
5. Henry JA. Me1hackinc: where arc wi: now? Ha~p Med 1999; 60: Pharmacopo eiz.s. Jn Eur: (seep.vii). Med 1995; 25: H.
t61-4. Ph. Eur. 6.8 (Methyl Nicotinate). A white or almost white pow-
6. f;iggiano F. c:t u!. Mc\hadonc maintenance at diffettnt dosages Percutaneous absor ption. Like other salieylates, methyl sal-
der. M.p. 40° to 42°. Very soluble in water, in alcohol, and in ieylate may be absorbed through intact skin.1 Percutaneous air
for opioid dependence. Available in The Cochrnnc Oa1.ab:.lsc of
Sy$tematic Reviews; Issue 3. Chichcslcr: John Wiley; lOOJ (ac- dichloromethane. Protect froin light. sorption is enhanced by exercise. h!!al, ooclusion. or disruption of
cessed ?8108108). !Profile the integrity of the skin. The amount absorbed will also be in-
7, Am.tJto L, et al. Methadone al tapered doses for 1hc management Methyl nico(inate is used in topical preparations as a rubefacient. creased by application to large areas of skin.
of opioid withdrawal. Available in The Coc:hrane Darobase or Resulls from a slUdy in heallhy subjects showed that a consider-
Syste1natic Reviews: Issue 3. Chichestct: John Wi ley~ 2005 (ac- Preparations
cessed 26106/08). able amounl of salicylic acid m<iy be absorbed throog)l the skin
Prop rietary P reparations (<k.t<1ils are given in Volufll( 0)
8. NICE. Mc1h~done and buprenorphine for the 1nanaJ:temern or UI{; f';cl<Je< Ct'ilbla;n Cream.
after topical opplication of products containing methyl sali-
opioid dependence: Technology App r~ i sa l Guidance 114 (issued cylate.i Bolh the :nle and cxl<.111 of absorption increased after re-
Janua1)' 2007). Avail:Jblc nt: http://www.nicc.org.uk/nicemcdial Mult i-Ingredient: Arg.: Medex Rub; Austral.: Deep Heat Auscrlo:
Bcrggcist; & lg.: Algipon; Emeocil; Pm:utalgine; Rado-Sprayt Chile: Cal· peated application; the bioavailability of the ointment prepara-
pdFffAI 14Ni<eguidonce.pdf(acccsscd 26106108) tion used in the study inc!C<lscd from 15% after the second dose
9. Mattick RP. e1 nl. Methadone m<'intenanc;e di.crap)' versus no 0>"\b Sport: Fnxiot. Konirubj: MentcbaJsamt: Fr" Atg;?"nj: Cap5ic; Cliptol
opioid replacement therapy for opioid dependence. Av:iilable in Sportj: D'Xcntmtyl: Get Rlbc!oflt Percutalgioe: Seda11ry~I; Ger.: Dole>· to 22% after the third to eigh1h dose. TI1e au1hors recorrunend
The Coc:hr.ine Da1abase of Sys1em;i.tic Reviews; Issue 3. C hich- ne<KOf; K)'tta·S.lsom f. Rheuma Bod; ~or.j: Tetesept &:lel<onzemrat that topical analgesic preparations containing methyl salicylate
c~tcr: John Wiley: 2009 (aCCt:Sst"d 11/11109).
Rhevmo &cft; Gr.: Far;;gel-Fone: Hffi: Hung.: Deep Heat Spray. Indio: or other salicv13les should be usc.d with caution in patients at in-
Algipart Flamarf: 11cdicrc;:i-.c; Rdaxyl; lndon.: Remalo·imf: 1,.1.: Algi~
Deep Heat Ra.lgei<: Ral{:t:X He~ Spray. lsroel: 0.?ep Heat S~-; Ital.: creased risk ofdeveloping salicylatc adverse effects (see Precau-
Preparat io ns Balsamo Sffcc.nina: Relaxar: Seda~n: Nech.: CremOf' C.1p!ici comp; ere. tions of Aspirin, p.23).
BP 20 10: Me\Ndor.e lrjectioo; Metnadone Llnctus; Me!Noone Ora~ So· mor Capsici ('()(:')posrtus:- KnJidvat Spier'balscm: Pol.: Deep Heat: Port.: Resulls fron1 another study showing high tissue to plasma ratios
Mid.;lgarrf; S.Afr.: O..ep Heat Sprayj: ln/r.robt Sloan"s He>t R.bt: Singo-
~~~jj/~=~ =~:o~~ction: Me1hack>ne HydrocH.oride pore: Qc.!p He.at:ng Spn.yf; Spain: Ooctofril Antimllamat Rl-~io Silil; after topical applicarion of a methyl salicylate formulation sug·
gest that direct penetrnlion and not rcci~ulation in the blood is
Oral Concentrate: Met)iadO'le Hydrochbnde Oral SolAioo; Meth!!dooc Switz.: K~ Baurne: Midalg2.n Nouvelle fonm..<c: Midalgant: ~'gl-t UK:
1-+jdrochlOOdc 1ablots: Mct."1<ione Hyd,.ochloriclc Toble<s '"' Or-.J Suspen- Cremalg'< Deep Heat Spray.~ Fie<y ld<k R<i<l•a<>-B Red o;i, Ralgex: responsible for the saliC)•lale concentrations found. The results
R<lgex Heat Spray (low-odour); Red Oa 1i-.nsvasin Heat Sp<ay; USA: h· also showed that methyl salieylare is extensively metabolised 10
thrican? Odor Frcci: ArJ'ricire T,..,ie Medicatedt. Musterole. s3licylic acid in the de1mat and subcutanc..--ous tissues after top1cal
Proprietary Prepa rations (details are given in VOiume 3)
Arg.: Gobbidor.z: Austral.: Bi.odcne; Physcptonc:; Austria: Hcptadon: application.
Belg.: Mephenon: Broz.: Metz.don: Mytedomt; Conod.: Meudol; Fin.:
Dolme<t. Hung.: Depridol; Metadon; l rl.: Phymel DTF: Plnadone DTF: Is- However. for a s·rudy suggesting limited absorption from ~patch
ra el: Adolan: Ital.: Eptadon~ Malaysia: _.Neptooe; MeK.: Rubidexol: Methyl S alicylate preparation containing camphor~ menthol. and mtthyl sahcylate,
Neth.: EP'.adcne; SymO<On: NZ: 8ioc:IOne: Melhaubs; Pclr>done; S.Afr.: Methyl Sal.: Methyle. salK:ylate de: Meth)ii Sat:cylas; Methytis sali- sec Menthol, p.2l67.
Phy!eptone: SpoJn: Metasedin: Switz.:·Ketalgine; UK: Eptadone; Martin- 1. Chan TYi\, rottntial danger$ from topical prcpar;itions <9111ain-
dale Mc.h<dooe l"ixlu<• DTF: Methado<e: Physeptonc; ~wtone; USk cylas; Methyl·salicyl~t Metil!'.akira;as; Mettls.lisilat Met~·szalicilat
Metylsalicylat: Mety!u salicylan: Metyylisalisylaatti: Salicilato de ing m~1hyl satic:ylatc. H11111 £.ip Toxicot 1 9~6; 1.s: 7~7-50. .
Diskets: Do&o,lfiine: Methadose. 2. Motta r. ,., ol. Serum concemr.uions ofsohcylic acid following
metilo. Methyl 2-hydroxybenzocte. lOpical applied s.aficylatc drri,•etiws. Amr Pliormru;olhf!r 19tl6~
MeTW\C<WiUMAa7 30: 93S-40.
Met hyl But etisalicylat e C 9 H 80 ; =152. I. 3. Cross SE. e1 .,, Is 1h~re 1irn.1t pem:tr:nion ;1fo::r appJica;.ion of
1opic;,I s~ l icylat.c formulsli<ms? Luncttt 1997~ 350: 636.
CAS - I 19-36-8.
&itetisalkilato de metilo: Methyl Diethyl2cet)1salicylate. Methyl ATC Herb - HM02i\W5005 (Gaultheria prcx:umber.s: es- Int eraction s
0-(2-eth)ibutyryl)sa11cylate. sential oil): Hlli02AW5001 (Betula lento: •ssentia/ oil). Absorp1ion of methyl salicylate throug)l the skin can occur a_ller
c,.H, 80, = 250.3. UNI! - lAV5U5022Y. excessive topical applica1ion (see Percutaneous Absorption,
The symbol t denotes a prepara1ion no longer aeti vely marketed
90 Analgesics Anti-inflammatory Drugs and Antipyretics
above). ond intemc1ioos would be expected to be a< for other sal· P reparations Incompatibility. See under Molphine Sulfale. below.
icylotes (see Interactions or Aspirii~ p.24). Proprietary Preparations (deiail• are aivrn in Volume U)
Anticoagulants. Po1entio1ion· of ..-a1fori11 anticoagulation has Jpn: Q;,opoin. Morphine Sulfate ©
bc!cn reponec1•·! aOct topical application of methyl salicylate MorliinislAfaatti: Mon•> Sulfai; Morlina. su!fato de; Mor1ino sulfa·
pre par.it ions. 1as; Morlinsu1fat Moritl-sul<at pentahydrat Morlin-srulfat: Mor-
I. U nlelon F. W3rf~rio 1nd 1 opi~I salicyhuu. JA,\fA 1990; 263: Morniflumate (W.N. 11NN) finy si.\rCL1n; Morphine. sulfate de: Morphine Sulphate (6ANM):
2888.
2. Tam LS. et al. Warfarin in1cu1c1ions with Chinese lr"ddi1i(lm1I Momiflumato: MomiOumatum: UP- 16'1. 2-Morpholinocthyl 2· Morphini sulfas: Morphini Sul<as Pen1ahydricus.
mcdicints: denshcn l\nd 11lc1hyl salicylale incdiceted oil. A11~t N (o..u.u-trifluoro-m-toluidino)nicotiriate. Mopiji<.1>1a CyAb<j>aT
ZJ Med 1995: 25: 258. MopH><~)'MaT (C 1 7H19NOJ)i.H2SO,,S H20 = 758.8.
J. Jou JO. l.cBlond HF. Pou:n1i11ion of war-farin Antic:oag.uJa1ion CAS - 64-31-3 (anhydrous morphine sul(ote): 621 t.15.
assoch1t1:d whh topic1I methyl salicylatc. Aun PltiJr,,,ocoll1<!'' C,9H2(fiN10, = 395.1.
2000: 34: 729- 3;. CAS - 65i:s4l-85-0. 0 (morphine sulfote pentohydrO(e).
ATC - A10/AX22. UN/I - X3P646A2j0.
Uses and Administration
ATC Vet - QMOIAX22. Pharmacopoeias. Jn Clli11.. Eur. (seep.vii), !111.• and US.
Methyl salicylale is• salicylic acid derh·a1ive that is irritant to the
UN/I- RI 33A1WH7XI. Ph. Eur. 6.8 (Morpt-one S""*'3te). A while or almosl whi(e,
skin and is used topically in nibefacicnt preparations for the relief
of pain in muoculoskclet:il, join~ and soft-tissue disorders. It is crystalline powder. Soluble in water; very slightly soluble in al-
also used for minor peripheral vascular disorders such as chil- cohol; practically insoluble in toluene. Protcc1 from light.
blains and as an ingredient in inbol•tions for the symp«>maric USP ll (Morptine s.Arate). White. fC3lhery, silky tTY>1als. cu-
relief of upper respiratory·tracl disorders. bical masses of crystals, or a white crysutline powder. Is odour-
less and when exposed to air it gradually loses water of hydra-
\V111tergrccn oil is also used in aromatherapy.
(ion. ll darlcensoo prolooged o.-posureto lighL Soboble I in 16of
Preparations waler and I in I or water a1 80°; solubl< I in 570 ofalcdiol end
BP 20 I 0: ~ 1\11.Mt. Melh)ol Sllocy'.ale l . . . - Mel¥ Saicytatt Orn- I in 240 of alcohol at 60'; insoluble in chloroform ond in ether.
_.., s..,<Jt 5tWIL S10tt in airtight containers at a (empcrann up to 400 as permit-
Proprietary Preparations (dca1ls are awcn in Volume 8) ted bY the manufacturc1. Protect from lighL
Alf" Rall Soll Get Auwol.: u-lt Conod.: 0..., ~ a.lie: U·
or\Jb Prctor. Ger.: - Nf: lr>dlo: Ooloodo ""°'
Mu.: 8'lsorno
~ fritcion Don ....I: Tollrc $.Afr" ~ Thai.:~ Hy-
Incompatibility. Incompatibility data for morphine have been
extcnsi,-ely stutlicd 1.l and may depend on many factors such as
gcsat UK: ~ Mul<lt Rob USA: e - f ; ~ Vcnu.: the fonnulation used, and order and ratio of mixing; 00-.-cver,
No.oLicf; lJllT>llf. Profile most slUdics ate usually only sbott term and ooolain few details
MulO.ini,..cr.. nt: ,..,..,...,.., prcpatOt'°"' n loted or.~ a. MomiOwnate. the morpholinocthyl CS(cr of niOumie acid (p.99). on mixing the same drugs in a variety ofdiJfe=t situations.
Homoeopathic: Cono<I" Strw L72t: "" l 71. is an NSAID (p.100). It has been used in inOamm•tory coodi· Morphine salts arc sensitive 10 changes in pH and morphine is
tions in doocs of 700 mg gi"cn twice daily orally or reel.Illy 1.< Jieble to be prccipilated out of solution in an alkoline environ-
suppositories. ment. Compounds incompatible with morphine salts include
M ofebuta.zone (rlNN) Preparations aminophyltine and sodium s;ihs of batbiturates and phcnytoin.
Mo<ebulatsoni: Mo<eoowon: Mofebvwona: Mo<ebvtazone: Pn>prietary Preparations (details are sivon in Voluni. 8) Other incompatibilities, somc1imes attributed to particular for-
Mofebu!azonum: Monobo.Jlazone: Monophenytbutai:one. 1- fr.: Nrft.Jrit Gr.: Ntiflamot hol.: Fbr'Nx: H~m: l""!Of'TWftu: NJ ant Spain: mulati011$, have included:
NillKtol. • Aciclovic sodium-precipitale noted 2 hours after admixture
Butyl-1-pllenylpyrazolidine-3.S·dione.
with morphine sulfate solution'
M*6yra:io"
• Chlorpromazinc hydrochloride injcciion-prccipitation was
C 1JHioN20; 232.3.= considered 10 be due to chlorocrcsol present in the morphine
CAS- 2210-63·1. Morphine (BAN) ® sulfale inj<-clion•
ATC - MOIAA02; M02AA02.
ATC Ve( - QMO/AA02: QM02AA02. Morliini: Morlin; Morfina; Morphinum. 7.8·Didehydro·1.S·epoxy· • Doxorubicin-addi1ion of morphine sulfa le I mg/ml to dox-
UNll - SPW36WU15Z. 17-methytmorphinan-3.6·dol oru bi c in hydrochloride liposomal injection
400 micmgramsimL in dextrose 5% resulted in turbidity
M~
ehanges5
C 17H 19 N0 3 = 285.3.
Fluorouracil······immediJile precipilDte fonned after admixture
CAS - 57-27-2 (onhyd1ous morphine); 6009-81·0 (mor-
of nuorouracil I or 16 mg/ml with morphine sulfa(e
phine monohydrcte). I mg/mL in dextrose 5% or sodium chloride 0.9%6
ATC - N02AAOI.
Furosemidt.~precipilatc noted 1 hour after admixlure with
ATC Ver - QNOlAAOI. morphine sulfate solu1ionl
UN/I - 7617G6Dl9C (mcr;>hine): 4iTQ665RIX (mor. Haloperidol-immcdialc precipitatioo seen after admixture of
phme mono~ydrcte). haloperidol and morphine sulfate soltrtion7
Profile Heparill sodium-incompatibility hos been rcponod from
MorehuW'.Onc. a deriVl>1ivc of phcnylbutnonc (p. 121 ), is on s1nigh1f01Wanl additive studics. 1 Another s1udy3 indicated
NSA!D (p.100). ll hos been used in 1he manaacmcnt m11sc1>- or th11 morphine sulfate and heparin sodium wen: only incoon-
loskde!al andjoinl disorders. The sodium salt hu boen given by
intramuscular injection. HO@
I h-
pa11blc 01 morphine sulfalc concentrations greater 1han
5 mafml and that this incompatibility could be pci.-.nted by
using 0.9% sodium chlondc solution as the adinixlUle diluent
P reparations
Proprietvy P re~nitions (de<oils ore g>Y<n in Volume 8)
q H rather than waler
Pethidine hydrochloridc--incompotibilily has been noted af-
~'" Moles.ll Nt· • NCH3
tt'T admixture with morphine sulfateI.•

Mofezolac (1IN'IJ HO-· h-

Prochlorpcnzine edisita1..-immcdiate prccipitaiion was at·
tribulcd to phenol in 1hc morphine sulfate injection
ronnulotion 10:ll
Mofezolac; Mofezolaco: Mofezolacum. N-22. 3.1·BIS{p-rnethoxy· Street names. 'The following lams have been used as 'strccl Promc1hazine hydrochlo~loudiness was reponed IO de-
phenyl}-5-isoxazojeacetic acid. names· (see p.vi)orslangnamcs for various fonnsofmorphine: velop when 12.5 mg of prome1huine hydrochloride wa.<
MO<j>e3C>MK Adolf; Block; China \Vhi1e; Cube; Dreamer; Dru& ston> elope; drawn into a syringe containing morphine sulfate 8 mg. 12
C,,HnNOs 339.3. = Drugstore dope; Emscl; First line; Gcnnan boy; God's drug; Go-
m3; Hard stuff; HospilDI Heroin; Hows; Hydrogen Bomb; M;
Others' have noted no incompatibility
CAS - 78967-07-4. • Ronitidine hydrochlorid~tal needles and/or sticky spols
UNIJ - RVJOBV3H3Y. Miss Emma; Mister blue; Mojo; Monf; Monkey; Morf; Morfs; seen in 3dmixtures of morphine hydrochloride and r:mitidinc
Morfa; Morphia; Morphina; Morpho; Morphy; Mr. Blue; M.S.;
hydrochloride in various ra(ios stored al difftrenl
MS; Mud; Murph)~ Nasly; Nazi; Sweet Jesus; Sweet Morpheus;
Tar; Unkie; White Sluf[ 1empcrorures1l
• Tetracyelinc~olour change from pale yellow 10 ligllt green
Morphine Hydrochloride (BAJWA)® 0<.-.:um:d when solutions or minocyclin• hydrochloride or tet-
racycline hydrochloride were mixed wi1h morphine sulfate in
Morfiinihydroldoridi: Monn HidrolJorur; Mortina. hidrocloruro 5% glucoi<e injcc1ion"
de: Morfin hido-ol<lorid; Moriin·hyd<ochlorid toihydrat Morlinhy- I. Pa1el JA. Phillips 01... A guide lo ph)'Sic.AI compatibility ofin-
drol<lorid; Morfono hidrochloridas; Morliny chlorowodorek: Mor- lravc.:nuus dru}l Hdmixlurc:s:. Am J }/<1$p Phorm 1966; 23:
phine. chloohydrate de: Morphini hydroc.hloridurrc Morphini Hy- 4()9-.11.
2. Vermeire A, Remon JP. St~bili 1y and compi1libili1y of morphine.
dro<:hlondum Trihydritum: Morphinii Chloriciim: MO<phirx.om Int J l'ltorm 1999; 187: 17-5 I.
Chloratum. J. Pu&" CD, #I t1l. Visual c.ompalibilily o( morphine suJphatc and
meJM'tidine hfdrochloridt wilh other injectable drugs during
MO~Ha r '1APO"''"P'IA simul11<d Y·111c in)cc1ion•.4m J Hosp Plwnn 1991 : 48: 123-5.
C11H19N0l-HCl.3H20: 375.8. 4. Cropper JB. Mixins c:hlorpromatinc and motphiflc:. BMJ 1975:
CAS - 52-26-6 (onl>ydrous r:iorphi.ic hydrochloride): i:l.>.

HO 0
6055·06· 7 (morphine hydrochloride (rihydrote).
UNI/ - )28GEOROVX.
5. Triuel l.A, <r ol. Compa1ibili1y of dcnorubiein hydrochloride
!ti~:~d~~:~::ti~~~ f~c~~P~t~~£.~:f~:~~! 1~~~:l1t~~1
PharmaGOpoeia.s. In Chin.• Eur. (seep.vii). /111., Jp11. and Vi•I. 2708-13. .
Ph. Eur. 6.8 (Morpl'ine ~) . Colourless, sill.)' nee- 6. Xu QA~ tr ol S1ab1hty and compatibili1y or nuorouraci1 with
Profile dles, cubical masses or a while or almost while, crystalline pow- morphine 1ulf11< •nd b)dromorpllooc hydrochloride. An• Phn,._
Mofczolac is an NSi\ID(p.IOO)given orally in the manag•'tnenl der. 11 is efflorescent in a dry anuosphac. Soluble in waler: mocorh<:r 1996; JO: 756-61
7. LeDelle MJ.• rt 111. Con1JNbb1lily of morphine and mid.:cotam or
ofpoin and musculookc:ldal and joint di.sordcrs. A usuel dose i$ slighdy soluble in alcohol; practically insoluble in toluene. Pro- ha'°Pefidol in p1rerueral admi.uurcs. Cnn J Hosp Pho!-111 199S:
15 mg three times daily. tea from lighL 48: 155~
All cross-refenences refer to enlrirs in Volume A
 Mofebutazone/Morphine 91
~. lh\~cr DE."'"'· Com1>::nibilit)' ofh-:parin sod ium und morphine Morphine is used for substitution therapy in the man- minis1ra1ion of a modified-release oral morphine prcparntio11
sulfoie. Am J H<n:p Phann 1985: 42: 1352-5. (MST-Cnn1i1111s: Napp. UK) and peak sen1m concenrrations were
agement ofneonatal abstinence syndrome (see Admin-
9. P:irl.:(:r WA . Physical crun1,:1tih1li(ics of pri!:lnC$t.hCtic mcd1ct1· almost lhree times as high. 2 Patients with ciJThosis had a grca.ter
lic.111~. Co11J llo.tpPlum111916~ 29: 91-:?. istration in Children, below). degree of sedaiion but none developed encepholopathy. It was
10. St~ vcuson JG. P~triarc:a C . Jncompaljbility ol' m<wphi1lc suli~le
:rnd prochlorpcru..ine edisyJotc in syringes.. Am J Ho.<:p Plwrm recommended ih3t the dose for modified-release prepara1ions
J98S; 41: 16~1. Adverse Effects and Treatment should be reduced and dw1 it be given less often when patients
IL Zuber ')EL. Comp;nibil i1y or morphine sulfutc inj1.:ctiu1'I :ind As for Opioid Analgesics in general, p. I06. have cirrhosis.
prochforpcro~ine edisylat{' injection. Am J llo.sp Phann 19Si:
44: 67. 0 References. In a lalerstudyl 15 pacients with liver cancer were given the same
12. f leischtr NM. r romethuine hydrochloride-morphine sulfme I . Cherny N. ttf tJI Str:Het{i..:~ lO m:m:igt the adverse effccls of otal
oral motphinc prcpara1ion and compared wich 10 he-•llhy sub-
incompatibility. Am J Hosp Plror·m 197:3; 30: 66.S. morphine: ;m e'-·i<.h:m.:e·bo1scd repon. J Clin 01rcol 2001; 19 ; jects from tl1e previous study; the area under the serum conc"Cn-
13. V~m1circ A. cf ul. A new mclhod to obtain and present compli.!te 2542-5~. 1rniiC1n-1ime curve of morphine was increased lhree- to fourfold
information on the compa1ibilit)•: snidy of i1s validily for eight in those whh cancer. 111e elimination half-life of morphine was
binary mixtures of morphine.: with drugs {r(.'(Juently used in pal· Effects on the cardiovascular system. For a refere11ce 10 the
effects of morphine on hisraminc release compared with some Jlso prolonged in patients with prhnary cancer when compared
liali\·c t:ire. Pollio/ Med2002; IG: 417-·24.
14. Nieves-Cordero AL, et ttl. Compa1ibilily of oarco1ic analgesic other opioids, see under Pethidine, p.118. witl1 healthy subjects and 1hose wi1h secondary met3'Utic dis-
solutio11s wilh v~nioos antibio1ics during simulated Y·site injec- ease. Adverse eftf:cts were more frequent in the primary cancer
tion. A"' J llosp Pharm I 9$5; 42: l I OS-9. Effects on the muscles. Severe rec1ovaginal spasms that nc- group and included 2 cases ofrespiratory depression; the authors
curTed in a patient givetl intralh~I morphine' were successfully commented thal altered blood-brain transportation may hilvc
Stabifity. INTRAVf'.NOUS PREPARATJONS. Solutions of morphine controlled with midazolam. been panty respoosible for such effects.
sulfate for intravenous infusion appear to be relatively stable. I. Liu1~U RA. et ul. Muscle spasms associated with intmthecal
Jn a study 1 solutions containing 40 micrograms/ml or t . Twyeross R. Wibx:k A. PtJl/i(J1ive Ccre Fc>nnulw:1'. 3rd ed. No1-
morphine therap)•: rrc~tm::nl wilh midnzot;nn. Clin Pharm 1992: 1ingham. Palli.a1ivcdn1gs.com L~d. 2007: 274.
400 microg:rams/mL retained more than 90% of their initial II: ~7-9. 2. Kotb HIM. e1 af. Pharmacol:ine1ies of controlled re'lease me>r·
concentration ofmorphioe sulfate when stored at 4° or 23° for Effects 01\ t~ nervous system. Myoclonus, ollen associated phinc.: (MST} in p~1 icnts wich Ii vet cirthosis. Br J Ai1oes1/t 1997;
7 days, "'11e1her or not they were proicctcd from light. Solu- . 79: &04-6.
wi1h hyperalgesi:i., has been reported in patients with advanced -'· Kolb HIM,'' 1d. Phaml3C(l,kinc1i c~ o r cC1nlrolted rele::ise mor-
tions prepared from commercially available i njection o r from
malignant disease treated with morphine. 1·' II appears Co be phine (M~'T) in paticms wj1h liver carciooma. Br J Anoestlt
powder. in 0.9% sodium ch loride or 5% glucose, and stored
uncommon with typic3l oral doses ofmorphine and is more often 2005; 9~: 95-9.
in PVC bags or glass bo!tlcs ~id nor differ in stobility from associated with high intravenous and spinal doses. Ncurocxcita-
one •nother. Jn a funher study- 10 ing/mL or 5 ing/mL solu- Phaeochromocyt0ma_ Morphine and some other opioids can
t(ll)' metabolites ofmorphine me often implico1ed in 1he develop-
tions of morphine sulfate in glucose or sodium chloride and induce the release of endogenous histamine and thereby stimu-
ment of myoclonus;::?.4.s however, other possible mechanisms
stored in porrable infusion pump cassettes retained more than late catecholamine release making them wisuitable for use in pa-
such as dnig interactions cannot be ruled out. 44
95% of their initi•I concentration when kept al 23° fo r 30 tients with phaeochromocytoma. For liirtherdetails, see p.107.
days. A -0.9% solution or sodiu1n chloride containing mor- It has been reported 1hat myoclC1nus indu.:ed by morphine can be
successfully controlled using a benzodiazcpine such as mida.. Renal impair ment- Severe and prolonged respirntory depres-
phine sulfate 2 mg/mL was stable for 6 weeks when scored in sion has occurred in patients with renal impaim1ent given mor-
polypropylene syringes at ambient temperatures in the light zolam.1 lndeed. some researchers' consider benzo<liazepines to
he the drugs of choice: clonazepam, diazcpam. and lornzcpam phine. Toxicity in 3 such patients was atlributed to the accumu-
or dark but a similar solution that also contained 0. 1% sodium lalioo of 1he acri\'e ine1aboli1e morphine-6-glucw·onide. 1 Plasina
metahisulfite lost 15% of its potency during the same period. 1 were mosr rrequently used. Dan1role11e5·t and gabapentin9 have
also been tried. · conccntr.itions of this metabolite were found~ to be ten times
Stability of such a solulion with or without sodium mclllbi- hi2lter th~n nonnal in a 7-year-old girl with haemo l)~i c uraemic
sulfite was considered to be unacceptable when stored in I. rotttr JM. Cl"'·
Myodoous :issoci:ikd with treatment wi1h h igh
syndrome given morphine inlr3venously although the half-life of
d oses of morphine: 1he role of supplemental drugs. BMJ 1989;
glass syritlg:es in the dark.4 299: ISO->. . morphine was also prolonged . .Plasrna concenltalions of mor-
A later rc,•icwS{which included some of the above studies) has J. Gfate PA. ti ul. Normorphine, a net1ro1oxic met.aboli1e? Lautt/ phinc-6..g lucuronidc were also rcported3 to be persislcnt1y in-
concluded that the degradation of morphine solutions is not af- 1990; 33S: 725-6. creased 19 days after slopping morphine by intravenous infusion
fected by oxygen, ligh~ diluent type, salt fonn, or morphine con· 3. Ot: Cunn<i F. f l 1,/. Hypcralgc:.sia nrtd ltl)'(h;lonus' with intralhCC-31
infusion of'high·dose morphine. Puin 1992~ 47: 337-9. in a J l·ycar~old girl with nonnal renal function. The authors of
ccnrration when stored w1der nonnal conditions; ic was consid- 4. Sjogren P. l!I ol. Hypcralgesia ;.md rny<.~donus in terminal canctr 1he report suggested that alrerations in bowel flora after antibac-
ered that morphine solutions could be stored for at least 3 months pa1ien1s 1rcated w ith con1inuous intr avenous m orphin~. Pnin terial therapy or inhibition of morphine·3·glucuronidc glucuro-
without st3bility problellls. 1993: 55: 93-7. nidation by lorazepatll might be responsible. It has also been
I. \l.:o('chio M . el t1I. ·rh~ stability of morphine inlravennu~ infu~ion
5. Mcf"('3<fantc S. ra1hophysiology and 1rea1mC""nt 01· opioid·rel:itcd rcpo11cd,. lhat acc·.nnulation of morphine can occur in renal fail-
myoctonus in cancer patients. Pui11 1998: 74: 5-9.
solo1ions. CcnJ Hosp Plrorm 19SS: 41: 5-9. 43.
6. Quinn N. M)'oclonus associalcd with high doses of morphine.
ure, although to a lesser extent than accumulation or metibolites
2. Walker SE. et al. Hydromorphone and mOfphine M;ibilily io pufl· BMJ 19$9; 299: 6$3-~. (see also under P'hannacokinctics. below).
nblc infusion puinp ca.MetltS and minibo.gs. Can J Hu.Tp Phann 7. Holdsworth MT. t)I nl. Continuous m id~w l am infusiM ror tlle I. Osborne RJ. f:I ;)(.Morphine into:dc:~tion in renal failure: the role
J98S: 4J: 177-82. management of morphillf·induced myocJonus. Ann Plwmwc:<'· ofm0<phinc·6·glucut0nidc. BM.J 1986; 292: 1548-9.
3. G rassby PF. Tht• s1ability of moq>hine sufphaie in 0.tJ prr cenl /her 1995~ 29: 25-'.l. 2. Hassclslri>m J. e! ol. Long f3$ting resp iratory dL'J>rcssion induced
sodium ch loride stored in p lastic syringes. Phorm J 1991; 248: 8. Ferris OJ. Conirolling myoclonus l'lftcr high-dosage morphine by morphin,~6..glucuronide'l Br J Clin l'harmorol 1989: 27:
HS24-HS25. infusions. A1r.J llen/1h.S1·11 Phon11 1999: 56: 1009-IO. SIS-JS.
4. Grassby PF. Hu1ch ings L. f";)cmrs tiffccting the physical und 9. Merc,;,0.ante S, el al. Gab~pen1in for opioiJ-rcla[ed myoclouus in 3. Calleja MA, ttl er/. rersistcnlly incre:.tstd morphinc-6·g_luc:u,-o·
chemic<il st:ibi1ity of morphine sulphate solutions s1ored in ~y · canter pa1ienls. S11ppor1 Care Ctmcer 200 I: 9: 20S-6. nide concentrations. Br J A11aest'1 1990; 64: 649.
ringcs. Jul J Plumu Proc1 1993; 2: jµ.3 , -L Osbome R, u1 af. T he pharma cokin~1ics of morphine and mor·
5. V..:nneirc A, Remon JP. Subilil)' llld compatibility of morphine. phin<: glucuronid<.'S io kidney foilure. Clin Pharmaro{ Ther '993;
/111 J Plt."ltW 1999: 187: 17-5 I.
Precautions 54: 158-67.
As for Opioid Analgesics in general, p.107.
OAAL PREPARATIONS. Sludics>.::? have shown that for optimum
stability of morphine cont<nt, Kaolin and Morphine Mixture Biliary-tract disorders. Seo under Precautions of Opioid·An- Interactions
(llP) needed to be stored in well-filled glass containers. algesics. p.107. for interactions associated with opioid analgesics, see
I. Hclllwe!I K. Giime P. Stabilily of moJl>hine in kaolin and 1nor. Breast feeding. Measurable blood concentr•Iions (>f morphine p.107.
phine.: mi~lun: BP. Phurm J 1981; lZ7: 128-9. have been detected in 2 breast-fed infants whose mothers re-
2. Hclliw'ell K. Jennings P. Kaolin and morphine m ix1ure OP: d- US licensed product infom1ation for some once-daily
ceivt-d oral or intratht.-cal morphine during ~nd after their prcg·
focts of con1::1incrs o n the stability of morph ine. Phm•m J 19$-:t:
nancies; hm~ver, no adverse effects were 1-eported in either of modified-release preparations of morphine sulfate
232: 68).
these infan1s.1.1 In a group of 7 women given patient-controlled states thal patients must not ingest alcohol, including
TOPICAL PREPARATIONS. When mixed with about 8 g of /11trn- analgesia with intravenous morphine at\er c::iesare3.11 delivery, alcohol-containing medicines, at the same time <lue to
site gel (Smith & Nephcu· Healthcare., UK) morphine sulfate. the conc..::ntnlions of morpl1inc ~md its metabolite morphine..6 the risk of rapid release and absorplion of a potentially
in a conce111ration of 1.25 mg/mL. remained chemically s1a- glucuronide in tl1e colostrum were found co be ve11• small.1 Al-
bJe over a 28-day period siored at 4 ° or at room lemperature. fatal dose of morph ine; in-vitro studies showed that al-
lhough no inf3nts were breast fed during the study~ it was consid-
irrespecfr,.c of light exposure. 1 However, uoless prepared un- ered 1ha1 rhe effecrs of matemal morphine on breast-fed inlllnts cohol accelernted the release of morphine.
der sterile conditions. the mixture should be used wi1hin i would be negligible.) The American Academy of PediaCrics' O For references to myoclonus associated with morphine and the
days bcc::iusc of the risk of microbial co11t:'lmination once the also stales 1hat the use of nmrphine is usually comJlGtible with coocu1re11t use ofo1her drugs. sc-e Effects on the Nervous System
gel has been opened. breast feeding. under Adverse ERects, above.
I. Zcppetdla G, et al. Stability of morphine sulphale and di:imor· I . Robieux I, l'l cil. Mo rphin~ <xcrc1ion in breosl m ilk and rcsulmnt
1
phine hydrochloride in lntrnsicc t;cl "'. Pollim Mtd 200!i: 19: cxpost1rc of a m.irsing infan1. J To.rif:oJ Cli11 To.ricol 1990; 28: Antibacterials. Potent enzyme jnduccr rifampici11 can reduce
I 3C-6. .lM~?O. the serum concet•••Hion of morphine and decrease its analgesic
2. Olierfam.Jr r Tf. t'I <ti. Prcn:na l and breast milk m orphine expo· effect;1 induce ion of the enzymes responsible for conversion of
sure follo wi11g m.J.lcrn31 in1rnthccal mor~'h i nc 1rcittmcn1. J Hum morphine 10 the active gtucuronidc metabolite did not seem to
Morphine Tartrate (at\NMj © LuCI 2000: J6 : 137-41.
occur.
Morlina. tartrato de. 3. B:llt3 N-E. ct al. Colositum morphine concentratiu ns <luring
postcesnrc:an intra.,..cnous paticnt·ccm trollcd enalgcsia. Am:'Slh I. Fromm MF. et al. Loss <lf :m.itgesic en'ect of morphine due to
McP4"><a TapTpaT Anolg 2002: 94: 184-7. coadmi11is1n'ltioo orrif:rnlpin. Pai11 1997; 72: 26 1-7.
(C n H;,l'J03)i.C,H606.3 H20 = 774.S. 4. Am.:rican Academy of Pedia1rics. 111e tr.ln$fCr of drugs and oth· Benzodiaz.epines. An addirive sedlltive eftecl is to be expe.:ted
c:r d1e111 it.-als into human milk. Pedio1rit:$ 200 1; 108: 7i6-89. between opioid analgesics :md bcnzodiazepines and has been re-
CAS - 302-3 1-8 (anhydrous morphine <artrote): 6032· (Retired Moy 2010) Corrcclion. ibid .; 1029. Also a v<1ilablc al:
59.3 (:ncrphme tarl:'o fe uihydrote). h u p: I:a appo Ii c y. a,. ppub Iic a 1ions . ors/cs i!c on ten t/fu 11 I p011ed wilh morphine and mido1olam. 1
Incompatibility. Sec under Morphine Sulfate, abo\"C. pt"diatric!>o/. 3b I 08/31776 (accessed 26.'06/08) For l'efel'ence to a suggestion that lorozepam may inhibit rnor-
Hepatic impairment- In view of its hepatic metabolism, cau· phine-3-gh.1curoll'dc glucuronidation, see Renal Impainncnt un ·
rion is generally advised when giving morphine lo patients with dc:r Precautions. above.
Dependence and Withdrawal I Tver~kov M. "' :1/. Mida2.0l3m.morphine sedative ioterac•ion in
As for Opioid Analgesics, p.105. hepatic impainnent {but :;ce under l'harmacokinetics, below).
The BNF 59 advises 1ha1 use should be avoided or \he dose re- p~1ients..'A11'::sthA11ul.~ 1989: 68: 23~-5.
Dependence associated with morphine and closely re- duced because of the risk of precipitating a coma. However, it Cisapride. Plasma concentrations of morphine have been in-
lated µ-agonists appears to result in more severe with- has also been noted that many paticots witJt hepatic impainncnt creased by or.JI ciiaptidc. 1
dmwal ~yrnptoms than that associated with ic-receptor tolerate morphine well. Ochers have considered that severe he- I. Ro~:botharn DJ.c•t o/. Eil'ccl or dsnpridc <'ll morphine absorp1io n
patic imJl"im1cnt may affecc morphine meubolism but less se- ofter oral JdmiDi!>lr31ion of sus1ai1lCd·1·clease morphine. Br J
agonists With mo1phine, withdrawal symptoms usual- vere impainnent docs not. 1 AHUf!Sllr 1991; 67: 421-5.
ly begin within a few hours, reach a peak within 36 to Tite mean elimination half:life of morphine in 12 patients with Histamine H 1-ant.a go.nists. See under Opioid Analgesics.
72 hours, and then gradually subside. ci1rl1osis wa~ ahnc><'t l\viee that in I 0 healthy subjects after ad- p.10$.
111e symbol t denotes a preparation no longer ac1ively marketed l11e symbol ® denotes a substance whose use may be restricted in cenain sports (seep.vii)
92 Analgesics Anti-inflammatory Drugs and Antipyretics
Local anaesthetics. Prior use of epidural chloroprocaine, $. McQuay H, Moore A. Me<abotism ofn<Jrcotics. BUJ 19S4;288; 11. Max MB, et al. Epidural and intrathecal opiates: ccrcbrospinal
when compared with lidocainc. has been reponcd lo reduce the 237. flu id and plasma profiles in patients w ith chronic cancer pain.
6. Moore A, ~I of. Morph.inc: kinclics during and <iftcr renal trans- Clin Phannocol 71ier 1985; 38: 631--41.
duration 1 and efficacy of epidural morphine analgesia. Howev- plantation. Clin P/iormac:ol Ther 1984; 3S: 64 J-S. 12. Nordberg G. e1 '11. ExtJDdural morphine: innucncc of adrenaline
er, a later study3 found no such ctfccis; the authors suggested that 7. McQuay HJ, tt al. Potency of oral morphine. lancer 1987; ii: admixture. Br J Ano.es1h 1986; 58: 598-604.
findings from the previous 2 studies were due to breakthrough t458-9. 13. Ionescu T l, el al. The phannacokinctics ofinlr3dur:il morph ine
pain caused by the early resoluCion ofchloroprocaine anaesthesia 8. Hanks GW, e1 al. En1crohc?3tic c;irculation of morphine. lancet in major abdominal surgery. Clin Phofmocokl11e1 1988; 14:
1988; i: 469. 178-86. •
occurring before the maximum onsel of morphine analgesia.
9. Osborne R, et al. Analgesic 3Cti,·ity of morphine·6--glucuronide. 14. Morgan M. The rational use of intralhccal and cxtradural opio-
f. Eisenach JC. et al. Effect ofptior at>e:nhetic solution on epidurnl lott<.'t l 1988; i: 828. ids. Rr .I Anoesth 1989; 63: I6S--88.
morphine ana1gel>ia. Ane.flhAnolg 1991~ 73: 119-23. 10. Hanks GW. Wand PL Enterohepatic circulation of opioid drugs: IS. Vi sc:u~i ER, et al. Pharmacokinetic.s of ex1endcd-rekase epidur-
2. Karambelkar DJ, Ramanathan S. 2-Chloroprocaine antagonism is it clinically rclc\'anl in the treatment of cancer patients? Clin al morphine sulfate: pooled analysis of six clinical ~ud i cs. Am
of epidural morphine analgesia. Aao Aruusthesiol Scand J997j Phonnacolcinel 1989; 17: 6S-8. J Htnlth-$}'1 Phann 2009; 66: t020-3Q.
41: 774-8. 11 . Paul D. et al. Phurmacological chsrnc1criz.ation of rnorphine-6p- 16. Osborne R, e1 al. Morphine iand mccabolite beha:vior .,.ftc1 difrf:'r•
3. Hess PE. et nl. Chloroprocaine may not affect epidural morphine glucutonide, a very p0tent morphine mc1.ab0Ji1c. J Pltarmocol cnt routes of morphine administration: dcm)nstration of the im-
for postccsarcan delivery analgesia. J Clin Anesth 2006; J 8: fap Tht:r 1989; 251: 477- 83. portance of the active metabolite morphine.6-glucuronide. Clin
29-33. 12. Hanna MH, e1 nl. Analgesic effic.acy and CSF pharmacokinc1ics Pharmuca/Thtr 1990; 47: 12-19.
of inuathteal morphine-6-glucuronide: comparison with mor- 17. Oabul N, Darke AC. Dis.position oC morphine and its glucoro·
Metoclopramide. The effects of mctoclopramidc on mor- phine. 81·J Anncsth 1990; 64: $47-50. nidc me13bo)ites after oral and rectal administration: evidence
phine have included an increased rate of onset and degree of se- 13. ~bnmc R. et al, Mnrphine and mctaboli1e behavior :ifter differ-
ent routes of morphine administr.rtion: dcmonslration of the im~ of route specificity. Clin Pllormocol Ther 1993; S4: 28~92.
dation when oral meloclopramide was given with modificd-rc- ponance of the active metabolite morphinc-6-glueuronidc. Clin suCCAL ROUTE. Conflicting results from studies on buccal
lcase rnorphine 1 and antagonism of the effects of morphine on Phormocol Ther 1990: 47: 12-19. morphine may reflect differences in formulation' and hence
gastric emptying by intravenous meloclopramide.2 14. Mc.Quay HJ. et cl. Oral morphine in cancer pain: inOut:nces (m
morphine and metabolite conccnlDtion. Clin Phormocol Thcr absorption. Sorne'2 reported equivalenl analg~sia wilh bucca1
I. Manara AR, et al. The effect ofme.oclopramidc on the absorp- and intramuscular morphine although others' found marked
tion cf oral controlled release morphine. Br J Clin Phormucul 1990; 48: 236-44.
) 5. ~~~~j~·:~ ~:i~h~~~:lt~~~.o~r'}°A~~~~~i>l~~ulc;uJ~~jld0c3:~~
1988;25: 5 18-21. interindividual variability wilh mean peak scrum concentra·
2. McNeill MJ. et ol. £ffec1 or iv metodopramide on gastric emp- tions of morphine some eight 1imes lower after a buccal tablet
16. Ponenoy RK. et ol. The metabolite morphine--6-gluc:uronide
t ying after opioid premedical ion. Br J Anoestlt 1990: 64: 450-2. contributes to the anolgcsio produced by morphine infusion in 1han after an intramuscular injection and occurring a mean of
patients wilh pain and norms) renal function. Clin Pharmocol 4 hours later. Morphine sulfate in aqueous solution has been
Tricyclic antidepressants. Both clomipromine and am- Tlier 1992; 51: 422- 31. reported to be modera1ely well absorbed from the buccal mu-
itripryline significanlly increased the plasma availability of mor- 17. Thompson Pl, et al. Respir.alOI)' depression followi ng morphine cosa.' Absolute bioavailabilily for morphine was estimated lo
phine when given to cancer patients talting oral morphine solu- a.nd morphine-6-gJucuronide in normal subjects. Br J Clin Pltar- be 23.8% after an oral soJUtion, 22.4% after a modified-re-
tion. 1 It was noted however that the polentiation of the analgesic mocol 1995;40: 145-52.
lease oral tablet (MST Conlinus: Napp, UK), and 20.2% after
effecis of morphine by these drugs might not be confined to in- 18. LOLSch J. GeissJinger G. Morphinc-~glucuronide: an analgesic
of the future? Clin PhormMokinel 200 I; 40: 485-99. a modified-release buccal tablet, with peak plasma-morphine
creased bioavailability of morphine; the dose oftricyclic to use
5
19. ~~f:P~ia~Co,;~,,;~~~~~·,r,::~~~~~~n~~~~s ~{~<'rphinc. J
concentrations al 45 minutes, 2.5 hours, and 6 hours, respec-
with morphine in the treatment of crncer pain should be decided t i\1ely; mean ratios of area under the plasma concenlration-
by clinical ev-•luation rather than by phannacokinetic data. 20. Wittwer E, Kem SE. Role of morphine's melaboliles in analge-
time curve for morphine-6-glucuronide to morphine in plas-
I. Ve~tafridda V, el al. Antidepress:i.nis increase bioavailability of sia: concepts and controversies. AAPS J 2006; 8: E348-E352.
ma were 11 :1 after buccal and oral morphine compared with
morphine in caocer patients. Ltmce1 1987: l: 1204. 21. van Dorp ELA, etc/. Morphine-6-glucuronide: morphine's sue·
ce~ for p0stopera1ive pain relief? Anesth Annlg 2006~ J 02: 2; I for intravenous morphine.' ·mere was considerable inler-
1789-97. subject variation in plasma concenlrations of the morphine
Pharmacokinet.i cs 22. Smith MT, et al. Morphine-3-glucuronide-a potent anlagonist metabolites, morpbine-3-glucuronide and morphine-6-glu-
of morphine analgesia. life Sci 1990; 47: 579-85.
Morphine salts are well absorted from the gasrrointes- 23. Morley JS, el al. Paradoxical pafo. LClncet 1992; 340: 1045. curonide after buccal doses of morphine as a modified-release
tinal tract but have poor oral bioavailability since they 24. Morley JS. et al. Methadone in pain uncontrolled by morphine. fonnulation,6 and lack of pain relief was subsequently report-
undergo extensive first-pass metabolism in the liver
Lonee/ 1993; 342: 1243. ed with this buccal fonnulalion.1 Poor abs·>rption of morphine
Administration. There have been many studies on the phar- from modified-release buccal tablets when compared with in-
and gut. After subcutaneous or intramuscular injection tramuscu lar injec(ion was a lso reported;& bitterness of the tab-
macokineties of morphine given by various routes and methods.
morphine is readily absorbed into the blood. The ma- These include the buccal route (see below), modified-release oral lets, leading to their premature removal, and poor dissolution
jority of a dose of morphine is conjugated with g)u- preparations, 1.l the rectal route,'" the topical route,l the pulmo- may have contributed.
curonic acid in the liver and gut to produce morphine- nary route,6.7 continuous subcutaneous compared with intrave- I . C:Jlveyrn, Willi3mS NE. Phannacokinctics ofbuccal morphine.
3-glucuronide and morph.ine-6-glucuronide. The latter nous infusion.,8 and U1e intraspinal route.9-IJ BrJ AnoeSlh 1990; 64: 256.
2. Bell MOD, et al. Buccal morphine-a new route for an3lgesia?
is considered to contribute to the analgesic effect of Slow dural transfer of morphine and its prolonged presence in Lancet l98S~ i: 71-3.
the CSF appear to correlate with its slow onset and long duration 3. Fisher AP, et of. Serum morphine «inccntrations ii\ er bu«:31 and
morphine, especially with repeated oral doses. Mor- of action by epidural and intralhecal injection." Modified release intramuscular inorphine administration. 81 J Clin Pbormocol
phine-3-g)ucuronide on the other hand can antagonise epidural preparations have further extended the duration of mor- 1987; 24: 685-7.
the analgesic action and might be responsible for the phine. u More lipid-soluble opioids, such as diamorphine and 4. Al·Saycd·Omar 0, "'al. lntluenoc of pH OD !he bucc:d absorp-
pethidine, enter and leave the CSF more rapidly than morphine. tion of morphine sulphate and its major metabolite, rnorphine--3~
paradoxical pain seen in some patients given mor- glucuronide.J Phorm Plrort11ocol l987; 39: 934- 5.
phine. Other active metabolites include normorphine, The phannacokineties of morphine given by 5 different routes- S. Hoskin PJ, ct al. The bioav3il;ibjlil)' :md ph:irm3c('lkinetics of
i.ntravcnous bolus injcc1ion and ora1, sublingual, buccal., and morphine after intravenous, or:.1 and buccal adminisua1ion in
codeine, and morphine ethereal sulfate. Entcrohepatic moditicd-rele.'.lse buccal tablets-were studied 16 with particular healthy volunteers. Br J Clirr Pltarmoeol J9&9: 17: 499-505.
circulation probably occurs. Morphine is distributed reference to morphine-6-glucuronidc, the active metabolite. Tiiis 6. Manara AR, et bl. Phuin;icokinetic.s uCmorphine foll owi n~ ad-
throughout the body but mainly in the kidneys, liver, metabolite occurred in large quantilies afler intravenous doses ministnlion by the buccal route. Br J ,inoc31h 1989; 62:
and plasma concentrations rapidly exceeded those of morphine. 498-502.
lungs, and spleen, with lower concentrations in the i. M1mara AR, et ol. Analgesic efiicacy of pcriopt!rati\•e hurcal
After oral doses morphine-6-glucuronide and morphinc-3-glu-
brain and muscles. Morphine crosses the blood-brain morphine. Br J Ar1ve~·1h 1990; 64: 551-5.
curonide were present in quantj1ies similar to those seen after in- 8. Simpson KH, e1 al. An inveSligation of prcmodicatioo wilh mor-
barrier less readily than more lipid-soluble opioids travenous morphine; morphine concentrations in plasma were phine giv~n by !he buccal or intramuscufar route. Br J Clin Phor-
such as <liamorphine, but it has been detected in the very low and the mean morphinc-6-glucuronide to morphine macol 1989; ?7: 377-80.
CSF as have its highly polar metabolites morphiJ1e-3- area under the concentration-lime curve ratio was 9.7 to I. There Cbildren. ll1c phannacoki11e1ics of mo.,:hine in children •re
glucuronide and morphinc-6-glucuronide. Morphine was delayed absorption with attenuation and delay o( pe•k mor-
generally considered similar to those inadult.s;'" in both an elim-
phine and metabolite plasma conccntrJtions afler sublini,'W!I or
diffuses across the placenta and traces also appear in buccal dosage.
ination half-life of about 2 hours has been reported after intrave-
breast milk and sweat. About 35% is protein bound. nous administrdtion of mo~hjne. In 11eono1es! ho~vevcr, clear~
Compared with orar doses, concentra1ions of morphine were ance is 11:eneral!y reduced ·1 and phannacokineucs are more
Mean plasma elimination ha11:1ives of about 2 hours higher and those of its glucuronides lower when morphine was variable.1· 10 Studies'·" have found significantly higtier plasma
for morphine and 2.4 to 6.7 hours for morphine-3-glu- given rectally," suggesting avoidance of first-pass metabolism. concentrations of morphine and a significantly lower morphine-
curonide have been reported. Morphine was not absorbed systemically when applied topically 6-glucuronide to morphine ratio in neonate.• when compared
10 ulcers although some absorption may occur when a large sur- with older infants and children; however, the morphine-6-glu-
Up to I0% of a dose of morphine may evcnt\1ally be face area is involved. 5 curonide to. mo~ine-3-gJucuronide ratio remains conslanl irre.
excreted, as conjugates, through the bile into the fae- J. ·Pinnock CA, et al. Absorption of controlled 1·cltase morphin~ spective of age. Elimination half-livesof6.7 and 10 hours have
ces. The remainder is excreted in the urine, mainly as s ulphale in the immediate postoperative per•od. Br J Ai;oesth been reported in tenn and pretenn infants, respectively afler a
1986; 58: 868-71.
conjugates. About 90% of total morphine is excreted in 2. S~varese JJ, et al. Steady- stitc pharmacokinctics of controlled single intravenous dose of morphine, with nearly 80% of the
24 hours with traces in urine for 48 hours or more. . rele3se oral mofl>hine sulph:ite in hcahhy subjects. Clin Phor- dose remaining unbound.a The reduced cleara~ce, which is. de-
macokl11e11986: 11: 505- 10. pendent on gesiational age and birth weigh1, 12·" 2nd higher mor-
0 Much has been published 011 the metabolism and disposition of J. Moolcnaar F, et al. Dras~ic lmprovcmcnl in the rectal absorplion phine concentrations are probably due to reduced meiabolism in
morphine and its relevance to the clinical use of morphine, in profile of morphine in man. e·,,,. J Clin Phannocol 1985; 29:
119-21. nc-onates as well as immature renal functio11: tbe capacity to con-
particular the analgesic effect of repealed oral doses and the rel- 4. Cole l, c1 al. fun her development of a morphine hydr0gel sup- jugate morphine by glucuronidation is reduced in prctenn in-
ative pocency of oral to parenteral cbses. There has been uncer- pOSitory. Br .I Clin Plmrmocol 1990; JO: 781-6. fants,6.9.•• and some premature neon•tes >n3Y lack the capacity
tainty as to the comribulions in mari of first·pass metabolism in 5. Ribci.ro MDC, et al. The bioavail3bility of morphine ~pplicd entirely.•
the liver and gut,'"' the possible role of renal metabolism.~•·• 111e topic:slly to cut3neous ulcers. J Pein Symptom Manage 2004;
27: 434-9. I. Stanski DR. et ol. Kinetics of high-dose inlravenous morphine
analgesic activity and clinical importance of the metabolite mor- 6. Masood AR: 'Jlloinas SHL. Sys1cmic <1bsorp1ion of ncbulized in c.ndiac surgery patients. Clin Phnrma::ol Thcr 1976; 19;
phine-6-glucuronide,2·'"" and entercl1epatic circulation.'° There morphine compared with oral morphine in healthy subject-.. Br 752~.
has also been interest in the effects of the me1abolite morphine- JC/in Phnrmacol 1996; 4): 250--2. 2. Dahlstrom 8 , er al. Morphine kinetics in children. Clin Pltormu-
3-glucuronide.1921-24 7. Ward ME. ef of. Morphine pha1macokinclics after pultno1lary co/ Ther 1979; 16; 354-65.
administration from a novel aerosol delivery system. Clln Phor· 3. Olk.kola KT, el al. Clinical pharmacokine1ics and pbamlac:ody-
I. Hanks GW, Ahet"ne GW. Morphine mclaboli.s-m: docs 1he renal moool Ther 1991; 62: 59H09. oamics of opioid analg_e-'!'ics in infant..: and children. Clin Phm·-
hypothesis hold wotcr'? Lancet I 98!; i: 221- 2. 8. Waldmann CS, et al. Scrum morphine lt:\·ds: 3 comparison be· mocokim!I 1995; S: 385~04.
2. H;,nks GW~ et"'· Explanalion (or pCitcncy ofrepeated oral doses tween continuous subcutaneous infusion and continuous intr3· 4. Koren G, ct ol. Postopcra1ive morphine infi.:sion in newborn in·
of morphine? Lonee/ 1987; ii: 723-S. venous infusion in postoperative pa1ients. A11ne.rtltesio 1984; fants: assessment of disposition charncleris1ics and safety. J
; . Moore RA, cf al. Opiate mctaboli!m and excretion. Bnillieres 39: 768-?J. Pediatr 1985; 107: 963-7.
Clin Anaesrhesio/ 1987; I: 829- 58. 9. Gustafsson LL. tu al. Disposition or morphine in c.erebrospin31 S. Lyn.n AM, Slattery JT. Morphine ph2rmaeckinctics in c:atly in·
4. Sodcnham A, et al. Extra.hepatic morphine mel3bolism in man nuid afte.r epidural administration. Lant:et 1982; i: 796. fancy. A11esihe.iology 1987; 66: 136-9.
during the ~ n h~tic ph:!SC o( orth»lopic liver 1ransplan1a1ion. 10. Moore A, et al. Spin;il Ouid kinetics or morphine and heroin. 6. Choona ra IA. el of. Morphine metabolism i11 children. Br J Clin
Br J A"nesth 1989; 63: 380-4. · Cll11 Phormocol Ther 1984~ 3S: 40-S. Pharmocol l989; 28: 599-604.

All cross·references refer 10 entries in Volume A

 Morphine 93
7. OouwinccJ.1er NJ, et al. Ase- and 1hcr::ipy-rcl3h:d cffoe ts on Uses and Administration • Doses of up to 15 mg have been given by slow imra-
morphine rcquir'l.!menrs ;:ind pl:.'ISma concentra1ions of morphine
and ils ml!tabolilcs in po.stopcrJth•c inr:uu~. Br J Anuesth 2003: Morphine, a phenanthrene de1ivative, is the main alka- venous injection, sometimes as a loading dose for
90: 642-S2. loid of opium (p.109}. lt is now commonly obtained continuous or patient-controlled infusion. For con-
$. Oho.1 R. et al. Pharm:icokinelics of a single dose of morphine i1l
prcte:rrn infants during \he lirst wed~ of life. J PeJmtr I 99(); from whole opium poppies (Popover somniferum) tinuous intravenous administration maintenance
117: 477-6 1. which are harvested as poppy straw; a concentrate of doses have generally ranged from 0.8 to 80 mg/hour,
9. Bhat R, et al. Morphine metabolism in acutely ill prctcrm n~\\'­ poppy straw is known as CPS. although $Ome patients have required and been given
born i11fzn1s. J Pediotr :992~ 120: i9!\-9.
IO. Harth:/ R. el ol. Phamucoki1,etiC$. of motphioe il\fusion in pre- Morphine is an opioid analgesic (p. I 08} with agonist much higher doses. Similar doses have been given
maturt neonates. Arch Dis Ch;tc.1 1993; 69: 55-8. activity mainly atµ opioid receptors and perhaps at K by continuous subcutaneous infusion.
I·1. Bouw11t~cstcr NJ. et of. Poscoperative pain in rhe ncon:uc: agc-
related differences in morphine requirements and metabolism. and Ii receptors. It acts mainly on the CNS and smooth For myocardial infarction, theBNF 59 recommends
/111e11.'iive Core Med2003: 29: ~009 - 1 5 . muscle. Although morphine is mainly a CNS depres- that 5 to I 0 1J1g may be given by intravenous injec-
12. Soon CS, er al. Morphine pham13cokine1its :ind pain asscss-
rnenl i't prcmaiurc ncwborns.J Pediatr 1999; 135: 423-9. sant it has some central stimulant actions which result tion at a rate of I ·to 2 mg/minute followed by a fur-
13. Saarcnmnu E. et al. Morrhine cl<"0;rance and effeclS in newborn in nausea and vomiting and miosis. Morphine general- ther 5 to I 0 mg if necessary; half Ibis dose should be
infants in relation to gcstationa I age. Clilt Phonnacol Tl1er
2000; ~8: I~.
ly increases smooth muscle tone, especially the sphinc- used in elderly or debilitated patients.
ters of the gastrointestinal and biliary tracts. • !ntraspinal doses are in the region of5 mg for an in -
The elderly. The pharmacokinetics of morphine were
compared 1 in 7 heallhy elderly ( 60 to 69 years) and 13 healthy Morphine may produce both physical and psychologi- itial epidural injection; if pain relief is unsatisfactory
young (24 to 28 years) subjects, after a single intravenous injec· cal dependence (see p. I 05} and should therefore be after one hour, further doses of 1 to 2 mg may be i:Jv-
tion of morphine sulfate I0 mg pet 70 kg. Although the tenninal used with discrimination. Tolerance may also develop. en up to a tola) dose of I 0 mg per 24 hours. The rec-
rate of drug. disappearance from plasma was taster in the elderly
group, apparent volume of distribution at steady state was about Morphine is used for the relief of moderate to severe ommended initial dose for continuous epidural infu-
halftl1at of the young group and ptasma clearance was reduced. pain, especially that associated with cancer, myocar- sion is 2 to 4 mg per 24 hours increased if necessary
I . Owen M., et al. Age~rcl:itcd niorphint kine1ics, Cli,, PhOrmor.ol dial infarction, and surgery. In addition to relieving by further doses of 1 to 2 mg. A modified-release
Tl>er 1183; 34: 364-8. pain, morphine also alleviates the anxiety associated fonnulation of liposomal morphine sulfate for lum-
Hepatic impairment. The liver is a major site of morphine wilh severe pain and it is useful as a hypnotic where bar epidural use is also available for the treatment of
metabolism and therefore hepatic impainnent could be expected sleeplessness is due to pain. It is also used in the man- pain after major surgery; doses range from I 0 to
to affect elimination (see under Precaulions. above). TI1ere is 20 mg, depending on the type of surgery, and should
some evidence thal in cirrhosis glucuronidation might be rela-
agement of neonatal abstinence syndrome (see Admin-
tively SJY<ted compared with otber melabolic processes and Iha! istration in Children, below). be given before the operation, or after clamping of
some extrahepatic me1abolism may occur. Several sludies have Morphine reduces intestinal motility but its role, if any, the umbilical cord if used during caesarean section.
served to illustrale d1ese points: in ihe symptomatic treatment of diarrhoea is very lim- It is intended for single-use only and no other drugs
• Hepatic extraction of morphine ;.,;s impaired in cirrhotic pa- ited. It also relieves dyspnoea associated with various should be administered into the epidural space for at
tienlS, bul less d1on expccled1 least the next 48 hours,
conditions, including that due to pulmonary oedema
Morptine metabolism was minimal during the anhepatic • Jntrathecal use of morphine and its salts has tended
ph~se of liver traosplanunion, hut increased markedly when
resulling from left ventricular failure. It is an effective
the new liver was reperfused 2 cough suppressant, but codeine is usually preferred as to be less common than epidural. Doses of
• Morpl:ine metabolism was vi1tually complete after liver trans- there is less risk of dependence; morphine may howev- 200 micrograms to I mg have been injected intrath-
plantation wi1h only 4.5% unchanged morphine being excrel- er be necessary to control intractable cough associated ecally on a single occasion.
ed in the uri1>e 24 hours after administrationl with tenninal lung cancer. Morphine has been used For details of doses in children, see below.
• Morphine elimination was reduced when hepatic blood flow pre-operatively as an adjunct to anaesthesia for pain re-
was impaired4
In acute pulmonary oedema 5 to JO mg may be given
lief and to allay anxiety. It has also been used in high by intravenous injection at a rate of2 mg/minute; half
1. Crouy 0, l!I al. lfcpalic C~lraction or morphine is impaired in doses as a general anaesthetic in specialised procedures
cirrhosis. Eiw J CJ;,, P'1(JrmCJc<>I I9$9; 36: 501-6. this dose should be used in. elderly or debilitated pa-
2. 0odenham A, el al. Extraheponic morphine metabolism in man such as open-heart surgery. tients.
during lhc anht!pa1ic phsse of orthotopic fo"er tr31lSplarnation. Br
J AINJ<ilh I989; 63: 3SH.
Morphine is usually administered as the sulfate, al· For the control of intractable cough associated with
3. SheJJy MP. r.1 tJI. Phnnn:Jcokinetics of morphine in plticnts fol- though the hydrochloride and the tartrate are used in te1minal lung cancer, morphine oral solution is given in
lowing orthotopic liver transplllnt:ition. Br J A1taes1lr 1989; 63: similar doses. Doses are expressed as the salts. Dosage
375.-9. an initial dose of 5 mg every 4 hours.
4. Manan AR, et al. Morphine elimination and l iv~r blood f1ow: 3
routes include the oral, subcutaneous, intramuscular, As a deterrent to abuse a combined oral preparation of
study h paticnls undergoing distal spleuottnal shunl. Br J Jfwp intravenous, intraspinal, and rectal routes. S\1bcutane·
M"f 1989: 42: 14$ (obs1ract). morphine sulfate and naltrexone hydrochloride is
ous injections are considered unsuitable for oedema-
available in some countries.
Renal impairment- Only a small amount of morphine is ex- tous patients. Parenteral doses may be intennittent in-
creted ur:chonged in the urine. There are conflicting reports of jections or continuous or inte rmittent infusions Administration. CONTINUOUS INFUSION. Both acute and
mo?;hine accum_ulnt~o.,n in patients '"ith renal impainnent; so?"e chronic pain have been conlrolled salisfactorily by continu -
for, ·• oU:ers agauisl.' .. Ii does seem cleor though U1at morph111e
adjusted according to indiv idual analgesic require- ous intravenous or subcutaneous infusions of morphine
mcaaboWcs accumulate in such paticntsS-9 including those on me111s. sulfa1e1·; but di•morphine hydrochloride or hydromorphone
periloncal dialysis;to the half-life of the ac1ive metobolite mor- Doses should generally be reduced in the elderly or de- hydrochloride may be preferred for subcutaneous infusion be-
phhie-6-glucuronide was reported to be prolonged and ils ~lcar­ bilitated, or in patients with hepatic or renal impair- cause their greater solubility in water allows a s111aller dose
ance reduced when 1norphioe-6-glucuronide was given to pa- volume. Continuous subcutaneous infusions may be preferred
tients with renal impalrment. 11 Opioid intoxication 12 and a
ment (see also under Precautions, above). to continuous intravenous infusions:' Continuous. subcutane-
prolonged opioid effea 11 in patients with renal failure has been For pain: ous infusion may be less effective than epidural morphine for
associated with 111orphine-6·glucuronide (sec also under Pr=u- • Oral doses are usually equiva lent lo 5 to 20 mg eve- relief of postoixrative pain;1 however, ii was slill considered
tions, above). 10 provide sirnplc and relatively effective analgesia with a low
I. Bl!.11 flJ, er al. Renal fai lvre and the use of morphine in intensive
ry 4 hours and may be given as an aqueous solution rate of adverse eOccrs.
c::ire. Lo11rt 1 1985; i: 784-6. of the hydrochloride or sulfate, as modified-release See also l'atient·controlled Analgesia, below.
2. Osl>ome R, et al. The phannacokinctics of morphine and mor· granules or tablets, or as immediate-release tablets. I . Waldm0;nn CS, et al. Scrum morphine lc,·ets: ~ comparison be·
phine s;lucuronidcs in kidney foilurc. Clin Pha,.mocol Thcr
1993; 54: 156-07. With modified-release preparations the 24-hour dose cween con1inuo11s subcut;aru:ous infusion and continuou$ intra\'e-
n~us infusion in postoperative patients. Anae.fthC!sia 198-4; 39:
3. Sawc J. e1al. Kinetics of morphine in P•lliet11s with tc::na1 failure. is usually given as a single dose or in 2 divided dos- 768-7 1.
Lonct'i i985; ii: 2 11.
4. Woolncr OF. e1of. Rcn;al faiJurc docs nol impair 1hc mctnbo1ism
es; in the USA, a modified-release preparation (MS 2. Goudie TA. el al. Continuous sobc-utsncous infusion of mor-
ot' inorrhinc. Br .I CUn Pharnmr'ol '986~ 22: 55-9. Contin, Purdue) that allows dosing every 8 or 12 phine for po5k>pcrative pai1l relief. Anaesthes;o 1985~ 40 :
$, Chat.:vin M. et al. Morphine ph:umacokinc1ics in renal fai1urc.
t086-92.
hours is also available. With all modified-release 3. Slu:in GJ. cl a/. Continuous imravcnous morphi11c: infusions for
Ancs1besiolog)' 1987: 66: 327-31.
6. S!l.we J, Odar·CederlOf I. Kinciics of morphine in pat)cnls with preparations, additional doses of a conventional for· 1crminal pain control: a rctrospeclivc review. Drug lnre/I Clin
Plrorm 1986; ?O: 968-72.
renal "::iilure. £'11r .f Clin Pl1armocol 1981; 32: 371-82. · mulation may be needed if breaktlU'ough pain oc- '°'· Dtexe-1 H. Long~1cm1 con1inuous subcutaneous and il\travenous
7. Wo lffJ, Cl al. lnOucocc ofrcna' function 0:1 the climin31ion or curs. As with the other routes, high oral doses may
morpl1ine and morphine gluc:uronidcs. £,,,. J Clin f'lmrmocof opioid infusions. lo11cc1 1991; 337: 979.
S. Hindsholm KB.~1 ol. Continuous subcutanc:ous infusion of mor-
tq8S:34: 3S3-7. be required for effective analgesia in palliative care.
8. Scar JW. et al. Studies on morphini:: disposition: influence of phine- all alterootivc lo cxtradur:::il n1orphinc for pastoper:itivc
re.oat failute on the kinetics of morphim: ;;md its inetubolilcs. Br • Motphine is sometimes given rectally generally as pain relief. Br J Auc~11l1 1993; 7i: 580-2.
J Ano!:.sth 1989; 62: 28--32. suppositories in doses of 10 to 30 mg every 4 hours. INYRA·ARTICUl.AR ROUTE. lnlfa.. articular injection of morphine
9. Peterson GM. ct al. Piasma it\·els of morphine and mor,>hine Oral modified-release preparations have also been
glucuronidc:s in the 1JC31men1 of cane<:r pain: relationship to re· into the knee at the end of arthroscopy has been reponed to
nal fu11c1ion :ind route of administration. Elw J Clin Plum11<Jcof used rectally although such use is unlicensed in the provide some degree of poslopcralive pain relief; '·1 snch pain
1990:38: 121--4. . UK and is generally not recommended except, pos- relief may be more pronounced lhan thal produced by the
10. P~ul i.M3gnus c. et al. Pharmacokinc1ie-s of morphine and i1s $~J1le dose given intfavenousJy 1 OT ifltr31DllSCUlarly. l The ef-
gll1Cuionides following intravtnous administri:uion ofmorphint sibly, in some emergency situations. fect appe~s 10 be due to the action of morphine on peripheral
in psticnt.s undergoing continuous ambul;uory peritolleal dialy· • The usual dose by subcutaneous or intramuscular
sis. N~·phrol Dif1/ Tnmsplant 1999; 14: 903-9. opioid recepiors 2 although a systemic effecl has oot been
11. Hanni MH, et al. Morphine--6-gJucuronide disposition in rC1)aJ injection is I 0 mg every 4 hours but may range from completely excluded.'
impairment. Br J Anae.slh 1993; 70: SI 1-14. 5to20mg. ·niere have been conflicling results on wbelher addition of mor·
J2. Osborne IU. ct of. Morphine inloxication in rcn;il failure: the phine to intra·anicular bupivncaine improves analgesia1·4 and a
ro le ofmorphin(>-6-glucur~nidc. BMJ 1986; 292: 154.8-9. • For prernedication, the BNF 59 recommends that up $ys1ema1ic review5 concluded illat from the few well-controlled
13. Hodd E., et al. Moqlhinc-6-glucuronidc 1nigh1 mcdiatt 1hc pro· to I0 mg may be given by subcutaneous or intramus-
longed opi\Jid effect of morphine in acute renal failutc. Ji111,, siudies there was no evidonce of an added analgesic effect of
£xp Toxicol 1990; 9: 3 17-21. cular injection 60 to 90 minutes before surgery. morphine compt.red \\oi1J) saline alone.
 94 Analgesics Anti-inflamr:nat ory Drugs and Antipyretics
Doses of morphine reported to have been injeclcd intra-articular· • 6 months lo 2 years: J00 to 200 micrograms/kg every 4 • for patient~ taking imrOediale.-rclease morphine preparations
ly have ranged from I 10 I 0 mg. hours every 4 hours. a double dose at bedtime is effective to prevent
I. Cupca A. et al. A S)1:1cmatic rc\'icw of the peripheral analgesic • 2 10 12 years: 200 micrograms/kg every 4 hours pain disturbingslecp
eITects of in1ra"rticul;,r morph ine. Ant>st/J Analg 200 1; 93:
• 12 lo 18 yean;: 2.5 10 10 mg every 4 hours if patients arc unable 10 take morphine orally the preferred al-
761-70. ternative route is subcutaneous. There is no lndica1ion for in-
2. Raj l'li. et al. CompariM>n of che anlllgc:sic ~fficacy and plasma B_y intravenous injection over at least S minutes:
conccnlratioos of hig.h-dc)se intrs-u1icular and intramuscular tramuscular morphine for cancer pain since subcutaneous
Jl1orphine for knee ~mhroscopy. £11r J Anocs1Jtesiol 2004: 21:
• neonates may be given 50 micrograms/kg every 6 hours dosage is simpler and less painful
932-7. • those aged l 10 6 months: J00 micrograms/kg evtTy 6 • when convening dosage, the relati\•C potency of oral 10 subeu·
3. L.aurcnl SC, e1 al Addition of morr.hine to inlr3·<1.rticu lar bupi- hours taneous morphine is between about I :2 and I:3, so 20 to
\'t>Caine docs not improve ann1sesia after day-ca.c;c: arth r~copy.
BrJAn0esth 1994; 72: 17()-3.
• 6 months lo l 2 years: 100 micrograms/kg every 4 hours 30 mg oforal morphine is equianalgesic to IO mg bysubcula·
4 . Heine MF. t:I of. 101,-.,..articular mc~ii'lc ::ir1cr anhroscopic knee • 12 to 18 years: 2.5 mg e,·cry 4 hours neous injec.tion
operation. Br J Anoesth 1994; 73: 413-1 S. The following doses given by slow intravenous injection are sug- in patients who need continuous parenteral morphine the pre-
5. Ros!:eland LA . NQ C\·idcncc for analgesic effe,cl of intra-articular gested as loading dos~ for continuous inn·avenou.s infusion: ferred route is by subculaneous infusion. However. in1rave·
morph ine after knee an hroscopy: a qualitative systematic re·
view. Reg An<!sl/J Ptli11 Med 2005; 30: 83- 98. • neonates may be given 50 microgramslkg nous infusion may be preferred:
• those aged J month to 12 year.;: JOO micrograms/kg in patients who already have an indwelling intravenous line
INTRANASAL ROUTE. An intranasal fonnulation of morphine
has been investigated for !he relief of acute pain. • 12 to !8 years: 2.S to 10 mg in those with generalised oedema
1110 loading dose may be followed by an infusion given as fol· ifery1hcma; soreness, or sterile abscess develop during subcu ..
1NTRASPINAL ROUTE. Morphine is given epidurally and inrrath-
lows: taneous dosage
ccally to relieve both acute 3nd chronic pain. However, re-
views on the role of spinal opioid$ have generally concluded • neonates: 5 to 20 micrograms/kg per hour in palienis with coagulation disorders
lbal they should be reserved for pain not controlled by more • l to 6 months: I0 lo 30 micrograms/kg per hour where peripheral circulation is poor
conventional routes.'·3 \Vhen converting from conventional • 6 months to 18 years: 20 to 30 micrograms/kg per hour • when converting dosag~ the relative potency of oral to intra·
routes it has been suggested that 1% of the Iota I daily dose venous morphine is also between about 1:2 and 1:3
could be tried as the daily intrathccal dose and 10% as the By moulh or rec111m:
• children aged I to 3 months may be given 50 lo the buccal, sublingual, and nebuliscd routes ofadmu1is1ra1ion
epidural dosc. 3 Conversion from in1rathecal 10 oral dosage
l 00 microaramsikg every 4 hours are not recommended in d1e absence of ~vidence for clinical
has also been investigated.'
advantage over more usual roules
lntrathecal morphine may be deli,'Cred continuously via an im- • those aged 3 to 6 monlhs: I00 to 150 microgram/kg every
planted programmable infusion pump for the long-term manage· 4 hours a small proportion of patients develop intolernble adverse ef-
ment of chronic non-maHgna;nt and cancer pain. fects wilh oral morphine (with adjuvant non-opioid analgesics
• 6 10 12 months: 200 micrograms/kg every 4 hours
as appropriate) before achieving adequate pa.in relief. In such
Sc-e also Patient-controlled Analgesia, below. • I to 12 years: 200 to 300 micrograms/kg every 4 hours patients a change lo an ahernative opioid, or a change in the
I. Anonymo\Js.. Spinal opiates revisited. lorw:c1 1986; i: 655-6. • 12 lo I& year.;: 5 to 20 mg every 4 hours route should be considered. Although switching between opi-
2 . Gustaf'sson LL. Wiescnfc1d·H311in Z. Spinal opioid analgesia: a
critical update. Drugs 1988; 35: 597-603. In polliati"e core, modified-release oral preparations may be oids complicalcs pain management; adequale pain relief for
;. McQvay HJ. Opioids in chro nic pain. Br J AnaeSlh 1989; 63: used; they are given as a single daily dose or in 2 divided doses. some may depend on the use of allcmutivc drugs, the use of
213- 26. By continuous subc11ta11eo11s ;nfusion: intraspinal routes.. or non·drug methods of pain control
4. Sylvester RK., el ol. The conversion challenge:: from inlrathecal Similar recommendations are given in guidelines issued by the
to oral morphine. Am J Ho.fp Pa/liar Care 2004; 2 t: 143-7. • children aged l to 3 months may be given
I 0 micrograms/kg per hour US National Comprehensive Cancer NelwC·rk.2
PATIENT- CONTROUEO ANALGESIA. Morphine is one oflhe most I. Hanks GW, ti ol. E.'lpen Working <'.ir0up ot che R·cscarch Net·
• those aged 3 months to 18 years: 20 micrograms/kg ptr work of 1he l::urope:in Association for Palliative Care. Morphine
frequently used opioid 3nalgcsics for patient-controlled hour
analgesia (sc-c p.4). Most experience has been with !he intra- and ahemati\·e opioids in cancer pain: 1hc EAPC recommends·
l11tra~pi110/ doses of morphine lhal have been Liied 1 in children tions. Br J Crmcer 200 I; 84: 587-93.
venous route, bul 1he intramuscula r~ subcutaneous. oral, pul·
arc a'i follows: 2. National Compri:hcosi\'e Cancer Nctwotk. Clinical praaicc
monary, and epidural' routes have also been used. Reuonablc guideli1lC'S in oncology: adull cancel' pain (versiOtl 1.2010).
initial settings recommended for ir.tr3venous uSe have been a • Caudal epidural block, l 00 micrograms/kg Available at: hup:!/www.nccn.org/profcssicnals/physician_glsl
demand dose of I to 2 mg of morphine sulfate (or ils equiva- • Tiioracic or lumbar epidural block, 50 micrograms/kg PDF/pain.pd( (accessed 02/0811 0)
Jen1) and a lockout interval of 5 lo I0 minules.2 • Jntrathecal doses of20 or 30 micrograms/kg have provided Dyspnoea. Jn the treatment ofd)·spnoea (p. I08). doses of mor-
1. SjOslrOm S. et al. Patient-controlled analgesia w ith c::ur.1dural satisfactory postoperative pain relief, but respiratory de-
morphine or pethidine. Br J Anaes t/1 1988; 60: 358-66.
phine tend to be smaller than tl105e used for pain relief. Morphine
pression occurred in I0 and 25%, respectively hydrochloride or sulfate may be given as an oral solution in care-
2. Grass JA. Paticm t con1rolled analgesia. AneJth Anolg 2005: I 01
0

(suppl): S44-S61. Guidelines2 for analgesia in children in Accident and Emergency fully titrated doses, staning at.a dose of 5 mg every 4 hours; as
departments in the UK recommend the use of intravenous mor- little as 2.5 mg every 4 hours may be sufficient for opioid-naive
PULMONARY ROUTE. For reference to the use of nebulised mor-
phine as an alternative to, or after initial treatment ";th, inlrana· patients.' In acute pulmonary oedema, 510 I0 mg may be given
phine sec Dyspnoea, below. sal diamorphine for sevenpain such as that associated with large by slow intravenous injeclion. In patients already receiving mor-
TOPICAL ROUTE. Morphine has been applied topically for local bwns, long bone fracrure or dislocation, appendicitis, or sickle- phine for pain relief the following doses have been suggesled:~
analgesia in oral mucosilis 1•2 and cuumcous ulcem.tion>·6 in· cell crisis, but it should be used with caution if 01ere is risk of • mild dyspnoea: 25 10 50% of usual analgesic dose
eluding epidermolysis bullosa.' depression of airway, breothing, or circulation.
• rnudorate d)·spnoea: 50 to 100%ofusualanalgesicdose
!_. Ccrchicui LC. er (1/, Effect of topical morphine for mueosi1is· In lhe UK, morphine is a1so ~d in lhe management of neonatal
associ.,,led pain following concoinitanl chemor3d)oth~rapy fot • severe dyspnoca: 1000/o or morcofusu31 analgesic dose
abstinence syndrome (p.1 06) under specialist supervision. The
hcud o:md ntc:k corc:inoma. Cancer 2000; 95: 2230-6. Correc1ion.
BNFC 2010111 recommends on initial oral dose of Patients have also obtaina:I relief from suhculancou.'li. injection.3
;b;d. 2003; 97: 1137.
2. Ccrchiclli I.. Morphine mou1hwashes for p:,infu l muc:osi1is. Sup. 40 micrograms/kg (incrca'e dose if necessary) every 4 hours un- Although it has been reported that a low dose ofncbulised mor·
..• portCurcCcncer 2007; 15: 115-16. til symploms are controlled; the dosage frequency should be re· phine (mean dose 1.7 mg) improved exercise endurance in pa-
3. Twillmon RK, el al. Trea1mcn1 of painful skin ulcers wi1h topic,a l duced gradua ll y over 6 lo 10 days until a dose of tients with dyspnoea due to advanced chronic lung disease~" scv~
Opioids. J Pain Symp<om Manage 1999; 17: 288-92. 40 micrograms/kg once daily is achie,·cd after which the drug era! subsequent sludicsS-7 have fai led lo obtain sig11i1icant
4. Kr.ijnik M. ~t tJ/. Porem ial USC$ of 1opic,al opioids in palliative should be slopped. improvements with doses up lo 40 mg. JI is considered that cur·
c:ire-r~port of 6 cases. Pain 1999; 80: 12 1-5. rent evidence docs not support lhe use of nebulised morphine for
I. Lloyd-Thomas AR. Pain rnanagc:men1 in p:1ed;a1ric !Ydlicnt~. 11,.
S. Zeppetclla G. et al. Analgesic effic:aty of m011>hiue applied lop- breathlessness.1·8-•0 Furthennore, bronchospasm can be a prob-
J A11at-s1h 1990; 64: SS-104.
ic:.Jly to poinfu l ulcers. J Pain Symp1om Manngc 2003~ 25-:
555-8. 2 . The College or Emergency Medicine. Clinical CCfcctivcness lem, particularly al high doses, and there is no consensus on the
6. Z.cppetell:. G, Ribeiro MOC. Mol'phine in l ntra~i1e gel applied Committee guideline for the managemcnl of pain in c:hildren optimal dose, schedule, or method of dose l!tration.
(May 2010). Availabl'e at: hUp::tsccure.collemergencymed.ac.uk/
topically to painful ukcrs. J Pain Syrnp1om Manage 2005~ 29: I. Oa\'ii; C, Percy G. Brcarh lcssncss. coush. and 01her respiratory
118--19. osp/d0<umeni ..sp?ID=4682 (accessed 30/06/10)
problems. Jn: Fallon M, Hanks G. eds. ABC ofpolliatiw: r:or~.
7. Watterson G, e1 ol. Peripheral opioids: i.n inn;ammalory pain. Arch Cancer pain. Morphine is the opioid of choice for moderate to 2nd ed. London: DMJ Publishing Gro\Jp, 2006: 13- 16.
Dis ChUd2004: 89: 679-81. severe canc<:r pain (p.5); guidelines for its use issued by the Eu- 2 . Twycross R, Wilcock A. PolU01iw! Care Furmu/(lry. 3rd ed.
Not1ingham. PaJliativcdrog.s.com Ltd , 2007. 280.
Administration in children. Opioid analgesics are used in ropean Association for Palliative Care1 include:
3. Orn~rd E, c1 al. Subcu1anc:ous m o.11>hine for dyspnea in cancer
children in the m•nagcment of mode:ate lo severe pain (see p.3); • the oplimal route for use is orally. For best effect, both imme- potients . Ami /111crn Med 1993; 119: 906-7.
morphine is lhe most widely used opioid for severe pain in chil- diate-release (for dose titration) and modilied-relcasc (for 4. Youns IH, c1 al. Effect of low dose nebvli$cd morphine on t x-
dren and is the standard agiiinst which other opioids are com- maintenance) dosage forms are required crcise cndur:mcc in patients with throJ>ic lung d isease. Tlmror
pared. Morphine may be given to children requiring acute analg- 1989: 44: 387-90.
• .lhe simplest ll"lethod of dose titration is with immcdiatc..rc· 5. Beauford w. el ol. Effcc(S of nebu1ized mo17hi11e sulf':ne on 1hc
esia as a result of surgery or invac;ivc p rocedures. h may also be lease morphine dosage every 4 hours, and the same dose for ~xercise tolerance of the ven1ilatory limil!:d COPO patients.
given for chronic non-malignant pain and is the opioid of choice breakthrough pain. TI1is 'rescue dose' may be given as often Chcs11993;104: 175-8.
for the oral lreahnent of severe pain in pall iative c:are. lls analge- as required, up to hourly. The 101al daily dose of morphine 6. Nos<:da A, ct ol. D isiibling dyspnoca in palit:n1s wi1h advanced
sic and sedative properties arc useful ln the management of chi I· should be reviewed each day and the regular dose adjusted 10 dis<asc: .1.ack of effocl o f nebulite:d m011>1'int:. Eur Rcspir J
dren in intensive care (seep. l 059); morphine is considered to be lake uilo account the amount needed for breakthrough pain 1997; 10: 1079-83.
a more rational choice than fentanyl in scrtin~ where long·tenn 7. Janke Ison D. ti ul. Lack of cffecl of hi&}\ doses of inhaled rnor·
infusions are required. Respiratory depression with morphine ifpain returns consislently before tl1e next dose is due the reg- phinc on cxu<:isc cnduranec in chronic ob~roct ive pulmonary
ular dose should be increased. Immediate-release formula- disease. E11r Rfl. spir J 1997; 10: 2270-4.
treannent js a risk in all children; however. neonates (and partic- 8. Pofosa R, et ol. Nebuliscd morphine fot se ...ere interstitial lung
ularly those who arc breathing spomaneously) may have an en- tions do not generally need to be given more often than every
d isease. Available in The Cuchr-.sne Oatab.,se of Sys1cmatic Rc-
hanced susceptibility because of the phannacokinetic differences 4 hours, and modified-release products should be given nc- \'iews; Issue 3 . Chichesler: John Wiley ; 2002 (ac·c esscd
of morphine in this age group (see above). co!ding to the intended duration of the preparation (usually 26/()6/08).
every 12 or 24 hours). Patients slabilised on regular oral mor- 9. f'oral PA.~' al. Ncbulizcd opio ids use in COPD. Chest 2004;
The following initial doses are recommended by lhe phine require continued access to a rescue dose for break- 125: 691-4.
BNFC 1010/JJ according lo age; doses should thereafter be ad- through pain I0. Br0w11 SJ, el al. Ncbuli:tcd morphinl! for relief of dysprlca due
justed according to response: to chronic lung d isease. An11 PhtJn11acotlter 200.S; 39: 1088- 92.
• if an immediate·release fonnulation of morphine is not avail·
By subcutaneovs injection:
able and treatment is staned with modified-release morphine, Preparations
• neom1tes may be given J00 micrograms/kg every 6 hours changes to the regular dose should 1101 be made more ofien
BP 2010: Chlorofo1m and Morphine Tinc1..,-e: Mor::>hi:ie and Atropin~
• those aged I to 6 momhs: 100 ID 200 micmgramslkg every than every 48 hours, which means that dose titration will be irie<;tioo' Morph'ne Sl/pllOte lrjec!Kxi: Morphine Suppositories: MorplW>e
6 hours prolonged Tablets; Prolonged·relea<'..e Morp~ Tablets;

All cross-references refer 10 entries in Volume A

 Morphine/Nalbuphine Hydrochloride 95
USP 3l: ~ ~ &<>endeo-R.1-..-- c_.;..: Mc<p->ne SU!a1t sons wilh ibuprofen' or tl:lpfoxen.~ A recmt ~,..;noted 1ha1 Nalbuphine Hyd rochloride
~ t"lorphne 5'.*'ae ~ 11m1ted compe12t1YC data suggesl lh1111abumclone has a similar
Proprietary Preparations (details arc given in Volume B) g;astrointestinal adverse effect profi~ to that of selcctiw cyclo- (BAl./M. USA.>J. riNNM}
Afl.' ~ . . . , _ ~ D.r..morjlhj: GNO; M>T Cont.-...; oxy11ensse-2 (COX-2) inhibitors. It bas been suggested' that
~ Aunn.I.: ~ c.poou-; Ka;>.w>ot Mome>< MS Can-
nabumetone may be a pn:fettntial 1nhib11or of COX-2 bul the EN-223'1A; Hidroclonso de nabJ6na. NaR>uMe ~;
W\ MS Mona Q'Clno: ~ Aunrio: ~ t:::aµ!lloct;l<apard; Nolbuphine. Chlothydr3te de; Nab.Jp'iini H)O'ochloridl.m 17•
11-0olor: Mcnpct l'Mddol Orvnorpi< ~ - ~,,~ Doc· sig11i(icanc.: of this in detennining 11S adverse effects is uncct1ain.
rnorine: ~MS Cot1'n MS o-t Or'"10tph: S~ Stcl- Cyclobut}-k'nethyl-7.S-dhydro-14-hydro>Cy-17~ hy·
I. Rolh SH. ~' '11. A controllc:d stud)' comp•:ring 1hc cfreru of
torp/w>e. 8'o.z.: atnC« Oolo Molt Canad.: Dclcnl: l:>dan M-l:slon: n1bumttone~ ibuprofen, and ibt.tproftn plus misoprOStOI on the d'O<hloride: i-H5R6S.14S)·9.rC~elh)ll-H-epoxy­
MOS. MS Corc.n: MSIR: S!at-..x: Chilo: M-E!lor"c C:..: Dolo.>rctj: ~it, upper C3~roin1es1inal tnic.1 mucoso. Arch lttttrn Med 199.3; lSJ: morphor.an-3.o. I 4·Uiol hydrochfonde.
HSI, MST Com.nus; MST U><>t: <:nmorpht S - Sl<e~ Sb...ig,nt. 2~6S-71 .
Wnci.t Otnm" C~n: Cl<polol"c Ooltord: Maire Rn.: Oepolln; Doi- 2. Roth SH. ~' nl. A lonau:rm endoscopic cv;fu:uion of patients Ha~Ha r"""'°"""1"1A
comirl; Our•l&ir>f; Fr.: Actlsk•.,."' Kap•nolt: Moscont"1; Or•morph:
~: Sl<tt\111; Ger.: C.pros: X.panot M-bc:".a: ~ M-1~ M·
wiih arthritis trc:aied with nabumc,01\ot \''S n3proxcn. J R'1~11motol
1994: l l: ti t&-23.
Ci,Hz,NO•.Ho 393.9. =
Siad•: Morpt-c Morphantorc HSI: MSll: MST: 0.-amc.1*'< P.!irlbre•k: Sevrcd· 3. Bann"''lrth 8. Safety of ihc: non.)i;:lcctivc NSAID nabumctcnt: OS - 20594-83-6 (nolbuphine): 1327i-43·2 (nolbu·
o4, Gr.: Morigol, Monc:om:n: OramO'J)I>: Hong Kong: M-Eslont. MST
Contit'M; Hung.: M·Eiloo: Moreurt: MST Continus; Sevredoi; India: Mor~ focus on gastrointe.stinol tolcrabili1y. D1·11g Sofcl.t1 2008; J l : phme /1ydrochloride).
cor.tn: lndon.: MST Continus: frt.: Ethiriin: MST Continu~ MXLt: 4SS-l03. ATC - N02AF02.
Or11norpll: ~I: lsrool; MCl1: MIR: M"'J'he><f: MSP: Ital.: MS Contirt 4, Oavio NM. Clinical ph1rm1cokinc1icg of n1bume1one: the daw11
01'11morpll: Sl<cr..,,t: Todnarc Twice: Jpn: !'1$ Cootr.: Moloylio: MST Con· orSi:lCCliv.: cyclu--oxy1cn11sc:·2 inhibhion? Clin P/101•mt1C()klne1 ATC Ve! - QNOlAF02.
tir..o: Mu.: Anatrtn: 0<.n!mort: Gra!en: Neth.: l(,panol: MS Conlin No· 1997: 33: 403-16. UN/I - Z U427S277R.
<'f)tint, Oramorph: 5""r"'1o1 Sk<nan: Norw.: Do:Conlirl NZ: Kapanot I.A Effects on the lungs. Pulmonary fibrosis developed in a 68-
Morplx M·Eslon: MST Com;,Mf; MST Monot. RA Morplt Se•lfcdot
PhllipP" M·Oolo<"t. Morin: MST Cootinus; Reffnat Pol.: Dollard; MST ycar-old woman laking nabumetone 1.5 g daily; symptoms ap-
Contjrus. 0.-amorph; Semdol Ve<1dalt; Port.: Ein:rf.nj: G:"morph: MST: pearC<l allcr 2 " 'Ccl<s of 1herapy and worsen•d during the nexl 6

HO~
MXlt: °'"""''!lit S."'edol: Sl<e<lan: s.Afr.: MST Con:.,us: SRM·Rnotard weeks. 1There was rapid resolution on stopping nabumetone and
Slnfopore: MST Co,,...,,,. SRM-Rhot.-dj: Statox: Spain: Dclq; MST
I '°
starting trcotmcnl with oral corticos1eroids.
Contirus; MST Un:Con-..-.J<j: ottost: pramorph: S....,.edot ~ Swed.:
!Apol•rc Oolcom:n: Switt.: Kap•not M·,,,..r.l: MST Ccntitius: ~long: I. Morice A, cl al. Pulmonlf)' fibrosiJ associo1cd with n::tbumctone.
S....edol: Turi<.: M-Esloo: Veidal: UK: Oepol)u<: filnorine: '1orcapt. Mor· PnSlg,.od McdJ 1991: 67: 1021-2.
"'11esic: MST ConlM\u$: MXL: Onrnorpl< Rholard: Sevredo1: Zomorph: 0 OH

N~
l/$"A: As1r.amorph: A\inu: OepoOur: 0...-..-notpi>: Etrbeda: lni.m:>rplt Effects on the skin. Pseudoporphyria characterised by blister-
~ MS Cantin: MSIR. Oril!>Ofllh; RMS; P""""°': Venez: MS Contioi. ing on the neck and hands dc\/Cloped in a 36-year-old woman \
Mu lt~lnve<fien t: Aurtrol: McrpNl:;nt. AllJtrio: Modiscopf: lrl.: Cy- taking nabun>elone and auranofin for rheumatoid arthriris. 1Slop-
dmoo'pl-c Ital.: Cardio<leno1: S.Afr.: Ooloropect Cycimorpl'< El'terod)fl<: ping auranofin had no cffcc1 on 1hc blis1ering, which only HO.·
Pec\rol)'..e: Swed.: Spasmolen: Switt: Sp.smosot UK: Cct6 en,..,...·~ Cy- resolved once nabumclOllC was withdta,.n. The authors of the
dmorplt Oio<;al'n C>.J&1 Aaaorc ()palirnM. repon staled that the UK CSM had rcoei1-ed 3 additional reports (nolbuphint)
of pscudopo<phyria sus:pccted 10 be caused by nabumetonc.
1. Vanna S, Lonigoo SW. P.-loporphyri• eauS<d by nabume1onc.
Morpholine SaJicylate .. Br J DennafO/ 199t; Ill: S49-l0. Correellon. ibid. IJ9: 7S9. Street names.. The following ~mu ha\IC been used as 'Slrcet
'1o<folnsalisylaatti: Morfolnsalicytai: MorphoMi SaEcytM; SaJi.
1"-1 names' (se;:p.vi)orslangnomes for,11rious fonns ofiulbuphinc
Interactions hydrochloride:
dato de morlorriio. 2-HydrOX)'benzoic acid ~ with Nubian.
For interactions associated wilh NSAIDs,see p. 103.
mapho(ne (I : lj.
Mop'°"'-" ~T Phannacokinet ks Incompatibility. !ncomp:uibiliry has been repotlcd between in·
jcctions of nalbuphine hydrochloride and nafcillin sodium,1 di-
C 11 H 1 ~NO• =225.2. Nabumelonc is 1\ICll abso<bed from the gastrointestinal tract.
Plasma conccnlnltions after ml doses are too small to be meas- azcpam? pmtobartiital sodium.2 or thiethylpcrazine mal~te.l
CAS- 147-90-0. US licensed product infonrl3rion states that nalbuphine is also
ATC - N026A08. un:d.11$ ii undctg<ll'S rapid and extensive fi1'$1·pass metabolism in
the liv"' to the principal ac1ive compound 6-mcthoxy-2-naphthy- physically incompatible wid1 kctorolac.
ATC Vet - QN026A08.
laccric acid (6-MNA) and 01hcr inactive metabolites. 6-MNA is I. Je,.lum EL. c1 al. Nafcillin Mdium i~mpilibilhy with 11cldic
more 1ha1199% bound to plasma proteins. It diffuses in10 synovi- solutions. Jim J HotpP/torm 1981; J8: '462-4.
al fluid. cr05$es lhe placenta, and is disuibu1ed inlo breast milk. 2. Jump WG. ~1 al. Compatibility o(natbuphinc hydr<K;hluride wilh
other pr~opetalive mc.dicaiions. Alft J Hosp Pltonu 1982: J9:
0
/ \NH T11ere is considerable interindividual variation in the plasma
climina1ion half-life of 6-MNA, especially in the elderly; some 841-3.
\_/ repented mean values at s1eady srale includ<: 22 to about 27 hours
for young aduhs and abou125 and 34 hours in elderly patients. 6· Dependence and W ith drawal
MNA eventually undergoes further mclllbolism by 0-methyla· As for Opioid Analgesics, p. I 05.
1ion and conjugalion. About 80% of a do.o;c is excreted in the
urine as in.c1ive or conjuga1cd me1aboli1es and less 1han I% as 0 A WHO expert comminee considered in 1989 tha1 lhe likeli-
Profile
Morpholi11C salicyla1e is a salicylic acid derivative (see Aspirin, unchanged 6·MNA. hood of nalbuphine abuse was low 10 moder:11c and was not great
enough to wanan1 intema1i0nal conlrol. 1Abuse had been repon-
1.1.21) 1hat has been used for musculoskeletal disorders. 0 References.
cd infrcquemly and lhc wilhdrawal syndrome p<oduccd when
Preparations I. BTirr M!;. e1 of. fopu lation pharnu1coldnc1ic1 of 1hc ac1h·e me· na1oxone was given after continuous nalbuphine dosa.gc was less
1ah0Htc of nabume1one in r(nat dysfunc1ion. C/111 l'harmocof
Proprie tary Pre parations (details arc n.ivcn in ~l umc B) T~t·r 1995; 57: 622- 7. severe than that in morphine dependence. Subsequcn1ly. 1he.-c
Fr.; f')<"adolt, ISIOCI: Ooliul, - 2. D:.vin NM. CliniClt1 ph3rnu1c0Lincti(S or nobun).::\Onc: 1he d~w n have been occasional rcpons ofabuse2J including misuse amon~
of scl~1ive cyclo-oxy~t'nn1t·2 inhibMon'? CUir PhorPmrcJ:i11c1 athletes.'-'
19<l7; 33: •03-16. I. WHO. WHO c>:pcn c:ommince oil dn1g dependence: twcnly·
Uses and Administration fifth rcpor1. lYHO Tech R~p Ser 775 1989. Also 1\••11,bfc ,,:
Nabum etone (8AN. WN. riNN) btlp'i/libdoc...110.inti1rs/WHO_TRS_77$.pdr(acccsscd 26/06/08)
BRL- 14m: Nabumeton: Nabumetcna: Nabumetoru>.: Nabumctone is a non-active prodrug whose major metabolilc is
an NSAID (p.103) SLrUehnlly similar to nap..oxcn (p.96). ll is 2. Spad;i;ri M. e1 ()/. Ph3rmtco.1Cpend1nce A la nilbuphinc (°l':U·
Natiumetone; Nabume1orC; Nal>.r'l'letonm 4-{6-Methoxy-2· bain): a ptopos de 2 c:as. Th~mp;t: 2002; S7: .S04-S.
used for 1he relief ofpain and inOammalion associated wilh 0$-
naphlhyt)bulan-2-one. 3. Klinzig F. ~t ol. H:1ir Joa:l~is by LC-MS as evidence or 1t11bu·
teoarthritis and rl1eumatoid anhritis in • usual oral dos.: of I g phinc abuse by :i. nursr. J A,.o/ To$~l 2001; 31: 62-S.
Ha6yi-eTOH taken as a siJ1llle dose in the e\IC!ling; if necessary 0.5 to I g may -t McBride AJ. tt #I. Thr« ~s of nalbuphrnc hydrochlortdc de·
C 1 ~H 160t =
228.3. be given additionally in the morning. It has been rec:ummcndcd pendenc:t auociatcd with aNbolic steroid U$e. Br J Spo1·11 ~ti
CAS - 41914-SJ.ll. thaladoscofl gdaily should not bcc.<cecded ineklerly patienlS 1996: 30: 69-70.
ATC -MOIAXOI. and lhat 500 mg daily may be satisfac•OI)' in some caSC$. 5. \Vi~s JD• ., al. Nalbupb1nc hydrochloride dep<ndonce in an>·
ATC Vet - QMOIAXCI. bolic •toroid uscn. .A,. J Addkr 1999; 8: 161-1.
UNll - LW0TIW155Z. o References.
I. Fric<l<t HA •., ol N>bum..-tone: a r<llj)PfllSal or'" 1lh>rmacolo-
JY •nd th=peutic use in rhcunu1ic d...-s. Drugs 199); ~S: Adverse Effects and Treatment
131-54. As for Opioid Analgesics in genenl, p. I06.
2. l'lrocc:edanp or a sympoamm «>nlinum; developments with
~bumcconc: an invutiplOC's' upcl'atc. A•J M#tl 1993; 9S (Sdppt Headache may occur. Nausea and vomiting occur less
2A): IS-OS. than with other opioids. Hallucinations and other psy-
l . Dahl SL N:11\>umC"t->nc: n •nonacidic.. nonsccroid01I arMimflam-
macory dn1ii:. ,fmt PhnrnwcotM.-1993: 27: 456-63. chotomimetic effects arc rare and have been rcponed
4. Hcdncr T, r:1 ol, Noburnctonc; thtrapcu1ic UK :and safety profile less frequently than with pentazocine. As nalbuphine
io the n~nasemctlt of o,.,1roanhrius ond rhcum:uoid anhritis.
Dri•p 2004; 64: 231 ~l. has both antagonist and agonis1 activily its effects may
Pha rmacopoe ias. In £11r. (seep.vii), Jp11, and US. Preparations be only panially reversed by naloxonc, but use of the
Ph. Eur. 6.8 (Nabumetone). A white or ah11ost white crysl.<llline latter is still recommended in nalbuphine overdose.
powder. Prac1ically insol<1blc in waler; freely soluble in acetone; BP 20 IO; Nobum•tone Or".ol Su~t N<bJ:i>CI<""' Tabltt>.
USP 33: N.1b\.ome1one Tab'ot>.
slighlly soluble in methyl alcohol. Protect from light. Effects on the respiratory system. Nalbuphinc produces
USP 33 (Nabumetone). A "hilc or almost white crys1alline Proprietary Preparations (details are 11ivc11 in Volume B) similar respiratory depression 10 morpliine at cquianalgcsic dos·
Belg.: G•mborilll< Conod.: Rt"oftnt: C..: Reiff<><: Rod•nol St: O.nm.' A<:· cs. bu1 1here is a ceiling efli:ct with nnlbuphinc and, unlike mor-
powder. Praclic.illy insoluble in waler; sparingly soluble in alco- Ut>c Fin.: R<Mc" Fr.: Nabuco><. Ger.: A<:KO'<: Gr.: Akl"atol: Arne<norc 1¥:>-
hol and in methyl alcohol; freely soluble in acelone. Store in air- l<r: Etllyfeo P.ogmed: Meved•t: Nabuton: Nadoone: Re~fei<. Hung.: Relife>e phine. respiratory depression docs not increase appreciably with
tight conlaincrs. P1'0tecl fiom light. Rod•nol St: Indio: NAl>ullam: lndon.: Goll¢>< lrl.: Ro<1fex: Rellger. lsrock higher doses.' In a cuinula1ivc-do>e sludf a plateau effccl wns
Nabucoc Retircx: ltol.: Artaxan: N1buse·: Reli'ft'IC Jpn: Relifen: MeK.: Na- seen with nalbuphine above a 101al dose of 30 mg per 70 kg in-
Adverse Effects, Treatm ent, and Precautions n•m< R•life>e Nech.: Mot>.o•n: Norw.: Rdf•x: Philipp.: Rel>f•x: Pol.: tr3venously. Similar venlilarory dcprc$$iOn has been nolcd1 wilh
As fol' NSAIDs in gem.Tai, p.100. Nabumetone is contra· indicat- Coxalg•n: Co•ctonj: Nabuton: Rel•lcx: R<oclanol S: Port.1 S.lmo>< Elll.lr:
Rus.: Rodanol (PoM.•,.)f; $.Afr.: Rehf•nt. R<i•""1: Ref.1onet. Spoin: Lis- single inl1"3veno1" doses of nalbuphine of 15, 30, or 60 mg per
ed in pa1licnts wilh severe hepatic impainnent. 70 kg; naloxonc failed 10 reverse the depression at lhc highcsl
tru1: Reli(: Sw.d.: Rchrex: Sw;u.: 8&1nl00<.: Th ol.: Aflttx Anre1t: Bvmetone:.
Effects on the pstrointestinal tract. Like other NSA!Ds E<Wd. f:~>< N>I>On<:; Nlbonett: Naflti<: Name:one: N<>-lonj: Ro!ifex; dose.
oabumetone can produce ad,'<rse effectson 1he gastrointestinal Turf<., Relfe:<. UK: llclifex: USA: l\otaftflt.
1. Klcpptr 10. e1 of, Rl.'spira1ory function rollowina. nalbuphine 111nd
lr•cl, al1houi:h some shlllics have produced favourable compari· morphine in anaCSLhcli~cd m::in. Dr J Auntith 1986~ S8: 6lS-9.
The symbol t denotes a preparation no longer actively markeled
96 Analgesics Anti -inflammatory Drugs and Ant ipyretics
2. Romagnoli A, Ke;i.ts /\S. Ceiling effect foT respir3tOry depres- dependent subjects.' Nalbuphine is structurally related to Suppositories containing naproxen may cause rectal ir-
sfon by nalbuphine. Cliu Phormm;nf 1'1'1l!r 1980; 27: 4'?S-8S. naloxone and oxymorphone. Phannacologically nalbophine is
;. Pugh GC. "'al. Effec1 of n3lbuphint hydrochloride on the venti- ritation and occasional bleeding.
qualitatively similar to pentaz0eine, but nalbuphine is a more pC>-
l3tory iind occlusion prcssur~ rcspc>Mes 10 carbon dioxide in vol- Naproxen should be used with caution in renal impair-
unteers. BrJ A1wc>11b 1989: 62: 601-9. tent antagonist at µ opioid recep1ors, is less likely lo produce psy-
chotomimetic effects such as hallucinations, and is reported to ment, and use is not recommended in patients whose
Pre cautions produce no significant cardiovascular t6Ccts in patients with is- creatinine clearance is less than 20 mlJmin.
chaemic hean disease. ll differs from pure µ agonists such as
As for Opioid Analgesics in general, p. 107. morphine in that its analgesic, sedative, and respiratory depre»- 0 Reviews.
sant actions are subject to a 'ceiling' effect and may not increase 1. BJnsal V, Nol. A took ol the safely profile of ovc:-r·the-counter
Nalbuphine may precipitate withdrawal symptoms if napro.xcn sodium: ci meta-analysis. JC/in Phormocol 2001; 41:
given to patients physically dependent on opioids. proportionately with dose.
127-38.
I. Preston Kl.. e1 al. Antagonist efTeets of nalbuphin e in opioid-
The dose of nalbuphine should be reduced in patients dt:pendem human \'o)unteers. J Pharnwc:ol E:cp Ther 1989; 248: Breast feeding. The American Academy of Pediauics 1 states
with hepatic or renal impainnent. 929-37. !hat there have been no reports of anyc.linical effect on the infant
Administr ation. References lo alternative routes ('IT dosage associated ";tb the use of naproxen by breast-feeding mothers,
Abuse. See under Dependence and Withdrawal, above. and that therefore ii may be considered 10 te usually compatible
schedules.
Pregnancy. When nalbuphine is used for analgesia during la- with breast feeding. The BNF 59 also considers thal the amount
J. Krenn H, e1 ol. Nalbuphinc by PCA·pump ror analgesia follllw-
bour there is more placental transfer and sedation in mo~iers and ing hystereclomy: bolu' application \•tr.>u!. con1jnuou5 infu.sion of naproxen distributed into breast milk is JOO small to be harm-
their infunts than with pelhidine. 1 Tl;cre ha\'C also been reports of with bolus application. I:.'ur J Pain 200 I; 5 : 2 19-26. ful to a breast-fed infant; however, some licensed 1iroducl infor-
bradycardia •nd respiratory depress:on in neonates whose moth- 2. Woollard M, ct ol. Hining 1hcm where it hurts? Low dose nalbu- mation recommends that breast feeding should be avoided dur-
ers received nalbuphine during labour?; It was considered that phine thcropy. Emerg MedJ2002: 19: 565-70. ing naproxen 01erapy.
nalbuphine should be given with caution during la!xiur, especial- 3. Sung KC. et al. Transdennal deli\1ery of nalbuphinc aod its pro- Jn a study2 ofa breast-fed infant only0.26%ofthe mo01er's dose
drugs by e lectropora1ion. Eur) Pha1'm Sci 2003; JS: 63-70.
ly by the intravenous route. Some2 have recommended subcuta- was recovered from the infant.
4. Gear RW, c1 ol. Dose ratio is imponam in maxi1ni2ing 1u1loxone
neous dosage and advised that nalbuphine should not be given enhancement or nalbophine ana l ~csia in humans. Neurosci Len I . Amer ican Academy of Pediatrics. The lraJ\srer of drugs and oth·
around the expec!ed time or deliver1. 2003; 351: S-8. er chemicals into human milk. Pedialric.f 2001; 108: 776-89.
[R~1 i rcd May 2010) Com:c:tion. ibid.: 1029. Also available ott:
funher references on the transplactnlal tr:insfer of nalbuphine 5. Liu KS, .i al. An1inociccptivc effect or a no,tl long•octing nal•
h tip ://aa ppo Ii c y. a ap pub Iic at ions. orgfc.g ilconte n t/ fu 11/
are ~iven under Phannacokinetics, below. buphinc prcpir.nion. Br J Anlleslh 2004: 92: 712-15.
ped;•lr;cs%3b l08/Jn76 (occcssed 08/t 1/07)
I . Wilson CM. n ol. Transplaccn1al gr3dicnt orpc1hidinc and nal- 6. \VooUard M, ct at. Less IS Jess: a randomised controlted 1riaf
comparing cautious and rapid nalbuphine dosing regimens.
2. Jamali f·. Stevens ORS. Naproxen cxcrctio• in mi1k and i1s up-
buphinc in labour. Br J Clin Plwrmoc:ol 1986: 2J: 571 P-572P. take by lhe infam. Drug lntetl Clill Phorm 1983: 17: 910-1 I.
2. GuiJlonntau M. ,., ul. Pezfo:nal t4d\·erse effects or n:ilbvphine Emerg MedJ2004; ll: 362-4.
g i\•c:n during parturiti01l. lcmctl 1990; 33S: 1588. 1. Gordon AT, ct ol. Open· label exploration of a n intraveno us nal- Effects o n the blood. Haematological adverse effects reported
~ . Sgro C. ct nl. Perio:ual advtt5c efft:ts ofnalbuphine {!ivcn dur- buphine and naloxone mixrure as an a nalge-$it ag.tnt following in patients given naproxen include haemol)tic anaemia,'" aplas-
ing Jabour. Lance/ 1990: l36: 1070. gynecologic sursery. Pain Med 2001; 8 : .S2S- JO, tic anaemia,; agranuloeytOsis;' and immune thromboc)1ope.nia.5
P repa rat ions I. Hughes JA, Sul.Jell W. He1nolytic anerria associated with
Interactions Proprietary Preparations (dc1ails are given in Volume B)
naproxen. Arthritis Rheum 1983; 26: I054.
2. l..o TCN, Manin MA . Autoimmune hacmolyiic anacinia associ-
For interactions associated with opioid analgesics, see A rg.: Gobbinal; Nahrox: Nubaina; Onfoc-: Aurtrio: Nu~int; Bn»%.: Nu- &ted with ncJproxen suppositoriC<s. BMJ 1986: 29?: 1430.
p.107. bain: Canad.: Nubaiin: CL: Nub~jn: Ger.: "'-hainf: Gr.: Mexif'en; '"~ 3. McNeil P. el al. Naproxcn·associatcd aplastic a naemia. Med J
H ont Kone: lntapanf: H uni.: Sufil'nort Nubain'f: lrl.: L.apaincl; Mex.: Su- A"st I 986; l45: 53-4.
~gen; llo'Jemt: Fab<ec: Natcryn: NZ: Nvbainf; PhWpp., NvbaW,: Nub;,,c:
-t. Nygard N. St.arkc:baum G.. Napro;xcn and agranuJocytoSi". JAMA
Pharmacokinet ics Port.: Nalpain; Singopor-e: Nubaii; Switz.: J\.'tJbaint. Thai.: NubaWlt: 1987: 257: 1732.
USA, N.A>aW.t: Ven•L: llulidol: Nvba2lf.
There appears to be considerable first-pass metabolism 5. Boug.ic D, Aster R. Immune 1hroinbocytopenia resuhing ftom
scnsi1i\iily 10 met:iboliles of oaproxen a nd acetaminophen. Blood
ofnalbuphine after oral doses. On intramuscular injec- 200 1; 97: 3846-50.
tion nalbuphinc has been reported to produce peak Effects on the cardiovascular system. For a discussicm of
plasma concentrations after 30 minutes. It is metabo- Naproxen (BAN. uSAN. t1NNJ the possible cardiovascular effects of napr())(en, seep. I00.
lised in the liver and is excreted in the urine and faeces Naprokseent Naproksen; Naprol<senas: Naproxen: Naproxene; Effects o n the CNS. Aseptic meningitis has been associated
as unchanged diug and conjugates. Nalbuphine crosses Naproxeno: Naproxcnum; RS-3540. (+)-2-(6-Methoxy-2-naph- with naproxcn therapy; 1.2 attacks may be recurrent and cross-
the placenta and sma II amounts are distributed into lhyl)propionic acid. sensitivity with other NSAlDs has occurrcd.2
breast inilk. Hanp()l(Cet< There has been a repor1 3 of a patient willl Parkinson's d isease
0 References. =
C,.H .. 0 3 230.3. whose symploms had previously been wen controlled but who
de1eriorated when she was given naproxai. She improved on
I. Sear J\V, et nl. Disposition of nalb\lphine in patients undergoing CAS - 22204-53-1.
withdra""•' of naproxen and 1he effecr was confirmed by rechal-
general a11acsthcsia. Br.I Anae... 11119fi7~59: 572-S. ATC - GOZCCOl: /1101A£02; M02AA12. lenge. It was noted that the UK CSM had recorded a case ofpar·
2. K.-y B, er al. Phanua<:okine1ics cf o;al nalbuphinc in poslopera-
ATC Vet - QG02CC02; QMO IAE02: Qj1102AA I 2. kinsonism associated with a combined prepara1ion of naproxeo
tivc p~1icn1s. Br J Anaest,, 1987: 59: I 327P.
3. Aitkcnhcad AR. et al. The phann acokinelies of or11I :md inlrav~ ­ UN/I - S7Y76R9AiQ. and misoprostol and I 2 other reports of tremor or ataxia precipi·
nous nalbuphinc in hcullhy •.:oluniecrs. Br J Clin Phormocnl tatcd by naproxen.
t 988; 25: 264-8. I. Wckslcr SS, Lchany AM. Naproxen-inducrd recunen1 aseptic
4. Jail Ion P. tf of. Ph:um:1cokinc1ics orialbuphinc in infants, young meningitis. DICP Aun Phorm«other I991; 25: 1183--l.
healthy volunteers, and elderly patiems. CJ;,, PliormClcol Thcr~ 2. S..:alon RA . France AJ. Recurrent aseptic nc::ningilis following
t 989: 46: 226-33. no1l·Stcroid::il ~n1i-inOomm:J1ory drugs - a rc:mindcr. P<Jstgrad
Preg nancy. References. Mt•IJ I999; 75: 771- 2.
3. Shaunak S. e' ol. Exacerbation oi idiopa1hic Parkinson's disease
1. Wilson CM. ct al. Tr.:msplaccn1;:tl gradient of pethidine and nal- by noproxen. BMJ t995; 311: 422.
buphine in labour. Br J Clln P/,nr111frcol 19S6; 21: 571 P- 572P.
2. C>.:ldabhoy ZP. ~, nl. Transplacenlal 1r.insfer of nalbuphine in pa· Effects on the eyes. Ker.ttoparhy. characterised by whorl-like
lic ncs undergoing cesare:in sect i on: ~ pilot study. Ac10 Anoestlu:- corneal opacities, occurred in a wo1nan laking naproxen; com-
siol /wl t981>; 3,: 227-32. P harmacopoeias. In Chin., Eur. (see p.vii),Jpn. and US. plete regression occwred after stopping the drug.1 There has also
3. Nicolle I;, et al. Thcr3pculic monitorins of nalbuphine: 1ran.spla- Ph. Eur. 6.8 (Naproxen). A while or almost white, crystalline been a report of exacerbation ofglaucoma io a 65-year-old wom-
ccn13I transfer und cs timatl!d pbarmacokinclics in lhc neonJtc.
EurJCli11Pharmoctll 1996;49: 48.S-9.
powder. Practically insoluble io waler; soluble in alcohol and in an give.u riaproxen.2
methyl alcohol. Protect from light. For reference to effects on the optic uerve associated with
USP 33 (Naproxen). A white to oft:white, proctically odour- naproxcn, see p.101.
Uses and Administration less, crystalline powder. Practically insoluble in water; soluble in I. Sm.yd L. Perry HD. Kera1opathy :JSSOCi:r.cd with the use or
Nalbuphine hydrochloride, a phenanthrene derivative, alcohol, in dehydrated alcohol, and in chloroform; SJl0ringly sol· naproxcn.AmJOµhthulnml 1985~ 99: 598.
is an opioid analgesic (p.108). It has mixed opioid ag- uble in ether. Store in airtight containers. 2. Finch:im J E. Exacer001ion ofgl:l.ucom::i in 31 e lderly fem ale lak·
iog nuproxcn sodium: a cttse report. J Guiolr Drug Thtr 1989;
onist and antagonist activity. It is used for the relief of 3: I 39-43.
moderate to severe pain and as an adjunct to anaesthe- Naproxen S odium IBA/\1"1. USAN. rlNNM)
Effects o n t he gastrointestinal t ract. Ga,1rointestinal ad-
sia. Nalbuphine hydrochloride is reported to act within Naprol<sen Sodyum; Naproxene sodique: Naproxeno s6dico; verse effccrs arc among the most frequ¢ntly reported during
15 minutes of subcutaneous or intramuscular ittjection Naproxerum natricum; Nalrii Naproxencm; RS-3650. short- and long-tenn treatment with naproxen. Acute protlocoli-
or with in 2 to 3 minutes of intravenous injection and HaYJ)>1<4 HanpOKc<oH tis associated with the use of naproxcn has bceu reported. 1
generally ·to produce analgesia for 3 to 6 hours. It is C,.H iJNa0 3 = 252.2. Oesoph3geal uleeration reponed in 7 patie.1ti' may have arisen
CAS - 26159-34-2. due 10 incorrect consumption (such as taking I.he dosage without
given subcutaneously, intramu.;cula_rly, or intravenous- fluids or lying down aJter a dose) but other causes could not be
UNI/ - 9TN87S3A3C.
ly. Intravenous infusion as pa1t of a patient-con1rolled dismissed.
analgesia system has also been used. Pharmacopoeias. Jn Cltin., Eur. (seep.vii), and US.
I. Ravi S, et al. CoUtis caused by non ..slcroidtl anti-inOammatory
Ph. Eur. 6.8 (Naproxen Sodium). A white or almost while, hy- drugs. Postgrod Med J 19R6; 62: 773-6.
The usual dose of nalbuphine hydrochloride for pain groscopic, crystalline powder. Freely soluble in water; sparingly 2. Kahn LH. at ul. Ovet-lhc:--coun1er napro.xcnsodium and esopha-
relief is 10 to 20 mg every 3 to 6 hours as required. soluble in alcohol; fh:ely soluble or soluble in methyl alcohol. A geal injury. Ann In/em Med 1997; 1 ?6: I006.
As an adjunct in balanced anaesthesia a usual dose is 2% ~olulion in water has a pH of7.0 to 9.8. Store in airtight con- Effects on the kidneys. Acute renal failure,' renal papillary
tainers. Protect from light. necrosis,2.l interstitial nepllfilis,• and hypcrkalacmia 1 have been
OJ to 3 mg/kg given inuavenously over 10 to 15 min- USP 33 (Naproxen Sodum). A while to creamy crystalline
utes ~t induction. Maintenance doses of 250 to reponed in palients receiving naproxen. As wilh other NSA!Ds,
powder. Soluble in water and in methyl alcohol; sparingly wlu· renal adverse effects occur more frequemly in patients wilh cer·
500 micrograms/kg may be given as intravenous bo- ble in alcohol; very slightly soluble in acetone; practically insol- tain risk factors such as volume depletion, (iuretic therapy, hean
luses if required. uble in chlorofonn a nd in toluene. Store in airtight containers, failure, and pre-existing renal dysfunction.•
Action. Nalbuphine is generally described as o mixed agonist I . Todd PA, Clissold SP. Naproxc.-n: a. rcapptaisal of its ph<irmacol-
and antagonist acting mainly as an •gonist at ~opioid receptors
Adverse Effects, Tre at ment, and P recau- ogy. and therapeutic use in rheumatic disnscs and pain states.
t ions Drugs 1990; 40: 91-137.
and as an antagonist or pa11ial agonisl at JI rcceptors. Jt has shown 2 . Caruana RJ, Semble EL. Renal p3pillary necrosis due 10 n3prox-
antagonist activity similar lo that seen with naloxone in opioid- As for NSAIDs in general, p. I00. en. J Rhcumotol )984: 11: 90-1.

All cross-references refer to entries in Volume A

 Naproxen 97
; KO\J~"'\ic Let cl Rcet:a.I poplll:uy necrosis indu«d I>)· napco:s- Tiie excretion of naproxen is delayed by probcnecid re- tion pack with misoprostol (p.2175) or lansoprazole
cn. PtdloH' Nrp/1,.,12003; IS: 826-9.
• Quizl~y MR• .ti cl. Concurrcnl napro.'tcn- and pcnicillaminc-in- sulting in raised plasma concencrations of napr0xen. {p.1891), or as a modified-release combination prcpa·
duccd rc-nal diJcasc in rhcvmatoid arthritis. .4rthritl$ Rh<11,,, Antiepileptics. For the eftecl of naproxtn on tht prulein bind· ration with esomeprazole (p.1880) for patients at risk
1982: 2~: 1016-19. ofNSAID-induced peptic ulceration.
ing ofralprok OC'ld. irtt p.555.
Efrects on the liver. 11icrc havt. been a f<w repor1S 1_, ofmoo-
0 Reviews.
er:itc to seven: jaunJk:t aurioo1ed to naproxen including one in Phannacokinetics L Todd PA. Clissold SP. N•pru>.1..~: :.i ,-cJppnis1I oru..1 ph1rmaco1-
which ~le patient at.o had a similar rc8Clion wiU1 fenoprofen.2
Naproxen and naproxen sodium are readily absorbed o~)'. and thcr:ipcutic us~ in rheumati< disc3ff1 ond ~in Milts.
I. Victorino KMM, ~' nl. Ji'undicc HJ.."'l'IC'iatcd with naproxcn. P<Mt- Dru~s 1990; 40: 91-13/.
1rod Mt:d J 1980~ S6: 368-70. from the gastrointestinal tract Peak plasma concentra- ~- Curran MP. Wellington K. Oclaycd·rdca.x lansopra?Olt plus
2. Andf'Cjak M, "' ol. trou hepatoco,;icity between n<m·sccroidal tions occur aboul J 10 2 hour.; after ingestion ofnaprox- n:i.pro.xcn. DruJ:.s 2004; 64; 191 5-19.
anli·in011mmatoty drugs. BMJ l9S7~ 295: 180-1. 3. Deny C, ~' ul. Single dose oral n:apt'\)X:e11 and noproxen sodium
cn sodium and about 2 10 4 hours after ingestion of for acucc pos1opt:Tativc pain in adults. Av.ail3Mc in ~11ie C'ochr.inc:
Efrects on the lungs. Ste Hypersensitivity. below. naproxen. Food l'cduccs the l'ate but not lhe extent of 0J1ab;tse of System:Jti<: Rcviewll.: lii;5uc 9. Chiches<tr: John Wi-
Effects on the salivary glands. For reference to salivary absorp1ion. Naproxen and naproxcn sodium are also ley; 2009 (ac:<<'Sscd 18/09!09).
gland swelling ~ssociatcd with naproxcn therapy, see Hypersen·
sith•ity~ below.
well absorbed rectally. Al therapeutic concentrations Administration in children. Jn lhe treatment ofjuvenile idio-
naproxen is more than 99% bound to plasma proteins. pathic arthritis, US licensed product information l'(.'COmniends on
Effects on the skin. C111aneous reactions repo11cd io patients oral dose of about I0 mg/kg daily of naproxen in 2 divided doses
Plasma conce!1trations of naproxen increase propor-
receiving nttproxen include crythcma nodosum. 1 lichen planus.2 for children aged 2 ycors and over; in the UK, 1his dose is Ji.
toxic pustular skin eruplioo.3 bullous dennatosis,4 and fixed drug tionally with dose up to about 500 mg daily; at higher censed for those aged over S years. In addition, higher doses may
eruption.! rhotodennutitis, characlcriS(.-d by vesicle fonnation or doses there is an increase in clearance caused by satu- also be used: lhcBNFC ll)Q9sugg<.'Sls a dose of up to IS ni!Vf<g
increased skin fragility on sun-exposed skin, has been reported in ration of plasma proteins. Naproxen diffuses into syn- daily (maximum of I g daily) in children aged 2 to 18 years.
adults6•1 and children.•.10 ovial fluid; it crosses the placenta and is distributed into For pain and inflammation in musculoskcktol disorders and dys-
A relapse of subacute cutaneous lupus crythematosus was re- breast milk in small amounts. Naproxen has a plasma mcnorrhoea, IN.BNFC ]l)Q9 suggeslS that those ai:ed I month to
ported to Ile possibly associaled "ilh napro.xcn. 11 18 years may be given an aral dose of 5 mg/kg twice daily (max-
elimination half~lifc of about 12 to 17 bours. About imum of 1 g daily).
For rcferen~ to facial scars of unknown origin de<eloping in
children 1-eceiving NSAIOs, and in particular naproxen, see un· 95% of a dose is ~xcrcted in Ul'ine as naproxen and Headache. An NSAIO such as naproxen is among 01e d1t1gs
dcr NSAl.Ds, p.102. 6-0-desmethylnaproxen and their conjugates. Less tried first forlhcsymp1oma1ic trea~nemofvarious lypcsofltead·
I. Cr;iuan CEH. Kennedy CTC'. Napro~tn induce!d nythema no- than 5% of a dose appears in the faeces. ache including migraine (p.670) and tension-type headache
dosun>. CM.I 1984; 281: 114. (p.671 ). An NSAID given at lllc onset of~·tnptoms can RICCCSS·
0 Refcr<nees.
2. Hcyinann WR. et al. N1proxc1....indUC'Cd lichen pbnus. J Am fully treat an arute atuck of migrnine.1· Co·treatmen1 with a
Acl>ll D•nuorol 1984; ID: 299-301. 1. Bruno R. ~ o/, Napro>.t'n kin<hCS m syno.,uil fluid of p.nients
3 ~tc Sk. Grauan CEH. Pustular reac1ion to napro.xcn wi1h wi1h CKtcn11rthn11s. /Ir J Cl111 PhnnHot-ol 1983: 16: 41-'. triptan may i:w<>vidc additional bcoefit and 3 preporalion cootain·
d>olcsL'lic: jaundice. BAIJ 1986; 193; 5t0. l. Bmirt P. f'f al. SodM.un mpro~en : conccntntion and effect M ing both sumatripran suc:cinatc and napmxen sodium (Tmln~I:
4. Boukttn MB. ct al Naproxen-3SSOCi;ned linear lgA bullous der· infbmmllOty response- mediators 1n hum.a" rhc:umatbid synovial GlaxoSmithKliM. VSAI is available.~
mllOSlS: USC r~por1 aod rcvi.ew. All1)'0 Clin Proc 2000: 7S: Ouid. EwJ Cfi11''"'1""°"" 1994; ~6 : 3-7. NSAIOs olso 8Pl'C'l1 to be effec1ive for the prophylaxis of mi-
967-iO. ) _ Da\riHNM.Andttson KE. (..'"h.n.ealpharmaMk1nc1ic.sofn;iprox-
S. Lcivo T. Hctlck11I H. Napr~c-n- induc~ generalized bullous gniine, although propr.inolof is gener:illy (X'Cferred. Studies have
<'ll. Clin Plu~lt>tf 1997: 32: 26&-93.
fixed dnia crvption. llrJ /Nf'1Uatol2°"': JSI: 232. indicated lha1 roproxen sodium 550 mg[equivalcnt to 500 mg of
6. Howard AM. ~t al. Pstudoporphyria due 10 n:iproxcn. Ltm«1 4. Bowalgw K• ., o/ S·N•p<OJ<tn ond d<11n<lbylo>pn>>Cft •tu·
cutOnid:ition by huJN.n liYC"r mtef'O'SOl'nCs :.nd rc<ombin3nl-h114 naproxcn) given !\\•ice doily may be useful for reducing the
t98S: t: 319-20. man UDP-gluc:uronocyl11·1nsfc:ruH tUGfl: role of!KlT?ll7 in number of anaeks suffered.~
1. Rivers JK. 8'.rneuon RS. Naproxcn...inductd b\allOU$ phoioder· tM climifta1ion of noproxcn. Br J ("flu Pltor•,orol 4,00S; '0:
m11i1it. MttJ Ausr t989; tSt: t67-S. I. Trews TA.. ,, cl. N<tprcucn sodiun1 vusus ttsot1n1inc annlc in
423-Jl. 1hc lrutmcnt of acul~ mi~rain< anuks. Ht'~lte 1992: 32:
! . ~")'ML. CJ ol, ~~proxcn-.induccd pseudoporph~71a: o disline-
llvt phocodtf'n1ac1l1$.J P«lrotr 1990; 117: 660-4. 2S0-2.
or
9. ~rndi A. «f nl. Possible naproxen-induced relapse sutr..c'Utt' Uses and Administration 2. Winner P. el ol. T"eh"t'-mo;uh tolmbility and safety of SU•
macripta.n-n:apro.'\en sodium for lhi: \((311nc:nl or acute misnin:.
cumne~ lupus cry1bem3tosus. JAMA 1992; 268: Sl-2.
IO. Lona 0A, F1nl:ayson LA. Naproxen-induced pscv<loporph)Till i11 Naproxen, a propionic acid derivative, is an NSAID MtQ'O Clin />toe 2007: 81: 61-S.
po1ients wilhjtwcuilc rh""maloid arlhritis. J Pediott· l994; 124: (p.103). 3. Bnmdcs JL. et cl. Sum<itrtpUin-n3proxen rot acute ltnlmcnt or
639~2. mitraine: a r:in<lomiz"'11rial. JAMA 2001; 297: I443-S4.
11. Co'\: NH. Wilkinson OS. Oerm3litis a.11e(ac1a as the prescnlinq Naproxcn is used in musculoskeletal and joint disor- 4. Sargent J, tr al. A comparison or naproun sodium to pro·
t4-J1IUfC or JUJIO.. t'rylhro~)'Ce sensi(i7Jlli(ln ~yndromc :ind napro,x'°:: ders such as ankylosing spondyli1is, os1eoarthritis, and pr.>nolol hydrochloride ind a pl.accbo conlrol (or the pt0t1hyl:axi1
~;;;;~~u~ r~~~upoq>hy1 ia in a sins,I~ patient. Br J Df?rmatol or1nigraine hcad:Jche. Heodatht 1985; 25: 32<>-4.
rheumatoid arthritis including juvenile idiopathic ar- 5. Welch KMA. t:I o/, Successful miirJinc prc.>phyl:•x1s wi1h
1hritis. It is also used in dysmenorrhoea, headache in- naproxcn oodiuin. Nt:11ro/og_l· lt)SS ~ 35: 1304- 10.
Hypersensitivity. In an early case-repoC1 in I I aspirin-se11sitivc 6. Sances G. ti tll. Naproxcn S<idiuin in mtnslrual misrainc proph·
asthmatic palieots. all developed rcnctions (rhinorrhoca, tight- cluding migraine, postoperative pain, soft-tissue disor- ylaxis: ;l douhlie·blind pl~ccbo controlled stody. HcmfnclHJ 1990:
ness of chesl. wheezing, dyspnoea) after taking naproxen in low del'S, acllle gou1, and to reduce fever. Naproxcn is 30: 705-9.
doses of SO mg or less. 1 More recently, angioedem• occurred af. 7. Suthisisanz_ CC.,., ol. Mc tc-:i n ul~if; of tht t0i1,:acr und safc:1y of
usually given orally as the free acid or as tl1e sodium n3proxcn S<.)dium in lht 3cu1e treatment ofiniar:ime. HMdMltc
lcr a single dose of naproxcn in a paticn1 k!lown to be aspirin-
sensitivc.= Hypcl'sensitivity to individual NSAIDs is believed 10
salt. The doses in the J ic~nsed product infonnation are 2010; 50: SOS- IS.
be closely linked to the extent to which Uocse drugs inhibit pl'OS- expressed in tcnns of the free acid or the sodium salt as Malignant neoplasms. Some NSA l0$ •uch as naproxon muy
tosl•ndin synthesis (see under Aspirin, p.22). 'There may 1here- appropriate for an individual preparation; however, the be of value both for the differential diagno.o;is and the manage-
fo1'C be a dc>te threshold below which no detectable symptoms doses given below arc expressed in tenns of the equiv- rnt:nt ofneoplas1ic feyer1-1as1hey a1>pear 10 be mon: dfcctivc in
occur. Such an effect has been reported 3 in a patient previously reducing lhis cype of fever than against fcvci· associnted wi1h in·
alentan1oun1 of free acid only. Each 550 mgofnaprox- fec1io11s. Howe'"'r, the reliability ofnapioxcn in the diopsis of
&tab1hsed on naproxcn for about one year who had a hyperseosi-
tivity l'C3ction af1ei· a dosaae increase. en sodium is equivalent to about 500 mg of naproxen. neoplastic fcwr has been que.1i0t11.-df In a group of 72 patients,
A hyporscnsi1ivity reaction ch•racteriscd by pulmonary infil- In the treatment of rheumatic disorders, the usual naproxen decre:ised body teinpr.rsturo in 55% of )laticnl' with
11111"" wid1 cosinophilia"" has been n:ported in patients taking. dose ofnaproxen or naproxen sodium is !he equivalent neoplastic disorders and 38% of palitnls with other oonditiol>S.
napto.\cn. Tiien: has •bo been a report ofa generalised hypersen- Thus, the sensitivity of th< ICSI was calculated as SS% and its
of 500 mg to I g of naproxen daily either as a single specificity as 62%. which the ~uthors considered to be too low to
sitivity reaction with acuie rosinophilic colitis in• 57-)~-0ld
woman ln:atcd with naproxt11 for ostroanlui1is.6 Bilateral swell·
dose or in 2 divided doses. US licensed product infor- Ile reliable.
ing of tllc major sali\'al)' glands. a generalised rash. and eosi- mation states that paliems who tolerdte lower doses I. C'haniJC. Gross HM. ~eoptas11c fCvcrrnpondstoth~ ttt:Mmt-1\I
nophiha SllS&tsth'C of a hyperseosiril'ity response was repul1«1 may have !heir dosage increased to 1.5 g daily for a pe- of•n adeqwuc: dose of ..ptoxm J Din 0..ol 19SS; J: SS2-8.
!. A:rc:anuddin SK. <ta!. The cfTccs of naproM11 on (ncr i:n chi I·
in another p:uient •tier use of naproxcn.7 LeucocytodaSlic vas- riod of up to 6 monlhs, if requm:d. For dosage in chil- drftl ..·ith m:sliwta.ncics. C'"'~t'Y 198?; 59: 1'66-S.
culitis wuh ~riphcral oeuropothy and nephri1is has also been dren, sec below. J. EcnnomM K. ;, nl. The cffl'Cl of na;nO'<C'ft on (C\"ef' m~lltnlS
noted in a 62·ycar-old woman after oopoxen tn:atmen1.s - , ..;~ ad't'ant.~d iynttolO!.ic m11i1nandc$. Grn«ol Otte01199'
t. Szcuklil. A, rl al. Asthmatic aU.acks ind~ed in aspirin-Sf'nsil~c In other painful conditions such as dysmeuorrhoea 56: 250-4.
po11cnu by d1elorcnac and PGproxcn. BM.I 1977; 2: !31-2. and acute musculoskele1al disorders !he usual regimen 4. Cunha BA~tt/ol. Fc--..-o-ofunkoownori;in(FlJO)aus~bymut ..
2 Gh1slain.P-O. Ghtsbm E. Oc:Jeme de Quinck~ de- la nuque induil tiplC' mydom:a: ihc d•a:no!U.1C' '"3tuc or lhe No-prosyn tC'Sl. Ht-url
r:ir l'ac1dc 11c.!lylulicylique. 11\CC rC:action croi:Sic pour It
is the equivalent of 500 mg of naproxen initially, fol- L11ng 2006: l~ 35'-62.
n:apto~f'I~ sodique. Ann Mtd ,,,,,rn, (Paris) 2000: 151: :n :-9. lowed by 250 mg every 6 to 8 hours, up to a maximum S. Vand<-rschuercn S. tfol. Lxk ofv.-.h--..:oflhc: Npro..'(en 1ut in lht
3. fh't.~OC·fh,-ycr L. Etal JV. Oyspn~a and periorbital eden~ fol· di0Crenti31 dia::-oosis o( prok>ns~d ftbril~ tllna"n. Am J M'd
daily dose of 1.25 g on the first day and I g thereafter. 2003: 115: ~72-~.
luwinii .m inc.:n:asr in naprn.\icn do.1c-. Aun P/Jan11,1cxxh(!r 199..t;
lS: 1110. In ncute gout an initial dose equivalent to 750 mg of Preparations
4 NOO~r DA. Schill:i.d RF. Pulmonary infillr:iCt'S wilh tc$inoptnli:i naproxen followed by 250 mg every 8 hours is used.
due 10 n•pro.\c•. Chw t 9S3: 83: 230-l. BP 2010: C..Slro·""'1an1 Napr"'°"' Tabltt~ hl'fJI~ 0r'15_.;o-c
Nc.proxen S~:;ories; N~o1'.ttt T~.blets.
~ - Busca-.Ha AJ. er al. Pul m(lnaty infillracc~ otssoci.Jted with
n•rtt1.\Cn. JAAIA l?S4: 15t: 65· 6.
For the treatment of migraine, the equivalent of
750 mg of naproxcn can be given at the firsl symptom
USP 33: N<p1"""° o..l>)'Cd·Rele><.e T•bl<IS: NalJf'O'«l'I Or•I
Napmxen S:i&m Ta!:lc".s; ~n lableu.
s....,.....,.,
6 Jlddg.ts AJ. rt ul. Acuti: eosi11ophilic colitis and hypfrseMilh•iCy
Jt:K'1ion associated wilh nRprnxcn thcrnpy.•./111JMPd1990; 89: of an impending attack and, if necessary, this may be Proprietary Preparations (ddails 3rc gi,·cn in Volum: 8)
S26-7. . followed after al least half an l1our by forther doses of Arg.: Aleve: Alicbse: llu'Nlltx \I: Coo~><: Otbrit Fabr<llsjna: Fld<hvicx
7. Knulsl AC.~' ti/, Silivary glnnd S,\-Clfing following naproxen Flixv"< flogocefalt; K<tdo<: Mclgv; Mona•it M0>< Nap1'CM0>e N~cn:
1hcrapy. Br J Dt!rmawl 1995: 133: 647- 9. 250 lo 500 mg throughout the clay lo a total maximum Noprcnl3f' Naprux: Neul'a!pror.at: s;cid<•llol Fll•t: Tondta; V.1·1dolt:
8. Sch:i1lir:1 I). t!I ttl. l\'aproxen·induct'd leukocytoclastic vasculilis. daily dose of 1250 mg. Sec Ilcadache, below for a sug- Austral.: A."'pro><: Cheinsts o...
n f'<.'f'iod Pair\ ~t remrnc Freet:
CJ/,, Rlmm111tul 2000: 19: 2.42-4. tnza. Naprogesic: ""'pt'O)yn: Proxen: Austria: Ale,~ Mirana.x: Nitpr'Obene:
gested dose for the prophylaxis of migraine. Nycoprent: p,..,..,,,
Belg.: AIM: Apr.Ina><: Naprollam: Napl'o1yno: Bro ..:
Paricinsonism. F(l( a n:port of a pa1ienl whose symptoms of A.max: N..,ronax: Napt'OS)'lt Nop.-ox; Conod.: An>r»O>< ~O·Nap<O-Na;
Naproxen has been given rectal~v in similar doses to Nap-ciao; N•prot"': Nov.>·N•ll"O" N\1-Nill"= Chilo: At•c: O...c°""I,
rMki11S011·s disease were cxae<>rbatcd by 11aproxen, see Effects
on the CNS, ab<m:. those used orally. Euroge•<: Flogotcoe: lnveoxelt. N31"ogosc: l1iox NF: Cz.: Ale,,.: f"""""'
Na.:tes<rc Naprobonet: Naprosyr01: N;ipsynj: Otnm.: Bcnrt MorM1..t:
Naproxcn has also been used as the pipcrazinc, ami- Napros)r•f: Fin.~ .A.lpox~ll; Eo>.. Mifi1.ntlx, Napromctin: Nipromt>e.:
N"l"""l'nt: Naxop1-.oj: f'ro">xon: Fr.: Al-. Apr>..,.: N.pros)'f'e' Ger.:
tnteractions nobutanol, and lysine salts, and as naproxeo cetrimo- Altcetan NNA: Ale-i.-e; Oofo.n)W't m1t ~f#CD(Cn: Orsmcri1lgit Hob.ta\
For interactions associated with NSA!Ds, seep. l 03. nium. Naproxen has been given as part of a combina- Sci'>ml!flt>bletten ""' N•proxen: prodolort: ~ Gr.: ANproo<; Aro<·

'f'hc symbol t denotes a preparation no longer actively marketed

98 Analgesics Anti-inflammatory Drugs and Antipyretics

~~~~af~: ~=~~~ ~~~~~~~~~=~~ %~n~:~g-So1e~

( ll), confusion (I I). cutaneous reactions such as erythema (7), in elderly patients) three times daily. Nefopam hydro-
pruritus (4), and unicaria (3). and anaphylactic reaclions includ- chloride may also be given in doses of20 mg by intra-
Hung.: A'°"'; ~ Napmel: Naprosyn; Indio: Artzge<>: Easy Dayz: ing anaphylac1ic shock (4) and angioedema (2). The anaphylac-
1~ap1·osyn: Xenobid: lndon.: Naxent. Synllext. Xeni!ar. lrl.: Gennap;
tic reactions were reported to have occu1Ted shortly after ne- muscular inj ection, repeated every 6 hours if neces-
Naprosyn; Syn1'ext: Israel: Naproxi; Na"OCin; NiX)n; Poirot h al.: Alcvc;
Algonopnlj: Aperdanj: Aog;•13X: Floxalint. Gibixent: Gynestrel: L.ser; Me>- fopam was given during the postoperative period. There was a sary; it has been recommended that the patient should
mendot Naprius: Naprocet: Naprorext: Naprosyn: Neo Ebtnon; Nit.ens: single case of fatal convulsion and no cases of ovcrdos.age had always be lying down when receiving the injection and
Prc''"' P~I: Syn.ilgo: Synflex; 1'cofle¢ Uninapro; Xenart: Malaysia: been reported (but see below). should remain so for 15 to 20 minutes afterwards. It has
Apo-Napr.rNa; ln?at; S•"""'" S; Seladi« Suiprox; Syn~ox: Mex.: Aaiq.
uim: ANlgen: Ana;>sf.t Ars.c.~al; AJ')(en: Atinant: Bioxan: Bi>cen: Dafloxen; 1. Ourr-ieu G. et al. French Network of PharmaCO\'igilance Centers. also been given by slow intravenou~ injection in doses
De1\•-nox: Di'eri>e<I; Dolxcfl; Donoprox Edem; Fagofen: Faraxc« Fbnax: Ove-rvicw of adverse reactions to nefop3m: :m analysis the or of20 mg every 4 hours up to a maximum of 120 mg
A""9XCn; Flaxendol: Flogen: Fwen: lnflan·:ix; lq:"a;ol; Ker.aproxt; l.n<Q&ant. French Ph"':macovigilance d3tabase. Fundom Clin PhormoeoJ
lut2pe'ett: Messelxen: Nallapen; Na:poxot Naproditf: Nawc:ant NllVi~ 2007; 21: 555-8. daily.
Nvcen; Nixopaar: Neona:xi~ Novaxcn: Part~ Praxedot Pro(a)ccn; Pl"0-
1"1: P.,,nax.pt; Pronaxi ?ronoxen: Prop;ona!; Pro><a!in: Proxemj: Salu· Effects on t he urinary tract. Jn January 1989, the UK CSM' Hiccup. ln two case series1.2 involving JO patients in Iota I, hie·
pr.int: Scrtrixe"< So<ixen: Tandax: Tani:rona: U:Welaxe<lf; Vanbr< Velsay; reponed that ii had received 53 reports in which nefopam was cups tefractory to standard therapy slopped after treatment with
Neth.: Ale"'; Momendot Naprelon; Napnx03tj'; Najlr<M!e; Ny<oprent. associated with the development of urinary retention or symp-
N orw.: Alpoxenj: Ledox Napren; Naprosyn: N Z: Naprogesic; Naprosyn; intravenous nefopam. For the management ofintractable hiccups
Naxen: Noftam; Sonaflam; S)'l'flex; Philipp.: Aip<oo: Flacidon: Aanax; Na· 1oms of hesitancy, poor slream, or dribbling. In one case there see under Chlorpromazine, p.1079.
flax; Napoxcn; Naprelant: Naprosyn; Saromed; Skebn; Pol.: Aleve; """ "'•Sa history of proslatism. I. Bi1ona F. Rosa G. Nefop:."lm for scvcfc hiccup~. N £ngl .I Med
pr<Sn; Apo.Napro: Boloxen: Emochotf; Nava>e Tarproxen: Port.: Momen- 1. CSM. Ne(opam hydrochloride (Acupan). Curr-e-nt Pr0blems 14 2000; 343: 1973-4.
dol: Napfocet Naprosyn: Revxen; Rus.: Nalgcsin (HaArcli.tH): S.Afr.: 1989. 2. Ui1ona f. et of. Ncfopam for refractory pc,c;roperative hiccups.
Acuspr.iinj: ~ Fi~xynt; Nafasol; NapOam: Naprosynj: Synflex Tr.i""
Aneslh Analg 200 1; 93: 1358-60.
moxj' Singopore: Aleve: APo·Nil(Jlo·Na: '""" Naprosyn: Nof<L-n-Nf: Overdosage. There have been reports of fa1al overdoses with
NuprafM; Sela«< Soden: SotJroxen; S}nle>< Zynalt: Spain: N....,f: AIM- Pain. Systematic reviews considered that there was little or no
omas; M!AIF}n; Den"""'°rc lundiran; M°"""" N"l""'yn; Napro;alj; Ta· nefopam. 1-' One report' also provided details of9 other palients
cron: Swed.: A'poxen; Eox; Nap:osyn: Prooaxen;; Swiu...: Aleve: Apran~ who recOvered with routine supportive treatment. c·vidence to justify lbe use of nefofam as an analgesic for the
Nycoprent; Pn)Xen; Thol.: Annoxen: &..pro)(en; N.aproRex Naprosian: I. Piercy DM, ti of. Death due ro overdoseofnefopam. BMJ 198 1; management ofpostoperati\•e pain . .?
Naprosyno Napseno Nanenf; Nasin; Naxeoe; Po!yxen; Proicen; Se:viprQO<· 28): 1508-9. I. Evans MS. er al. Nefopant for the prevention of postoperalive
ant; Son•p: Soproxen: Synllex: Synogin; U.Prox)'rc Vonscn; Turk.: ,t_-Nox; pain: quantitative systematic review. Br J Anaeslh 2008; JOl :
2. Urwin SC, Smi1h HS. fa1al nefopam O\'trdosc. Br J Anoeslh
~~;~~:;~r;v~<~::tti~~~=z"::'~I=~ t 999; 83: 50t-2. . 6t0-17.
2. KakJ<ar M, et al. Single dose oral nefopam for acute poSi.opera·
Mcdf\ap; Naponal: Nap<ldol; Napren; Naprodev. Naprode.-; Naprosyn; 3. Trai:qui A, el al. Fatal ovcrdosage with nefopam (Acupani'). J tivc pain in adul ~ . Available in The Cochrane Da1abase of Sys·
Naprotob; Opr.ilcs; Relokap; Romal<sen; Romatr.I; Rumazoll<irt S-..rokscn; Anal ToxicQI 2002; 26: 239-43.
tematic Reviews~ Issue 3. Chichester: John Wiley; 2009 (ac-
Syn;ix; Syndol; UK: Art"'°""': Feminax Uhra: Napratec: Na~ Syn- 4. Kerr OE, Fletcher AK. Fatal ncfopam overdose. Emerg Med J
Oe:x; Ukr.: Ccfecon N (Ue~OH H); Nalgesin (HaMe3'*1): Pfomax cessed 28/07/1 OJ.
2010; 27: 407-S.
(flpoMaicc): USA: Aleve; Anaprox: Naprelan; Napn:>S)'n: Pn!:vacid Napt;J- Shivering. Nefopam is one of several druss tried in the preven-
PX:~ Vimovo: VeneL: Apranaxt, Synaprosynt.
tion of postoperative shivering (p. I 935).
Multi-ingre d ien t A11.: Nap<ot'ltag Re~ Naprux Dmen: Papi1Sine; ltoL:
Preca utions
References. ·
Nefopam is contra-indicated in patients with a history
~'1~~~~~~~r;;F~~~r:~;.~c:u-~.=t.: of convulsive disorders. It should be used with caution
l . Bilolla F. e1 ul. Nefopam and tr~madC>I for th! prevenlion of shiv-
ftoxen.f; Oecosit De~max Plus: Dok>ta.ndax: Drunen: Fancen; Febrax; ering during neur3xial 3nesthesia. Rt•g Ancsth Poin Med 2002~
f'tverdol; flaxen<lt AucoJt; Grife<!; Kensedat Me>'"'< Naprodil ?lost Naxo- in the elderly and in patients with glaucoma, urinary 27: 38~.
dot Nedoxat; Neo.-pan Plus: Onexmol; P.....nsodil: Polet: Profcn!ax: Pfcx:alin 2. Piper' SN, el ol. A comparison of nefC>pam tnd clonidinc (or lhe
Pius; Raxenot Revconil: Somalgm Tmnanj: ~!Je.N: ve1say.5 Com· retention, or impaired hepatic or renal function. prc\•cnlion of post.anaesthetic shivering: a comparaLive. d<.'Uble·
puesto; Vipkis; Xenorac's: Rus.: Cefec.oo N (lJe¢ieKOH H); f'entalgfn-N blind .:ind pl.::icebo-conlrollc<I dosc-rnnging study. Anaesthesia
(neHT"""*H); USA: Trex;met. Abuse. Abuse of parenleral ncfopam has been reported in 3 pa· 2004; 59: 559-64.
1ients with a history of chronic pain. ' Psychostimulant-like .>. Biloua F. et ol. Ncfopam or clonidine in the phann.acologic pre·
symptoms such as agitation.. impatience, and violence, were not- venlion or shivering in patients u ndergoing conscious sedation
ed in 2 of the patients; an1imuscarinic effects were also seen. All for intervenlionaJ neuroradiology. Anocs1he;ia 2005~ ()0: 124-8.
3 patients well? found to be psychologically dependent; in 2 who
Nefopam H ydrochlo ride attempted to stop nefopam, withdrawal symptoms were noled. Preparations
(BANM. USAN, rlNNM) 1. Villicr C. MallareL MP. Ncfop1m abuse. Ann Pharmaro1her Proprietary Prepara tio ns (details are givtn in Volume B)
2002; 36: 1564-6. 8 t<lg.: Acu~ Fr.: Acup.an: G er.: Si-Sentant Gr.: Leoplexamil"'( Palopiker·
Benwxa.tocine; Fenazoxi'ie: Hidrccloruro de nefopam: Ne- on lrl.: Aaipan: Ito/.: O>adoll; N Z: Acupan; Rus.: Qxadol (O<cao.o•~
fopam, Chlorhydrate de; Nefcpami Hydrochlorichxn; R-738. Breast feeding. No adverse cflects have been seen in breast- UK: Ao.pan.
fed infants whose mo1hcrs were receiving nefopam, and the
3. 4,5.6-1el1'lhydro·S-methyl- I -phef¥1· I H-2.5-benzoxazocine
American Academy of Pediatrics considers' that it is therefore
hydrochloride.
usually compatible with breast feeding.
H*nai.-.a r"APOXllOP"A
Nepafenac (USAN.11NNJ
Studies in 5 healU1y nursing mothers given nefopam for post-epi-
C 17H 19NO.HCI 289.8. = siotomy pain indicated thal ncfopam was present in human milk AHR-9434; AL-6515: Nepafeoac; Nepafenaco; Nepafenacum.
2-(2-Amino-3-benzoylphenyt)acetamicle.
CAS - I 3669-70-0 (ne(oporn); 23327-57-3 (nefopom in an equivalent concentration to that in plasma.2 It was calculat-
hydrochloride). ed that on a body-weight basis a breast-fed infant would receive Hena<j>e><aK

ATC - N02BG06.
less lhan 3% of the maternal dose. CosH ,.N,01 =254.3.
I. Amcric.an Academy of Ped fairies. The 1ransfcr of drugs and oth- CAS - 78281-72·8.
ATC Vet - QN02BG06. er chemicals into human milk. Pediatrics 2001; 108: 776:-89. ATC - SOIBCIO.
IRelircd May 201 OJ Correction. ibid.; 1029. Also available. a1:
UN/I - 685)4 8£ I 3W ATC Vet - QSOfBCIO.
h u p ://aa ppo) i C)'. aa p pub 1ica1 ions .org/cg ii con 1e nl i(u 11/
pcdia1rics%3bl0813n76(ac<ess.'<I IOll0/06) UN/I - Oj9L7)6V8C.
2. Liu DTY. e.t ol, Ncfopam excre1ion in hom;m milk. Br J Clin
l'hormacol t9S7; 23: 99-101.

Interactions
It has been recommended that nefopam should not be
given to patients receivi11g MAOls and should be used
cautiously in those receiving tricyclic antidepressants.
The adverse effect~ of nefopam may be additive to
(ne{opom)
those of other drugs with antimuscarinic or sympatho-
mimetic activity. Profile .
Nepafcnac, an NSAlO (p. I 00), is a prodrug of aonfcnac. It is
Pharmaco poeias. In Chin. used in the b'eatment of pain and inflamm1tion following c.:ita-
Pharmacokinetics ract surgery. An ophthalmic suspension containing ncpafcnac
Nefopam is absorbed from the gastrointestinal tract. 0.1 % is instilled 3 times daily starting on the day before surgery
Adverse Effects and Treatm ent and continuing for 2 weeks after surgery. to a maximum of 3
Peak plasma concentrations occur I to 3 hours after an
Adverse effects occuning with nefopam include gas- oral dose and up to 1 hour after intramuscular injection. weeks if necessary. An additional drop should be instilled 30 to
trointestinal disturbances, such as nausea and vomit- About 73% is bound to plasma proteins. Nefopam is
I 20 minutes before surgery.
ing, sweating, drowsiness, insomnia, urinary retention, distributed into breast milk. II has an elimination half- 0 References.
dizziness, hypotension, tremor, paraesthesia, palpita- Jife of about 4 hours. It is extensively metabolised and I. Colin J. Paqucuc B..Comparison or the aoolgesic efficacy and
tions, lightheadedness, nervousness, confusion, safety of nepafenac ophthalmic suspension compared wilh di·
excreted mainly in urine, in which fess than 5% of a clofcnac oph1ha1mic solution for ocufar piin i!nd pholopho\>ia af·
blurred vision, headache, dry mouth, syncope, an- dose is excreted unchanged. About 8% of a dose is ex- lcr cxcimcr laser surgery: 3 phase JI, randomized. doublc-
gioedema, allergic reactions, and tachycard ia. Eupho- masked trial. Ciin 11tt:r 2006~ 28: 527-36.
creted via the faeces. 2. Lane SS. Nepafcnac: a unique nonstcroidal prodrug. Im Opl1-
ria, hallucinations, and convulsions have occasionally 1holmol Clin 2006; 46: 13-20.
been reported, as has temporaiy pink discoloration of 3. Lane SS, e1 ol. Ncp3fcnac ophthalmic suspension 0.1% ror the
Uses and Administration prevention and treatment of ocolar inflammation associated with
the urine. Symptoms of overdosage have included Ncfopam hydrochloride is a non-opioid analgesic con- cataract surg_ery. J Cotorocl Refrac1 Suit 2007; 33: 53-8. Cor-
CNS and cardiovascular toxicity. sidered to act centrally, although its mechanism of ac- rccrion. ibid ; S64.
Incidence of adverse effects. lb~ French Phannacovigilance tion is unclear. It also has some antimuscarinic and Preparations
System has reported ' that, from January 1995 to December sympathomime.tic actions. Nefopam hydrochloride is Proprietary Preparations (details are gjvcn in Volume B)
2004, it bad received 324 reports of adveisc reactions associated Arg.: Nevanac; Chile: Nevanac: Cx.: Nevanac; Gr.: Nevanac: lrl. :
with the use of ncfopam. TI1e most frequently reported reactions used for the relief of moderate acute and chronic pain. Nevanac: Maloysio: Nevanac:: Mex.: Nevanac, Pftitipp.: Nev"cina'; Po rt..:
were sweating (15), nausea (10), tachycardia (8), malaise (6), The usual oral dose range is 30 to 90 mg three times Nevanac Thoi.: Nevanac: UK: Neva.nae; USA: Nevanac.
and \•omiting (5). Unexpected reactions included hallucinations daily; the recommended initial dose is 60 mg (or 30 mg
All cross-rcrcrences refer to entries in Volume A
 Nefopam Hydrochloride/Nimesulide 99
Nicoboxil i"""'J Nimesulide bcladox (nimesulidc betacy<;lodcxtru1 complex) has
ButO><)'elhyl Nic-.ate: NtcoboT.lio: f'<icoboxilurn. 2-&ltO>C)'Clhyl been ustd similarly.
H
nicobnate 0 Refcrenc.:s..
N NPCF3

CX
H~"" I. Bcnntll A. et al. Nimesulidc; a muhifactorial chenpeuuc •Po
CnH 1NO! 223.3. = I~ proach to lM inflammatory procCM? A 7-ycar clinical t'\pcri-
ence. Drvg> 1993; 46: (•uppl I): J-lU.
CAS - 13912-80-6.
UNll - GS05B9USOW.
coo 2. ~nna GE. e1 ol. NimC$ulide in the tttM111~n1 orp11ients iT1toier-
•nt of aspirin aad ocher NSAJOs. Drug So(ery 1996: JC: 94-103.
3. Vt7.z;ard i M. e1 ol. Nimesulidc beta cydodcxtrin (nuncsulide:-
Pharmacopoeias. In Eui: (sec p.vii). betadex) versus nimcsulide in the: ueatment of pain. after 1rthro.•
Ph. Eur. 6.8 (Nillumc Acid). A ptle yellow, crys1alline powder. scopic wrgery. Cun· Th~r Rts 1998; 59: 162-7 t .

tt'Nl Practically insoluble in water; soluble in alcohol and in methyl

alcohol; freely soluble in acetone.
4. Bemareggi A. Clinical pharmacokine1ics of nimesulide. C/ln
Phormocokinel 1998; 35: 247-7.it.
5. Shah M ~1 al. Selec1ive inhibition of COX-2 in humans is H·
~O~O~CH3 Adverse Effects, Treatme nt, and Preca utions
As forNSA!Ds in cencral, p.100.
SOci3ted wilh less gastroin ltslinal injury; I comparison
nime$Ulide :rnd n:1proxcn. Gm 2001; ~8 : 339-46.
or
0 Fluoride-associated ostcosis has been reported with prolonged
or
6. NUing RM. t i ill . Pa1hogcnc1ic role cyclooxyscnose-l in hy-
pcrpros1.aglandio E syndrome/antenatal Banter syndrome: 1hcr1-
use. Niflumic acid should be stopped if hypcrsensitiviiy skin re- peutic use of the cyclnoxygena$C-2 inhibitor ni1nesulide. C/m
Proflle ac.cions appear. Phormocol Ther 200 I ~ 70: 384-90.
Nicoboxil is a nicolinole used in topical preparations as a nibcfa- Adverse effects. Although 1/rrombocytopt11la is a common
cient. It is also included in some topical preparations used for t.hc Effects o n the skin. From a case-control study' ofchildren ad-
mitted to a hospital emergency department in Italy it was calcu- feature in patienlS infected with HTV, a group of workers consid·
treatment of acne vulgaris. crcd that thrombocytopenia in one oft heir patients was related to
lated that the oddNutio of users ofniflumic acid, or its derivative
Preparations momi flun~tc, developing serious cutaneous reactions was 4.9. lite use of nimcsulide. 1
Proprietary Preparations (dc1ails arc given in Volume B) Given this fii;ure and the fact 1ha1safer drugs were available the There have been rej>orts1-< of htpatoto;rlclry atier trcalmcnt with
Mvttl-lnarediont: Aurtrot: f"'ll"": Aunrio: m•I&<"" G....: finalgcn: authors considered that there was no indication for which niflu- nimesulide. Data from spontaneous reports have also suggested
Gr~ m.taon: lroL: Mti·Acne: Port: FIN!gon: Rus.: Belilgon (6oTaNOH): mic acid was required in children. However, a large cohon studyl that nimesulidc may be associated ";th a higher risk ofhcpalc>
Bc,.noc.,..,,..,, (6o-~ F~ (Gloo.....,OH): Spoin: FnoJ:oot im·oh•ing 193 727 children 1gcd between 0 and 14 years found toxicity than other NSAIDs.• A cohon study' involvins about
VI<: AcV>act: Vier~ FNlgon (-.,..). th•t niOumie acid was not associated with a higher risk of muco- 400000 usess of NSAIDs in one region ofltaly between 1997
cu!Jlncous reactions when compucd with other NSAIDs or P.ra- and 2001 found !hat lhose taking nimcsulidc were 1.3 times more
cctainol. The authors oflltc latcrstudy 9Uggestcd that the conclu- likely to develop hcpatotoxicity than uscrsof otherNSAIDs and
N icomorphin e Hydrochloride(M'i~ t!NNM) sions of the original study m3y have been confounded beause 1.9 times more likely 10 suffer severe liver injw-y. Reports of se-
there was no adjustment for age or indicotion. rious hcpalotoxicity had led to lite suspeosioo of market in& au-
1-idrocloruro de nicomorina: Nicorrorpme. Olloril)'drate de; thorisations of nimcsulidc in Finland and Spain in 2002. This is·
I. Mcnniti-lf'l'OlilO F•., ol. Ninumk •cid and CUWICOUS rcac1ion$
Ncomoiphin' Hydrochlorirun. 3,6-0;.0.nicotinoylmorphne in childrm.•4nJi Dis Clri/dlOOI: 8-1: 430-1 . sue was also reviewed by the EMEA6 and in 2004 lltcy reponed
hydrochloride; (-)-(5R.6S)-45-fpoxy-9a-methytmo<phin-7-- or
2 . Sturlc.cnboom M, rt ol. Incidence mucocuuneous rcac:tions in that the risk/benefit ratio for nimcgulide remained favourable;
3.6~ <fll'liar.nate h)O'ocNondc. children trc:llcd with ninumic x1d. other nonsr.uoidat 1ntiiit- however, they l<COIJUTlefldcd that its indteatlons be ieslricied to
lbmm•tory drup, or nonopiold 1111>l'°5ks. Abolnct: P<diotric> acute pain, dysmcnonboca, and oslcoarthritis for systemic for-
HMMO"'°J+- rl<Aj)O~ lOOS; 116: 212.
C19H21Ni0s-HCI ,S32.0. = full vcnion: hup:/Jpcdi1trics aappubliauion.s.0"1"cgi/con1tnt/
fullfl 16/l/e26 (KOCssed 08/1 ll07)
mulations, and lo the relief of sprains and tendinitis for topical
fomiulations. It was also rccommell<kd that lite oral dose be re-
CAS - 639-48-5 (nic:>morphint); 12N0-4 1-4 (nicomor-
phme hy</tochlotide): 35055-78-8 (nicomorphine 1<HCI). duced ID a maximum of 100 mg twice daily. Subsequently, in
Uses and Administration May 2007 the Irish regulatory authority "itbdrew nimesulide
ATC - N01M04.
Niflumic acid, a nicotinic add dcnvative, is an NSAID (p.103). from the Irish market a fter concerns about hepatotoxicity. 1 Since
ATC Ve1 - QN02AA04. It has been 11'Cd in inflammatoay and musculoskeletal and joint being licensed in 1995, ni1nesulidc had generated 53 advme re-
disorders in usual oral doses of about 250 mg lhrcc or four times action rcpor1S involving liver toxicity, including 9 cases of liver
daily; up to l 500 mg daily bas been used in severe disorders. ll faillllC, 3 of which resulted in death and 6 in liver transplantation;
has also been used topically as a 3% oinnnent or 2.5% gel. The there had also been I other liver-related fatality. The withdraW11I
morpholinoclltyl ester, momiflumate (p.90). has similar uses. prompted another review by the EMEA1 which concluded that
Niflumic acid glydnamide has been used 1opically in ioOamma- die risk/benefit ratio of systemic fonn ulalions of nimcsulide was
tory mouth d isordctS. still favourable; however, since most hepatic reactions were not-
Preparations ed a.fler 2 weeksoflrcahncnl. it was recommended thaltrcalment
witl1 nin1esulide should be limited lo 15 days.
Pr-opriecary Preparations (details arc given in Volume B) There have been rcports9•10 of toxic p11shllodcn na (acute gener-
A~. : Floa~: 8rlf .: _ N •r\J&cl: Nffiuritt: Cz.: Nillv&•I: N1flurilj: Fr.: flunift alised exanthematous pltstulosis) with oral nimesulide. Fl1<ed
Nil!ugot Niltvn"l: Gr" tNOmc>< 1'1\'0<l:lllot N1~amol: N~e: Raaoog!O: drug eruptions have also been seen. 11
~~::~::~P~~~~~~!f.'·: NiAam: Port.: Ninunt us.: Oonatr,in An infant developed hypotension and hypolbermia after inad-
Multi·ingredlcnt: A,,.: Rogo6~•n. vcr1ently taking an o verdose or 8 times the recommended doily
dose of nimcsulide. 1 ~ The patient recovered ofter gastric lavngc
with activated charcoal and supportive therapy.
t. Pasticci M B·, et ol. NimesuJide, thrombu.;ylOp\'.n\~ purpura, .. nd
Nime suiide (8»1. '"~NJ human lmmunodcfi c icncy v irus (HIV) infection. Ann /men'
Med 1990: 112: 23µ_
Nirnesulid: Nimesulida; Nme>v'idas: Ni'nesulide: Nimesulidi; 2. McConnic:k PA. el cl. COX 2 inhibitor and r1.1fmhu1nt hepatic
Profi le Ninesulidinum: Nimesulid'-"I; Nimesrulid; R-805. 1'-N"rtro-2' - fail uTc. lon('el 1999~353: 4~1.
ph~thar>esu!phonan lide. 3. Sbci1 W. e;1 oi. Nimcsulidc-induced ~ulc hcpa1i1is:. Aim PliOI"•
Nicomorphine hydrocblo.-idc is an opioid analgesic (p. I05) used •t0e0ther 2001 ; 3S: I049-S2.
in the trutment of moderate to severe pain. Ir is given in onil H"'-'«Yll>IA 4. Macii MA. el al. Hc~totoxici:1y as$0Cialcd with nimcsulide:
doses of S to I0 mg daily or by intramuscular, slow intravenous, CnH1 2N 20sS = 308.3.
data from the Spanish pharm3C'ovigilance system. Clin J>ha,.,,,o.
or subcutaneous injcctioo in doses of I0 to 20 mg; higher doses NJ/ Thn 2002; 72: S%-7.
haYC also been used. It may also be gj\om reaally in usual doses CAS -- 51803-78-2. 5. TnwcrA U ~1 ol. Cohor1 study ofhcp•Jtolo:<ieity ossoclottd with
of 10 lo 20 mg daily. ATC - MOIAXl7; M02M26. nimcsulldc a nd other non-steroidal an1i-inflHnm11ory drup.
8W2003; 327: 18-22.
ATC Ver - QMOIAXI 7. 6. EMEA. CPMP opinion following an 1ntdc ; I refcm I:
ORefcrenoes. UNll - V4TKWl454A1. nim6uli<k conLainintt medicinal products (issued 7th May,
I. Koopm.&A·K 1mtttai PM. a al. Ptl3mU1coki.nietics of itltraYCnOUS- 200<4). A••ilal>te at: hnp#www.ema.wl()pll.cu/odfs,'hum;m/
fy adminisicred n1comorp?1inc and its nlC&abolitcs in m:m. Etw J n:ferralini-1idcll 7HO-.pdf(ac:c.:$$Cd 08/04110) -
Anowl>aiol 1993: 10: llS-32. 7. Irish Medicines Board. hnmcdiatc svspens.on of the nutkecina
Koopman-K1mttai PM, ~1 o/~ Rtctal administration of nicomof- of m~icines con1ainin: nimesutide (lsJUCd 15th May, 2007).
phine in pauenu improw.s biological 3.vailability of morphine Avail.lblc at: hnp:f/www. imb.ie/ENIS1rcay--Qu:alilyl
and its a lucuronidc conjugates. Plwnu World Sci 1994; J6: Advisory-Warning-·R~ull-No1 i cu/ Humon-Mcd icincs:/
248-53. :iimesulide--Su$pension.u px?pa.~c· I &noticecypeid-· I &ye
l . Koopman-Kimcna1 PM," nl. Tii.e bi0;tivailabiliry of inlramU5al· or-2007 (ac<:cSS<:d OS/11/07)
l1rty Mlmini.stertd nicomorphinc (Vilao) with il.5 mcl3bolitcs and 8. EMEA. Que.s;ions and ans,~rs on the CHMP rtcommcncbuon
on nimC$ulide-containini medicines (i:tSucd 2l$l S.:ptembtr,
~~:,,1n::o,99~:c;!~~~~~~n surg.k1I ri~ticnt.s. Jn1 Jen,, PhD,.. 2007). Available it: hup;.'/www.tntC.l.turopa.eu/pdfslhum~n/
opinionl4309S807en.pdf(..,cuscd 08/11/07)
Pre para tions 9. late:o S. Borfo MJ. Localiud to.~ic pu.stul•ldcrm<1 11.)soci:.tcd
with nimesulidt lh~npy confirm ed by potch tcsiins- Br J fk,....
Proprietary P reparatio ns (details are given in V~ uine B) motof 2002: 147: 624-S.
Austrio: Vilan: Denm.: Vd1rt Neth.: MorZt-t: \'llanf: Sw itz..: Vdat'\ Pharmacopoeias. In Eur. (seep.vii). I0. Teixeira M~ el of. Acute ecncralized e!<:mthc:n11tous puslulo)is
Ph. Eur. 6.8 (Nimesu!ide). A yellowish crystalline powder. Ir induced by nimc:n•lidc. Dermatol Oulhtt J 2006; 1l: 20. Avail·
exhibilS polymorphism. Practically insoluble in water; slightly able a1: h 11p;/idcrmatotosy.cdlib.or&f llMcHe_prc.scn1ttions/
soluble in dehydrated alcohol; fi'eely soluble in acetone. age pl1cixe ira.h1ml (at:cesscd 08/J 1107)
Niflumic Acid (BAN. '1NNJ 11. Malhc iro D. t i ol. Nirncsu lide-induced fixed drug eruption. Al-
Acide ninumique; Acido ni1h'.mico: Acidum niOumi::llm: UP-8 3. 2- Profile lcrgol lmmuncpmhol (Modr) 2005: 3~: 2SS-7.
Nimesulidc is an NSAID (p.1 00) rcp0rtcd to be a selective inbib- 12. Y::ipakci E. e1 of. Hypoglycaemia ;ind hypothcmlh• dui: to
(<u1a·TriftuOl'O-m·to!uidino)nko~nic acid. ninlcsulid(' overdose . .-4r<'h Dis CMld2001~ 85: SIO.
itor or cyclo-oxygenasc-2 (COX-2). lt is used to treat aculc pain,
H*•)"o<Ollilll KMo.ora osteoarthritis, and dysmcnorrhoca in oral doses of up to 100 mg Pregnancy. Irreversible end.stage rennlfai/1we has been report·
C11H,FiNP2 = 282.2. twice daily; use in the EU is limited 10 a ma.,imum of 15 days cd in a neonate bom 10 a mother given nimesulide as a tocolytie
CAS • 4391-00-7. due to reports of hepototoxfoity (see Adverse E!fcclS, below). It from tbe 26th to the 32nd week or pregnancy.' Others have re-
ATC - M01AX02: M02AAI 7. has also been given rectally in a dose of 200 mg twke daily. Jn ported neonatal renal failute associated with nimcsulide.2 Pre-
ATC Vet - QMOIAX02; QM02AA 17. the symptomatic 1rca1ment of sprains a11d tendinitis nimesulidc ma1u,-e closwe of rite ductus arteriosus leading, in some cases, to
UNll - 4U5MP51U08. has been applied lopicnlly as a 3% gel. per.;ist~nt pulmonary l(>jx!J"fension has also been seen in I0 neo-

The symbol t denotes a preparation no longer actively n1arkctcd

I 00 Analgesics Anti-inflammatory Drugs and Antipyretics
nates whose mothers self-medicated with nimesulide during the Profile were 133 reports ofagranuloc}1osis (45 fatJ:I) and I87 of neutro-
third trimester of pregnancy. 3 Nonivamide is a S}'!1tl1etic analogue of capsaiein (p.33) that is penia (15 fatal). The most frequently implicated NSAID was
I. Peruzzi L. et al. Neonatal tald·suagt: renal f~ilure <;:issociated with used in topical preparations for the relief of mu;;cular and rheu- phenylbutazonc with 7~ reports ofagrnnulocytosis (39 fatal) and
ina,cm31 ingc-slicin of cyclo-oxygenase-1ype-2 selccti"e inhibitor matic pain. 40 ofneutropcnia (4 fatal).
t1imcsulide as locolytic. Lancet 1999; lS-1: 1615. Correction. Nonivamide has also been used as a food Oavour and in ·pepper 1. CSM/MCA . Orug-induced ne utropenia and ag_n nulocylosis.
ibid. 2000; 3SS: 238. sprays' for law enforcement and self defence. Cm·r1n1 Problems 1993: 19: 10-11.
2. Balasubramaniam J. Nimcsulide and neonatal renal fail ure. la,,-
cet 1999; 355: 575. Prepa r ations Effects on bone. Prostaglandins have been shown to play an
3. Paladini D, et ul. sc ..·crc duct1;1.I conniction in the third-trimester Proprietary Preparations (derails are given in V<>lume B) impor1ant role in the bone-healing process and, consequently, the
fetus fo1lowing maternal self·medi~tion with nimesulidc. {;'/.. Au stria: ABC Hydrogel-Warmeplaster : Ger.: Gothaplast Capsio..Nn- decrease in prostaglandin levels produced by NSAID use may
1rosom:tl Obsu!I G_,.necol 2005; 25: 357-6 1. Wanneplaster; Ma.rtsap!ast. ABC Warme-Pllaster Sensi'tivef. impair the healing process. 1 Under experimental condit ions.
Multi-Ingr edient Austral.: Finalgon: Au.strio: Fi.oa.lgon; Rut:rinent; Cz.: many NSA!Ds including the cyclo-oxygen•se-2 (COX-2) inhib-
Premature labour. Nimcsulide has been tried as an alternative Caps.:o!le; Pain E>q>eHert. Ger.: Fl~gon; RJ\eu!'r.asalbtj: R.ubriment;: Gr.: itors have been shown lo reduce healing.J However. clinical evi-
to indomctacin to delay labour in patients witl1 a history of pre- Finalgon: Port.: F'°"lgon: Ru.s.: 8etalgoll (6e-raN"OH); Beta:licomyton dence of such an effect is r.ire. 2 There is alro concern that some
term delivery (p.2166). Nimesulidc was given from 16 to 34 {Sen~): capsicam (Ka.'101KaM}; Finalgon (QM;HaAroH): Spain: fj.
NSAIDs such as indomctacin may aoceleratc the rate ofcartilage
weeks of gestation and a suc<:essful delivery suirted 6 days after nalzont: Switz.: Hist~!eane: ~dAlein; l ht.>n'l'locutant Thai.: AmmelU:
destruction in patients with osceoarthritis.3.4
withdrawal. 1There appeared to be no adverse effect on fetal re- Ul<r.: f"onatgon(<I>"'""°")
I. Harder AT. An YH. The mechanisms of the inhibitory effect~ of
nal function or the ductus arteriosus. The authors suggested that nons1eroidal ~nti·i n fl a mnlatory dn.ig.s on bore healing: 1t concise
fetal prostaglandin synthesis might )c mainly mediated through review. J Clin Pbt1rmncol2003; 43: 807- 1.S,
cyclo-oxygenasc· l (COX-I )and that a rel3tively selective COX- 2. Glassman SD. et nl. The effect of postoperative nonsteroidal
2 inhibitor such as nimesulide migt.t produce fewer ad\•erse ef- N o nste roidal Anti-inflammat o ry <1nti-inOamma1ory d rug administnuion on !pinal fus ion. Spine
feets on the fetus than other non-sele<:tive NSA!Ds. However, in Drugs 1998; 23: 834-8.
3. 'Rashad S, et al. EITecl of non-steroidal antt.fnfla.mmatory drugs
a small srudy short-term effects on the fetus were similar for
nimcsulidc, indometacin and sulindac. 2 AINE: AINS; f armoCOS antiin!lamatorios no esteroideos; on the cours.c of ostcoar1hritis.. Lonc~r 1989; ii : 5 J9-2?.
1
NSAIDs: NSAliler. 4. Hus.kiss.on EC. er al. Elfet:1s oC antiinOammatory drugs on the
Adverse effec1s have been reported in some neonates whose progression of OSlCO:.HthritiS of the knee. J Rhe11mutol 1995: 2?:
mothers received nimcsuHdc during their pregnancies, sec HnBn: HnBC: Hcne.n: HeCTepo1<1AHb1e npoT~sosocnaA· 1941-6.
above. lo1Tel\bHble npenapaTbl
Effects on the cardiovascular system . Bl OOO PAESSUAE.. A
I. Sawdy R, et al. Use of a cye1o·OX)l£cna.se 1ypc~2·sclectivc non- m•ta-analysis1 of 50 randomised studies of the effects of
steroidal cinti-infl~mmatory agent t:> p revent prc.1enn delivery. Adverse Effects and Treatment NSA!Ds on blood pressure in a total of771 patients found
Lanc'1 1997; JSO: 265~. The commonest adverse effects ofNSAIDs are gener- !hat NSAIDs had elevated mean supine blood pressure by
2. Sawdy RJ, et ol. A double-blind randomiztd siudy of fclal side 5 mmHg. Piroxicam, indometacin, and ibuprofen had pro·
eflCcts during and aft.er the short-termmatcmciJ administration of ally gastrointestinal disturbances, such as gastrointes(i-
indomcthacin. sulindac, and nimcsu,ide for the treatment ofpn:- nal discomfort, nausea, and d iarrhoea; these are usually duced the greatest increase but theeffect was only found to be
lerm labor. AmJ Obltel Gynecol 2003; J88: 1046-51. statistically significant for piroxicam. Aspirin, sulindac, and
mild and reversible but in some pa1ients peptic u lcera· flurbiprofen produced the smallest elevation in blood pres-
Preparat io ns tion and severe gastrointestinal bleeding may occur. It sure whi le the effect of tiaprofenic acid, diclofenac, and
Proprietary Preparation s (details are given in \k>lume 8) is generally agreed that inhibi(ion of cyclo-oxygeriase- naproxen was intermediate. The increase was more marked in
Arg.: Aldo<-on; F~I NP, Vorobr()I'( Austrio: Auhrc Mes~t &:lg.: 1 (COX-J) plays an important role in the gastrointesli· studies in which patients had received antihypertensivc ther-
Mcs.u:,ct Broz.: Anti~~ t: Arlie><; Cimer.de; De~ Deltafian; Fasulide; apy than in tl1ose where such treatment had not been used.
F~'Gt tr.P~llct M~ Neowlida; Nimalgext; Nirnedainj: N#nefl>nf; nal effects of NSA!Ds; the selective inhi bition of NSA IDs had antagonised all antihypertensive therapy but the
Nimesilam: Nimeslbat Nimc5lltt Nimcsvrix f\5.mesulon: N~nt. Ni$0- COX-2 improves gastrointestinal tolerance. effect had been greater against beta blockers and vasodila1ors
~:.·~~~
~~~~;t,·~~,~~5.t~~~ ;~!~' ~ CNS-related adverse effects include headache, vertigo, than against diuretics. An earlier meta-analysis of interven-
Mesuli:i: Nimed Ninesit; Fin.: Nimedf: Fr.: Nexen: Gr:: A(.ogen: Af<:ncast: d izziness, nervousness. tinnitus, depression, drowsi- tion studies had produced similar results.? Of the 1324 pa-
~~:li~;~ciof~~eti~i~~~~~~:!=F~i:~ ness, and insomn ia. Hypersensitivity reactions may oc-
tients who had received NSAJDs, increases in mean a rteri al
pressure were greatest in hypertensive patients who h3d taken
Ram: Kartat La.lidc: Lasazirt lerne.ilt Li:epar londopon; Lovirem: Meli· cur occasionally and include fever, angioedcma, bron· either indornetacin, naproxen, or piroxicam. a lthough results
ute: Mefin~t Mesilex;; Mesulict Mesuporx Min-A-Pon: Momit Multi-
rorm!t My><ina: Naoftct Neo-L.emesit Nibe-arc Nimegel; Nimekfe: Nimesu~ chospasm, and rashes. Hepatoroxicity a nd aseptic were only significant for indomelacin 3nd naproxcn. Sulindac
Omnibus; Rhemid; ~lolzit: Rit.dmioe; Rola.ket; Scaflant Specilkt Svdinet; meningitis, which occur rarely, may a lso be hypersen- and aspirin had minimal effects on mean arterial pressure.
TramXalm; Vent.or; Vdonteo: Hong Konr: MesUd Nidot Nifl'lt'tl H ung.:
Melulid: Nldol: Nimelid; laox: India: fleta Ni:ip: Mewlict N'otip: N1ide; sitivity reactions. Some patients may have visual dis- It has been suggested that the use ofNSAIDs in the elderly 1nay
Nimcet Nimfast Nimia; Nimodol; Nimuid; Nimusyp: NJnut.ab: N"rnvista; turbances. increase the risk of the need for antihypcrtensj"c therapy.3 A
Nise: Niter. W.tgo; lndon.: Arnicft: Au:int; Ncoxt; Nrned; Nim~t. So· study' <lf94 I I patients aged 65 years·or older who had just st.art·
tv.>ramt: Xrne<l., Ir/..: Pdri: Mes'net: Mesuroct luuel: Mesuiid; Ital.: A'gi- Haematological adverse effects of NSAIDs include ed trea~ncn t with antihypertensives found that 41% had used
~e~1r'~~';Et.t(' t,:.~a;E~~~~~~~~,.;::~;,~: anaemias, thrombocytopenia, neu tropenia, eosi- NSA IDs in the previous year compared wilh 26% of9629 con-
lde.lidt: lsooot Le<loli<ft: Ledcr<n: Mcsullct Migralcs<t: Neretid: Nidet nophilia, and agranulocytosis. Unlike aspirin, inliibi- trol patients not being lreated with antihypenensi\'es.
Nimedex; NimcnoJ; Nimesilt; Nime!.ule:ie: Nims: N~t: No.x2Jidet: I. Johnso n AG. et nJ. l>o nons1ero;dal anti-intlammatO(y dru&s af·
Oronime: Pantame;: RemC>r. i\esUlint Sdving s.Ma•no<: 5.ilid., M oloy- tion of platelet aggregat ion is revers ible with other r~l blood pressure? Ann lntern M~d 1994; 121: 289-300.
sio: Noott M<><.: Apol>de; (Ngespnt Defam: Degorflan: Dexhn: Eskaflam; NSA IDs. 2. Pope JE. et ol. A mc1a-a nslysis of 1he dfccts of nonstcroidal
Fenoxil: Fbmide: Flamozin; l~a: lnim: lc>idcn; Luscmin: Medan( Mel:Oen; 3n1i-inflimm31ory drug.$ on blood prcssurt. A ~h Intern M ed
Mesulidf: Mi.nus: Nidoiin; N"iAdcrt Nimcpis; Nil:urY': Qu:dof1; Recbr.am; Some NSA!Ds have been associated with nephrotoxic- 1993; 153: 477-84. -
S.,.,nn; Sid<>t Sitoclel: SuSd-;k; s-,:idol-GS; 5undir: VI-Flam Philipp.: Aulint, ity such as intersti tial nephritis and ncphrotic syn-
Flamcsu!t: MesulKft. Nidofidf: Sorinit SulOirc Pol.: A\Jin; Cc»<tral. Mi"l~Su· 3. Gur1.vjtzJH, c1<1/. Initiation cifamihypcrtensivctrc~t men1 during
drome; renal failure may be provoked by NSA!Ds es- nonstcroidol anti-inl'lammatory drug therapy. JA.4.1A 1994: 272:
lin: Nimesit Port.: Aulin: Oonuhde: Gerilde: jabast.lde: Ndmide; N;malEe:
N man.in: Nime<t NimcsOOnc: Rcumolid<: Sulidor: Sulimed Vitolide; Rus.: 7$t-6.
pecially in patients with pre-ex.isting renal impairment.
Actasulid (A'O"aCyl'.HA); Aponil (AnOH•VI): Coxttal (KOKC'rpa.A); N1mesit
(H•v.CCW>): Nomka (Hv.w.Ka): Nimulid (-l""Y'><A): ~(HOO): Slngo- Hacmaturia has also occurred . Long-term use or abuse HEARTFAILURE. The recent u~eofNSAIDs has been associated
pon:: Nidolt. N;set, Swin..: AtAn: Nisu~d Thai.: Emdon; Nemil-Os; Nep-.
with an incrca$ed ri$k <>f devel o~ing hean failure in elderly
of analgesics, including NSAIDs, has been associated patients.' A case-control study· found that the use of an
tide: Ntdok Nilide: Nimesf: Niml1; Nim~:id; Nirride: Nino: Nim.t1id: Veedot
Turk.: Coxu6d: Mcsuiidt: Moti.,;al NimelD: Nimes: Sulidin: Ukr.: Me~ulid w ith neplu·opathy. NSA!J) in the previous week doubled the odds of being ad-
(Mccy....)f: Nrnesi (H..,~•Y\); Nise (Ha'3): RtmelUld (P.,.ecyNIA); Re- Fluid retention may occur, rarely precipitating heart miued to hospital with heart failure; this risk was increased
mis.id (PeM:Y.C1o1A): Venex. : Ainex: Aulin: Drexel: Nimecox: Nimelid;
Nmep>·ext: Ni>roidet: N;,et Normosilent: Re<f~rc Sc•tlan. failure in susceptible patients. 0 1her cardiova~cular ad- tenfold in those with a history of heart disease. TI1e study also
suggested an association between both high-dose and long
Multi-ingredient Arg.: Mio Aldoron; Mto·Virobron: Indio: Q:>zen N: verse effects ofNSAIDs, including (hose selective for drug plasma half-life and an increased ris~ ofhean failure.
Nciilex-T: Ni:.:ip Cold: Nicip 0: N'icip MR: Nlrjp P!us: Nicip Superget Nicip COX-2 inhibition, arc discussed in detail below.
T; Nicispas: Nin'lica Pius; Nimu:id MR: Nirruf:id Nugct Ninl.Jlid SP: Nimvisia I. Oleumink GS. ti (J/. Nonsccroid31 onli-inOarmn alory drug~ and
Plus: Mex.: ~idide: Zitro!larn; Ukr.: Nilef {!-la.bep). Other adverse effects include photoscnsitivity. A lveo- hcan fa ifurc. Drugs 2003; 63: 525-34.
2. Page J. Henry D. Consump1ion ofNSAIDs and the development
litis, pulmonary eosinophilia, pancreatitis, Stevens· of congestive hc.Jrt fai lure in elderly patients: an unde:rrecog·
Johnson syndrome, and toxic epidem1al necrolysis are nis.:d public health problem. Arch lmer.1 Mecl 2000; 160:
777-li4.
N onivam ide (tlNNJ other rare adverse effects. Induction or exacerba(ion of
colitis has also been reported. · THROMBOTIC EVENTS. Afier 1he introduction of the sdective
Nor1ivamida; Nonivamidum; Noniw•rnid; Nonylvanilanide; PA· cyclo-uxygenase-2 (COX-2) inhibilors, concerns arose that
VA. Pelargonyl Vanil)'lamide: Pseudocapsaicin. N-Vanillylnona- Funher details concerning the adverse effects of the in· the risk of thrombotic evcncs such as mvocardial infarction
mide; N-((4-Hydroxy-3-methoxyphenyf)methyl]nona.-.amide. dividual NSAIDs may be found wider their respective and s1roke might be increased in pa1ienti treated wilh these
HCH:.18aMl1A monographs. selective NSA!Ds, and their safety was continuously re-
C i;H2;N03 :: 293.4.
viewed by some regu latory .bodies. Subsequently, clinical
Inciden ce o f adverse effect s. The r elative tox icity of study data conlinncd· that there was a snull increa$Cd risk of
CAS - 2444-46-4. NSA!Ds is a subject of debate.. 1 Artempts have been made to these events with the ,COX-2 inhibitors which prompted the
r•nk lhesc drugs according to their toxicity on various body sys- general world-wide withdrawal of rofecoxib (see p.125) and
tcms.2 The toxicity of selectil'e cyclo-oxygenase-2 (COX-2) in- valdecoxib («e p.138). For those selective NSAIDs that re-
hibitors has also been reviewed.) For further details sec below mained, prescribing restricti<lns were imposed (for further de·
under individual headings. tails, see under Celccoxib, p.35).
I. Skeich KJ. ti of. Differences in NSAID tokrabiJity profiles: fa<:I
or fiction? DrugSofet)· 1994; 10: 183-95. Concerns have also been raised that the increased risk of01T0n1-
2. CSMIMCA. Relative safety of oral non-aspirin NSAIOs. Cur- bo1ic events seen with the selective COX-2 inhibitors may also
rent Problem$ 1 994~ 20: 9-l I. apply to the non-selective NSA!Ds. After a review ofdata avail-
3 . Chaiam nuay S. et al. Risks Ytrsus benefits of cyclooxygenasc-2· able at the time, the FDA 1reported in April 2005 that the use of
~elec tive nons1croid.aJ amiinflcimmatory drugs. AmJ Htul1h-Sys1 non-selective NSA!Ds may potentially inc1t:a'e cardiovascular
Phann 2006; 63: 1837-51. risk. In August 2005, the UK CSM advised that any cardiovas-
Effects on the blood. The UK CSM has provided data on 01e cular risk with the non-selective NSA!Ds "as likely to be small
NC>Tfi. Use of tl1c term 'syn(hetic ca1'5aicin' to describe noniva- reports ii had received between July 1%3 and January 1993 on and associated with continuous long-tenn treatment and higher
mide has arisen from the use of nonivamide as an adulterant for agr11J1ulocytosis and ncutropcnia. 1 Severa l groups of drugs were doses~~ no c hanges to cunent prescribing practices were recom-
capsaicin and C3psicum oleore.'iin. commonly implicated. among them NSAIDs for which there mended. This advice was endorsed a few months later by tl1e
AU cross-references refer to entries in Volume A
 Nonivamide/Nonsteroidal Anti-int1am matort Urugs I UI
EMEA on Europe.l Howa·cr, new infonnation has sintt be<:ome Alzhcimcr'sd•<eaSC ( - Ocmcnua. under Uses and AdminiStra- • ibuprofen carried die IO>~t risk (l:>ut this may be rcleted lo
ovailoblc 3J1d, ir. October 2006, lhe EM£A updated ilS advice.• iion. below). dose. see bdow)
Based on dala which included the MEDAL programm..S and re- I Hoppcnann RA. ct ol. Central nuvous :1ys1crn side cftttts ornon~ • piroxicam, kctoprofen, indomctacin. ll3pto.\CO, and di-
views of se,-cral importont epidemiological slUdits"" lbe follow- Sleroid.:al anli-inn2mmalory dtvp: aseptic mcnin9itiS. psycho.sis. clofenac had an inlenrietf10te risk: ii was considered that the
ing poinlS were made: and cngnitiv~ dysrunc11on Arrlt /ntun M<!d 1991 ; 151: risk for pimxicam might be higher than for rhe other NSAJO:\
• the results from die MEDA L programme suggest diot m- t309-13. with intermediate to.xicity
c/Q/.,nuc (I SO mg daily) has a risk of thrombotic e•-ents simi- 2. Orider G. rt ul. NSAID·rclated pl)'Chialric a<fvcDc tvcttlS~ who A later updatc13 by the CSM confanned chcsc findings.
,. ••risk~ Drugs l(J(H. 6•: 2619-17.
lar to lhat of etoricoxib (60 mg or 90 mg daily); however, fur- The relative gastrointestinal loxicitv ofNSAIOs has also been
lhcr issues n.:cd 10 be oonsidered before this can be considered 3. Saaa KO. t:t ul. Nousacroidal amiinflammatory drugs and CQ~ni­
ti\·c decline in 1hc elderly. J Rh#etmotol 1995; ll: 2142-?. reviewed by ihe EMEA" using daui from epidemiological stud-
oonclusol'c ies and spontaneous adverse drug reaction rcpons. Available ev-
4. KarpluJ TM. Saas KG. Nonsteroidil on1i·inn3mmatory dni;s
• based on srudy and epidemiological evidence, diclofenac, par- ind co9ni1h·c function-do they hav~ 4 btncficial or deleterious idence suggested that piroxicam and kcloprofcn, particularly in
ticular!)' at a high dose ( 150 mg daily), may be associated wioh effect? DrngSo/cl)• l99S: ''' 427-33. high doses, were associalCd with the greatest risk of itaslrointcs-
an increased risk of thrombotic events tinal toxicity when compared wilh diclofenac, ctodolac, ibupre>-
Effects on electrolytes. Sec Efl'ccts on the Kidneys, below.
• clinical study data suggest that high-dose ib11profC11 (2.4 g dai- fen. indometacin, meloxicam, nabumctone. naproxen, and
ly) is associated with an increased risk ofthrombolic events; Effects on me eyes. Ocular clfeclS such as blurred vision oc- nimesulide. No firm conclus ions were made for the olhcr
however, overall, epidemiological srudics do nol support an cur rarely in palicnls takins NSAIOs. Other more serious effeclS NSATDs ahhough there was weak evidence Lo suagcs1 that the
increased risk wilh low-dose ibuprofen (1.2 g daily or less) on the eyes associated with NSAIDs also appcarlO be rare. In tl1e risk of toxicity was stighcly higher for indomctacin and naproxcn
11op1oxe11 (I g daily) may be associated with a lower risk for USA the Nolional Registry of Drug-Induced Ocular Side Effects than for diclofenac and ibuprofen. As ~ rcsulc of lhi~ review the
thromholic evcn!S than the COX-2 inhibitors, but a small risk analysed 144 reports they received of possible adverse optic EMEA carried out a full benefit-risk asscssmcn1 for piroxicam
cannot be excluded; overall, there is no evidence of a cardie>- nerve reactions ossocioled with the use of NSAIOs. 1 Of the 24 and subsequently placed restrictions on ils systemic t.Sagc (~
protcctivc cfrec1 cases ofpapilloedemo with or withoul pscudolumor cerebri more p.123).
• for all other no11·selec1il'e NSA!Ds Jhere are in.wfficienl data than half were associated wid1 propionie acid derivatives, but it In a systematic review~• of conlrolled epidemiological studies
IO assess U1e 1hromb01ic risk and oonsequendy an increased was considered that the dalA indica1cd that, on rare occasions, that found a relation between NSAIO use and hospil41 admission
risk cannot be excluded; a small increase in absolule risk most NSAIDs could cause this cffccl; lhc number of reports for for gastric haemorrhage or perforation, the low oisk of serious
seems mosl likely when used in high doses and for long-tcm1 individual drugs was: 7 for ibuprofen, 5 each for indomelocin gastric toxicity wi!h ibuprofen appeared Lo be anribuiablc rnainly
trcalmCJll and naproxen, 3 for mcclofcnamalc, and I each for diOunisal, to the low doses used clinically; higher doses of ibuprofen were
ketoprofcn, sulindac, and tolmclin. Almost two-thirds oftl1c 120 associated with a similar risk lO indornc1acin and naproxen. F0<
Jn February 2009. the UK CHM9 reported that rtsullS from 2
more recent epidemiological srudies10:11 suppot1 the \•iew thal an cases of Oplic or rctrobulbar neuritis "ere also associated with reference Lo an association between aspirin and the most severe
propionic acid derivatives; the number of reports for individual gastric lesions compared with otllCr NSAIDs, sec p.22.
incrca~ in lhrombotic risk is associated with af/ NSA/Ds and is
drugs was: ibuprofen 43, naproxcn 17, indomclacin 9. bcnoxa- RcsullS fromcon1rolled studies have confirmed that theselectlve
independent ofa palicnt"s baseline cardiovascular risk fae1ors or
profcn 8, phcnylbucuonc 8, piroxicam 8, zoonepinic 7, sulindac COX-2 inhibitors art associated with a lower incidenccofseri·
duration of NSA I0 use; however, the ahsolure risk for health)•
users is--r low. The American Hean Association 11 has also is- 6. fenoprofen S, U.\)'phcnbuwooe 3, meclofciumatc 2. 1olmetin ous gastrointestinal effects. such as bleeding, perforation, and
2.diflunisal J,tllldkCIQprofen J. · obstruetion, than the traditional NSAJDs" (5« al!lO Celeoox1b,
sl>Cd a S1atemcn1 aboul lhc cardi<wascular.elfecl~ of NSAIDs.
II has been suggested that NSAIDs may redUce the cardioprotcc- Ocular adYCtSC effects have also been reJ>Ollcd with the selective p.36 for further details). However, since the risk of such effects
tive efTC>CI ofaspirin. but see under Interactions ofAspirin, p.24. cyclo-oxygemsc-2 (COX-2) inhibitors.- is inhacnlly low in those with no histocy of peptic ulcer disease,
There have been rcpons of ~e corneal toxicity associa~ the general prescribing of sel~vc COX-2 inhibilOrS to all pe--
I. FDA. FDA announce• series orchoa,cs to !he: class or onlll:ctcd
non·.s1croidal 1n1i-innamma1ory drugs (NSAIOs) (issued 7th with the use of some 1opical NSAIOs, such as diclofenac and ticnls requiring an NSAIO is questioned, particularly in the light
Aprol. 200S). Avail1blc ao: hup:J/,.·ww.fda.sov/bbs/topi<sl ketorolac, in the eye (see p.47). of oonccms about their cardio\'OS<:Ular cffi:cls (sec Thrombotic
ncwsll~EWOl 171.h1ml (KCUScd OS/1 IJ07) Evcnls. above). In the UK, lheuscofselecrive COX-2 inhibitors
2. CSM. Cardiovascular ~fe:ry of NSAJDs: roic\¥ of evidtnct". I. Fnunfclder FT. et al. Possible op1i< nerve side: crTeccs a»0eiatcii is limited to patienlS with good cardiovascular health and al high
Mcuaa< from Profc$$0t G Duff. Chainnan ofCSM (issued Au- with nonstcrcudal anci-inn1mm110ry drup.J To.ncol C11ta1f <Ja,/
1\'lt 200S). Auil•blc al: To.•icol 1~: 13: 311-16 risk of developing serious gastrointestinal problems if aivcn a
l111p:J/www.mhra.gov.uklhomc/idcplg"!Jdc$crvic'e• G£T 2. Coulter OM. ti al. Cclccoxib1 rofecoxib. and ocute c~mpor.iry non-selecti'"e NSAID. High-risk patients include 1he elderly,
Fl LE&dOoc:Name-con I 004303&.RevisionSekctfonMt:lhod; visual iinpairm<nL BMJ 2003; 327: 1214-tS those already receiving gastro<oxic druss, and those with exist-
l.11c11 (ec:ecued OS/ll/07) ing gastrointestinal disorders.
3. EMEA. European Medicines Agency update on non-selectiv.: Effects on fertility- Reversible infertility bas been rcporled in
NSAIDs (Issued 17th October, 200l). Available ao: bup:I/ There has been concern lhat topicol use of NSAlDs may also be
women on long-term NSAlOs. 1•3 Proslaglandins are considered associated with gastrointestinal toxicity but a cose-oontrollcd
~:.~:.·~ ~os~Csjcu/pdrs/hum•nlpress/prf29896•0Sen.pdf
9 to be involved in the processes ofovulation and it is 1hougbt that
NSAIDs mny compromise ovulation via inhibition of cyclo-ox-
studf6 concluded that this route was not associated wid1 signif-
4. EM£A. Opinion or the Com1ninee: for Medicinal Produc1s for icanl upper gastrointestinal bleeding or perforation.
Muman Use pursu1rnt lo anicle 5(3) or rt:gultnion (EC) no ygcnasc-2 (COX-2). Women trying to become pregnant may
72612004, for non·stltt1 h•c non slcroida1 anti-infhmmatory Apart !Torn the seleclion of an NSA!D with a lower risk for gas-
need Lo avoid creatmenc with NSAJOs. troin1cs1inal toxicity, 01her methods used for the prevention or
druis (NSAIDs) (issued l81h Ococbcr. 2006). Avail•blo ut:
hup:l/www.cmco.turop3 .eufpdr~u rnan/opiniongcn/nsaids.pdr I. Mcndon~a LLF. tt al. Non'"'5tcroidal on1t .. inOo.1nm31ory drugs as treatment cfNSAID-associaled ulceration are discussed under
(•cceued 0611 1107) & pos1db)cc1use for rc"crsiblc: infc.nilhy. Rluwmarology (Ox/on11 the trealTnenl of peptic ulcer disease on p. I85 I.
S. Cannon Cl>.,,, al. C3rdiO\fbcular outcomes with e1oricoxib and 2000; 39: 680-l .
dictorcf'loc in p11ients with ('111o'teoonlll'ilis and rheumatoid anhri·
1is in the Muhinntinnal F.rorico:.ib 21ld Diclorcnac Anhritis
or
2. Nonnon RJ. R.cprod'uctivc con«qucncts COX~2 inhibition. I. J(wo PY. Tn:::mainc WJ. Nons1eroidol Gnti-in0 :1mm31ory drug·
induc~d en1erop:i1hy: c:i.st discus.sion nnd rc\•icw ()f the litcrn·
l o ..w 2001: 358: 1287-8.
LC>Ol!·lcrm (MEDAL) prognonmc: ;a rondomi5ed compari~on . 1ure. Mayo CUnProe 1995; 70: 55-61.
i.Dnctl 2006: 368: t771-S L J. Stone S. et i11. NanstC'roidal anti·1n01mmatory drugs ;and revers- 2. Gleeson MH, ~'al. Non-Steroid:il anti-ionommalOI')' drugs. 111t·
ible fcmolc infertili1y: iJ lhcrc i link? Dl'ug Safety 2002: 25: icylates. and colitis. L<m('N 19~6: 347: 904-5.
6. Kt:imey PM. 4!1 nl. Oo !tlccrivc cyclo-oxygenase-2 inhibilors
Md 1rodi1ionul ni.>n-steroidal anti-inflammatory drugs increase
1he risk of a1hcro1hron.bosi.s? Mct3-ar.alysis or randomised tri-
545- 51. 3. Evans JMM. el ol. Non-s1eroidal onti-innaunrn:uory dru91 are
<:SSOCiah!d With Cfl'CClCl'ICY :admission 10 hospil:sl ror colilt$ dut
Effects on the gastrointestinal tract. NSAlDs can cause 10 i nflamm~1Clry bowel disease. c;u11997; 40: 619-22.
ols. HMJ 2006: 332: 1302-S.
7. tf crn6ndtz.·Diaz. S. et al. Noo-s1eroidal a111iinOammatory drugs clinically important damage oft he ¥3•1TOinlestinal b·act, increas- 4. HayUar J. Bjarnason I. NSAIDs, Cox· l inhibitors, a~ the:. guL
an<J 1ht risk of liCU(C "'Y~rd ial infarclK>n. Basic C!in Phormo- ing the incidence of bleeding in the upper gostrointestinal tract Ltmcet 1995: 346: 521 - 2.
rol Tox/C<l/ 2006: 98: 266- i4. and of perforation. all hough serious compli.:ations and death arc 5. Bjorkman OJ. Nons.teroidat an1i.-inna1nmt1ary druj-induced
S. Mc.Gcui;ain r. H~nry D. Cardiovascular risk and inhibition of r~latively infrequent. They have also been associated with dam-
gaslrointcs.lina1 injurv. Am J Mt!tf 1996; 101 (suppl IA):
cydooxyacnasc-: o .sy1te1n1ttc review of the observational s-tud· 2SS-32S. -
ies of.sdccl1\•t and llir'WUefecU\'C inhibitors ofc.yclooxyge.nase 2. age to the distal small intestine and colon. 1·> 6. Soll A. P:?lhogcnesis of nonsteroida1 "n1i.inflamma tory dru1..rc·
JAMA 2006; l'6: 1633-44. The oomple.• mechanisms in\'Olvcd are nOI fully undaslood, al- lated upp<r ~astroin1cstinol 1o>ici1y.AmJ MnJ 1998; IOS(suppl
9. MllRNC'l iM. Non·stcroicb.I 1nti·tnllammatory drugs: ardi°"" SA): IOS-16S.
lhough it is generally accepted that the inhibition of cyclo-oxy- 7. Hawkey CJ. COX-2 inhibuors. l.<tnttt 1999: )SJ: ;)07-14. Cor-
vascul>.r ri'1t- Drng Safety Updo1~ 2009; 2 (7): 3-4. Available at:
~-1 (COX-I) plays a role in ps1tOin1estioal toxicity and rection. ibid.; 1440. [Jos.}
~'F~u~~~~g;86~r<!~r:~~uid•ncci 0rvi:-
10. ~~!r~~f':!~;ili~~~~~:=~~;;, =:
dal uti.. inflam.nuwry drugs in the general popubtion. J ADI
Col1Cartlio/200S; Sl: 1623-36. ·
lhat lhe selective COX-2 inhibitors are less g;aSIJOIOxic lhan lhe
traditiunal NSAIOs (5« below).'-' The p.Wie mucosa is dam-
aged bod1 by local and systemic effects ofNSAIOs.5 The IOC31
effect is pH-dependent and varies bct"ccn individual drup. The
8. Wolfe MM.~ of. G:r.suointestiri1'1 toxicity of nons1crotd1J 1n1i-
innammata<y dnJgs. /'I Eng/J Mm 1999; 340: 1888-99.
9. Seager JM. Hawkey CJ. ABC orlhe uppu l\lstroin•rstinal .,..,.,
indigestion ~d rt0n·.stcroidat a:n1i-influn.m1tory dni&J. BW
200 1: 323: 12'6-'I.
11. Foobol EL. •t nl. Ri•k or rnyocan!i•I infa~tion and dcalh asso- systemic etfCCI is pH-independent, can occur with any route of 10. MuJbttt AE. rt <ti Identification of fte>tlUrn>idal aociinOarn.ft'Q·
ci~t..!d wi1h lhC' use ot nonsttroid;;il :u\li·infiamn1a1ory dnlg,s odm1niStrarion. and is less dtui: spc<:ific; it is lhis effect lhal is tory dris-induccd g3:WOdvodeMI injuty in children with juYC•
(N!\AIDs) among. htallhy individuals: a muionwidc cohort thought 1oil1\'0lve COX- I inhibi1ion. nik ~matoid antvirK.J l'Minlr 1993; 111: 647- 9.
stody. Cliu Pl"""1ocol Thcr 2009: 85: 1~7. 11. Pwndcr RE. Hclicobxtet pylori •nd NSAIDo-the ond or chc
12. Antman EM. #tnl. Uscornonstero.idal amiinfl:amm3torydmg.s: Risk f:telors oootinue 10 be srudicd and r.c> far the m05l imp<inanl debate-? Lancet 2002~ JSI: 3-4 .
an updat~ flX chnidanS-3 scientific $fatemcn1 from lhc Am«- paticnl·rclalcd faclOrs for upper ga_<1roin1cscinal loxicity are old I:?. Mac:DonaldTM, ttal. Assoc1aliorlofUPf'l'C"P.'Orointt'\liNI lox·
1c11n Hearl Anociation Circttla1;01r2001; llS: 1634---12. age. o histOI}' of peptic ulcers or bleeding of the gastrointestinal :~c~~'°~:!:~Y:'"Jrt~99 ~1;~o;r ~')f7~ilh conunucd
1 1
Effectt on the CNS. A tiLcral\Jle review 1 revealed lhat head- tract. and concomitanl use of cortic05lcroids.• It has also been 13. McUemkjacr L, et al. Upper gastroinlcs.ti1ul hfttd1ns a1non1 us-
ache, hearing loss. ond liMin1s arc the most frcquenl CNS od- suggested that risk is increased in children.to Helicobac1er pylori cn ofNSAIDs: a popuJa1ion--ba.sed cohon 11ud'y in Denmark. Dr
vcrse effects in palicnls taking NSAIDs. Aseptic meningitis had infection exacerbates the 1·isk ofulccralion, bl~ patients remain at JC/inPharnm<ol2002:SJ: 173-11.
ino.:rC'.sed risk even ifinfcctioot is crndicatcd.U Duration oflher- 14. Ka ufm~n OW. ~t al. Non~lc:roida) an1t-inOan1m11tory drui u.sc in
oecum:d rarely in patients using NSAIDs such as naproxcn. relation lO major upper ga.9.rointe~tin.al blcedins- Clin Phom;o·
sulindac, or 1olme1in, bul the most oommon reports were in pa- apy is not though! 10 influence the risk for :icrious cven1s; a co- ,·ol Th<r 199:;: SJ: 4 SS-94.
ciems with Sl.E who were r=iving ibuprofen (see also p.67). ho11 srudytl found that tho risk of gasu'Oinlcslinal blcc-ding or
perforation with NSAIOs was oonslanl throughout trcalrnent, 15. ~~~J:n::!~ii~~o;j~'i!o~ia~~:.~~ ~~~~iJ:,s,t~oc!;:~:~~~~~
Reports of psychosis appear to be rare'-2 and have involved in-
and risk quickly declines after NSAlO withdrawaJ.'l d~I Q.nti·in03rUm3tory drug$. Lancet 1994: 343: 769-72.
domclacin or ~u1iudac, but in some reviewers' experience it was 16. Langman MJS. e1 al. Risks nr bleedina peptic ulcer as.soei11tcd
probably under-reported and was typically seen in elderly pa- Several $1Udies"·'1 hove been conducted on the rclntivc toxicity with i ndivid~I non-5tc:roidal znli-i11R11numHory drugs. l..011~''
ti~nts given lndoonciacin.1 of oral NSAIOs on the upper @llstroh11cs1inal lract and various 1994; 343: 10/S-8.
Adverse <.:NS cfteclS hove also been rerrted with lhe selective rankings of these drugs have been discuSS(:d.11.22 The UK CSMlO I 7. Lcwls. SC.,,, ol. Dosc-rc.-.ponse rela1ionships bc1wcen individ·
c•amined 10 epidemiological studies for 7 oral non-aspirin 1111.l nonaspirin nonsttroidi\l irnti-inOammatory dru,gs (NAN·
cyclo-oxyi;cnase-2 t<.:OX-2) inhibitors.
~~~~~~ ~~~e~~~d~\~~~1s;::r:~~~:,~~~r ~ ct:,"J~k~,,~,~~'~
1
'Ole role ofNSAIOs in the development of cognitive decline in NSAIOs and olso examined the spontaneous reports they had re-
the elderly is unclear. TI1ey have been associated with memory ceived of gastrointestinal effects associated with NSAIOs. The 2002: 54: 320-6.
CSM concluded 1ha1: IS. Batc,han ON. NSAIDs: rim« lo re·evaluMe gut toxidty. lnncct
impairment and ancntion dcficils in elderly paticnis.U especially 1994: 343: 1051-2.
when given in high doses;' however. NSAIDs have been report- • aupropv.one was associated '"ith the loighct1/ risk ofgastroin- 19. Smilh CC. "' ol. NSA IDs and gut toxicity. Lo1r«t 1994; 3 44:
ed 10 1·educo: the rate ofcogni1 i\•e decline or the risk ofdCvcloping testinal reactions 56-1. .

TI1e symbol t denotes a preparation no longer aclively marketed

 l 02 Analgesics Ant i-inflammatory Drugs and Antipyretics
20. CSMIMCA. Refa1i\·c safc1y of oral ncm-a~rnn n NS,4. ll)s. Cur- 10. Winkelmaycr W~ et ol. Nonsclective and cyclooxy_£eMsc-2- Concern by the EMEA over the serious nature of sk.in reactions
rent Problems 1994; 20: 9- 1l . selcc:live NSAJDs and aCu le kidney injury. Am J Med2:008~ 12 1:
1(192-8. associated with piroxicam has led to resrric!ions on the systemic
11. L.aportc J-R. el 11/. Upper 1l.1.Stroin1es1inal bleeding associated
wi1h lhe use ofNSAIDs: newer versus older agcArs. Drrit: Sn/ti)' 11. AdverSe Drug Reactions Ad,·isory Commiuee {ADRAC). ACE
use ofpiroxicam in the EU (see p.122).
2004; 27: 41 1-20. inhibitor. dillretic and NSAl l): a dangerous CQmbin1111ion. Ausi See also Hypcrscnsitivily, below.
22. EMEA. Public CMMP a.c:sessmcnl report ormcJicinal produclS Ad~-crse Drug Rcocf Bull 2003; 22: 14-lS. Also available at: J. Bigby M, Stem R. Cutaneous rea.c1io11s to oonstcrolcbl 31'li·in ..
containing 11on-klt'(;li\·c non slcroidal anti-inOammatol)' drugs h11p://www.tg:s.heal1h.gov.auiadr/aadrb/:1.:1drOJO&.htm (~c­ Oammatory drugs. J Am Acad Dermatol 1985; J2: 866-76.
(NSAJOs) (issued 7th No\•embel'. 2006). A"ailable at: hllp:// cessed 08/11/07)
2. La Grenudc L. et al. Comparison of reponi;ig of SIC\'COS·John-
www.cmea.curop".cu/pd (s!humonlopiniongenl442 I 301)6en.pdf 12. LobozKK. Shenfield GM. Dtugcombinacions and impaired re-
(•.,,•ss•d 08Jl 1/07l son syndrome and toxic epidermal nccrolysi,; in associa1ion wilh
nal fooction-thc 'triple whammy'. BrJ Clin Phnrmm:cl2005: sekotivc COX-2 inhibitors. Dn•g Safery200S; 28: 917-24.
23. CSM/MCA . Non·SU:roidal Anti-lnfla.mm:iiory Drugs S9: 239-43.
{N.SAll>s) and gas1rointes1imd (G I) sarci.y. Current Problems 3. Layton D. e1 ol. Serious skin reactions and selective COX-2 in·
13. Peccrsson 1, et al. Water intoxication associ3tCd with no1i.stcroi- hibitors: a case: series from prescription-event monitoring in
2002; 28: 5. dal anli-inflammatory drug 1herapy. Acta M1td Srond I 987: 221:
24. Henry 0. et al. Variability in risk or gastrointt-Stinal compJica- 221-3. England. Dntg Safety 2006; 29: 687- 96.
lions w"ilh individual non-steroidal 3J1li·in0amm:ttory drugs: re- 4. Wallace CA, et al. Increased risk of facial s-::ars in children tak-
14. Cheung NT, et al. Syndrome of inapproprtate secretion of anti· ing nonstcroidal a.n1iinnammatory drugs. J Pedian· 1994; llS:
sults of a co11aboroli\'e meta-analysis. DJ,,fJ 1996; 312: 1563~. diurclic hormone induced by diclofonac. BMJ 1993; 306: 186.
25. Fitzgerald GA. P31rono C. The c01Xibs. selec-1i\'t inhibitors of 819-22.
IS. Ravns.kov U. Glomerular, tubular and imerSti1i:il nephritis asso· 5. Checkcns SR. et al. Nonsteroidal anfi...jnflammatory-induccd
cycloC1xygena'\.C-2. N Engl J MFd 2001: 345: 433-42. ciated with non-steroidal antiinflammatorydrugs. Evidence ofa
26. Evans JMM. ct al. Topic.a) non-steroidal anti-intlamma1ory common mechanism. Br J Clin Phormoccl 1999: 47: 203-10. pseudoporphyria: is there an ahcmalivc drug? C11tis 1999; 63:
drugs and admi.s.sion to hospital for upper gasuointestinal blctd- 223-S.
16. Sandler OP. et ol. Nonsteroidal anli-inflarnmatory drugs and 1he 6. Al-Khcm1ium S, et ol. Pscudoporphyria injuccd by propionic
ing 3nd pcrforalion: a record linkage c-ase..con1rol study. BMJ risk for chronic rcn.aJ disease. Am1 Intern Med J991 i 115:
1995: 311 : 22-6. 165-72. acid de:riv:itives. J Cr11an Med Surg 1 999~ 3: 162-6.

Effects on the kid neys. NSAJDs can produce renal disorders 17. De Broe ME, E1seviers MM. Analgesic nephroparhy. N 1:.·ngl J Hyp ersensitivity. NSAIDs have produced various hypersensi-
M•d 1998; 338: 441)-52. tivity reactions jn susceptible individuals; the most common in-
on systemic or toj)ical usc, 1 some of which are doc to 1heir inhi- JS. Sandler DP, el ol. Analgesic use 3nd chronic renal disease. N
bition of prosiaglandin synthesis.' 3 ln the presence of renal va- Engl J Med 1989; 320: 1238-43. clude skin rashes, urticaria, rhinitis, angiocdema. bronchocon-.
soconstriction the vasodilator action of prostaglaodins increases 19. Dubach UC, et al. An cpidemiologic s-ludy of abuse of 3naJgesic striction, and anaphylactic shock. Hypersensitivity 10 NSAIDs
renal blood flow and thereby helps to mainL'l in renal function.•J drugs: effeetS of phenacetin and salicylate on 01on.ality and car· appears to occur more frcqucn1ly in patients with 3Slhma or oller-
Patients whose renal funclion is being maintained by pros!aglan- diov~scular morbidity (1968 to 1987). N Eng/J Afo:I l 991; 324: gic disorders but other risk fac1ors have been identified (for fur-
dins are tlierefore at risk from NSAIDs. Such palicnts include ISS-00. tlier delails, see under Aspirin, p.22). The occurrence of aspirin
20. PcmegerTV, etal. Risk ofkidncy faih,1reassoci.-.tcd wilh the use sensitivity in patients with asllvna and nasal polyps has been re-
those with impaired circulation, the eJderly, those on diuretics, of acc1aminophen, aspirin, and nonslcroidttl amijnOammatol")'
and tl1ose with heart failure or rerul vascular discasc.l,. Olher drugs. N Engl J Med 1994; 331: 1675-9. ferred to as the 'aspirin triad'. 111cre is coosiderable cross-reac-
risk factors for renal impaim1enr wiri1 NSAIOs include dehydra- tivity between aspirin and other NSAIDs and it is generally rec-
tion. cirrhosis, suigery, sepsis,' and a history ofgout or hyperuri- Effects on the liver. A retrospeclive study im•olving over ommended that pa1ients who have had a hypersensitivity
caemia.6.' The half-life of an NSAID may be a more important 220 000 adults who were either using, or had used, NSAIDs reaction to aspirin or any other NSA ID shou:d avoid all NSAIDs.
determinant of the risk of developing functional renal imJl0ir- identified a small excess risk ofserious, acute non-infectious liv- For references to hypersensitivity rcacrions associated wirh
ment than the ingcslcd dose.' Evidence of renal toxicity due to er injury; in current users there was a twofold increase in risk and NSAIDs, sec under individual monographs. Sec also Effects on
cyclo-<>xygenase-2 (COX-2) selective inhibitors is less cxlen- !here was a predominance of the cholestalic type of liver injury the Skin (p.76) for a repor1 sugge>ting tha.t kctoprofen is more
siYc; however, such NSA JDS appear to have effects on renal among such patients. Nonetheless, admissions to hospital for liv- allergenic than other topical NSAIDs.
func1ion similar to those ofihe non-selective NSAIDs. 8·• A large er injury had been rare. 1 lo a review2 of cohort and case-control
studies describing an association between NSAIDs and liver dis- Overdosage . Jn general, symptoms of NSAID poisoning arc
phannacoepidemiological analysis 10 of elderly patients taking mild, aod usually include nausea and vomiting, epigasuic pain,
non-selective NSA IDs or selec1ive COX-2 inhibilors found Ihat ease. the strongest evidence emeiged for sulindac. There were
also a significant number of reports ofhepatotoxicity on rcchal- rinnirus, headache, drowsiness, blurred vi3ion, and dizziness.
about l in 200 patients aged over 65 years developed acute k.id- Gastrointestinal bleeding may also occur. There have been iso1at-
ney injwy within 45 days ofSlatting therapy. Mosl NSAIDs were lcnge with dic)ofenac. Evidence of hepatotoxici1y for other
NSAIDs was weak. although the risk appeared to be high when ed case reports of more serious toxicity, including seizures. hy-
fol.ind to have a similar risk when comp:ired with celecoxib; polension, apnoea, coma, and renal failure, although u:>ually after
howe\ er, rofecoxib, iboprolCn, and indometacin (listed in in·
1
1hey were used with other hcpatotoxic drugs. However, the over-
all incidence ofliver disease ";d1 NSA!Ds was very low. ingeslion of substantial quantities. Exacerbation of astluna may
creasing order of risk) all showed a higher risk. occur in asthmatics. Seizures arc a panicular problem with
ACE inhibitors and angioknsin receptor antagonists can aJso A later review has also concluded that NSAJD-induccd hepato- mefena1nic. acid ovcrdosage.
produce renal impairment and combined use wi1h NSA!Ds toxicity is an uncommon even1.:; Nevertheless, an increased risk
TreatmentofNSAlD overdosage is entirely supponive. The ben-
should be undcr1ak~'fl with great care.' 1.1 2 l1le Australian Ad- of hepatotoxicity has been a.ssociated wilh lhe selective cyclo-
oxygenase-2 (COX-2) inhibitor lumiracoxib which led 10 its sub- efit of gastric decontamination is uncertain although activared
verse Drug Reactions Ad,·isory Comminee 11 staled in August charcoal may be of benefit within l hour of ingestion of a poten-
2003 !hat over SO% of cases ofrenal failure reponed to the com- sequent withdrawal in many counlries (see p.82). For similar rea·
tially toxic amount. Muhiplc doses of activated charcoal may be
minee were associated wilh use ofNSA IDs, ACE inhibi1ors, or sonSt nimesulide has been withdrawn in some countries and its useful in enhancing elimination of NSAlDs wi1h long half-lives
use is limited in others (see p.99).
diuretics (alone or 1oge1her); where 211 these were taken 1ogether such as piroxicam and sulindac. Forced diuresis, haemodialysjs,
1he fatality rate for reponed cases ofrenal failure was lO'/o. 1. Garcia Rodriguet LA, et al. The role of no11°s1croidal ;i nti~in· or haeniopetfusion are unlikely to be ofbenefil for NSAID ovcr-
Oammatory drugs in acute liver injury. BMJ 1992; JOS: 865-8.
Prostaglandin inhibi1ion may also le<d ro salt and waler retention Correc1ion. ibid.; 920. dosagc, although haemodialysis may be required ifoligutic renal
particulJrly when there is pre-existing hypcncnsion or sodium 2. Maooukian AV, Carson JL. Nons1eroidal 3nti-inOamma1ory failure develops. ·
depletion.' NSAIDs, therefore, tend lo counteract 1he action of drug-induced hepatic disorders. Drug Sa/tr)' 1996: 15: 64-7 1.
diuretics and anl ihypcncnsivcs.2.4 There have been isolated rc- 3. O'Connor N, et al. HeJ,'\ltoccllular d:unO'lgc fro1n uon-stcroitlisl Precautions
porlS of severe hypona1racmia and other symploms resembling anti-inOammatory drugs. Q J Me<l 2003; 96: 787-,9 1.
A ll NSA!Ds are contra-indicated in patients with ac-
the syndrome ofinapprof;riate antidiuretic hom10nc secretion in Effects on the lungs. Adverse pulmonary effects such :is pneu-
patients taking NSAIDs. '·"
tive peptic ulceration; in addition, tlie non-selective
monitis, alveolitis, pulmonary infiltrates, and pulmonary fibro-
Potassium homoeoslasis is less dependent on prosla&landins and sis, often suggestive of an allergic or immune reaction, have been
N.SAIDs should be used with caution, if at all, in pa-
hyperkalaemia occurs infrequently with NSAJl)s.' It is more reponcd wiih several NSAJDs. For references, see under individ· tients with a history of such disorders. To reduce the
likely to occur in patienls with specific risk factors such as 1hose ual monographs. risk of gastrointestinal effects, NSAJDs may be taken
receiving potassium supplements or potassium-sparing diurct· with or after food or milk. Histamine Hi-antagonists,
ics.' lndometacin appears to be the main NSA ID implicated. Effe~ts on the pancreas. A review' ofdrog-induccd pancrca·
1i1is considered that sulindac was amongs11hc drugs for which a proton pump inhibitors such as omeprazole, or misopr-
NSAIDs may cause acute interstitial nephrilis, pcrhap<S involving definite association with pancreatitis had been established. There ostol may be used for a similar purpose in high-risk pa-
an allergic resp<mse,2•3-'S and ii may progress to in1erstitial fibro- had been isolated reports of pancrcatitis with ketoprofen,
sis or papillary necrosis.'- 16 tients taking non-selective NSA!Ds (see Peptic Ulcer
mefenamic acid, and piroxiCam but any .association was consid· Disease, p.185 1). However, food, milk, and such
Analgesic abuse or prolonged excessive use can produce neph- crcd to be questionable. A more reccnl population-based, case-
ropathy, a condition charac1erised by renal papillary nccr05is and controlled study found a sub<itantial variation in 1he risk of pan· measures may reduce the rate and extent of drug ab-
chronic interstitial nephritis, and, eventually, renal failure.I'' crcatitis between individual NSAIDs.l 111c increase in risk was sorption. The UK CSM recommends that NSAIDs as-
Phenacetin, a para-aminopbenol derivative, has long been recog- highest fordiclofenac and ketopro!Cn (adjusted odds ratios ofS.O sociated with the lowest risk ofgastrointestinal toxicity
nised as bein~ one of 1hc main drug.• responsible for analgesic and 4.8, respectively), with indomctacin and ibuprofen showing (see Effects on the Gastrointesti nal Tract, under Ad-
nephropathy, 1 -' 9 bul nephropothy has also bc~n =cia1cd wilh smaller but nonetheless significant increases (odds rnlios of 3.6
1hc long-tenn use ofNSAIDsand paracelamol wi1hou1 phenace- and 1.S, respectively). Of the 01her NSAJDs slUdied (celccoxib,
verse Effects, above) should be tried first in the lowest
lin.~ ctodolac. naproxen, and rofecoxib), all 'howed a small bul recommended dose, and not more t han one oral
I. O"C"ullagh11n (A, et al. Renal di~uc and use of topical noo- no1i·significam jncrcase in ri~k of pancreatil.is in current NSAID NSAID should be used at a time; selective inhibitors of
stcroid3l 3nti-inflomm:nory drugs. BMJ 1994; 308: 110- 11. users. cyclo-oxygenase-2 (COX-2) should be reserved for
2. Kendall MJ, HMon RC. Clinica1·phrm3cology and 1hcr<1pcu-
1ios. l'ostgrod MedJ 1990; 66: 166-85. For further references sec under individual monographs. patients at highest risk of uleer, perforation, or bleed-
3. Whehon A. Hamillon CW. Non&eroidal anti-inOammalory I. Underwo<'d TW, Frye CB. Drug-induced pancrc.;.Hitis. Clio ing, and after assessment of cardiovascular risk. There
drugs: effe(tS on kidney function. J Clhl Pharmncol 199 1; 3 1: /'harm 1993; 12: 440-8.
S8~98. 2. Sorensen HT, f!t al. Newer cyclo-oxygcnoisc-2 seJcctivt inhibi- is no evidence to justify the use of gastroprotective
4. Harris K. The role of pros1agl:l 11din~ in the con1rol of ren3I func- ton:, other nan-sleroid-al an1i-intlammatory drugs and lhc risk of drugs with selective inhibitors of COX-2 to further re-
tion. Dr J A1'0tJth J992; 69; 233-5. iicure p:mc-rcatids. Aliment Phormacol Ther 2006; 24: I I 1-16.
S. Kenny GNC. Potcn1inl renal, h:iemat.ologic:il and 31ktgic ad-
duce the risk of gastrointestinal effects.
verSc elltc1s :is.sociated wi1h nonstcroid31 3nti-in0ammatory Effects o n t he ski n. The diverse culaneous reactions to All NSAIDs are contra-ind icated in severe heart fail-
druws. Drugs 1992; 44 (suppl 5): 31-7. NSAJDs including those seleclive forcydo·oxygenasc-2 (COX-
6. MacDonald TM. Selected sidc-crr~c.s; 14. non~s1i:rQidal anti- 2) inhibition have been icvicwed. 1·3 ure; furthermore selectiveCOX-2 inliibitors should not
i nfl:11 nm~tory drvS$ an(t renal d~m~1e . f"rt;S(ribcrs · J 1994i J.f:
Of250 children attending a rheumalology clinic 34 (13.6%)
be used in patieots with moderate l1eart failure, isc;hac-
77-80.
7. Henry 0. et al. Coosumplion ot'non·steroid:sl a111i-infl3mma1ory were found to have 4 or more facial sc•rs of unknown origin.• mic heart disease, peripheral arterial disease, or cere-
drugs •md the devdopment of funaional renal impainnent in 111is number of scars was found in 22.2% of tlie l 16 children brovascular disease. NSA!Ds should be used witli cau-
~!!~~r ~;4~~~~ ~t;~~~- or :. CllSr-control s1udy. Br J Clin Phcr-
1 who had received rn1proxen and in 9.2% of the Si who had re-
ceived other NSAIDs. Children affected were more likely to
tion in patients with hypertension; the selective COX-
8. Prrazclla MA, Tray K. Sclec:tive cyclooxygc11a~e·2 inhibitors: a 2 inhibitors should also be used with caution in patients
pattern of nephrotoxi.:ity simifor 10 u:idi1ional noosteroidal anii-
have light skin and blue or green eyes. 11 was unknown whether
this was a fonn ofphotoloxic reaction bul pseudoporphyria-likc with left ventricular failure, oedema, or a history of car-
innammt:tlory drugs . .4m J Med 2001~ 11 1: 64-7.
9. Noroian G. Clive D. Cyclo·<.lxygcn:>sc·2 inhibitors a11d the kid- eruptions associated with NSAJDs and naproxcn in particular
1
diac failure, and in patients w ith risk factors for devel-
ney: a case for c~ut ion . Drug Sa/e1.1•2002; 25 ~ 165-72. (see p.97), have been rcportcd.s.6 oping heart disease.
All cross-references refer to emries in Volume A
 Nonsteroidal Anti-inflammatory Drugs 103
NSAlDs should be used witl1 caution in patients with NSAID-1rea1ed childl'en.1 Ahhough these. and a few reports in ~. L~rtcquc: F, "' u( Protein bindin~ and stcr00$clcclivi~y of nons-
the li1ernturt:l_; could nol establish a causal rclalion, it was con- t~rC'id nl ;mti·inllammt11ury drugs . (/in Pluwmar11ki11er I993 : 25:
infectio!'is. since symptoms such as fever and inflam- 1l5-2~.
sidered prudent 10 avoid the use of NSAIDs in children with 5. 0Jv RO. «''"'· Pharm<1coki1l(llCS of nonstcroidul unti -inflomma·
mation may be masked (for the suggestion that. they chickenpox.. and licensed product intbnnation for the 1l!lcvanl lor;· dru~s in symwi:il n~:id. (!in Plmrm(ICOkim:t 1999; 36:
should not be used in children with varicella see be- drugs was to be modified appropriately. 1More rccenlly, a nested 191-210.
low). Tiiey should also be used with caution in patients case-control study' of nearly ~50 000 palicnts with chickenpox
with asthma or allergic disorders. NSAJDs (including or thingles in the UK General Practice Research Databas<: found Uses and Admin istration
topical NSA IDs) are contrn-indicated in patients with a an increased ri~k of severe skin and son tissue comp1i<:-ations as- Given as single doses or in short-term intennitlent ther-
sociated with the use ofNSAIDs. mostly in children with chick-
history of hypersensitivity reactions to such drugs, in- enpox. apy NSAIDs can relieve 1nild to moderate pain. How-
cluding !hose in whom attacks of asthma, angioedema, I. Ag,cncc Fran~:i.ise de SCcurile $41nit:iirc dc-s Produits de SanlC. ever, it may take up to 3 weeks ofuse before their ant i-
u11icaria, or rhinitis have been precipitated by aspirin or L·u1i1isation d'anti-inllamin:noires nons1fro'idiens (AINS). daus inflammatory effects become evident. The combined
1e 1railcmcnl de la fic':vre c:lfou d< la dc.)ulcur, n'est p3S recom-
any other NSAJD. m41ndCc chc:i l'cnfam ::iucint de v:iriceJlc (issued 15th July. analgesic and anti-inflammatory effects make them
Olher general precautions to be observed include use in '.?004). Available· at: h1tp;t/www.agmcd.sante.gouv.rr1htm/lO/ particularly useful for the symptomatic relief ofpainful
filhrp>cllp(»0701.h1m (accessed 08111/01)
patients with haemorrhagic disorders.or impaired renal 2. Zen OM. et al. A casc-.con1rol study of nccrotizing fa.sciitis dur· and!or inflammatory conditions including rheu1natic
or hepatic function. Patients undergoing therapy with ing primary ,·aricella. PedkJfric:s 1999: I03: 78.3 -90. disorders such as rheumatoid arthritis, osteoarthritis,
3. Le~ko SM. al ol. Invasive g.roup A strepcococcal infection and and the spondyloarthropathies, and also in peri-articu-
some NSA!Ds may need to be monitored for the devel- nonstcroidal antiin fl:annnatory drug us«.: among children wilh pri·
opment of blood, kidney, liver, or eye disorders. mary vericclla. PediafriG.·s 2001: 107: 1108-1 S. lar disorders, and soft-tissue rheumatism. Some
NSAJDsshould be used with caution in the elderly and 4. MikacloffY, el o/. Nonsteroidal anti·inflammatory d11.1s, ust and NSAIDs are used in the management of dental or post-
the risk of sever.: skin Md sofl lissuc complications in patients
may need to be given in reduced doses. wi1h ''aricelh1 or zoslt:.1' dise3st:. Br J Clin P/l(Jrmocol 2008; 65: operative pain. Some NSAJDs, but not aspirin or other
Some NSAIDs can interfere with thyroid function tests 203-9. • salicylates, are also used to treat acute gouty arthritis.
by lowe1ing serum-thyroid homione concentrations. Generally, it is considered tl1at there are only small dif-
Interactions ferences in anti-inflammatory activity between the var-
Fuit her detai Is concerning the precautions of the indi- Interactions involving NSA!Ds include enhancement
vidual NSA!Ds may be found under their respective ious NSAIDs and choice is largely empirical. Respons-
of the effects of oral anticoagulants (especially by az- es of individual patients vary widely. Thus, if a patient
monographs. apropazone and phenylbutazone) and increased plas- fails to respond to one NSAID, another drug may be
Pregnancy. Most licensed product infonnation recommends ma concentrations of lithium, methotrexate, and cardi- successful. However, it has been recommended that
avoidance of NSA IDs during pregi>ancy, wiless tlie propos¢d ac glycosides. The risk of nephrotoxicity may be NSAIDs associated with a low risk of gastrointestinal
benefil ot1weighs tlte risks, but in many cases published data on increased if given with ACE inhibitors, ciclosporin,
use of the drugi; in pn:gnancy arc scanty or absent, making an tox icity should generally be preferred and the lowest
infom1ed decision difficult Use of NSAlO~ during pregnancy tacrolimus, or diuretics. Effects on renal function may effective dose used. Treatment with NSAIDs that are
may delay tl1e onset of labour and increase its duration. lead to reduced excretion of some drugs. There may selective inhibitors of cyclo-oxygenase-2 (COX-2),
Use of NSA!Ds during U1e tliird trimester of pregnancy may re- also be an increased risk ofhyperkalaemia with ACE such as celecoxib, is limited in the UK to those patients
sult in the prematun closure ofj€ta/ ductus .arten'osus. A recent inhibitors and some di uretics, including potassium- with a history of serious gastrointestinal problems or
meta-analysis1suggested that the short-tenn use ofNSAIDs was sparing diuretics. TI1e antihypertensive effects of some considered to be at high risk of developing such prob-
associated with a fifteenfold increase in the risk ofpremature clo-
sure when compared with eitlter placebo or other non-NSA!Ds. ant ihypertensives including ACE inhibitors, beta
. !ems if given a non-selective NSAID (see Effects on
·mere were insufficient cl.11a to predict the outcome of long..tenn blockers, and diuretics may be reduced. Convulsions the Gastrointestinal Tract, above).
NSAID ueatmcnt in late pregnancy; however, it seemed likely may occur due to an interaction with quinolones.
that the risk of premature closure would be even greater with NSAJDs are usually given orally, with or after food,
NSAIDs may increase the effects ofphenytoin and sul-
such treatment although some such as diclofenac, ketoprofen, ketoro-
fonylurea antidiabetics.
Results fT•Jm a case-.;ontrol interview study1 suggesled that pre- lac, parecoxib, piroxicam. and tenoxicam can be given
natal ingestion of aspirin or other NSAIDs might be implicated Use of more than one NSAlD together ~including aspi- intramuscularly; diclofenac, ketorolac, parecoxib, and
in p~rsistent pulmo11ary hypertension of the newborn. Thi! au· 1i11) should be avoided because of rite increased risk of
tenoxicam can also be given intravenously. Some
tho"' suggested that these drugs may be 1esponsible for ges1a- adverse effects. 111e risk of gastrointestinal bleeding
tional sl!u:tural or functional alterations of the pulmonary vascu- NSA IDs are appl ied topically or given rectally as sup-
and ulceration associated with NSA!Ds is increased
larure. However, lhe primary cause might also have been the positories.
undcrlyi n~ disorder for which 1he NSAIDs or aspirin were in-
when used with corticosteroids, the SSRls, the SNRI
Several NSAlDs are used in ophthalmic preparations
gested. They were unable to pinpoint in which trimester the venlafaxine, the antiplatelets clopidogrel and ticlopi-
for the inhibition of intra-operative miosis, control of
drugs might have their proposed action. A more reccnrstudyl has dine, iloprost, erlotinib, sibutramine, or, possibly, alco-
found that ~rsistent pulmonary hypeitension of die neV:·bom i• postoperative ocular inflammation, and prevention of
hol, bisphosphonates, or pentoxifylline. There may be
significanlly associaled wich in ..ute1'0 NSAID exposure. particu· cystoid macular oedema.
an increased risk of haematotoxicily if zidovudine is
larly lo 3$pirin, ibuprofen, and naproxen. felal exposure to an
NSAID was C(lnfinned by mcconium ~nalysis. used with NSAIDs. Ritonavir may increase the plasma Action. Cycl0-<>xygenascs play an imponant role in the biOS)11·
The risk of miscatrioge may be increased with NSAlD usc:"·.s concentrations ofNSAIDs. Licensed product informa- 1hesis of prostaglandins (p.1607). Non-selective NS AIDs inhibit
both c)clO:oxygenase-1 (COX-I) and cyclo-oxygenase-2
however, !his observation remains to be confirmed. One stud'f tion for rnifepristone advises of a theoretical risk that (COX-2): Ille idea 1ha1 inhibition of C'OX·1 is associa1cd with
also found no association between NSAIO use and congenital prostaglandin synrhetase inhibition by NSAIDs or as-- adverse gastrointestinal clll-cl::. while inhibition of COX-2 is as-
abnon naliti~s, low binh weig)11. or preterm birth.
pirin may alter the efficacy ofm ifopristone. There have sociated with anti-intlammalory activi ly, 1 "" led Lo the
I. Koren G. e1 "'· Nonsl~roida l :111t1inflan·11nacocy drugs during 1hirJ
lriintsttr and 1hc risk of pn: m3turc closure of th1! ductus ort<!rio· been occasional reports of increased adverse effects development' of preferential or selcclive inhibitors of COX·2.
Meloxicam and niinesulide are preferential inhibilorsofC'OX-2,
sus: n 1nei:1.:malysis. Am' PhonHtJco1he,• 2006: 40: 824-9. when NSAIDs were given with misoprostol although (i.e. they have a higher selecti,•ily forCOX-2 than COX-I bul are
2. V:.n Mtrter LI, f!/ al. Pc~ii;tcn l pulmonary hypc:r1e11sion of the such combinations have sometimes been used to de- not exclusive COX-'.! inhibitors): etodolac and uabumelone arc
newborn ::ind smoking and aspirin and nonst~roidal antiinnam-
maiory drug eonsumplion duri1l~ p1'C@n:t1H:y. Pediu1rJts J996; crease the gasrrointestinal toxicity ufNSAIDs. also claimed to 1,.ve preference for COX-2 although there is less
97: (>58-63. Further details concerning the interactions of the indi- evidence for this. Drugs with a very high selectivity for COX-2
3. Al:mo \.1A. ct al. Analysis of nonstcr<>id::il antiinllammmory are also available: celecoxib nnd parecoxib are two examples.
Jrugs ia rrM::conium and i1s relation to pc1"$istcnl pulmonary h)'- vidual NSA!Ds may be found under their respective Although 1he selective inhibilion of COX-2 may be associated
pc11cns:oo of the newborn. Pt:diotrks 1001; 107: Sl9-2j. monographs. with reduced gas1rointesrinal 1oxicity? advc.rse effects associated
4. Nicls-:nGL. qf (1/, Risk of adv~ric birlh outcome and misc3rriagc
in prtg.nant usctsofnon·steroidal anti~inll:unm:itorydrugs: pop- OReferences. with such inhibition have been noted in Olher body systems, see
ula1ion l°'<\s.cd obsc:n•;11ional stud)' tuld ccist•COl'ltrOI ~\lid)'. BA1J I . Brouwers JROJ. d(' Smet PAGM. Pharm<\cokinctic.pharlll3COdy·
Thrombotic Eve1ns under Effects on 1he Cardiovascular Sy$tem,
2001; JU: 266-70. namic drug intcra,tions with nonsctrQidal <1n1i·inflmnmattll'Y and Ettects on the Kidneys, above.
5. Li D·K,f!tol. E,;po~urc: 1onon·Sll.!roidal ami.inllammacorydrug::. drug~. Cli11 Phon1w~(lki11e1 l994; 27: 462-8S. There i• C\idcnce that NSAIDs may also have a central mecha-
dm'ing !)regnanc)' and risk or misc:aniage: popt1la1iun ba$ct.l 1.:o- 6
hor1 $Inly. DMJ 2003; 327: 368-71. Antihypertensives. For reference 10 the relative ellecis of nism ofae<ion thal augments 1he peripheral me<:hanism.
Renal impairment. The BNF 59 recomm~nds that NSAIOs in NSAIDs in ~mtagonising different types of antihypertensive Many NSAIDs pJssess centres of chirality within their molecu-
general should be given at the Jowest effective dose for the sho1t· drugs, sec Effects on the Cardiovascular System and Elfec!s on lar structure. with different cl1iral forms (cnantiomers) having
1hc Kidneys under Adverse Elfecls, above. diflbrent degrees Jfpham1aco1ogic~l aclivity.8..9 For example. in·
est possible duration to patients wilh renal impallmtnt and that domctacin, its analogues. and some arylpropionic acids are chiral
renal function, aod sodium a11d w~fer retenfion. should be care- Aspirin. II has been suggested thol NSAIDS such as ibuproti:n dru2s wi1h the .'i{ H-cnalltiumer in most eases showing dt< dom-
fully monilored. may reduce the cardioprotcctivc elTccl of ~spirin but see wider ina;;-1pham1acolcgical acti"i1y. However, die ratio ofSIR activity
See also under individual m0t1ogrnphs. Interactions of Aspirin. p.24. \:aries between dnigs and hctween animal species. NSAIDs .are
Thyroid function tests. RcfcreJ1cesl.1 lO the interference with gencrnlly used cliiically as lhe racemate with only a few current-
1hyroid fonction tests by som~ NSA!Ds. Pharmaco kinetics ly being given os the S-ena111iomer (for example, dexibuprofen
I. Bishno A, t•I nl. Efftt' or cu1lm1only prtstribed non~el'oida.1 Details of the phannacokinetics of individual NSAIDs and dexkeloprofen). The chirality of' a drug may have sub1le ef-
;inti-iofhrnnnatory drugs on thyroid hormone: mcssuremc:ntc:: . ..tfm may be found under their respective monographs. fects on its toxicity and interactiMs. and it may be more desirable
J Med 1994; ?~: 235-3, I(} use a drug as ilS aclil'e enmniomer.•
2. Samutls MH. et ul. Variable cffc:c1s of nonsu:roidal an1iiRllam· 0 General rcvievv-s. I. l--foylt3r J, Sjarnason l. NSAIDs. Co:<·2 inhibitors. ond lhe gu1.
m;:itory agcnl$ on thytoid ccsl resuhs. J Cli11 Emlocl'i11ol Mewb I. Woodhouse Kw. W)1lnC H . TIH! phannacc.1ki n ~ticsor
llOIHi-ltroi· Ltmt•e/ lQQ5: 3-4-6: 5?1-2.
200}; 88: 5710- 16. d~I omi·inHammatory drugs in the elderly. Clin P/Jarmoroldnet 2. BCl\llCll A. Tavares: IA. NSAID~. CC'>:·2 inhibitors, and the gut.
19&7~ 1l: '11-22. lmlCt'I 1995; J~6: 1 10~.
Varicella. The French rcgula1ory authorities noted in July 2004 3. Vnnr JR. NSA IDs. C\)X·2 inhibitors, find the gut. La11c-c1 1995~
~ . W<'lso:"I PD. Mottensi:n ME. Pha.nuacokinelics of common atml·
that after Jhe report of3 cases of septic shock, I fatal, in children gesics. anli·innammato1·ie-s and an1ipyre1ics in children. Cliu 346: )1 (15~.
1reated with NSAIDs for fever and pain, pharmacovigilan~-e Phnmiacokitw 1989: 17 (suppl 1): I 16-37. ~. Jol1:tt"&111 J. Y. ''' iii. C)·cltl•O,-<.ygenase isoenzymc-s: how
recent
smdies hod discovcrc-d several other cases of severe compliea- 3. Simkin PA. el al. Articul:n ph;irmacoliinctics of protein-bound findings ~fftct lhinking :\l>Out nt>nst\!roidal flnti·inOammalory
llons rek~ing 10 infeclion of the sltin lesions of chickenpox in a.nlirhcumt'ltic ~gent~. CJ;,, Pluuw1ncokim!I 1993~ 2S: 342-50. drugs. Dru.~s 1"97: SJ: ~63-S2.
104 Analgesics Anti-inflammatory Drugs and Antipyretics
5. Richafdson C. Emery P. The clinical implications o(inhibi1ion or cle contracture.3 Although there is no consensus on treatment, macular oedema after cataract surgery although lopicol ketorolac
the indocible form ofcyclo·oxygenesc. Dnrg Safery IC)96: 15: early, regular and cautious physioi11erapy is recommended to may have a positive effect in chronic disease.
249-60.
mobilisejoints; J.j aggressive manipulation may cause further os- I. Colin J. The rote ofNSAIOs in the managcmen1 ofpostopCJ11.1ivc
6. Cashman JN. The mechanisms of acrion ofNSAIDs in analgesia.
Drugs 1996; 5l (suppl S): 13-23. sification. ophtho.Jm;c inflammation. Dmgs 2007; 67: 1291-13013.
1. Hawkey CJ. COX-2 inhibitors. Lonce1 1999; JSJ: 307- 14. Cot· Prophylactic measures include radiotherapy or drug therapy. 2. Jampol t.M. Pharmacologie lhcrapy of:iptukic and pseudopl1a·
rection. ibid.: 1440. [dose) kic cystoid macular edema. Ophthalmology 1985; 92: 807-10.
While prophylaxis docs not always prevent the development of
8. Kean WF. et ol, Chirality in amirhaimalic drugs. Lancet 1991; 3. Flach AJ, ~' ol. Effecliveness of kelorol3c lromcthaminc 0.5%
ectopic ossification, i1 can decrease its occUITCncc and scvcrily. ophthalmic sotu1ion for chronic aphakic and pseudClphakic cyst-
338: 156~8 .
9. HaybAll PJ. Chirality and nonstcroicaJ anti-inflammatory drugs. Prophylactic measures should be begun as early as possible and oid macular edema. ,'4m J Ophtholmol 1981; I 03: 479-86.
Dn•gJ 1996; 52 (suppl S): 47-58. wilh regard to orthopaedic surgery may be started before the op- 4. Jampol LM, e1 of. Nons.tcroidal anti·infl:ammatory drugs and c"t·
eration. Prophylaxis is also required if mature ectopic bone is to a.ract surgery. Arch Ophlholmol 1994; tJ?: ~91-4.
Colic pain. Prostaglandins have been implicated in the aetiolo- be swgically excised in order lo minimise lhe rate of reclllTCnce. S. Ital ion Diclofcnac Study Group. Efficacy ofdiclofcnac cyedrops
ID' ofbilinry colic (p.5), and some NSAIDs such as diclofcnac, Lew-dose radiotherapy is as cffec1ive as high-dose, and pre-op- in prevcncing pos.topcrativc inflammation and long-tcnn cystoid
indomctacin, and ketoprofen have been used lo relieve such pain. erative irradiation is as effective as postoperative.' Stud.i ts sug- macular edema. J Cotaroct R~froct Surg 1997; 23: J183-9.
6. Sivaprasad S. et al. Non-steroidal anii·intlamn1a1ory agems for
Dementia. Although NSA!Ds have been associaled with mem- gest that NSAID prophylaxis is of similar efficacy to radiothera- lrealing cystoid macular 0tdema following calaracl surgery.
ory impainnent and attention deficits in the elderly (see Effects py.• NSAIDs appear lo sigilificanlly reduce 1he incidence of Available in The Cochrane Database ofSysu:matic Reviews; Is·
on the CNS, above), some studies have shown thal long-tcnn use ectopic bone formation,l·~ possibly by inhibitiny inflammation sue 3. Chkhes1er: John Wiley: 2004 (3cccssed 25/09/09).
may reduce the rote ofcog11i1ive declinc'-1 or the risk ofdevelop- and suppressing mcsencbymal cell proliferation. Wl1ilc contro-
Fever. Paracetamol, salicylalcs, and some cU1er NSAIDs are the
ing Alzhcimer's discasd-l (sec Dementia, p.392). A systematic versy exists as lo duration and doses, indomemcin is considered main anlipyrelics used 10 control fever (p. I0). Paracemmol is
review• of obs~"tVational studies, which included some of these the NSAID of choice by some; naproxen, tenoxicam, and di·
usually the antipyretic of choice in infants and children but ibu·
studies, also suggested that the risk of developing dementia is clofenac may also be ofbcnefit. 4 Ibuprofen has been ttied; how- profcn is an effective alternative; allemation of the two may be
lo.wcr in patients who are taking NSAIDs. However, a ran- ever. a study6 has found that, although it significan1ly reduced lbe
bener than either alone, although this is controversial. Salicylates
domised study7 found no benefit from treatment with naproxcn rate of eclopic bcmc formation, there were no clinical benefits 6
are gencrnlly contra-indicated in these patients because of the
or rofecoxib in patients with exiSling mild to moderate Alzheim- lo 12 months afier surgery. Bisphosphonates that inhibit the min-
possible link between their use arid lhe development of Reye 's
er's disease. Another systematic reviC\0 has suggcs1ed that the ernlisation of lhe deposilcd bone, such as etidronate, have also
syndrome (see wider Adverse Effects of Aspirin, p23).
beneficial effects ofNSA!Os seen in some studies are likely 10 been used but 1hey do not prevent the ronnation of the osteoid
be due to biases such as recall introduced by lhc sludy's design; matrix. A1so when etid.ronate is stopped, some mineralisalion Gout. NSAIDs are the drugi; usually used first for the treatment
the benefit of NSAIDs in preven1ing demenlia or cognitive can occur, resulting in delaye~ ectopic or rebound ossification, of acute attacks of gout (p.600). Since the drug treaunent of
impainnent was 50% in studies wilh prevalent (pre-existing) though it is usually less severe. Prolonged treatment may be chronic gout can lead 10 lhe mobilisation of urate coystals from
dementia cases, which decreased to 20% in studies of incident needed.2.3 A systematic review,7 however, found insufficient ev- established tophi to produce acute attacks, NSA!Ds may also be
demcolia cases (those developing dt.uing the study period), and idence to recommend the use of etidronate for the treatment of used for the prophylaxis ofacute gout during the first few months
was absent in those which used cog1rtive decline as an end-point acute ectopic O!;Sification. ofurate-lowcring therapy.
Furthennorc, a more recent randomised primary prevention I. Shehab D. et al. Hctcrotopic ossificotiofl. J N1tcl Med 2002; 43:
Headache. An NSAID is often tried first for the symplomatic
study9 concluded that nei1her naproY.en nor celecoxib had a pro- 346-53.
treatment of various types of headache including migraine
tective effect and !here was some evidence that naproxen had a 2. Vanden Bosschc L, Vandernrae1en G He<erotopic ossification: a
revie1,1.·. J Rehobil Med2005~ 37: 129-36. (p.670) and lension·type headache (p.671 ). NSAIDs may also be
detrimenml effect when compared \\>ith placebo. A large popula- 3. van Kuijk AA, et al. Ncurogenic hctero1opic ossific11ion in spi· effeclive prophylactic drugs for misraine, •!though propranolol
tion:basedcohort study 10 of the elderly also did not·find a reduc· nal cord injury. Spino/ Cord 2002; 40: 313-26. is generally prefened. Paroxysmal hemicrania, a rare variant of
lion in the· risk of dementia or Alzheimer·s disease among 4. Fijn R, er ol. Prevention ofhete:rotopic ossification after total hip cluster headache (p.670), responds to indomeracin.
NSAID users. lnslead, previous S~lained use ofNSAJDs was reptacemenl wi1h NS.AJDs. Phorm World Sci 2003; 25: 138-45.
found to be associated with an increased incidence of dementia 5. Fransen M, NcaJ B. Non-slcroii:laJ an1i-inflammatory drugs for Kidney disorders. Although NSAIDs can produce adverse cf·
and Alzheimer's disease; lhe authors suggeSled that NSA1Ds preventing hctero1opic bone fonnation after hip arthroplasty. feclS on the kidney (see above) they may have a role in the man-
Available in The Cochrane Database of Systematic Rcvic:Y•rs; Is-
might only delay the onset ofdemen:ia. Further studies are need- sue 3. Chichester: John Wiley; 2004 (actt!'!Oed 0811 J/07). agement of some types of glomerular kidney disease (p.1641 ).
ed to detennine the role ofNSAlDs in demenlia. 10 or
6. Fransen M, et al. Safety ind efficacy routine postoperative ·Ibey may be ofuse for the control ofproteinuria due 10 nepllrotic
1. Karplus TM. Saag KG. NonsteroiCal anti-inflammatory drugs ibuproren for pain and disability relaled to ectopic bot1e fom1a- syndrome except when there is overt renal failure.
and cognitive function-do they have a beneficial or deleterious 1ion after hip replacel'l'tent surgery (HIPAID): r.indomised con-
effect? Drug Sa/cry 1998; 19: 427-J3. u-olled t1ial. BMJ 2006; 333: 519-21 . Malignant neoplasms. An early study b~ the American Can-
2. Rozzini R. ~10/, Prolcctivc effect of chronic NSAlD use on cog- 7. Huan M, et al. Pharmacological interventions for 11eatingacu1e cer Society' suggesled thal regular use of aspirin might reduce
nitive decline in older pcrSons. J Am Geriotr Soc 1996; 44: hctcrotopit ossilica1ion. Available in The Cochrane Oataba!tt of the risk of developing fatal cancer of the oesophagus, stomach,
1025-9. Systematic Reviews; rssue 4. Chichester: John Wiley~ 2004 (ac· colon, or rectum. Death rates due to other gastroinlcslinal can-
J: Stewart WF, et al. Risk of Alzheimer's disease :ind duration of cc=:<I 0811 1/07). cers did not appear to be affected. Some sn1dies2• 12 appear to sup-
4. ~s.7~1ds9_,te:,~~~o~::;oi!~1 :Z"i~ riamma1ory drugs and
6 2
Eye disorders. Miosis resistant to convenlional mydriatics of. port this reduced risk of colorectal cancer (see Prophylaxis. un-
the ri:i;:k of Ab.Jieimcr's disease . .\'Engl J Med 2001; 34S: Jen develops during ocular surgery, possibly due 10 release of der Malignant Neoplasms ofthe Gastroinl~linal Tract, p.725) in
1515-21. prostaglandins and other substances associated with trauma. regular users of aspirin or olhcr NSAIDs, particularly in high-
5. Vlad SC, <!t ol. Protective eff'eeU or NSAIDs on the develop·
incnt of Alzheimer di$easc. Newt'l11gy2008; 7U: 1672-7. NSAIDs, which arc proslaglandin synthetasc inhibitors, arc risk pa1ients, conclusions that were cautiously endorsed by a sys-
6. Etminan M, er ol. Effect of OQn·t.reroidal anli·inOttmmatory therefore used prophylacrically as eye drops before ocular sur- temalic review. 13 Furthennore, a pooled anolysis" of dala from
drugs on risk of Alzheimer's disC3se: systcma1ic review 3nd gery to aroeliorate intra-operalive miosis but there has been some 2 randomised siudics concluded that taking 300 mg, or more, of
mel3·snalysis i>fobservarional s1odi:s. BMJ2003; 327: 12&-31. doubt that Jhe effect thl')' produce is of clinical significance. aspirin daily for al least 5 years is effective in reducing the risk of
7. Aisen PS, et al. Effects oftofeco:o.:ibor naproxe1l vs placebo on colorectal cancer, with a lalency of I 0 years. Howev.:r, other
Alzheimer disease progression: a rindomi2ed conirolled trial. Those commonly used include diclofenac, indomctacin, and
JAMA 2003; 289: 2819-26. flurbiprofen. lbcse drugs do not possess intrinsic mydriatic studies 15.1 6 have found no evidence of an ass:x:iation between the
S. de Crtien AJM, et ol. Mera-analysis of nons1c:roidal ttntiinOam- properties. use ofaspirin or NSAIDs and the incidence of colorectal cancer:
matory drug use and risk of demeatia. Am J Epirlemiol 2005; Some NSAIDs are used topically or systemically in inflarnmato· ihe authors suggest that these results may be expbined by the
161: 114-20. short trcabnent period and 1he low dose of aspirin used. More
9. ADAPT Research Group. Cognili\l: func1ion over time in the ry ocular disorders, including intlammation and cystoid macular
A lr.heimer's Oiscase Anti-infbmmatory Prevention Trial oedema following ocular surgery (sec below). Topical NSAIOs recent reviews 17.18 prepared for the US Preventive Services Task
(ADAPT): rcsuhs ora r.mdomized.controlled rr-ial of naproxen are also elfective analgesics when used in the management of Force (USPSTF) indicated U1al aspiri11 and NSA!Ds, including
3nd cdecoxib. Arch Neurol 2008~ 65: 896-905. corneal abrasions. However, their role in Jhc treatmenl of macu- selective cyclo-oxygenase-2 (COX-2) inhib.lors, reduce U1e inci-
10. Breitner JCS, ti ol. Risk of demen1ia ;rnd AD with prior expo- dence of colonic adenomas, and that aspirin and NSAIDs also
sure to NSAIDs in an elderly comrDJnity-b;:ascd cohon. Neurof~ lar oedema associated v.;1h uveitis (p.1653) is less clear. NSA!Ds
og>· 2009; 72: 1899-1905. are also used in the treatment ofsclcrilis (see p.1650). Diclofenac reduce the incidence of colorecJal cancer; however, the USPSTF
and ke1orolac have also both been used in the management of issued a stalemenl 19 that, because of lhe adverse cardiovascular
Diabetes insipidus. NSAIDs such as indometacin have been seasonal allergic conjunctivilis (see p.614). and gastrointestinal effects associated wilh these agents, !heir use
used in lhe trcahnenl ofdiahetes insipidus; for some references, 10 prevent colorectal cancer could not be recommended in U1ose
see p.71. References.
I. Flach AJ. Cydo-oxygcno$C inhibilors jn ophthalmology. Sm"Y at average risk of colorectal cancer.
Ectopic ossifica tion. Ectopic ossification (hetero1opic ossi(i· Ophtholmo/ 1992; 36: ~59-84 . The potenlial role that inhibition ofCOX-2 niay play in the man-
calion) is a condition in which mature bone develops in non·skel- 2. Keay P. The emerging rolesof1opital non-steroidal anti-inOam- ·
matory :igents in ophthalmology. Br J Oplu/1(1/mol 1996; 80:
agement of cancer has been discusscdlo.21 and a study22 has
etal tissues, commonly 1he connective tissue of muscles. Ii oc- found that regular u~e of aspirin appears to reduce the risk. of
480-5.
curs after local trauma, for examp'e after joinl dislocation or J. Schalnus R. Topical nonsteroidal :i.n1i-inflammatory 1hcrapy in colorectal cancers that overexpress COX-2 but not !hose with
surgery such as tolal hip replacement. and al~o after neurological ophthalmology. Ophtliolmologi,·a 2003; 217 : 89-98. weak or absent expression ofCOX-2.
damage such as severe head or spinal cord injuries. 1•2 Ectopic 4. Calder LA, el nl. Topicol nonsteroidal anti-innammotory dtug,s A large case-conlrol study," using data held on the UK General
bone formaJion usually slarts abo•t 2 weeks after 1he injury, for corneal ~brasions: meta.;:inalysis of r:.indomi.ted trials. AcoJ Practice Research Database, bas examined infonnation on
1h<>ugh symp1oms, which include localised pain, fever, swelling, . Emtf8 Mcd2005; 12: 467-73.
NSAID use and lhe developmen1of commo> cancers. This study
erythema, and resliiction of movemml, may not appear for 8 lo POSiOi>ERATIVE INFLAMMATORY OCULAR OtSOROERS. Corticos- also found that the use ofNSAIDs (includbg aspirin) may pro-
J2 weeks. 1J Newogenlc ectopic ~!"ification may develop t\len teroids arc used lopically for the control of postoperative oc· tect against cancer of the oesophagus, stomach, colon, and rec-
several years after spinal cord injury.3 A congenilal fonn of ec- ular inflammation but caution is required as they can delay tum. However, the sllidy failed to show any decrease in risk of
topic oosificalion, myositis ossificans progrcssiva (fibrodyspla- wound healing and mask pos1opcra1ive infection. They non-gastrointestinal cancers. Subsequently, 2 meta-analyses24.2s
sia ossifieans progressiva), also occurs but is rare. The principal should only be used for short periods as 1hey can cause glau- have also suggested that aspirin and NSAID use reduce lhe risk
complications of eclopic ossificalioo are loss of joinl mobility coma in susceptible individuals. Topical NSA!Ds have also of other gastroin1es1inal cancers such as oesophageal or stomach
and function. •.:> been tried and appear to bt as effective as corticosieroids in cancer. ln addilion, one analysis" considered the effect of
Ec1opic ossification should be distinguished from the calcifica· controlling signs of inflammation al\er ocular surgery,' but NSAID and aspirin use on non-gas1rointcs1inal cancers: aspirin
tion ofsoft tissue which may occur in coruiective tissue disorders there has been some concern aboul reports of corneal toxicity use showed a chernoproteclive effect in pancreatic cancer al-
or in parnthyroid disorders as a resul!of high circulating concen• (see p.47). though this was not significant statistically; there was also a
trations of calcium and or phospho1e; in these conditions calcifi- Cystoid macular oedema may follow caLar•cl or retinal detach- slight, but nonetheless significant, reduction in tl1e risk of breast
cation occurs without bone fonnation. ment surgery due to a disttirbance of the blood-retinal barrier. cancer associated with both aspirin and NSAID use. The resulis
Swgical resection can improve joint motion'·' in patients wi1h NSA1Ds 1·• such as diclofcnac, flurbiprofen, indometacin, and for other sites, namely ovary, lung, bladda-, and prostate, sug-
ectopic ossification, bul may be associated with severe compli- kerorolac are used lopically \\'ith or withoul corticosteroids to gested no effect or possibly a slight reduc~ risk. The authors
cations and poor 0111come, and ossificalion may recur postopcra. prevcnl or relieve cystoid m~ular oedema. NSA!Ds including considered that ii was unclear if any potential benefi1 i11 non-gas-
1ivcly.3 Delaying surgery as long as JDSSible un1il bone fonnation indomeracin are also used systemically in ilS management. How- trointestinal cancers may be offset b)' the known adverse effects
has decreased may lessen the likelihood of these complicalions, 1 ever, a systemalicreview6 has found insufficient evidence for the associated with the long-term use of Jhese drugi; panicularly in
although earlier surgery m•y preven1 fibrous ankylosis and mus- efficacy ofNSA!Ds (topical and oral) in acute or chronic cystoid those cancers with a low incidence.
All cross-references refer lo entries in Volume A
 Nonsteroidal Anti-inflammatory Drugs/Opioid Analgesics I 05
Truuncnt Wlth sulind<lc (see Gastrointestinal Disorders, p.132) be used in the treatment of teute low bGclc r:xun (p.8) ifparaceta- return to normal for several months after the acure
has b<al found to reduce lhe number of polyps in patients with mol fails to p!O\•ide adequate pain rd1ef. NSAIDs may al<o be withdrawal syndrome.
familial adenomatous ix>iyposis. • condition which predisposes used as an adjunct to opioids in lhe management of severe pain
to de""lop1nent or co~•I can=. Cdecoxib has similar ef- such as cancer pain (p.SJ and are patticularly effeai"" in bone Withdrawal symptoms may be terminated by a suitable
fects (see p.37) and it is now licensed for use in such patienis. pain of malignant origin. NSAIDs may be used for postoperativ'C dose of the original or a related opioid. Tolerance di-
l. ~~"~~~; ~ ~tt~5f~~." use and lh~ risk of fa~I cancer. Conc~r analgesia (p.4), and arc ofpattacular value af\er day-case surg~ minishes rapidly after wi1hdrawal so that a pre\'iously
3
2'~~::;:~~d~c~ ~; ~:i1e~~e~~1:a~::~b::!~~~~.i~~;;,c;::
because or their lock of sedali"" effects. They are not usually
considered to be strong enough as the sole analgesic after major
tolerated dose may prove fatal.
For a discussion of the treatment of opioid dependence
c.r lnJ/ 1991; ¥3: JSS-&. surgery, bur may be used with stronger analgesics and may allow
3. Loaan RFA. et ol. Effect of 8.$pjrin and nQn-s1eroi<fal ami-in- dosage reduction of opioid.s. Tiie pain of mild sickle-cell crises and neonatal abstinence syndrome, see below.
flomn,a1ory druas on colorcclli1I adenomilS: ca!tt:-control study of (p. 10) moy be controlled by analgesics such as NSAIDs or less
subjtccs panicipadns in the Nouing.ham (3eeal occult blood <>Review.
potent opioids, forexomple codeine or dihydrocodeine: NSA!Ds
scn:.:11in11 programme. BUI 1993; 307; 28S-9. I. Van Rec JM.~' ol. Opioids.. reward and addiction: an encountu
4. Gio,·annu«i £,cl ol. Aspirin use and the risk for coli:irccud cin- may be used with more potent opioids Stich as morphine for se- of biology. psychology, and mcditint. Phormocol Rti· 1999; St:
ccr and ;idenoma in male hcaUh professionals. A1111 /111em Med vere crises. 341-96.
t99•: 121: 2.i--0. ·, Dependence and 1olernnce arc not a problem wilh non-opioid an-
S. CiiO\'~nm~c i E, et al. Aspirin and the rlsk of colorectal c:mcer Diagnosis. Naloxone (p.1596) and other opioid an1agonists
algesics suclt as NSAIDs, but there is a ceiling ofefficacy, above lmoe been used lo diagnose opioid dependence.
In won1<n. N f.11g/J MIU! 1995; 333: 609-14.
6. Sandler RS. et ul. Aspirin and nonstc:toidal anti~inflammatory which, increasing the dose has 110 funher tl1crapeu1ic effect. ' ·
~J;S~'J:;~ ~f~/or colorec:tal adencnna.s. Gos1roc111trology Treatment of opioid dependence. The 1rcacment of opioid
4 Rheumatic disorders. NSA!Ds provide symptomatic relief
for rheumatic disorders such as rheumatoid llC1hri1is (p.12) and
dependence hos been the subject of many reviews and.discus-
7. Smalley W, el cil. Use of nonstcroidal ant'·innamm'lltory drugs sions.1·10
and ineidtnoc of colorcc.tal cancer: a population-based study. spondyloarthropathics (p.14), but Ibey do not alter Ute course of
A1~h/nttr11M<d1999: 159; 161-6.
Planned withdrawal (detoxincation) may be effected slowly or
the disease and additional antirheumatic drugs may need to be
8. Jolly K, ct al. NSAJDs and g.astrointcs1inal cancer prci.·ention. given toprevcn1 irrcvcl'siblejoint damage. NSA!Ds may also be rapidly. Tiie usual method in many coun1rics is to replace lhe
drug of dependence with 1'ne1/todo11e (an opioid agonisl) given as
~::i'ffe;':'J.:.~!~. ~!;°~~miud
9
9. of
trial aspirin to prevent
color:
ccUil adenomas in paticnl$ wi1h prcviou$ colorcc1al cancer. N
used as an alternative to paracetamol for os1eoanhri1is (p.11).
Shon-term use of oral NSAIDs may help to relieve pain and re-
a liquid oral p1'Cparation, and lhcn gradually withdraw lbc meth-
adone if possible. Methadone is suitable for widtdra*al lhcrapy
£1111/ J Mod 2003; 348: 883-90. duce inflammalion of soft-tissue rhcumarism (p.13); ropical for-
10. Baron JA. ~ ol. A randomi1cd trial of aspirin 10 prc...-cn1 color- because it can be given orally and its Ion: half-life allows once
mulations of some NSAIDs •re also used.
cctal >dcnomas. N Engl/ Mod2003; 348: 891-9. daily use. Oral diomorphitte has been used similarly 10 metha-
l J. Chan AT, t.t oJ. Long..a.erm we of aspirin and nonsteroidal anti· Scleroderma. NSA!Ds should be used wilh caution in sclcro- done; reefers cootaining diamorphinc have also been used in
innammatory drup and risk ofcolorcctal cana:.r•. JAMA ZOOS; derma (p.1975) because oflhe risk ofexncttbating rcn•l and oth- some centres. Dihydrrx:xxkitte tablets have been used successful-
29~;
9.. -23.
ll. Chln AT. C'I al. Aspirin dose and duration ofus:e and risk of er problem.s . ly. The partial opioid agonist bupnnorphlne, &iven sublin1'ually,
co1ortcul cancer in men. Gas1rom1uologr 1008; 134: 21~. is another alternative to methadone in !he trealment of opioid de-
13. A..no Til Mcleod RS. Non Slcroid:tl onli-in0an>m3te<y drugs pendence, and "'ilhdrawal symptoms may possibly le$0lve more
~.~~.:."!::~~.. r~-r.:~:,o:i;!~~,,,.:o:i~ Opioid Analgesics
quicklyt:hanwilh methadone. 11 However, it should only be given
ro patients with JDOdeQte dependence; those dependent on high
RcvitwS: Issue I. C'hichatci: John Wiley; 2~ (accesud
08/11/01). doses of opioids may have withdrawal symptoms when ghoen
14. flo.smaM E, Rochwell PM. British Ooaon Aspirin Trial and Analge.icos opioides u opiKeos; Anal~ Opioide;; Opio- buprcnorphine. The methadone derivative /~1hodol
the UK-TIA Aspirin Triol. Ell'<et of upirin on long-term risk o( icl-analgetil<a. wasa more rcctnt introduction but its proorrhylhmicefl'ecu have
colorcebl anctt: Mll.\iSlcnl evidence from randomised and of>. led to its use being suspended.
~>le M<W'eTHl(M
s<M11iooal studies. Lonc.t 2001; 369: 1603-13.
IS. S10rmC'f' T. *-' o!. As.pirin use and coJorecr:al cancer: post-trial Iatrogenic opioid dependence may occur in patients receiving
follow·up data from the Physicians' Hta.hh Study. Aun ltrran
Dependence and Withdrawal ,...agonists such as morphine, fentan)i, 0t pethidine f0t the~
M<d 1998; ll8: 713-20. agcmcot of acute pain or in an intensive core setting for more
16. S1Grmcr T, ~1 ul. Colorec1al c:tnc('f after start of
>01i-1nn11nma1e<y dru11 use. ,i., J MIU! 2006; 119: 4~S02.
noosteroidil Repeated use ofopioids is associated wilh lhe develop- lh•n Sto I0 days. Methadone has been used succenfullv 10 man-
I 7. Roscom A. Cfol. U.S. Prcvcfllive Scrvi«s Task Force. Nonstcr- ment of psychological and physical dependence. Al- age opioid withdrawal in adult intensive core palients.•f Howev-
oidal an1i·inOainmatory druss and cydooxygcna.sc-2 inhibitorS though this is less of a problem with legitimate thera- er, some 1 ~ avoid using mdhadone to manage withdrawal in chil-
for primary prt\•e111lan of c:olorcccal c::anc:er: a sy~te1natic rtview peulic use, dependence may develop rapidly when dren because of the stigma of its associations wilh managing
pttpared ror the U.S. rrevcntivc Scrv;ccs Tosk Force. Ami,,,_ withdrawal in dntg addicts. In physically dependent but noo-ad-
ltl'llAfod2001; 146: 37~9- opioids are regularly abused for their euphoriant ef- dict<d patients, gradual wtaning using the s:unc opioid that was
I3. OuW C. el ol. U.S. Preventive Services Task force. The use or fects. Drug dependence of the opioid type is character-
aspirin for primory prevention ofcolorccral cilnC:cr: a systematic used therapeutically is preferred where possible, allhough in
review prepared for the U.S. Pte\•tnti\•e Setviccs Task f orce. ised by an overwhelming need to keep taking the drug some cases, ii anay be necessary to change to• diffcrenl opioid
Arm /11tt1'n Mad 2007; 146; 36S-1S. (or one with similar properties), by a physical require- because ofease ofu•e, duration ofaclion, and abilily to taper ahe
19. U.S. Preventive Services Task Force. Routine aspirin or nons· dose; \'irlually any oi>ioid can be used.ll
tcroidal anli·intlammatory dru~ for the primary prevention of ment for the drug in order lo avoid withdrawal symp·
colorec111I cancer: U.S. PtC"Ventive ScivicC$ Task Fo1ce .-ccom- Other drugs used in the management of opioid wilhdrawal in-
men~1ion ~uuemcnt Aun Intern .l.fcd2001; 146: 361-4.
toms, and by a tendency to increase the dose owing lo clude alpha2-adrenocep101 agonists Sta<:h as c/011/dlne and opioid
20. Lino 'I.. d al. Cyc l o~oxygcnase-2 ;md itc: inhibiticm in cancer: is the development of tolerance. antagonists such as nolrnrcone and naloxone. Clonidine may
thcr< a rnlo? D"'X' 2007; 67: &21-4S. help lo suppress symptoms of opioid wi1hdmwal, such as a.nxie-
2 1. M1111kowiti SO. Aspirin and colon canc:.et-(atg.tling ptcvcn- Abntpt wi1hdrawal of opioids from persons physically
aion? N £•191.1 Mtd2001; JS6; 2 19S-&. dependenl on them precipitates a withdrawal syn- ty, insomnia, and muscle aches. It appears to be more ctrccri""
22. Ch;.n AT, c:J ul. •-'spirin and the risk ofcolorcctal c:tnccr in rch•- when used in the conlrol of symptonis after abrupt withdrawal
1ion co the c,'tprc5Sion of COX-2. N Ei1gl J Med 2001; 3S6: drome, 1he severity of which depends on the individu- than when used during gradual withdrow:il of mclhadonc. Hypo-
2t31-42. al, the drug used, the siz.c: and frequency of the dose, tension may limit its usefulness in some patients. The clonidinc
:n . Lon¥n"in MJS. ~' ol. Effect of.anti-inflammatory drug.son over- and the dura1ion of drug use. Withdrawal symptoms analogue lo/exidine may produce similar resuhs 10 those ob-
all risk of common c3ncer: c:ase-c:ootrol .study in sen.cral prac-
aict rcscar<:h d11abue. BMJ 2000: 320: 1642-<i. may also follow the use ofan opioid anlagonisl such as toi11ed with clonidine and appears to be less hypotensive. 14
2•. Gonziltz.- PCJ~z.A~ c1 al. Effccu ofnon-steroidal :.nti-inflainma· Noltn:xonc and naloxonc block the euphoriant cO'ccts of opioids
1ory dru"6 on cancer sites Other than the colon and rectum: a naloxone or a mixed agonist and antagonist such as
mo<>-•nalysis. BMC Corrc<r 2003; 3: 28. ,.,..ilabl• at: hnp:// although their use as monolher.apy in detoxification is limited by
peotazocinc in opioid-dependent persons. Neonatal ab- unaeceptablc opioid withdrawal cffeets. Naltrcxonc may be used
www.biomc:d«nlral .com/1471·2~7.13123 (a.:ccsscd 08/11/07)
lS. Wanf WH. ~I ol. Non..steroidal anti·it10<l'mmatory drvg use :and stinence syndrome may occur in the offspring of opio- with alpha2.adrc:noccptor agonists such as clonidinc Ot lofc>d·
tht reR of iaslric cancer: ._ systems.tic rcvie\1.- and md.:J·analy· id-dependent mothers and lhese infants can suffer dine to ameliorate symptoms but there arc insufficicnl dat1 to de-
sis. J N111/ Co11«r /rut 2003; ~S; 1784-91. temtine whether such combinations reduce the dW111ion of with·
wi1hdrawal sympt0ms at birth.
Menstl'Ual disorders. Menontiagia (p.2334) is diougJ1t to be drawal treatment or increase the rate of lr'Onsfer to mainrenancc
usoc1aled with abnormalities of proslaglandin production. Opioid analgesics can be classified according to the re- therapy with an opioid anlagonist.•• Naloxooc and naltfexone arc
Treo1nicn1 with NSA1Ds such as ibuprofen, mefenamic acid, ot ccpt0rs at which they act (see Uses and Administra- also being used in the rclati..,lv new locluiique of i'Pid or uhn
naproo.en during menstruation, can reduce uterine blood loss by tion, below) and withdrawal syndromes are character- rapid opioid dctoxiftcation,1..'' which is achicwd wMe the pa·
an average ofJ00.4 in women with meoorrtaagia. lbere does not istic for a receptor type. Cross-tolerance and cross- tient is heavily sedated or under geJ,.,.,,,
011DeSrhesia and hence
lppc1r to be any evidence lhat one NSAlD is more effective than ur.aware ofany 1111pleasan1 withdrawal symp10111s. H~, al·
nnocher.
dependence can be expected between opioids acting al thwgh dcioxifacation anay be achieved within 24 hours 111d has
NSAIOs arc usually the ftrsl choice for the pain of dysmcnor- the same receptors. Dependence associated with mor- a higb initi:ll suocess rate, the i«hnique iL'IClfis DOI \\ilhout risks
moca (p. 7). Mefenamic acid may have a theoretical advantage phine and closely related µ-agonis1S appears to result in and ia does nor obviarc the need for maintenance treotment (sec
overolher NSAJOs in being able to inhibit bolh the synthesis and more severe withdrawal symptoms than those associat- below).
the periplu::al action of pl0$1oglandins, but clinical studies have ed with ic-receptor agonislS. Onset and duration of Concomitanl counselling and other psychosocial services have
noc shown fenomalcs lo be more effective, and systematic review withdrawal symploms also vaty according to the dura- 1>«11 shown to be imponant in rhe outcome ofwithdta.-al lhera-
M> su"esl•d that ibuprofen may have the best rislJbenefit ratio. py.1•~ Oetoxificotion alone does nor ensure long-term absti-
tion of ac1ion of lhe specific drug. With morphine and nence.
Migraine. Sec Headache, above. diamorphine wirhdl"owal symptoms usually begin Several other dru'1S may be of use as adjuncu in tilt manage-
Orthostatic hypotension. Fludro::onisone is usually the firsl within a few hours, reach a peak within 36 to 72 hours, ment of v.ithdraw';.1 symptoms. Dip/1e111u-y/01e wirh atropine or
dntg lried in lhc trcauncnt of onhostatic hypotension (p.1669) and then gradually subside; they develop more slowly /Ofl<'J·omide may be used for the control ofdian·hoca. Promet/10:-
when nonphamiacological tTCalmcllt has failed. NSA.l.Ds such as il1e has been u:;cd for its antiemelic and sedative action.~. Beta
tlurbiprofca\ ibuprofen, or indomctacin may be used alone or with me1hadone. Wilhdrawal symploms include yawn-
blockers such as prop.-0110/0/ may be of use for palicnts with pro-
added lo 1rca~ncnt if lhe response is inadequate. ing, mydriasis, lachrymation, rhinorrhoea, sneezing, nounced somatic anxiety symptoms. Be11zodiazcpi111is 0t clomc-
Pain. NSAIDs have o similar analgesic effect ro aspirin and pa- muscle lremor, weakness, sweating, anxiety, irritabili- thiazole can be given to relieve anxicly •nd associaled inson111ia
racetamol in single doses but, in regular full dosage, they ho"I> ty, disrurbcd sleep or insomnia, restlessness, anorexia, but only short courses should be used in order 10 minimise the
bolh a lasring analgesic and on anai-inOammatOI)' effect They nausea, vomiting, loss of weight, diarrhoea, dehydra- risk of dependence and abuse.
arc used jn 1he management of mild to moderate pain (see Choice tion, leucocytosis, bone pain, abdominal and muscle Long-rerm mainrenanc-e trciumcnl (stabilisation rrcalmenl) with
of Analgesic, p.2) and are of panicular value in pain due to in- an opioid may be tried, with psychosocial support, lo e11able lhe
Oamim1ioo. NSA!Ds may be of benefit for inflammatory pain in
cramps, gooseflesh, vasomolor distut'bances, and in- patient 10 acquire some fom1 ofsocial Stability before, ifpossible,
infanls and child1'Cn (p.3), altltough paracetainol is generally the creases in heart rale, rcspiratol)' rate, blood pressure, planned wilhdrawal. Merhodone is most commonly used; the use
pt'Cfcn-ed non-opioid analgesic in Ibis age group. NSAJDs may and temperature. Some physiological values may not ofdiamorphine although f03sible21.21 is con1roversial~1 and is ad·
 I 06 Analgesics Anti-inflammatory Drugs and Antipyretics
vocated by only a few individual ocntres. Buprenorphi11e is an- shonly after birth to 2 weeks of age, although most symptoms Morphine and some other opioids have a dose-related
other possibility.1' The use of methadone for maintenance has appear within 72 hours. Some symptoms moy persiSI for 3 histamine-releasing effect which may be responsible in
been reviewed"i>ZT Naltrexone can be effective in maintaining months or more. It is important to remember that inan)' in-
abstinence in opioid addicts after detoxifica1ioo, especially after fants may have also been exposed lo other licit and illicit sub- part for reactions s uch as urticaria ru:d pruritus as well
rapid or ultra rapid detoxificalion. It is considered that naltrcxonc slances1 including alcohol as hypotension and flushing. Cont2ct dennatitis has
would probably be of most use in highly motivated addicts with The American Academy of Pediatrics (AAP) 1 recommended been reported and pain and irritation may occur on in-
good sociological and P.sychologicol suppon to discourage im· that treatment of the neonate with abslincnce syndrome should jection. Anaphylactic reactions after intravenous injec-
pulsive use of opioids. •i 29 be mainly supportive and considered that many infanls with tion have been reported rarely.
The prob1e1ns associated with lhc iT.anagcmcnt of thcJregnant signs of drug withdrnwal could be managed in this way. They
patient with opioid dependence hav: bet:n discussed. ·nie aim advised adopiion of abstinence scoring methods to judge the <> TI1e adverse effects associated wilh individual opioid analge-
should be to stabilise the patient first using methadone since need for drug therapy, although such systems do not appear to sics may reflect lo some extent cheir acLiv:ty al spt.-cific opioid
acute withdrawal can result in fetal death. Drug withdrawal is have been validated. Drugs that have been used for opioid with- receplors (see Uses and Adminisrration, below) or may result
best done slowly during the second trimester. Jt has been suggest- drawal include paregoric (a USP 33 preparation containing opi- from a direcl toxic elfca. 1 ~ Some ad\·ttsc effects ofpure opioid
ed that if patients present during the final trimester and cannot be um), diluted rinclUte of opium. morphine, methadone, diazepam, agonists. such as the respiratory depressan'. effect of morphine.
detoxified, maintenance with diomorphine migl11 be preferable chlorpromazfoc, phenobarbital, and clonidine. Naloxone should arc dose related,. whereas agonisl~antagoni~1s such as buprcnOr·
to the use of methadone as it mi~ht produce less severe with- nol routinely be given to infants of opioid-dependent mothers tx.~ phine, bu1orphanol, and nalbuphine exhibit 3 'ceiling effect' as
drawal symptoms in the neonate.l The managemenl of neonatal cause of the risk of seizures with abrupt opioid withdrawal. The the dose ineteases.
abstinence syndrome is discussed below. AAP 1 made no definite recommendations but considered that, The lype and extenl ofadverse effects seen in practice may de-
1. Herridge P, GC1ld MS. Pharmacological adj uncts in the l.rca.tmcnl when appropriate, specific drug therapy should be used for treat- pend on whether or not opioid·sensitive pain is present, whether
of opioid and cocaine addicls. J Ps.rclwac1iw Drugs 1988: 20: ment ofwithdrawal symptoms. Thus for opioid wi1hdrawal, tinc- the opioid analgesic is being given for lhe control of chronic se-
233-42. vere pain or acute pain.and the route used. Jn a rcvicw3 of the use
2. Guthrit S K. Pharmaoologic imet\•tntion.s (or' the treatment of lurc of opium was the preferred drug. Others favour treatment
~~ioJ~ ~~p;;::;:~ and wilhdnwal. DICP Ann P'101·maco1l1cr wi1h oral morphine solution. B The BNFC 2009 also notes that ofopioids in ¢hro11icpain it was noted that, dcspilc worries to the
2 morphine is widely used and the dose can be easi ly adjusted; C<lntrary, respiratory depression and dependence liability arc nol
J. Wodal: A. Man•ging illicit drug use: • practical guide. OrJtgS however, it is stated that methadone may provide sniooU1er oon· generally a problem when appropriate doses are used to treat opi-
1994; 47: 446-S7. trol of symptoms. o id-sensitive pain. Jn facl the presence of opioid-sensitive pain
4, Mattick RP, Hall W. A rc dctoxificalion programmes effeclivc'!
/,<meet 1996; 347: 97-100. Practice varies widely and evidence for the efficacy of paniculor appears to prolect against the respiratory depressant effect, al-
S. Scivcwright NA, Greenwood J. Wl':at is impor1ant in drug mis- drugs in the management of neonatal abstinence syndrome is though it may occur if the source of opioid.sensitive pain is rL-.
use treatmenl? lancet 1996; 347: 313-6.
scanty and difficult lo compare.'-5 It has bct<n suggested !hat di- moved (e.g. by surgery) wilhout adequate reduction in opioid
6. National Concens\JS Development Panel on Effective Medical dooage. 11le adverse effects of opioid analgesics wlicn used in
Tre41tment of Opiate Addiction . Ef'Jcctive medical treatment of aiepam may be less useful than phenobarbital or paregoric but
opiate addition. JAMA. 1998; 280: 193H3. the use of paregoric (which contains both camphor and alcohol) advanced cancer have also been discussed.' Conslipalion was
7. O'Connor PG, FieHin DA. Pharmacologieal ire-atment orheroin- has been questioned. Jn the UK, chlorpromazine has also been considered to be the most troublesome advt.'rSC effect; significant
dej>cndent paticms. Ann /11ttrn Med 2000; 133: 40-54. widely uscd6 although a systcmalic rcvic~7 found insufficient respiratory depression was rarely seen wil.h recommended regi-
8. Gonza l ez~ ct al. Treatment of heroin (diamorphine) 3ddiction: mens, since pain antagonises lhe t.."tntra] dc:prcssan1 effects of
current ~pproachcs and future p1ospecL-;. Dr11gs 2002 ; 62: evidence to suppon such use. The authors' also found that phe-
nobarbital may reduce the scvcrily of withdrawal symptoms in morphine.
1331-43.
9 . Rttisch ow~ et ol. Opioid dependence trcatmcn1, including bu- those receiving an opioid; there was insufficient evidence to sup- In the context of acure pos1opera1ive pain opioid-induced respi-
prenorphine/naloxone. Ann Phormtcolhf!r 2002; 36: 312-2 1. pon the usc of clonidine. ratory depression is of concern but short-tenn postoperative use
10. DoH {Engl:ind) ;ind lhe de\'olved administra1ions (:?007). Drug is unlikely to cause dependence (although see Trealment ofOpi-
misuse and dependence: UK guid~lines on dinicol management l. Americ11n Academy of Pediatrics. Commiucc on Drugs. Neona-
(updated Sep1e1nber 2007). London: Department of Heallh tal drug wi1hdrawal. Pedia1rk~· 1998: J 01: 1079-8&. Correc:.lion. oid Dependence~ above for references to ia1rogenic physical de-
(England), the Scottish Govemmenl, Wel~h Assembly Govern .. ibM.; J02: 660 (dosage morl. pendence).' It was hoped that giving opioids by the spinal route
ment and Nonhcm Ireland Sxccufr:e. Also ovailablc ::it: http:// 2. Grt'gg Jr;M, et of. Maternal n~rcotic 3busc a1ld 'he newbom. would resull in fewer adverse effects, especially respiratory de-
www. nll•.nhs.uk/ uploads/c:lin ical _e.uidelines_2007 .pdf (ac- Arch Dis Cliild 1988; 63: 684. pression. In postoperalivc pain relief with spinal opioids, the in-
cessed 02108/10) J. Jan.sson LM, Cl al. The opioid -exposed newborn: assessmcnr and cidence of adverse effects is said to be low when patients are
11. Gowing L. ct al. Buprenorphine foe the management of opioid pharmacologic management. J Opio id Monog 2009; S: 47-5$. prope.rly monitored.6 However, some' have reported pruritus,
withdra\\"al. Available in The Cochrane Databa~e of Systematic
Re"icws; lssuc 3. Chichester: John Wiley; 2009 (acccss.cd 4. Theis JG\\', et al. Current management of the neonatal abs1i ~ nause3 and vomiting, and urinary retention to be common and
02/08/10). nence syndrome: a c-ritical analysi~ of the evidence. Bini Neonou~ respiratory depression to occur; more seriously the appearance of
12. OOhrer H. et al. Methadone trcatm:nt of opioid withdrawal in 1997; 71 : 34S-56. respiratory depression could be considerably delayed. These cf·
imensi,·e care patients. Lo11cet 199}.; 341: 636-7. S. Johnson K, tt 111. Trea1men1 of neonatal ::abstinence syndrome. fects were more common with morphine, tut all opioid analge-
13. Yasler M, et al, The msn3gcment of opioid and bcntodioncpinc Arch Dis Child Fetal Neo1101ol Ed 2003; 88: F.2-fS.
dependence in infants. children, <1nd adolescents. Pedia1r;C's sics had the propensity to produce respiralory depression when
6. Monisoo CL. Sincy C. A survey of the managcmcn1 or nconata1I given spinally.' Delayed rcspiralory depression has been attribut-
1996; 98: 135-40. opiate wi1hdrawal in England and Wales. Eur J Pcdlotr I996;
14.Gowing L. ~t al. Alpha~-adrenergic agonisu for the manage· 155: 323-6. ed to the poor lipid solubility of-morphine, but docs occur after
mem of opioid withdrawal. A\•ailable in The Cochrane Datahase other opioids. Some have considered that despite earlier worries,
of Systcinalic Rcvie\'••S; Issue 2. Chichester: John Wiley; 2009 7. Osbom DA, et al. Sedati.,.es for Opiate withdrawat in newborn
(acces$cd 02108/10). infants. Available in The Cochrane 03tabasc or Sys1cma1ic Re· po1entially fatal tale respiratory depression was as rare wi1h the
15. Gowfog L. et al. Opioid antagonist~ wilh minimal sedation ror views; lss:Jc 3. Chic;hcs1cr: John W il ey ~ 2005 (accessed spinal route as postopcmtivc respiratory dep-c:ssion wilh the con-
opioid withdrawal. Available ln The Coc:h1'3nc Dara base of Sys- 26106/0S). ventional route.~· Disputes regarding the frequency of respirato-
tematic Reviews; Jssue 4. Chiches-ter: John Wiley; 2009 (ac- ry depression associated with even convcr.tional use of opioid
cessed 02108110). analgesics mighl be due to the methods used for measuring res-
16. Justins D. Rapid opioid detoxification unde.r anaesthesia. Hosp Adve,r se Effects
M •d 1998; S9: 180. In usual doses the commonest adverse effects of opioid piratory cffects. 10 The incidence of vc:ntihllory depression has
17. Cook TM. Collins PD. Rapid opioid detoxification under anats· been reponed to be higher aOer inlrnthecal Jhan epidural usc Qf
thesia. Hosp Med 1998; 59: 245-7. analgesics are nausea, vomiting. constipation, drowsi- morphine. 11
IS. Gowing L, er (I/. Oeioid an t~go n ists under heavy sedation or ness, and confusion; tolerance to these (except consti- I. Duthie OJR, Nimmo WS. Advcr!'c effccls of OJ>ioid analgesic
anaesthesia for opioid withdrawal. Available in The Cochrane
0:.ltabost of Systematic Reviews; Issue 1. Chic:hcstcr; John Wi- pation) generally develops with long-term use. Mictu· drui-5· Br J Anoe!ith 1987; S9: 61-77.
2. Schug SA, et al. AdverSC effects of systemic opioid analgesics.
l<y; 2010 (accessed 02/08/IOl. rition may be difficult and there may be ureteric or Drug S<1f <ry 1992; 7: 200-13.
19. Mcl.dlan AT. ct ol. The effects of psychosocial services in sub.. bi liary spasm; the latter may be associated w ith altera-
stance :ibuse .trcolmcnt. JA/o.f.A l993; 269: J9Sl-9. 3, McQuay HJ. Opioids in chronic pain. flr J Ano esth 1989; 63:
20. Amato L, e1 pl. PsychosociaJ and 9 harmacologic~I treatments tions in liver e nzyme values. There is a lso an antidiu- 213-26.
\'Cr$uS pharmacoloBical trea1ments for opioid de1oxification. ..J. Twycross RU l..oic1' SA. Oral morphi11rt Jn mlvonced cancer. 2nd
A"ail~b l e in The Cochrane Dat11bas1.: of Sysl<:rn:itic Rc"icws: Is-
rctic effect. Dry mouth, d izziness, sweating, facia l ed. Beaconsfield: Beaconsfitld Publishers.1989.
sue 4 . Chichester: John Wiley; 200! (accessed 02/08110). flushing, headache, ve11igo, bradycardia, tachycardia, S. Mitchell RWD. Smi1h G. The eontrol o( acute postoperative
:!: l ..Pemeger TV. er ol. Randomised 1riai of heroin mainlC'nanct pro- pain. Br J Anoesrh 1989; 63: 147- 58.
gr:unme for oddict.s who roil in cowcntionel drug trci.umcnts. palpitations, orthostatic bypotcnsion, hypothennia, 6. LulZ LJ, Lamer TJ. Manttgemen1 of postopcralivc p:iin: review
BMJ 1998; 317: 13-18. restlessness, changes of mood, decreased libido or po· o( currcnl teC'hniques and melhod~. Mayo C/;11 Pmc 1990~ 6S:
22. Rehm J, et ol Feasibility, saftt)'. and efficacy of injectable her- tency, hallucinations, and m iosis also occur. These ef- 584-96. .
oin prcscrlplion for refractory opioid addicts: e follow-up study. 7. Morgan M. The r:lilionat use of i ntr~nhecal t.nd cxtradural opio·
lancct2001 ; 35!l: 1417-20. fects lend to occur more commonly in ambulant pa· ids. Br .I Anu& th !989; 63: 165-88.
23. f'3rrcll M. Hall w. The Swiss heroin trials: 1cs1ing alt..:mativt: tients than in those at rest in bed a nd in those without 8. Anonymous. Spinal opiates revis ited. LAnct1 1 ~86; i: 65$- 6.
approoches. BMJ )998; 316: 639. 9. M<Quay HJ . Sp;n3l op;3tes. Br J Hosp Med t987; 37: 3S4-5.
24. Kttkko J, PJ al, 1-y<.>ar relent ion 3r.d ,;ocial function after bu~ severe pain. Raised intracranial pressure occurs in 10. Whtatley RG, ct ,,1. rost<-'pcra1ivc hypoxe...m i:1: comporison of
prenorph i ne -~h;t c:d relapse prt.vcntion treatmcn1 for heroin de· some patients. Muscle rigidity has been reported alter cxtradurnl. i.m. and paticnl·con1rollcd opioid analsC$ia. 81· J
pendence in Sweden: a randomistd. placcho-con1rolled triul. h•oesth 1990; 64: 267-75.
Lnncct 2003; 361: 662-8. high doses. The euphoric activity of opioids has led to 1J. Gustttfsson LL c1 '11. Adverse cffcccs of cxtradural and in1rath-
2~. Farrell M, et ol. Methadone maintenance 1rea1ment in opia1e de· their abuse. For a discussion of opioid dependence, see ccal opiates: report of a na1ionwide sur"~)' in Sweden. Br J
pendence: a review. BMJ 1994; 309: 997- IOOL Anae.<lh 1982; 54: 479-SS.
26. W:irrl J, et of. Role of maintcn:ince tre1ume01 in opioid depend· above.
ence. Lunw 1999: 353: 221-6. Effects on the cardiovascular system. For reference to his-
2i. Bell J, Zotdor D. A risk·benefi1 an<'.llysis of methadone mainte- Larger doses ofopioids produce respiratory depression ta1nine rcleast and cardiovascular effects following the intravc·
nance ueatmcnt. Drug Safety 2000; 22 : 179...90. and hypotension, with circulatory failw-e and deepen· nous administration of some opioids see under Pelhidinc, p.1 1S.
28. Ginzburg HM, MacDonald MG The role of naltrcxont: in che
management of drug abuse. ftl1.:d Totlcol 1987; 2: 83-92. ing coma. Convulsions may occur, especially in infants Effects on the endocrine system. Endogenous opioid pep-
29. Gon2.a1ez JP. Brogden RN. N;iJ1rexone: a review of its phanna- and children. Rhabdomyolysis progressing to renal tides may have a role in dle regulation of cndoCrine function.
codynamic tnd pharmat:okinciic prcpmies and therapeutic effi-
<:ac:y in the management or opioid dtpcndcnee. Drugs 1 9~8; 35: failure has been reported in overdosage. Death may oc- Like cndorphin and enkcf halins, morphine has been found to
192- 213. cur from respiratory failure. Toxic doses of specific stimulate prolactin release and sy111he1ic an~logucs or morphine
30. Gcrada C, et ul. Managcmcnl of the preg.nanl opiate user. Br J arc reported to have siii1ilar properties; long·tem1 intrathecal opi-
Hosp Med 1990; 43: 138-41. opioids vary considerably with the individual and reg- oids (1norphinc or hydromorphone) hal'e been reported to pro-
31. Thoma ~ C5, Osborn M. Jnha1ing heroin during pregnancy. BMJ ular users may tolerate large doses. The triad of coma, duce hypogonadQtro phic hypogcmadism. a1rcnal insufficiency,
1988; 296: I6i2. pinpoint pupils, and respiratory depression is consid- and growth honnone deficiency, alihough tolerance to the effects
NEONATAL ABSTINENCE SYNDROME. Jnfants born lO opioi d ~ ered indicative of opioid overdosage; d il atation of the on prol~c.1in develops with long-tenn use.2 Opioids such as mor-
dependent mothers ma)' suffer withdrawal, with signs includ- phine ar" also pan of a large group ofdrugs implicated in causing
ing CNS hyperirrilability1 gastrointestinal dysfunction, respi~
pupils occurs as hypoxia develops. Pulmonary oedema
hyperglycaemia.'
ratory distress, yawning, sneezing, mottling, and fever. Onset afteroverdosage is a common causeoffata lities among I . Hell K. Wem2e H. Drvg.-induc<.-d change-sin prolac;1in secretion:
of symptoms is panly dependent on the drug and \'arics from opioid addicts: cl inical implicfltions. Med Toxicol 198&; 3: <63_.98.
All cross-references refer 10 entries in Volume A
 Opioid Analgesics 107
::. Abs R. t•t al Endocrine con:>c:quen«s ~I loni;-1..:rm inu;ath(UI Therapy .with opioid analgesics should be stopped ity. It was also rttommt:ndcd that ontl immcdiate·n:lcase or
Old1ni111$lttlU'U of opitlith;, ./ Cltu EIH/cNrmt1I M<-tc1h 2000: 8~: parcmcral. short·actin; opioids were preferable 10 long-.acting
1215... 22. gradually in patients who may have developed physi·
prepnracions such as trnn~nnal or moditicd-rcle= formu1<1-
,~. O"l)ymC" S. fa: ly J. Effects "rtJniJ;~ on J:luc~ tu l cr:mc~ in non· cal dependence, io avoid precipitating withdrawal 1ions.
in~uhn~ndcnc d i~bi:t i ci.: (part It). Dn~s 1990~ °'O: 203-19,
symptoms (sec Dependence. above). Opioid analge- I. Davis M. ( 'hutcs1:.sis 31wl endn~nous opioids: li v~ r disca.sc ::md
sics with some antagonist activity, such as bup1wor- c.\~<nous opioid fll\;1m1xntindiCS. Clm Plmrmu<"Okind 2007:
Treatment of Adve rse Effects phine, burorphanol, nalbuphine, or pentazocinc, may 46: 8:.?5-SO.
Activated charcoal may be given orally in conscious precipitate withdrawal symptoms in physically de- Pha.eochromocytoma. Morphine and some other opioids can
patients if a substantial overdose has been ingested pendent patients who have recently used pure agonists induct the relta~ of endogenous hislDmine and thereby scimu·
within I hour provided that the airway can be protected lo1e co1cchol3mine n:least. Boch diumorphinc1 and pethidine~
such as morphine. 1\3\'C been reported IO cause hypcncnsion when giV<.'11 to patients
(see below): it shou ld be considered in all patients if a
substantial amount of a modified-release preparatio11 Drowsiness may affect the ability to perfonn skilled with phaeochromoeytoma and hiscamine-releasing opioids
has been ingested. tasks: those so affected should not drive or operate ma- shoold be avoided iusuch peticnts.Alfentanil, like fentanyldoes
chinery. no1 relusc hisuimine and may bt the 0pioid of choice in lhc
Intensive supportive therapy may be required to cor- anacslhctic mana11cmc111 or patients with phacochromocytoma.'
Asthma. Opioids appear to be safe ind may be used with cou- I. Ch11unc:di NC. ~t tlf, Oiamorphinc·induccd attack or ~roicy8.­
1-ec1 respiratory failure and shock. In addition, the spe- lion in controlled asthma; howtver, they should be avoided dur· ma1 hypcNcnsu>n in ph:1cochromocytom:.. BJ..U 1974; l ; SlS.
cific amagonist' naloxonc is used for rapid reversal of ins acute exaccrbOtions.1 2. Lawtcnct CA. Pethidine-induced hypencn.sion in pha('()("hromo-
the severe respiratory depression and coma produced I 81mcsl'J. C hun! KF. DilflC\lllasthm•. BMJ 1989; 299: 10)1-2. <>•••••· BM.I 1978: I: 149--50.
3. Hull C'J. Phat'Oetlromocy\01na: diag.nosi~. prcopeTttive pttl)"ll·
by excessive doses of opioid analgesics (see p.1 595). Biliary-tract disorders. h is usually recommended that opio- 1ion 11nd :in:ic.uhetic m:1noscmcnc. Br J A11a~s1'1 1986: 58:
Since naloxone has a shorter duration of action 1han ids such as morphine should eilher be a\-oided in pacients with t4S:l-6S.
many opioids patiems who have already. responded biliary disorder$ or that they should be given with an antisp:tS· Renal impairment. A literature review' concluded d1at c<>-
modic. Morphine can cause an incrtase in inlr.lbili4ry pressure as
should be kep1 under close oh~rva1ion for signs of re- a result of eff<CIS on the sphincter of Oddi' und muy thercfQl·c be
deine •nd m0<phinc nre beSl avoided in pa1ien1s with renal failure
lapse and repeated injecrions given according to the and/or on dialysis: hydromorphone may be us..'<! with caution
expected co c.accrtlote rather than relieve pain in patients "'iCh and moniloring. 1nd u~t of fcntanyl and methadone appeared to
respiratory rate and depth ofcoma. Altematively, in sit- biliary colic (p.5) or Other biliary-1rac1 disorder$. Biliary-type be S1lfe. Sinular recommendations have been made f0t patients
uations where repeated administration is required, such pain after cholecys1cc1omy has also been associated wi1h wich <nd·stage renal disease who arc not undergoing diol'ysis.'
as where a longer acting opioid is known or suspected codeine' and morphine.' Sec also under the individual 1nonogruphs.
to be the cause of symptoms, a continuous intravenous Morphine tl!uscd a more marked delay in gallbladder emptying I. D<nn M. Opioids in r~I r1ilurt and dialysis paticn1s. J Pain
1han pethidine, pc:ncazocine. or bu1orphanol in a study" in healthy S1.,ir111tm1 MtmtrJ!f.' 2004: 18: 497-S04.
infusion of naloxone, adjusted according to response, subjcels; this was considered confirmation that morphine should l . Mun~gh FE. ct"'· Tilt u.sc of oPoid ~RO)lgcsia io c11d·jUlfC rcNI
may be used. All patients should be observed for at be "'"'idc::cl in biliary disorders. lo anocher studr fentanyl and d1snse patients manaicd wilhoul di-alysis: rccomine11d:111on.s (or
least 6 hours after die last dose of naloxone. sufencanil did not cooscricc che common bile duct like 1norphine; prt(ti«. J Pain Polllut Co1't' PhormaCOllH!r 2007: 2 t: S-16.
they may be suitable for periopcra1ive p•in control in pa1ico1s in
The use of opioid antagonists such as naloxone in per- whom spasm of the common bile duel is undesirable. The s._.g- Interactions
sons physically dependent on opioids may induce gestion that pethidine should bt p<tfem:d to morphine in patients As serious and some1imes fata l reactions have fol-
withdrawal symptoms. "'ith acucc pancn:•1i1is (p.91. btc:lusc of ils lesser eft'ect on 1hc
lowed use of pethidine in patients receiving MAOls
h1le duct. has been questioned.'
Activated charcoal. The Nacional Poisons Jnfonnacion Serv· I. Hehn Jr, ~' 11/. Efft'~ls of 1norphinc on che human s1>hlnct~r of (including moclobemide), peth idine and related drugs
ice in the UK considers the benefit of gastric decon1amina1ion in Oddi. Gut 198$; 29: 1402-7. arc contra-indicated in patiaits taking MAOJs or with-
!he management of ovenlosage wiU1 opioid anat1.c..sics to be un· l . Oruan·Blazy A,~' al. TI1c undc..'RSlim3t~d role- of 09i:ues in pa..
cenain. However. il is suggested thator.ti ac'livatc:d charcoa~ may tientJ with S'USpecltd sphincter of Oddi dysfunc1ion aficr d~ol e·
in 14 days of stopping such treatment; other opioid an-
be considered if4tiwn within I hc<1tof ingcstion and the quancity cys1tt1otny. Cmtr«utrrol Clin Bio/ 2005: 29: 1220-3. algesics should be avoided or given with eKtreme cau-
of opioid analgesic is subst:lnllal ot, for these specific drugs. ex- >. kobcn.s·llwnuon IC. ~' ol. Sympalhetic ocdv11inn: a mec.ha· tion (for further derails, see p.449). Life-threatening
nism for morphine indu«d pain 1.1ld rises in lh•cr enzymts •ftet
ceeds the following amount: choll!cyt:tec1omy? Gu' 1990: 31: 217-21 . reacrions have a.lso been repo11ed when selcgiline, a se-
• bup<cnotphine: 100 rnicroi:rarn~(adults and .:hildren) -I. Hahn M. et al. ·nu~: tffttt of four n~rcoc~s ou c holccystok.1nin lective inh ibitor of monoamine oxidasc type B, was
oct;apeptfJ< stimul31ed lfltl bli1ddet contracfion. Alimcnr Pho,.-.
• codeine: 3 mg/kg (adult$ and children) ntt~ Tltt,. 1988: 2: 129-34.
given with perhidine. The depressan1effects of opioid
• dihydrocodeinc: 3 mlP!<g (adults and children) 5. V'ecu':> ZEG. er al. fa-atu~tion or fonlanyl and sufcnumil on 1he analgesics arc enhanced by other CNS depressants
di:tmttcr of lhe commCln bile dl>CI by ul1rasonogrnph.y in man: 1 such as alcohol, an~esthetics, anxiolytics, hypnotics,
• methadone: any amount in an opioid-naive pa1ien.1.:>r more dovblc blind. pl;ccbo c.;.mlrulkd s•udy. Int J Clf11 Pllnr11wcol
than the prescribed doily dose ifon methadone t~pculitally T/ie1· 1994~J?: ?i4· 1. tricyclic antidepressants. and 3ntipsychotics. Cyclizine
• lr.tmadol: 500 mg(adult): 10 mg.t1'g (child) 6. Thompmn DR. Na.rcodc analgts.ic cfitcls on lhc sphinc.ttr of may cou111erae11he hacmodynamic benefits of opioids.
Oddi: a review of the cbt~ and 1hcrnpt>ulic implic:uion~ in trcll·
Soe also under individual n1Q110gr•phs. ing. pancfca1111s. AmJ G1~1n:wn1~1"(1/ 200 1; 96: 1266-72. Cirnctidine inhibits the metabolism ot some opioids,
Constipation. For reference 10 lhe use of opioid ancagonis1s. C hildre n. Children under 6 mooths of age may be more S¢11Si- especially pethidine.
particularly naloxone, 10 r~l ievc opioid·induced cons1ipo1ion 1i'~ to opioids~ ncomues in particular mny be more scns·iti"c: IO The actions of opioids may in tum affect the activities
\\'ithou1 compromising un1'1gcsic control in patients receiving respiratory dtprcssion with morphine thon adult$. Phormocoki· of other drugs. For instance, their gastrointestinal ef·
lon&·lcnn therapy with opio1ds, sec Reversal of Opioid E1Tee1s nctic diffcrent.:es may contribute to this increased sensitivity.
under Uses and Admimscrnlion ur Naloxone. p.1596. Nonethclcs.'- neonates con be 1rcntod with opioids such ~ mor-
foas may delay absorption as with mcxiletine or may
Reftrences. phine (see p.94) if r=iving respiratory support. be counteroctive as with cisapride, metoclopramide, or
I. Kuf1. A. Sc.~ ler DI. Optoid·indutt<I how~ I dysfu1\C'1ion: pa1bo- Oldc1· infants and rhildra1 can bt treated cffecuvcty with mor· dompcridonc. Opioid prcmcdicants such as papaverc-
physiuluvy alld po1cn1i:al nt"' 1htr.ipiu. Drugs ~003; 63: phine or ollm opioid 1n•lgesics and from chc age of 5 ot 6 tum have been reponcd to reduce serum concentrations
649-71. months morphine metabolism follows the course seen in adults. of ciprolloxacin.
for a discussion of the choi"" of analgesic in children see p.3.
The use of opioids for sedation and a1111lgesia in neonates in in- Alcohol. Rapid relea>C Of dose-dumping of hydromorphone
Precautions from a motlifotd·l'el<:l>SC preparation (Polla<lone: Purdue Freder-
Opioid analgesics are generally contra-indicated in rensive ca~ is mentioned on p.IOS9.
ick. USA) has been associated with the in&es1ion of alcohol (for
acute r~'llpiratol)' depression and obs1rue1ive airways References.
Curther dcwils. see under l111er.1ctions of H)'dmmorphone, p.66).
J, C'hao1111ra IA. P1i111dit>r. Arch Di., Cl;Jltf 1989;6-I: 1101-2
disC3St, although opioids such as morphine arc used in H~altl1 Canadl1 hfts wame<I dr•l this intcroction m3y occur wich
2. Lloyd·Thf'ma$ AR... J>3in m:an:a;cmcn1 in p:;tcdia10c p;atten1s. Dr
some forms o( dyspnoca (Stt below). TI1ey are also J .4'/mmh t990:64: 85-104. all mod1ticd-n:leasc fonnulaiions of "Pioid analgesics. Lil!erlSCd
3. llh:111-Meh1<1 V. Currtnl au1dclincs for the 1 r~.a1mcn1 or acute rain product infmnacion for <ome modifoed·release prepara1ioo1• of
contra-indicated or should be used with great caution in child1'en, Or".~ 199(•: $1: 160-16. morphine mdfote also warns against such use (see lnl<ractions of
in acute alcoholism, convulsive disorders, head inju· 41. ~br:lb OF. i:t '11. Opioid s~-s;tcms and lhc n ~'""'-Hn . Or J AutK"Slb Mo~~1ine, p.9 1).
ries. and conditions in which intracranial pressure is 1997; 79 : 787-9S. I Hcahh C;inada. Pott1111:.lly (ml ;nt,t;:icliCtll b\:tWl."<R i1('1W'·c'C>
raised. 1l1ey should not be given to comatose patients. The elderly. Al:ema can a1Tec11hc phannacotcinctics and ph•r· lnse opitl1d paiol.:1111:1" and :)kohol (iuul!d 3nJ Augui.1. 200S).
n»codyn:imics of opioids although the n<t effects of these 4,ail:Jbh: .at:h1 11l:l/www.hc -n.s.cc~/~hc-asc/mcdia/
They have an inhibito1y clfect on gastrointcstinal 1110- •d•isori""'1>1..._WOS/200S_s.>-.:11j!.php (a<t<SS<d 26106/08)
change.~ on opioid analgesia in 1he elderly remain unclcar. 1Prac·
ti lity and should be avoided in patients at risk ofpara- li(.-af rccommcncbtions include carcrul rcv~w of indication for Antivirals. hl1Cl"ll<lions between opioid analgesics and HIV·
l)-1ic ileus. opioid use both initially and nc regular inceivals there:ifler, scan- protease ;,,/,ibiton or IY!W!l"Se trtm~·C'rlpttUe inhibitm"S arc com-
Opioid analgesics should be given with caution or in inJ.t opioids cautiously at lo" er doses and with longer dosirig in- plex, and the results of the timi1ed number ofSllldios and repons
lcrv~ls. :ind regular consideration given lo dose rcduc1ion and in ,·fro have not always barnc oot p1\.'dic1ions ahout the n:uurc of
reduced doses 10 patients with hypothyroidism, adren- drug ~hsti1u1io11 or discon1inu:11ion. If possible, further drugs potential int<ractions.
oconical insufiiciency, asrhma or decreased respiratory ~uld not be prescritie<l 10 manage lhe adverse elTecis of opi<>- • Sub$cuncial decreases in the area under the plasma conc:cncra-
reserve, renal or hepatic impainnent, prostatie hyper- ids. 1ion·time curve ( AUC) and in the plasma conccn1rn1ion have
plasia, hypotcnsion, shock. inOammatory or obstruc- I. Wildtr·Sm1lh OHG Opioid osc in the ckSttfy. £,,,. J Poiu lOOS: bttn rcpon~'<I for pc1hidi11t when given with rito11m·il~ how-
9 : 137-40 ever, pbsma co11ccn1rn1ions of1hc 1o•ic m~abol ite norp<thi·
tive bowel disorders, or myasthenia gravis. Dosage
should be reduced in elderly or debil itated patients. Hepatic impairment. TI1< phannacokinctics ofopinids 1nay dine are greatly increased, and lioensecl product infonnation
be allcr<d in patieolS with hepatic Jy.function. A re''icw1o(opi- for rilona"ir com1~ls againscsuch combined ~. Ritonavir is
Opioid analgesics should be given wirh great care to oid us.: in this patient groupco...idcred that opioids sucll as mor· prtdic1od 10 reduce plasma conccn1m1ions of morphine. Plas-
infants, especially neonates. Their use during labour phin~ ;111d hydmmorphonc Iha! are metabolised by glucuronida- ma coneen1ra1ionsofmt1h.1done may be reduced if gi...,n with
may cause respiratory depression in the neonate. Ba- 1i<101 were relati"ely safe "-hen compared with chose mc1aholiscd HIV-protease inhibitO<S although the effect may not be elini·
by cytod11ornc P450 isoenzymes: the half-lives ofgluc11ronida1- cally signilicanl. The NNRTls 11e1-iropi11e and efovi-z have
bies born to opioid-dependent mothers may sulfer cd opioids wtr< found to be main1.1incd un1il late disease whc,.,,. also been reported 10 rcdtJCC pl>Sma-methadonc levels and
withdrawal symptoms (see Neonaral Abstinence Syn- as th< J)(Ulong.:d half-lives seen with opioids me1abolised by w11hdrawal •ymptoms hove occurred when given to pali<nts
drome, above). N 50 isocnt}lllCS wen: no! accurately prediclcd by disease sev.r· rett1vin~ mcth.:M:1011c. (ror further details c>n lhe iuteractions
 I 08 Analgesics Anti-inflammatory Drugs and Antipyretics
of methadone wilh antivirals, see p.87.) In addition, cfavircnz • IC-analgesia (mainly in the spinal cord); less intense 2. Plcuvry BJ. Opioid rcccp1ors and .. warCOC$$ of tht Greek :1lph1·
has been rcponed 10 decrease Ille AUC ofbuprenorphine (see miosis and respiratory depression, dysphoria and bet. BrJ Hosp Med 1992: 48: 678-81.
p.31). 3. Atchc'On R, Lambert OG. Update on OJ)ioid r~$. /Jr J
psychotomimetic effects Anoath 1994; 73: 132-4.
• In con1111si, an increau in AUC and in elimination half-Jjfe of -4. C>Nwan ON. tt al. lntcrn1tio1UI Union o( Phannacology. XII.
fcntanyl has been rcponed in subjecls olso receiving ritonavir • &-less certain in man, but probably analgesia; se- Classification or opioid rooep4ors.. Pliar1tt«OI Rel· 1996: 48:
(see p.59). Licensed product infonnotion for ritonavir also lective for enkephalins $67-86.
considecs that increased pluma concentrations of buprenor- 5. lntunisi CE. Clinic11 pharmacology of 0pioids lbr ~in. Clin .I
phinc (p.31), dcxtroprop0>.-yphcnc, aod tramadol, with an in- • Other recep1ors include a (sigma) and c (epsilon) re- Poin2002; 18(4•uppt): S3-Sl3.
creased likelihood ofopioid toxicity, may occur ifthese drugs ceptors. The psychotomlmetic effects of agonist-an- 6. Gourlay OK. Advances In ~pioid pharmacok>gy. S11pport Care
Cone" 200S; 13: I S3-9.
are gi\"en during ri10navir 11eatment. Licensed infonnation for tagonists such as pentazocine that are poorly antago-
meptazinol also stales that increased plasma concentr;1tions of f!ised by naloxone have been thought by some to be Administration in children. See under Precautions. above.
mep1a1Jnol have been no4ed when giV"'I with ritonavir. The mediated by a receptors Administration in die elderly. Sec under Precautions, above.
NNRTI delavirdine has been reported to increase the plasma
concentrations or buprcnorphine (see p.31) and methadone Opioids act at one or more of these rCQ!plors as full or Anaesthesia. Opioid analgesics have been given intravenously
(p.87). partial agonists, or as antagonists. Morphine and simi· as supplements during gcncnl an~esia wilh inhalational or
Jar opioid agonists (some1imes called µ agonists) are intravenous dn.tp. They ha'-e also been widely used as prcmed-
Histamine. For the effect of opioid analgesics on histamine ication bcfO<C surgery to reduce anxiety, for smooth induction of
given exoge11ously, see p.2542. considered to act mainly at µ and perhaps al 1C and 6 anaCSlhesia, to reduce overall anaesthetic requirements. and to
Histamine H2-antagonists. Histamine H2-antagonists may receptors. Opioid agonist·antagonists such as pentuo- provide postoperative pein relief. Such use of opioids is now rare
enhance the effccts of some opioid .,,.lgesics. Ci1~icline was cine appear to act as K agonists and µ antagonists and is restricted to paticots already in pain or 10 thooc who win
reported 10 alter !he clearance and volume of distribution of whereas buprenorphine is a partial agonist at µ recep- be in pain before induction of anacsthes~. Very high do5es of
pethidine' whereas ronitidi11e did not. 2 Morphine hos been con- morphine have been infused intravenously to produce anaesthe-
sidered less likely to interact with cimctidine than pethidine ~ tors with some antagonist activity at IC receptors. 1be sia for cardiac suri:cry, but shorter acting drugs such as fcntanyl
cause ofdifferences io metabolism. In a study3 cimctidinc did not opioid antagonist naloxone acts at µ, K, and 6 receptors. and related opioids arc generally used now; some may prefer ag-
affect the disposition of morphine in healthy subjecls. A later In addition to differing affmitics for particular recep- onist·antagonist opioids. Sedation and respiratory depression
study' in patients undergoing major surgery suggested that pre· tors the degree of activation once bound also differs. may be prolon;cd necessil.\ting assisted \'tntilation; l'C\ersal of
or postoperative intravenous cimetidinc did not sig))ificantly af- these effects can be achieved by opioid ~ntagonists such as
fect outcomes $\lCh as morphine consumptioo and incidence of The full agonist morphine produces maximum activa- naloxonc. For a discussion of the various drugs used to achieve
adverse efTeclS when compared with placebo. Nevcnhclcss, tion at lhe µ receptor and its effects increase with dose, and main1ain cooditions suitable for surgery. including the use of
there have been isolated rcpons of possible interactions between whereas partial agonists and agonist-antagonists may opioids in tho induction and maintenance of anaesthesia, sec
moq>hine and Hrantagonists; apnoea. confusion. and muscle show a 'ceiling effect' in that above a certain level their p.1936. Opioid analgesics, DIOSI commonly fcntanyl, have been
twitching have bccn associated with cimetidinc plus mo'1'hine,5 used with an antipsyehotic 10 induce a state known as ncurolcp-
and confusion associated with ranitidine plus morphine. There ellects do not increase proportionately with dose. tanalgcsia in which the patient is calm and indifferent to the sur-
has aloo been a rcpon7 of a patient receiving regular analgesia Other differences between opioid analgesics may re- roundings yet is responsive to commands. For a brief dis=sion
with oral methadone and subcutaneous morphine who became late to their lipid solubility and pharmacokinetics; of neurolcptanalgcsia and similar anaesthetic techniques, sec
unresponsive 6 days aftec staning cimetidinc for prophylaxis or speed ofonset and duration of action may influence the p.1936.
peptic ulcec; 11canncnt with naloxonc was required. l'OSTOPERATtvf SHIVERING. Pclhidincappears to be effective in
I. Ouay DRP, elol Cirnecidine 1htrs pethjdine d1sposj1inn in m3n.
choice of analgesic.
Br J Clin Phar-moco/ 19&4; IS: 907-14.
the treatment of postOpcr•tivc shivering (p.1935) but not all
Opioid analgesics have tradi1ionally been classified as opioids are necessarily effective.
2. Guay ORP. et al. Ranitidine docs not a1ler pethidine disposition
in nun. BrJ CUn Phmwocol 198S; 20: SS-9. weak or strong opioids but use of such terms has the
Cough. Opioids are used to suppress cough (p.1686). Pholcod-
3. Moj:!Wrian P. «t ol. Cimctidine don not altct morphine disposi- potential to mislead or lead to suboptimal care. An al- ine (p.1710) and dexiromcthoq>han (p.1694). which lack classi-
lion in mutt. BrJ Clhr Phtmnuc;ol 1982: 14': 809-13.
... Chia Y-Y, tt ol. Random~.. double-blind s.rudy comparmg ternative classification is that used in the WHO lhrec- cal analgesic activity and have fewer adverse effects, are the
postopcriti\"C cfl'ecis oftratmtfll timins with histamine Hr·rc.- step analgesic ladder (see Cancer Pain, p.5). Jn this sys- mC>St commonly used opioids. Of the analgesic opioids, codeine
:C/s'~9.ltlt.agonist ci1netidine. At10 AmHsthniol Scum/ZOOS~ 49: tem opioids are divided into those that are used for is lhc most widely used as a cough suppressant However, these
mild to moderate pain and those that are used for opioids are seldom sufficlenlly potent LO be effective in severe
S. fine A, Churchill ON. Potc.ntially lethal interaction or cimeti· cough. Morphine and diamorphine are used for the relief or
djne and mnrphinc. Co11 Mtd AssocJ 1981 ; 124: 1434, 1436 moderate to senre pain. Examples of opioids in the
6. Man.ine-.t-Abad M, er ol. Ranihd1ne-inductd confusion with con- introctable coogh in tcnninal illness, although morphine is now
comitant -i>hinc. DM<gln1<1/ Clln Phonn t988; ll' 914-15. first group include codeine, dextropropoxyphene, and preferred. Methadone has also been used but should be avoided
7. Sorkin EM. Ogaw1 GS. Cfmetidinc pottn11at1on or narcotic ac- dihydrocodeine; such opioids are distinguished by the as it has A long duration of acrion and tends to accumulate.
1ion. D111g /mel/ C/fn Phorm 1_983: 17: ~I. existence of a ceiling effect and are often used with Cough suppressants containing pholcodinc or similar opioids
non-opioid analgesics. The principal opioid for the (such ascodeinc)arcgcncrallynot recommended for use in chil-
Uses and Administration dren, and should be avoided in those uncler6 yc31S ofage.
Opioid analgesics possess some of the properties of treatment of moderate to severe pain is mOlphine. Oth-
ers include diamorphine, fentanyl, methadone, and Dianiloea. Oral rehydration therapy, which is the treatmcnl of
naturally occurring or end ogenous opioid peptides. choice for acute diarrhoea (p.J 842), prevents dchydmlion, but it
pethidine. does not necessarily shorten the dwation of the diarrhoea. Prep-
Endogenous opioid peptides are widely distributed in
the CNS and are also found in other parts of 1.he body. Tn addition' lo the relief of pain, opioids are used in arations containing codeine, morphine. or other opioids have
They appear to function as neurotransmitters, modula- anaesthesia for premedication, induction, or mainte- therefore been used f..-theirantimotilityaction as adjuncts in the
nance; however, pre-operative use is generally limited management of ~cute diarrhoea. However, the WHO considers
toi:s of neurolransmission, or neurohonnoocs. Their that such antidianhoeal drug therapy is of limited value. and
presence in the hypothalamus suggests a role in the to patients who require control of existing pain. In bal- should never be given to children. Furthermore opioids should
regulation of endocrine function. Opioids have been anced anaeslhesia they are used with an anaesthetic not be used in conditions where inhibition ofperistalsis should be
shown 10 stimulate the release of some pituitary hor- and a neuromuscular blocker. When used wilh an an- avoided, where abdominal distension develops, or in diarrhoeal
tipsy<:hotic they can produce a state of mi ld sedalion GOndinons such as severe ulce.rotivc colitis or anlibiotlc-assochu-
mones, including prolactin and growth homione, and ed colitis.
to inhibit the release ofothers, including corticotropin. with analgesia called neuroleplanalgesia.
Dyspnoea_ Dyspnoca (• subjective feeling or abnormally
Endogenous peptides include the enkephalins, endor- Some opioids are used for analgesia, sedation, and sup- uncomfonablc, di fficul~ or laboured bteathing) is associated
phins, and dynorphins; their polypeptide precursors pression of respiration in the management of mechani- with diseases that interfae with oxygenation of the blood. The
may also be precursors for non-opioid peptides. Pro- cally ventilaled patients under intensive ca re(p. l 059). course of dyspooca should be csiablished since it is often best
enkephalin is the precursor of met- and leu-enkephalin; Opioi<ls such as codeine, hydrocodone, and hydromor- relieved by lJeltmcnt ofthe underlying disorder (the inaonent of
dyspnoea associated with asthma and chronic obstructive pulmo-
pro-opiomelanocortin is the precursor of beta-endor- phone are used for the suppression of cough; for intrac- nary disease (COPD) is discussed on p.1220and p.1224, respcc.
phin, beta-lipotrophin, melanocyte-stimulating hor- table cough in terminal illness morphine may be used. tively). Where this is impossible or ineffective, symptomatic
mone, and corticotropin; and prodynorphin is the pre- Opioids may relieve some forms of dyspnoea; mor- management is required.
cursor of dynorphins and neoendorphins. phine and diamorphine are probably the most com- Oxygen may reduce dyspnoea in some patients e111:n if dyspnoca
Pharmacologically the opioid analgesics are broadly monly used in the UK, but dihydrocodeine, hydroco- is not related IO hypoxia. A Oow of air direded across the face by
a fan can also be effective. O~ite the hazards of using benz.o<li-
simi lar; qualitative and quantitative differences may be done, and oxymorphone have also been tried. azcpines in patients with any form of respirn10ry dqression or
dependent on their interaction with opioid receptors. Methadone and buprcnOfJJhine are used in the treat- pulmonary insufficiency (sec under Precautions of Oiaupam.
There are several types of opioid receptor and they are ment of opioid dependence (see above). p.1093). drugs such as diazepam, lorw.cpam, or midazolam may
distributed in distinct p<!tlems through the central and be helpful in po.ticnts with advanced canocr who have rapid shal-
0 References. low respiration, especially when this is associaled with anxiety. 1
peripheral nervous systems. The three main types in l. Cherny NI. Opioid anals,c.slcs: compar;,1ivc fnture<S und rrc· uvomcpromuine is occasionally used 2$ an alternative.
the CNS were originally designatedµ (mu), K (kappa), sc.ribing g:uH:Selincs. Drugs 1996; 51~ 713-37. Opioids may relicYc some forms or dyspnoea,""' such as those
and 5 (delta) although they have been reclassified as 2. Upton RN~ el al. Pho.nnlCOlcinctic optimisa1ion or opioid trtal• due to acute left ventricular failure. pulmonary oedema, and ma·
ment in acule pain therapy. CJJn Pborn1acolcin#t 1997: JJ:
OP3, OP2 , and OPi. respectively. Activities attributed 225-44. lignant chest disuse. Guidclincs'·6 (some based on 1hc findings
to the stimulation of these receptors have been as fol- 3. Walsh D. AdnnCQ in opioid Chcnpy and formuLitions. S11ppor1 of systematic rcvie·ws') and expen consensus statomenu' issued
lows: Cort Car.cor 200S: 13: 138~•- for tlic management of dyspnoea in palliative care recommend
•· Hanks GW~ Reid C. Contribu1ion to varia~hcy in response to that opioids should be considered in po.ticnts with severe :ind un-
• µ~algesia (mainly at supraspinal si1es), respirato- 01>iolds. SMpport Cort! Cor.ttr 200S; IJ: 14$-Sl. relieved dyspnoca. Doses teod to be lower and increments small-
ry depression, miosis, reduced gastrointestinal mo- $. Smith HS. Opioid mttabolisf'rl. J.fo)'O Clin flroc 2009; 84: er than those used for pain rclicf.1 Thc use ofopioids is generally
613-24.
tility, and euphoria; µ 1 (supraspinal analgesia) andµ~ nut advised, or only with extreme caution, in patients with ob-
Action- Some rcfcrenccs 1"" to opioid receptors. structi\-e airways disease whose dyspnoca may be relieved by
(respiratory depression and gastrointestinal activity) other means. However, they may be useful in patients with ad-
I. Plcuvry DJ. Op.oid rcccp1ors ind their HgaPd.s: no.tu1al and un·
subtypes have been postulated n~ lunl. BrJAnaa,tth 1991;66: 370-30. vanced COPD whose dyspnoca is resistant to conventional man-
All er0$S·references refer to entries in Volume A
 Opioid Analgesics/Hydrochlorides of Mixed Opium Alkaloids J09
a2Clllcn1.• Morphine and diamorphiM arc commonly used op10- ~- Mou~habsh:ib AV. ~I of. Manag.cmcnl of auaononuc dysfone1i-on Ph. Eur.: Op.um Drye.v.ct. Sw1Qrdisod. Optum Tonctu'e. ~<ised;
ids for dyspnoca, but dihydrocodcinc, hydroeodone, and in sever~ 1ec1mus: lht usie of fcnunyl. C1m J A1toe11h 1995: 42: USP 33: 0pun Tnc-.- Por<::""·
ox)111ofl)il0ne hove also been tried. his unclear if all opioids are 9!S. Proprietary Preparadons (defai l~ s.re 3iw.:11 in Voluolot Bl
3. Bhag~·anjet S. c•1 al. M•n~emcin oraymp:ilhc1ic overacti,•ity in
equ:llly efl"cciive.' 1c11nus with c:pidur:'I bupivae1inc and 141fcntanil: expc:ricn"
Broz.: E1xo1· P..-egonco: lsroel: ()pi Scnp'ex.
Ncbuliscd morphine, hydromorphooc, or fentanyl have been with I J p:11tcncs. Crit Care Med 1999: 17: 1721-S. MulO.i'\= Broz.: C~ ElxY :St M.:arin~t: Denm.~ ~­
tried for the managemcnl of dyspnoea, and llierc arc anecdotal t. Fr" Colch"'1il< Lrr.u1f: ~rque: Hang Kon~
t)'t Fin.:
ero.,,.. 11o<kn_ lsroel: Davillat; DO¥<n: SJ.fr~ P""l"'iesc.£1w...,t Tan~
rerorts ofbenefi1. cspeaally in palliative care, but e-~~ from PJ"d~t. Spoln: Digest°"'1Wf: Tanu<l Switz.: l!rornoeod N; FloC\0-
controlled studies 10 dare does not suppo11 such llllC._J..!.IO.b Sec calmne: USA: 8 & 0 SUol><•n.s No I SA: 8 & 0 Supptettes No. 16A:
also under Morphine, p.94. Opium Vcn ..a.:AtJ'(:lbet
In patients wilh advanced cancei and in1rac1able dyspnoca unre- Gum Opium; N~rs 6pOan: Opijus. l3'avinis: Opio: Opiun brut: Homo•opathk: "'" FormAI cit l'Abbe cn.up.1,.,, "" 9: fertrtJ!e ~e
sponsn., lo the above measures, chlorpron1a:zinc may be useful Opium crudum; Opium ~: Raalcaoopiumi; Nop<.m; Raw TAbbo Oiaupilre no 7.
to relic'• air hunger and sedate dying pati<flts who have unre- Opiurr.
lieved distrcSS; 1 n1ida2.0lam may be used as an ahemativc. Pro· On")'M
methazine has also been used. Higli doses of a c:orticosrcroid ATC - A070A02; N02AA02. r-tydrochlorides of Mixed Opium Alkaloids
such as dcxamethasone may help to relieve dyspnoea in p:nienL~ ATC Vet - QM70A02; QN02AA02.
with airways obstIUCtion due to a tumour by reducing oedema Alkaioidos<.m Op1i Hydrochloridi.n1: Exlnct\rn Concenl<atlMll
ATC Herb - HN02AA5001 (Popover somni(erum: dry lo·
Opii· ~>clas de hidrodoruros de alcaloides def opio; °""1op-
around lhe tumour. 1cx): HR05DA5001 (P<ipover somniferum. dry lo1ex):
1. W:Jlsh O. Oyspnoea in 1<hoa1'<ltd cancer. Lo11ca1 1993: J.41: HN05CW5004 (Poporer somnifervm: dry lotex); onum; Opiak.fn: Opr..m ConcentratUTl'l
4!0-1. : HA03ADSOO I (Po;>o•er somniferuni: dry lotex): r..ApoXl>OP•.Abl CNewaHHl>IX AN<aAOMAOa OnHA
2. Davis C. Pete-)'_ 0. Breathlessness., couJ,h.• and othet rc:spinrory HA07DA500 I (Popover somni(erum: dry latex).
problems. In: F1llon M, Hatnks Ci. ~ds. ABC o/pollioril>:tt cunt. Pharmacopoeias. Preparations ofthe hydrochloridcs ofmixed
2nd •d. London: BMJ Publishina Group. 2oo6: tl-16. Street names. The followine. tcnns have been used as 'stn:el opium all'31oids are included in Jp11.
names' (seep. vi) or slang names for various forms ofopium:
· f~~:~~:.~tt:;:·~~:::e~°n' ~~ct~~~': ~~i~stS;!~
3
Ahpenyen; All-pct>-yen; Aunti; Aunli Emma; Big O; Block;
1cma1ie R~vi~ Issue 3. Chiches1er: John Wi1ey; 200l (•c- Black pill; Blaclc shit; Black slutf; Black 1ar opium; Block; Bou· Papaveretum (llAN)
ccssed 26/06/08).
4. kYole PA. et al. American Colleae ofChcs.t Physict~ns. Lung
lene; Chandoo; Owx!u; China; Chinese molasses; Chinese to- A m:xture o( 153 parts of r.icxphinc h)d'ochlonde. 23 parts or
conc<:r: palliath« c>r<. Chm 200); 12) (suppl): 2S4S-311S. bacco; Chocolate; Ouz; Dopium; Dover's deck; Do-'s pow- papavcrine hydrochlonde. dnd 20 p.irllo of codeine hydroch!O·
Also available, ~n: hnp:ifw'""'.C'hestjoumal.orsJcaifrtprinlll23/ der; Orea111 i;um; Dream gun; ·Dream stick; Dreams; Dutch ride.
i_suwll284S.p<lr(accuscd 2~) coura11.:; Easing powder; Ficlonic; Fi-do-nie; Fun-foon-fong;
5. l..ankm PN . ., ol. A1'S End-ot:LifeCau Task Fore<. An official Gee: God's medicine; Oorna; Gondola; Gong; Ooric; Orca1 to- nanaecpel)'M
A1nertcan Thoracic Society cllnical policy Jtac.emcnt: palliarivc bacco; Oum; Ouma; Hard stuff; Hocus; Hop; Hops; Incense; In· CAS - 8002-76-4.
care ror ~cnu wuh respiratory diseases and critical Illnesses. doncsian bud; Joy plant; Mash allah; Marerial negro; Midnight ATC- N02AAIO.
Antl R•1pir Cri1 Cort M•d2008; 177: 912-27. Also a\-ailable oil; Mira; Mud; O; Oj; Op; O.P.; Ope; O.Roclt DC; Pen yan; Pen
~~:ftt~~)°ujo<>m1ls.or4<1csifrcprinlll 77/8/9 l 2.pdf (••· ATC Vet - QNO 2AA I0.
yen; Pin gon: Pin yen: Pox; Skee; Tar; 1in; Toxy; Toye; Toys;
When-shce; 2e; Zero. NOT£ Do not con.fuse papaveretum wilh papcivcrinc (p.2394).
6. Qasccm A. at of. Clinical Efficacy Assessmenr Sultornm1t1ce of
the Amcriean College of Phys.ic11ns. EYidencc-bued iAl<rw:n.. Pharmacopoeias. In Chin.. Ew: (sec p.vii). and US. Pharmacopoeias. In 81: .
lions to hnpro"·c the palli.ativ~ nrt ofpain, dyspnea, 2nd ckpru.- Chin.. Eur.. Rnd US include a monograph for prepared or pow· Bl' 20 I0 (P~). It contains 80.010 8M% of anhydrous
sion at the end of life: a chnical practice auidcline from lh-e
Amcric.sn CoJlc¥c of Phys.icians. Ann /n/<:1-n M"d 2008: t.is: dcn:d opium. Eur. al~o conl.3ins monographs for standardiStd morphine hydrochloride. 8.3 lo 9.2% of popaverinc hydrochlo-
141~. Al50 a'•a1l.1bfe Al: h11p:/Jw"·w.ann1ls.Of8/con1entJl48/2J opium dry cxtracl or standarchscd opium tincture. Jpn includes ride, and 6.6 to 7.4% of anh)'drolts codeine hyd1'0Chloridc. A
t41.full (acttSSed 02/08110) poq>ored opiwn and a dilured opium powder conlllining I% of whit< or almost white crysL3lline powder. Soluble in waler, spor·
7. Lorenz KA. <t ol. Evicknc< (or iinprovina palliuive care at 1he anhydrous morphine. ingly soluble in alcohol. A l.5%solu1ion in wntcr has ft pHof3.7
end of lift>: a sys;eernatic review. Ann Int~ M~ 2008: 148: Pb. Eur. 6.8 (OpO..m, Raw: Opi.Jrr. BP 2010). The a.ir-dried latex to 4.7. Protect from light.
147-59. Corrccoon. ihid 2009; !St: 674.
3. Mahler OA, et o/. Ammcan ColleJe of Cl><st Ph~icians cnn- obtained by incision from rhc unripe capsules ofPapuver ,omni· Profile
scnsus lllltincnl on the man3gcmcnl ~rdyspnea in paticms wilh fcnrm L. It has ft characteristic odour and a blackish-bro''"' col- The opium alkoloids :ire the prototypiul opioid analgesics
advaoc~ hmg orht:an diSCHC'. CMst 20 10; 13i: 674-91 . our. It should conain not less d1an 10% of anhydrous morphiM, (p.J 05). Mixtures or opium alkaloids such as papavcretum hove
9. Rocker U "'al. Palliation o( dyspnoca in adva11ccd COPO: rc- not less lhan 2% ofanhydrous codeine. ond not more than 3% of
v1si1ing a rgl~ for opioids. Tht>t'O~ 2009~ 64: 910-1 S. the analacsic and sedative properties of morphine (p.93) and arc
anhydrous tbebainc. Protect from light. used in tl1e 1rcau11ent of moderate 10 severe pain including poo;t·
10. Chandler S. Nebulizcd opioids lo lrt.t.1 dyspnca Am J Hosp Pal-
l/ct c... tm; 16: 418-22. Ph. E....: 6.8 (Opium. Prepared;Opi P\JMs Normatus). Raw opi· opcr•tivc and severe chronic pain. l11cy may also be used for
11. Fonl PA, et ol. N•buliZ<d opioids us<: in COPO Chest 2004; um powdtred and dried at a temperature not exceeding 70". It is pre-operative sedation and as an adjunct to anaesrhcsia. Papa\ct-
t2S: 691-4. a yellowish-brown or dark brown powder and contains 9.8 to etwn (BP 2010) 15.4 mg contains theoquiv•lenl of about 10 mg
12. Brown SJ.~' ol. NcbuJizcd morphine for relief of dyspnea due I 0.2'!. of morphine and no1 lc.'s d1an 1.0".4 ofcndeine, calculated of the major component. anhydrous morphine.
to chronic Jun& discate• .Ann Ph'1rnroco1lltr 200S; 39: 1083-92. wirh reference to the dried dn1g. The content may be adjusted by
13. Kallet RH. The rok: ofinh.alcd opioids ind furosemidc for the adding a suitable excipicnt or raw opium powder. • In the UK, papavcrcnun formerly contained the hydrochlo-
1reatm<nt of dyspnca. Rupir Core 2007; 52: 900-10. USP 33 (Oflo.11'1'1). nie air-dried milky exudate obtairied by in-
rides of morphine. codeine. no= pine, and papaverinc. How-
Pain. Opioid analgesics arc used fnr the relief of acute and cising the unripe capsules of Popover somnifemm (Papaverace- ew.r. because of concem over lhe potential gcnotoxicity of
cluonic pain (sec Choice of Analgesic, p.2). Nol evc1y l)lpc of ae). falcmally ii is pale oli~rown or olive-grey; inrcmally II is
noscapine (sec Pregnancy. p.1706) UK prepora1ions contai11-
pain responds; neuropathic pain, for example, may not be •llevi- reddish-brown. II has a very characteristic odour and a very bitter in2 papaverctum w..-c rcfonnulatcd to exclude the noscapinc
3led by opioid lhcnpy. For funher discussion of specific pain taste. It yields not less than 9.5% of anhydrous morphine. mponenl and the name papavcrctum w~ rcdef'_lled in _ll•e
s~11es and the role of 0(1ioid an•lgesics in their 11eatmcnl see p.S
BP 1993 10 reOcct this change of formulallon. It 1s possible
USP 33 (Po~red Opium). Opium dried ot a 1empera1ure not
onwards. c.cecding 70". and reduced 10 a very fine light brown nr moder· th•t in otltcrcow1trics the term f)3paw.retun1 is still being used
10 describe a mixture conraining noscapinc.
llicre bas also been 1ntcrcst in the local anal11esic elTc:cts of opi· a1cly ycllowish·bro\loll powder thot yields not less than I O'.I. and
oids themselves.•.: not more rhan I 0.5% ofanhydrous morphine. It inayconlllin any DO$CS. Papavcretum is gencmlly given by subcutaneous or in tr~-,
of d>e pennitted dilucnts with the exception ofstareh. muscular injection in doses of7.7 10 15.4 mg every 4 hours 1t
The use ofopioid analgesics in opioi<klepcndent patie.1ts reccl\'- necessary. The initial dose in the elderly or debilitated patients
ing maintenance trcannent with an optoid is the subject ofmuc:ll Profile should nol exceed 7.7 ma.
debate; however, some consider such use to be appropriare in the Opium is the air-dried la1ex obtained by incision from the unripe In the treatment of pain and.as an adjunct in anaesthesia. plJlll·
management of acure pain in these paricuts and recommcnd3· capsules of Popt1,.er som11iferu111 (Papaveraceac). It contains verctum may also be given inrnm:nously in doses ofone-quarter
lions haw. been issued.' morphin•, codeinc, and thebai1>e and a variable mixture of olhor 10 one-half th< corresponding subcular>eous or intramuscular
t, Thnn1pson OF. Pier« OR.. l.ocul unalgb"ia \\;lh opioid dru:s. alkaloids including noscapinc and papaverinc. The exuded latex dose. For pre·opcra1ive medication P8Jlll''trtmm is given intra·
Amt Phor111oco1hcr 199S; 19: 189- 90. is dried and manipulated 10 form cakes of uniform eomposirion, muscularly or subcutanoously sometimes wilh hyoseinc hydro·
2. S1ein C. The eonarol of p.'\in m ~riphe:rol 1i5.suc by opioid$. N variously shaped according 10 the country of origin, and known
£1rg/J M•d 19</S; ll2: 1635-90. bromide.
in commerce as Twltish, Indian, or European opium.
3. Alford OP, tt al, Acute p1in manq:ement for patients receivins For details of doses in child""1, see below.
mainlem1nce n1etl1~done or buprcnorphine therapy. Ann /nJem Opium has d1e propcnies of opioid anal~esics (p.105). Its analg-
.l~d2006: t44: t27-34. esic and sedative ac1ions arc due mainly to its content of mor· Oral preparations containing papav.:reiuin with aspin~ have
phine (p.93). It acrs less rapidly than morphine since opium 3p- been given for the management of moderale to •cvcrc pam.
HEADACHE. Opioid analgesics such :is codeine arc sometimes pears to be more slowly absorbed; the relaxing 3ction of l11e OPapaveretum has been confused with p.1p<1.vcrine (p.2394) ~d
included'" oral c:ompoond analgesic preparations used in the papaverine and noscapine on intestinal 1nuscle makes ii more in one such ca."'' a patient became uncool(1011S aOer self·onJCO-
initial treatment of migraine (p.670) or tension-type headache constipa1ing 1han morphine. lion of pap•l\<eretmn in mistake for papa\lefine.
(r.671 ), but arc best a,·oidcd, especially in raticnts who have
frequent attacks. Opiwn is inrendcd only as tl>e st~ning material for tllC manufac- I. Robinson L.Q, Stephenson TP. Sel( inj\."Clion treatmc-nc for impo·
ture of galeni.-111 prepar•tions and is not dispensed as such. 11 is tmce. BM.I t9!9: ~9: 1568.
Restless legs syndrome. Some opioid.s inay be b<,'l)cficial in used as Prepared Opium (Ph. £ur. 6.8), as Powdered Opium Administration in children. Pap:iveretum may be gh-en to
the trcatmenl of rcslless legs syndroino (s« Sleep-associated (USP 33). as Opium Tincture <BP 1010 or USP 33), or as Cam- children in the treatment of moderate 10 severe pain including
Movement Disorders, p. I060), althou¥h evidence is scanty. phoratcd Opium 'Tincture (BP 1010) or Paregoric (USP 33) in postoperative and severe chronic pain. l< is also used for rwe-oi>-
various oral preparalions. The<e have included Opiate Squill <llltivc sedation and as an adjunct to anacsd1csia. Popavc:retwn is
Sedation. In addirioa 10 their analgesic action opioids have Linctus (BP 2010) (Gee's lincni.<) for cough.
been uscJ for their sedative propcnics. Mention of !his use of generally given by subcutaneous or intramuscular injection eve-
opioids cun be found in the discussions of anaesthesia (p.1936). Paregoric (USP 33) has been advocated in the USA for the treat- ry 4 hoon if n~uy. according to age as follows:
endoscopy (p.1059). and intcn~ive care (p.1059). ment of nconal.31 abstinence syndrome.
• neonares: 11 S microgra1nslkg
Tetanus. Opioid analgesics can be used to provide analgesia Abuse. Reporls of squitl-associa1ed cardiotox.icity rcsuhing • l to I2 months: IS4 microgl'•ms/kg
and additional sedation in patients undergoing llealment for tel· from die abuse of opiate squill linctus (Gee's linCJU.S). 1.:
• I to 6 years: 1.93 to 3.85 mg
anus(see p.211 and p.206S). Opioidssuch as fenl.3nyl, morphine. I. Thurshm 0, Tay101 K. Ote's linc:l\.1s. PlwrmJ 1984: 233: 63.
2. Smith W, rt nl. Wcnckcb1ch'$ phcnon~non induced by (:()Ug.h • 6 to 12 years: 3.85 to 7.7 ms
and sufcnt1nil have also been given 10 conttol rhe sympathetic hnaus. BAIJ 19S6; 192: 868.
overacri,;ty in such pa1ien1s. 1•3 Older children may be given the u.u•I adult dose (see abo\'e).
I. Rocke DA, Cl ol Morphine in tctanus-c>K: maN:geme.11 o( sym- Preparations ln the trealment ofpain and as an adjunct to anaesthesia p:ipavcr-
ptlthctic nervous syst!m ovtracrivity. S .ij'r Med J 1986~ 70: 8P 20/0: U:.-r4'flO"lted Opium Tinctur<. Cont....,..,ed ~~«•led etum may also be given intravenously in doses of one-quancr to
666-8. Opi1rn r °"''°'"' Opun Tnc1.....: one-half the corresponding subcutaneous or intramuscular dose.
The symbol t denotes a preparation no longer actively marketed
110 Analgesics Ant i-inflammatory Drugs and A ntipyretics
Preparations although in os1eoarthri1is, pa~w body-weigh1 or mild Oxycodone Terephthalate ®
BP 2010: P•poveret.,m ll¥?<1iol\ disease should be given an ini1ial dose cquivalenl ro 600 mg once 0Ykodona. terefta/ato de. 4.Su·Epoxy-14-hydroxy-3·mctho>.y-
Proprietary Preparations (details arc given in Vo1umt B) daily. The recommended maximum daily dose is 1.8 g or
26 1nglkg, whichever is the lower. 17-me1"lylmorphinan-5-one l.4·benz"'1edicarboxylate (2: 1) salt.
S.A(T.: Omnopon.
0KC•KOAOHa Tepecj>TaAaT
Multi-ingredient: UK: Asp.avt. For doses in palients "'ith renal impainnent ond in children, see
below. (C 1aH 21 NO,)i.C*H~O< :: 796.9.
CAS - 64336-55-6.
0 References. UNI/ - M04XWV43UF.
Oxaprozin (SAN. USAtJ. •NN) I. Miller LG. Oxaprozin: a oncc-d3ily nons1eroid:il ami·inflamma- Pharmacopoeias. In.US.
1ory drug.. Clin Phann 1992: U: 591- 603.
Oksaprotsiini: Oxaprozina: Oxaprozine: Oxaproz:num: Wy· 2. Anonymous. 0,;aptozin tOr arthritis. Mt·d Leo Drugs Ther 1993: USP 33 (Oxycodone Terephlhalate). S1ore in airtig/ll contain-
21743. 3-(1.S-Diphen)<1oxazol-2-yl)propionic aci<I. 35: 15-16. ers.
Oxcanpo3HH 3. Oallcgri F. l!I 111, I\ review of the emerging profile of 1he anti-
inflamm:uory drug mcapcozin. Expert Opi11 Pltormnco1her 2005: Dependence and Withdrawal
C , 8 H1sN0 3 :: 293.3. 6: 777- 85.
CAS - 2 I 256-18-8.
Administration in childre n. Oxaprozin is given orally in the
As for Opioid Analgesics in genera!, p. I05.
ATC - MOIAE/2.
ATC Vet - QMOIAE 12. 1rca1tnen1 ofju,'Cnilc idiopathic anhri1is in children aged 6 years Oxycodone has been subject to abuse (see under Ad-
UNI/ - MHJ80W9LRB. and over. Doses are c><prcsscd in tcnns ofbody-wcighl and may verse Effects, Treatment, and Precautions, below).
be given once daily as follows:
O Takotsubo-likc cardiomyopothy developed in a 6 1-year-old
• 22to31 kg: 600mg woman when her dose of oxycodone was inadvertenlly and
• 32 10 54 kg: 900 mg gready reduced 7 days aficr surgery for degenerative osleoarthri-
• 55 kg ond over: 1200 mg 1is.1 TI1e patient had a chronic history of qiioid dependence and
Administration in renal impairment. US licensed product had been trcaled with oxycodone (80 mg daily) and hydromor-
infonnation for oxaprozin recommends 1hat tl1e ini1ial oral dose phone (4 mg every 3 hours as needed) for several monlhs before
In palients wi1h severe renal irnpainnenr or on dialysis is 600 mg swgciy; posl()petativcly, her dost of ()Xj'CO<fone had been in-
once daily. The dose may be increased to 1.2 i; once daily, if nec- creased to 120 mg daily -.;th additional doses for breakthrough
essary. pain.
I. Rivt'ra JM. et ol. .. Broken heart syndrome• aO.cr separation (from
Preparations OxyContin}. Mayo C/in Proc 2006; SI: 825-8.
USP 33: Oxapr02;,, Tableu.
Pharmacopoeias. In Chin.. Jpn.. and US. Proprietary Preparations (details are &ivc11 in Volume B) Adverse Effects, Treatment, and Precau-
Austria: Z~t: &lg.: Dutaprox: Cono4.: Dil)pl'O: Chile: O.ir•?·
USP 33 (Oxaprozio). A while 10 yellowish-while, crystalline tions
powder. S1orc in airtighl coniaine-,, at a 1empera1Ure of 20° to ~~~~Da~o~~~~~~~~~~7tft.'.~~><~~ As for Opioid Analgesics in general, p. I06.
25°. Pro1ec1 from light. !:Nraprox: USA: Oayp<o. .
UK licensed product information contra-indicates the
Oxaprozin Potassium (BAllM rlNNNI} use of oxycodone in patients with moderate to severe
Kalii Oxapro1jnum: Oxaprozina potasico: Oxaprozine Potas-
hepa.tic impair:ment or severe renal impainnent; how-
O x ycodone (BAN. uSAN. rlNNJ 0 ever, product infonnation in the USA pennits its cau-
sique.
i<aMR 0Kcanpo3'1H Dihydrone: 14-Hydroxydihydrocodeinone: NSC- 19043; Qk. tious use in patients with severe hepatic or severe renal
=
C 1sH,.NOl.K 331.4.
CAS - 174064-08-5.
sikodooi: Oxicodona: Oxi<odon: Oxycodonum. 6-Deoxy· 7.8-<li-
hydro- I ~ -hydroxy-3-0-methyl-6-oxornorµhine: (-)·(SR.6S. 14S)-
impairment although doses may need to be reduced.
Abuse. Oxycodone hydrochloride modified-release 1ablcts
.'\TC - MOIAE 12. 4.S-Epoxy- 14-hydroxy· 3-mcrhoxy-9a-mc1h)llrnorphinan-6-one.
have been subject to abuse.'" The crushed 1ablets have been in·
ATC Vet - QMOiAEI 2. 0KC.'1K0A0'1 haled or injected by addic,ts and in some cases this has resulted in
UNI/ - ML5602Z921. C,eH21 NO, = 315.4. fatalities.
Adverse Effects, Treatment, and Precautions CAS - 76-41-6. I. Wolf RC, e1 al. One hundred seventy two deaths involving lhe
As forNSAIDs in general, p.100. ATC - N02AA05. use of' oxycodoru: in Palnl Beach County. J Fonmsic Sci 2005;
SO: t92-5.
Diagnosis and testing. False-Fosi1ive results for testing of ATC Vet - QN02AA05. 2. Cicuo TJ, ~'of. Trends in abuse ofOxyContineand other opioid
benzodiazepioes in urine have been reported in patients taking UNI/ - CD35PMG570. anatic5ics in 1hc Uni1ed S1a1es: 2002·2004. J Pain 2005; 6:
oxaprozin.1 The manufaciurer' has commenled thal lhe interac- 662-72.
tion occurs with some immunoassay tests and that thin-layer 3. Ad laf EM. ti of. Use of OxyContin by ad~csccm students. C."on
Med A.uoc J 2006~ 174: tj03.

H3CO~
cluomalography can successfully discriminate between benzodi-
azepines ond oxaprozin. False-positive results for a fluorescence Effects on the respiratory system . Refcrcnces1·1 10 respira-
polarisalion immunoassay for phenyloin have also been reported
in patients receiving oxaprozin.l
I~ tory depression occurring in children given oxycodonc.
I. Olkkola KT.~' ol. Phl.lrmacokine1ics <111<1 vcn1ilawry effects o f
I. Pulini M. F';ilsc-positi\•c btn:todiaupinc urine test due to oxa· 0. OH intravenous oxycodonc in postC'pcntive ch ildr<:n. Br J Clin
prozin. JAMA 1995: 273 : 1905. Phormoco/ 1994: 38: 71 ~.
2 . Raphan H, Adam~ Mli. Fal~e-pO$ ili ve bentodiatcpinc urine 1cs1 ._ NCH3 2. Kalso E. J>harm1'cokinttiC5 and ventilatory effects of intravenous
dueto oxaprozin. JA~« 1995; 273: 1905-6. oxycodunc in po:>h>perativc ch i l d r<~n . Br J Clin Phurmocol 199 5~
3. Patel T, ~t of. Assay in1crxtion between oxa.pro2in :md pheny- 39: 214.
to in. Ann Pharmoco1her 1997; 31 : 2S4. 0 Hepatic impairment. The clearance and c limina1ion of oxy-
Effects on the liver. Faial fulminant hepalilisotcurred1in a 56· codone were prolonged in 6 women with end-s1age liver cirrho·
year-old woman who had received 600 to 1200 mg ofoxaprozio NOTE. Compounded preparalions of oxycodonc may be repre- sis awailing liver 1ransplantations. 1 Significant ,·en1ilatory de-
daily for about 6 weeks. In anotherpatienl symptomatic hcpalilis scnled by rhe following names: pression also occurred. Pharmacokinetic v.lues after succe.<:sful
developing during oxaproiin use resolved on slopping 1he drug.2 • Co·oxycodAPAP (P£Jl.'}--0xycodone and paroceiamol. transplantation were s imilar to lhosc previously reported for
I. Purdum PP, ct al. 0xapro7.in-induef:d tiilminanl hcpati1is. A11n healthy adulls. II was reconunended tha1. when giving oxyco·
Phormacorher 1994; l8: 1159-61 . done to patients wilh end-s1age liver disease, the dosing frequen-
2. Kclhu SR, e-t al. Oxaprotirrinduccd symp1om~ti c hep3totoxicity. Street names. 111e following tenns have been used as 'sttecl cy should be reduced and the dose lowered.
Ann Pharmocothe.r 1999; 33: 942-4.
names' (sec p.vi) or slang names for various fonns of oxyc<>- I. Tallgrcn M. cl al. Ph3rm:icoki11c1ics and ventilatory effects of
Interactions done: oxycodone bcfor<:•:.nd aflcr li"cr t ran~plari 1atio n . Ch'n l'Jumno~
For in1erac1ions associaled wi1h NSAIDs, see p.103. 40; 40-bar; 80; Blue; Cotlon; Hillbilly heroin; Kicker; OC; Os; eol Th•r 1997: 61: 655~1.
Ox; Oxy; Oxy Conon; Oxyconon; Peres; Petks; Pills; Pink Porphyria. Oxycodonc is considered 10 be unsafe in palients
Pharmacokinetics spoons; Rushbo.
Oxaprozin is slowly but ex1ensively absorbed from the gas1roin- with porphyria because ii has been shO\'m to be porphyrinogcnic
1estinal trac1; ii is 99% bound to plasma pro1oirtS, mainly albu- in animals.
min. Peak plasma conccuirations occur aficr about 2 10 3 hours.
Oxycodone Hydrochloride (8ANM. USAN. rlNNM) ®
At sleady s1a1e, the biological half-life is about 44 houn;. Oxapro- 7.8-Dih)di-o- 14-hydroxycodeinone hydroch!onde: Dihya-one Interactions
2in is metabolised mainly in the liver by microsomal oxidation Hydrochloride: Hidrodoruro de oxitodooa: Oksikodonihy- For interactions associated wilh opioid analgesics, see
and conjuga1ion wilh glucuronic acid 10 form inactive mclabo- drokloridi: Oksil-.odono hidrochlorida.s: Oxikodonhydroklorid: p.107.
liles which are cxcre1ed in lhe urine (65%) and faeces (35%). Oxycodone. chlorhydrate cf: Oxycodoni hydrochloridum: O>t:y-
cone Hydrochloride: (),i:ykodon-hydrochlorid: Thecod,ne. Antibacterials. Ncga1ive urine oxycodoue screening 1ests have
OReferences. bc.'Cn reported' in a palient laking oral oxycodone liQ mg daily
l. Karim A. Inverse nonlineu pharmacokinetics of lotal and pro- 0KC"'"OAOt<a r11APOXllOP"A
with the potent enzyme inducer rifompicin, amongst other drugs.
tein unbound drus (oxaprotin): clinical and phann acokinetic im-
plications. J Clin Phonnocol l 996i 36: 9SS-97. •
=
C 1sH2 1NO"HCI 351 .8. ll1e presence of oxycodone me1aboli1es in the urine led the au-
CAS - I 24-90-3.
2. Karim A, c,; ol. Ox~prozin and piroxicam, non:neroidal an1iin- 1hors to conclude that rifampicin increased 1he m.elabolism ofox-
ATC - N02AA05. ycodonc, necessitating an increase in the ctJse of the laner. A la1-
nammatory drugs wi1h long half-lives: effect o r p rotein -binding
differences on stcady-$131e pharma:(ll:inctics. J CJ;,, Pbnrmocol ATC Ve1 - QN02AA05.
er pharmacokinetic studyl found Lh•I rifuonpicin decreased the
1997: 31: 267-78. UN/I - CIENj2TE6C.
AUC of inlrnvenous and oral oxycodone by 5~% and 86%, re·
3. Oa\'it'.s NM. Clinical pharmacokinctics of oxaprozin. Clin Phor- Pharmacopoeias. In Eur. (see p. vii) and US. Jpn includes the
m0<'.okine1 1998; 35: 425-36.
spectively, and decreased 1he ornl bioavailability of oxycodone
trihydrate. from 69% to 21%.
Uses and Administration Ph. Eur. 6.8 (Oxycodone Hydrochloride). A while or ahnos1 Conversely, the enzyme inhibi1or telithrom.vcili was foundl lo in-
Oxaprozin, a propionic acid derivative, is an NSAlD (p.103). while, hygroscopic, powder. Freely soluble in wn1er, sparingly crease the AUC of oral oxycodone by 80% und decrease its
Oxaprozin may be given orally os the base or potassium S311 al- soluble in dehydrated alcohol: pracric:illy insoluble in 1oluene. clearance by 43%; it '~ suggested that the dose of oxycodone
though doses arc expressed in 1cnns of 1hc base; oxoprozin po- Slore in airtight coniainers. Pro1ect from light be reduced by 25 to 50% when used with tcliUiroinyein.
iassium 678 mg is equivalent 10 about 600 mg of oxaprozin. For USP 33 (Oxycodor.c Hydrochlo1ide). A white to off-while, I. Lee H· K. ti ol. J\tcgative urine op;oid screening <:3used by ri~
the trealmO'lt of osteoarthritis and rlleumatoid arthri1is, a usu.ii odourless, hygroscopic crystals or powder. Soluble in water; f!mpin· mediatcd indu: 1iC1n of oxyCodonc hep.: uic mttabolism.
dose equivalent to 1.2 g of oxaprozin may be given once doily, sligl11ly soluble in alcohol. S1ore in airtig)lt containers. Clfo Chim AcU1 2006~ 367: I96-200.

All cross-references refer to enlries in Volume A

 Oxaprozin/Oxymorphone Hydrochlonde I 11
2. Nieminen Tii. ~ "'· Hir~mpln grt"a1fy rcctu«s the plasm,. cC1n· ration of oxycodone hydrochloride and naloxonc hy- roU ~cocet:
Pe1cod¥\ ltoL: Ce-'~ Meox..: Pie)()(odnn: USA: Com-
ce111rations of i.ntf'lvi.-nous tend orJJ O.\)•codone. A1u.rrlu:.'t1ulugy - Endocet M~ N""""C Fen:o.:tt f'<1't0d•rc ~ Ph'.UV:
20011: 110: 1:371-8. drochloride is available in some countries. ---·~ R:»<ilo>e~t: T)b>C XQb>..
~. Cir6nlun<i J. rt ul EO"«:« <'f1elithton1ycin on lhc pharmaeokintl· for details of doses in children, see below.
t\.') 11.nd pharm8cody11a.mics ~r or-;11 oxycodont. J Cli11 Ph,,,..u1t::t1I
lOIO; 5-0: 101 - 8. For opioid-naive patients, intravenous doses of oxyco-
done hydrochloride range from l to I 0 mg initially, Oxymorphone Hydrochloride (6ANM. r.N/'.llAJ ®
Antidepressants. For reference to possible <:a$CS of SCl'Olonin
syndrome associated with use of oxy.:odonc and SSRJs, sec Opi- given over l to 2 minutes, and repeated not more often 7,8-0ihydro-1~-hydro~ hyd<ochloride: K'ldro-
oid Analgesics uoocr Interactions of Fluoxetine, p.428. than every 4 hours; a dose of 2 mg/hour is the recom- cloruro de oximorfona: Oximorphone H)odroch!oride; O><ymo•-
phonc. Chlorhydrate d': Oxymorphonl Hy<irodlloridl.rn. 6-De-
Antifungals. In a study,1 the mean AUC, peak plasma coricen- mended starting dose as an intravenous infusion. The
oxy·7,8-<iihyd<o- I 4·hyd-oxy-6-oxomorptme hydrochloride:
11111ion. and elimination half-life of oral oxycodouc were in- intravenous route may also be used for patient-control- (-)-{SR.65. I15)-'4,5·Epoxy-3.l 1-dhydroxy-9a-m~
creased 3.6-. l .7-, and 2-fold, ~lively. by the enzyme inhib- led analgesia. When given subcutaneously to opioid- 6-one hydrochloride.
itor w>riconazole; lower doses of oxycodonc may be needed naive patients, Lhe starting dose is 5 mg every 4 how-s;
when used togClbcr. OKo•MoP+o... f1<.4POY.AOjlMA
I. Hag.clbcrt NM. t'I al. Vbriconatolc dras1ic:illy incrf'lsef. dJ»"
subcutaneous infusions should be started at 7.5 mg dai- C 17H,,NO..HCI = 337.8.
sun to or#I oxyc:Od(lfle. Ertr J Clm Pharmm:ol 2009; 65: 263-11. ly. When transferring be{wecn oral and parenteral oxy- CAS - 76·4 1-5 ( oJ<ymorphone): 35 7.07.3 ( oxymorphone
codone, UK licensed product information advises that, hyd1ochloride).
Pharmacokinetics UNI! - 5Y2El94NBC.
as a guide, 2 mg of oral oxycodone is equivalent to
Oxycodone is absorbed !Tom the gast.rointestinal rract; about I mg of parcnleral oxycodone.
oral bioavailability is about 60 to 87% due to lower

HO~
Oxycodone has been given rectally as suppositories
pre-systemic and/or first-pass metabolism compared
with other opioids. About 45% is bound to plasma pro-
conta ining 30 mg of oxycodone (as the pectinatc)or I 0
or 20 mg of oxycodone hydrochloride; the dose may
I . ~
teins. It is metabolised to noroxycodone, via cyto- be repeated every 6 to 8 hours. 0 OH
chrome P450 isoenzymes of the CYP3A family, and, For doses in patients with hepatic or renal impainnent,
to n lesser extent. to oxymorphonc (p.111) via see below. O • NCH3
CYP2D6. Both metabolites undetgo glucuronidation Oxycodone terephtbalate is also used orally.
and aie excreted with unchanged drug in urine. Tiie
elimination half-life of oxycodone is reponed to be 2 to Administration in children. Although oxycodonc hydro-
chlondc is not licensed in the UK for use in children under I 8 (oxymorphone)
4 hours. Oxycodone crosses the placenta and is distrib- years old, the BNFC 2()()9 suggests 1h11 it may be &)ven for the
uted into breast milk. trcahllent of modenue to severe poi~ in palliative care. Those Pharmacopoeias. In US.
aged from I month 10 12 )":3J'Smay be given initial oral doses or USP ll (Oxymorphone Hydrochloride). A "11i1e or slightly off'-
0 References.
200 microgro1nslkg (up to S mg) every 4 to 6 hours increased white odourless powder. darkening on exposure 10 light Its
I. P6yhil R, n uf The phonuacokinetics ofoxyc<Klonc ancr intra· thercafler as neC<liSal)' according to response; older children may
''enous injection in adults. Br J Cli11 Phan11ocol 199 1; 32: aqucoos solutions arc slightly acidic. Soluble I in 4 of water, l in
S16-IS. begi'"" lhe usual adult dose (see above). Oxycodone hydfochk>· 100 of alcohol, and I in 25 of methyl alcohol; very slightly solu-
2. Leow KP. ~' ol. Sing.le-dose and stead)'-Stl'lle pharmacokinctics ride may also be given orally as a modified-release preparation ble in chlorofonn and in ether. Store on airtight containers al a
:md pharmacodynamit5 O( UXycodOOC in patients -.rith CIO(('f. every 12 hours to those l£Cd 8 years aoo older. tempernrurc of25°, excursions pcnnined between 15° and 30°.
Clin PhtJrn•.col Tlt<r 1992: 51: ~81~S. Protect from light.
Administration in hepatic or renal impairment. The
3. Mandcma JW, cl al. Chsir:.cic;jt.-ition and validation of a ph1rm1·
cokinelic modet ror contrOlltd-rckaw oxycodonc. Br J Cliu plasma con<X.11tr.tlions of oxycodone ma)' be incre!ISed in pa- Dependence and Withdrawal
PhurmU<ol 1996; 42: 747-56. tients with hepatic or renal impairment and consequently dosage A$ for Opioid Analgesics in gt11erol, p.105.
4. K.aiko RF. ~' ul. Pb.an.1l:acukinc1ic-ph1rmacodynamic ttlatiOn· adjU>1ment ma~ be necessary in such patients. In the UK, li-
.,hips of coouollW·rdeuc oxycodone. Clm Pho,.,,uxol Titer censed prodUCI mfonnation recommends that the oral starting Adverse Effects, Treatment, and Precautions
1996: 5 9: 52-61. dose for adult patients with mild hepatic impairment or mjld to As for Opioid Analgesics in general, p. 106.
).~=~r:~~~ ~.~ii~~:s~r:~;:~rJt;~~~~:~i~~~~
JC/inP,,.,..HtC0/2002;~2: 192-7.
moderate renal impairmc:nt should be 2.5 mg given every 6
hours: ii contra-indicates the llSC of OX)'Codonc in those with
for details on the use ofO•ymorphonc in pmients with hepatic or
renal impairment= below.
moderate 10 severe hepalic impainncnt or severe renal impair- Interactions .
6. Lalovic B. ~' ol. Phann:iwkinc1ics and phannKodyoamics of
or.ii OX)'C°'°°'1t in heahh)' hdnu111 subjects: role of circul~inJ ac· ment US product infonna1ion pcm1its the cautious use of OK)'Co- For intcraclious associated wilh opioid analgesics, sec p.107.
1ivc mc1aboli1es. Clin Pltnf'R10tt>I Th~r 2006; 79: 461-79. done in adult patients with severe hep.iic or se'= renal impair-
Licensed product infom1•tion for o modified-release preparation
7. Liu.kn A. 11 al. Plasma conccntraiion.s or oral ol:ycodonc ar<: ment.
grc11y incn:ascd in lht elderly. CUu Plwnuocvl Ther 2008; 34: ofoxymorpboru: hydrochloride (Opm1a ER: E1ido. USA) states
462-7. Paln. References. that patients inusl not ingest ulcohol. including alcohol-conlllin-
I C•tf'lis GB. •'al Rtlnti\'e po1cncy of controUed·refcuc oxyco- ing medicines. tll the same time due lo the risk of increased plas-
Children. The phannacoki11etics ofoxycodone in children h"ve done and con1rollcd-rc l e~.st morphine in a pos.roperntivc pain ma conCCf\tralions •11<! a potentially faral overdose of oxyonor-
been Sllldied1-' aoo ore se~lly considered similar IO illOSe in model. EnrJClm Phanuacul 1999; SS: 4~~9.
phone.
aduhs.1" However. pharmacokinctics may be more variable in 1. Gimbel JS. Cl ol. ConttoHcd ·relc~tC oxycodone ror pain in dia"'
infants ascd fron1 0 to 6 months, p.1niq1larly those aged 2 betic: r.curopalh)•: a randomi.zied controlled trial. Nt11ro/ogy200l~ Pharma.cokinetics
60: 927-34. Oxymol'phone hydrochluride is absorbed from the gastrointcsii-
months and under:\ ; , OkUield V1 Pcn·y CM. Oxycodondibvprorcm c:o1nbin1:.1lion 11blcc
I. Olkkola KT. r1 al. Phamuu::C'tcin~tit.-s and vcn1ilatory cfrec1s of 1 rtt1~ or its use in 1hc mum1_semeru of acute pain. Drugs 200S~
nal tiact after oral doses. bot bioavailohility is only about 10"/o
introivenoi:s c.u:ycodone in posloperah\-.C ctuldrc-n. Br J Cllu 6S: 23l7-S4. because offitst-pass metabolism. Absorption is increased after a
Phormncol 1994: ll: 71~ 4. I( also E. Oxycodonc. J Pni11 $.1'11ptom Mo•inx<' 200l; 29 (•uppl); high·fal meal. About 10% is bound to pblsma pro1eins. Oxymor-
2. Kokki H. et"'· MlJrm1eokinctics of o:i.ycodonc afie:r 'ntrave-- S47- S;6, phune is ext:nsivcly n1etabolised in tbe li'"' by glucuronidation
nous. bucc::1I. i111rmnu.:.1.;ular and :AS&tic odminis1ra1ir,n 1n chit· ~ . Bcrcovi1c:h M. Adun.1ky A. Hish doJc co1llroll«l-rcJtue o:<yco.- and less than 1% of a dose appc.irs in the urine ind faeces as
drcn. CliJJ PltantUJt'Uki1w1~004; -U : 613-2:!. donc in hospice corf'. J Pam Poitier Care Pbarnrocotl~r 1006; unchanged drug. With re(!;lrd 10 its major metabolites belwcen
3. El-Tahtawy A,'" al Popofo1>on ph:lrmtcoki:nc1ies of oxycodooe 20! 33-9.
in children 6 nqdli 10 1 yc<irs old. J CJ;,, Plron1a«JI 2006: 46: 6. Rdd CM. l!l Of. Oxycodonc ro, conctt•rclatcd pein: mcta•Maly· 33 aod 38% of• dose is excreted in the urine ns oxymorphonc-
43342. tis of randomi.r.cd corn rolled uia1s. Arch lnta-n MoJ2006; J 66: 3-glucuronide and less than 1% as 6-0H-oxymorphonc. Oxy-
.a. Kokki H, <t ul. Comparison of O\)'codom: pham\lcokinctics 3f- S37-•0. Corrocdon. ibid.: 2387 • morphone crosses the placenta.
1cr bucc~I ~nd Jvblingu:il admu'liseration in children. Cli" Phor- 7. Por1cnoy RK, f'I al. Lona.·tcnn use of c:onuo11cd·rde:ase O.l)'CO•
done ro, noncancer pJin· ra.1lu of a 3·)'t'Or rc&istry study. Ciin O References.
lllOC'Okiull 2006; 4S:· 74S-S4
J Pain 2001: 23: 287-99 I. Adlrns MP, Ahcfich H. Pharntxokinc1ics and dose.·proponionll.l-
.S. Pokela Ml.."' ril, M~rkcd vor;21M>n in o~ycodont ph.m nacoki·
nc:tii:s in inrants. P<i«liotr Auuc<Jth 200S: 15: S6~S65. 8. Pan II . .r ul. Effic•<Y and 1olc1>bili1y of o•ycodone hydrochlo- ity of oxymorphonc CMcnckd tdcasc and h'< metabol11n; resullS
ndc controllcd-tcltMt i.blcts in modetatc to severe c:incer µ.:.in. or 3 randomitcd CrOUO\•e r Sll.ldy. Pl1c11'1H(l('(l//J(!rOpy ~004: 24:
Clin Drwg ln~st 2007; 27: 2S9-67. •6'-76.
Uses and Administration 9. GaskcU H. tt cl. Single dose on.I oxyc.o6one 3nd o.xycodonc plus Adlm$ MP. Ahdith H. Sini?le· 2!1nd molhpf~-doS< ph3rm•coki·
p1trauuuno1 (acttuninophcn) rur acute po$10pC:nt1\'C p3ih in nctic and d0St-·proponionoi11y study of ox)morp(lonc inm1edi·
Oxycodone, a phenanthrene derivativt:, is an opioid an- Dduh$. Av<'!ib1blc in Th-c C"ochr~M Do1ab0sc or Sy11cnui1ic Re- otc-r<lcase 11bl<1s. [)n,gs RD 200S: 6: 91-9.
algesic (p.108). Oxycodone hydrochloride is given views; l~s u c l . Chich~uer · John Wilty: 2009 (acc·c.sscd
Uses and Administration
orally or by subcutaneous or intravenous injeclion for 18111 1(19).
Oxymorphonc hydrochlondc, a phcnanthocnc dcri\'ati""• is on
the relief of moderate to severe pain. P reparations opioid analgesic (p. I05) with lid ions and uses similar to those of
A usual oral starting dose for opioid-naive patients in USP 33: 0-'l}'<O<looe atld A<...moo~ilct'l CapsJt~ Oxy.:o«ne ond morphine (p.90), apart from a lock ofcOIJ&h suppressalll activity.
A<etamiMpi>en Ti!b'ets: O>cy<oclone ¥>d Asponn T•l:lels: OX)'Codont H)" Oxyroorphone is given orally, parentcrally, or rectally for the re-
severe pain is 5 mg every 4 to 6 hours increased there- 0<cxhlo<'1de E><tend<d·Ro!ea>c: Tablets; Oxycodone H)"lrocNoode Oral lief or moderate lO severe pain, including pain in obstetrics, and
after as necessary according to response. For patients S"'--' O>y<odone Hydrod'olondo T.a:ote-.s. is reported to pro,·id.: analgesia for 3 to 6 hours. h may also be
who have been receiving a strong opioid analgesic the Proprietary Preparations (deuils an: given in \\Jlume B) used parenterally forprcmcdicotion, a.s an adjunct to anaesthesia,
Ari.: ~ Oxi"°'~.!' O><y<c>nton: Auruul: &idone: Ox)<cntin; aoo to relieve d)'1pnoca due to pubnonaryoedcma resulting from
initial dose of oxycodone should be based on the daily Q><)!'lonn: fT'Oladc:tt: Auttrlo: Oxytomon: Oxy.'lomt a.1,,: Oxycontin:
opioid requirement; UK licensed product information Broz.: Oxyc°""' Conod.: Oxy ill. 0x"!<on\A: 5"pa.dot Otllt: 0X)'Con- lefl ventricular &ilurc.
.... Cz.: Oxyt°"""' T~ O.nm.: Oxycontin; Ol()"<ll'I'\ Fin.: 0....,...: . . usual oral saning dose for opioid-noive patients is I0 to
suggests that l0 mg of oral oxycodone is equivalent to Oxycomin: 0~ fr.: °"J<Olltll> Oxynorm; Gor.: O~..:: Ti!fV< 20 ong of oxymorphonc hydrochloride every 4 to 6 hours adjust-
about 20 mg of oral morphine. Most patients do not re- H1111g.: O<)i:ontirc lrl.: Dane<>< OX)'Corr.in: Ox)do« Oxyoom'l: 1irgin: ed !hereafter as neces.<ary. some patients may be staned on IOWtt
fsro•f: 0><,ICod. Oxytontin; fro/.: 0~ }9n: OX)'<~ Moloyslo:
quire more than 400 mg daily. Preparations containing Oxytor1r< Ntth.: °">'«>"in; 0>C)'fl0mt Norw.: O><ycont"1; O><)'!'IO'r're doses of 5 mg. For palicnlS \\ho have been receiving a strong
oxycodone hydrochloride and aspirin, ibuprofen, or NZ: OX)'CO"lt\ ~ Phil/pp.: OX)'ContM"C 0>qnorm: Po/.: Oxycon· opioid analgesic the initi•I dose of oxymorphonc should be
Port.: Oxycontrt ~ Slngopore: OX)'<"'*' O><)nonn;
lire based on the daily opioid requirement; licensed product infonna-
paracetamol are also used. Oxycodone hydrochloride Spaim 0x)'C<>•irc OlC)'10'TT'< Swed.: Oxy(onton: O)()'lOfTlt SwlU.: Oxy·
tion suggests thal 10 mg of oral oxyonorphone is equivalent to
may also be given orally as a modified-release prepa-
ration every 12 hours. To counteract opioid-induced =~~~-=~~:·w.:~ g:!:.o.i- about 30 mg of oral morphine and recommends giving ha[f the
Clllculllltd equivalent dose·ofoxy1norphone initially. Oxymor-
Hultl-inll"'diene Ari.: °""""'>s C~ Conod.: Enclocet: Et>do-
constipation a combined modified-release oral prepa- dint: f'n:<><rt Per<odan: ratio·OX)'Coctt ~od••i; RNacocet Ii- phone hydrochloride may al.o bt given orally as a modified·re-
The symbul t denotes a preparati~n no longer acuvely marketed The symbol® denotes a substance whose use may be restricted in cenain spons (seep.vii)
112 An~lgesics Anti-inflammatory Drugs and Antipyretics
lease preparation evuy 12 hOWll. Or11l preparations of oxymor- Paracetamol (BAN. rlNNJ Subsequently, a furll1er srudy and a review have found an in-
phone ~hould be takco on an empty S10mach. acase in the prevalence of ast!una2.l and COPD2 wilh frequent
Acetarri~ofenot Ac:etam~ N-.1\ce:yl·p·aminophe:>ot (daily or weekly) use of paracelamol. A link bclween paracelJ>·
o~ymorpbone hydrochloride is given by intramuscular Ot sub-
a11on-.s lnjecrio11 in ini1ial doses of I 10 1.5 mg, repeated every Asctaminofel'\; Paracetamol; l'aracetamolis; Parac.umolum: Par· mol use in pregn:1ncy aod asthma in children has also been sug-
4 to 6 hours as necessary; 500 micrograms may be given by in- asetamol; Parasetamoli. "1'-Hydroxyacetanilide: N-('4-Hydroxy· gcslcd (see Pregnancy under Precau1ions, below). However. an-
b'avenous injection. The usual dose for analgesia during labour is phenyl)acetarride. other rcvicW" stated th:lt there have bcco very few acrual reports
0.5 10 I mg iniramuscularly. When lransfcirin& between oral and flapauen><OI\ of p:incctamol causing asthma; fwlhermore, bronchospasm is
parenteral oxymorphone, licensed product information advises
1hat, as a guide, 10 mg of oral oxymorphone is equivalent to
C 8H,NO, = IS 1.2.
not a ~ised feature of paracetamol ovcrdosage. This review
concluded that a s1rong link between paracetamol use and asth·
about I mg of parenteral oxymorpbone.
CAS - I 03-90·2. 10a was unlikely.
ATC - N016£0 1. More recently, analysis of questionnaire da11' for 205 487 chil·
Oxyniorphone hydrochloride is also given rectally as a supposi- ATC Ver - QN026EOI.
tory in a dose of 5 mg every 4 to 6 hours. drcn aged 6 10 1 years from 3 I countries suggested that the use
UN/I - 36209/Tl90. of paracetamol in the first year of life and later childhood was
OReferences. associated with an inaeased riskofaslluna and also sympton1s
I. Prommcr £. 01ymorphonc: a review Svppo'1 Core Conctr of rhinoconjunctiviris and cettma However, after considering
2006; 14: 109-IS. lhis srudy, lhe UK CHM 6 expressed concerns over data interpre-
2. Chamberlin KW, e.r al. Oral oxymorphonc ror pain managcmitnL tation and concluded lhal il did no• provide strong evidence that
Ann Phormucother2001: 41: I 144-S2. paracetamol use in infancy can cause asthma; lhc CHM reiterat-
3. Mayy-J.s F. ~ ol. A sy1tem1t1ic review of oxymorphonc in the ed that paracetamol remains a safe and •f'lll'Opriate analgesic for
manaicmctu o(chtonic p~in. J Pain S)'mpto• Monag~ 2010; 39: clu1dren.
296-308.
I. Shaheen SO. r.t ol. frequent pa13eeu1mol \IJe and Nlhma in
Administration in hepatic impairment. Advice on the use aduhs. Thorox 2000; SS: 266-70.
ofoxymorphone in patients wilh hepanc impairment is oonflict- iron. Compounded prcpintions of paracetamol may be repre- or
2. McKeever TM. tt al. The associ111ion acetaminophen, aspirin 1
sented by the following names: •nd ibuprofen with rc$pira1ory dbeaJC and lung (\lncaion. Am J
ing. Licensed produa anfonnation for one r11nge ofpreparations
Rupir Cri1 Care M•d 2005; 17 t: 966-11.
(Opo110 and Opana ER tablets: Endo, USA) recommends ceu· • Co-bucafAPAP (PEN)-butalbital, ~mol, ind caffeine
J. Endi I. et al. Acet11.minophen and the risJc of as1hm1: the epidc-
rion in patients with mild hepatic impairment; th~• patients • Co-<odomol xly (BAN}-where x and y are the strengths in mioloeic and palhophysio)ogic evidence. Chest 200S; 127:
should be started on the lowest ~I dose and tilrated slowly milligrams of codeine phosphate and paracetamol respective- 604-12.
dxscafter. In addition, it is stated that oxymorphonc is contra· ly 4. Nuuall SI., ti al. Dots pa11ect0mol causo uthma? J Cli• l'hoM1
indicated in lhose with modcntc or severe impairment. Howev- Th<r2003: 2$: 2Sl-7.
er, licensed infonnation for another oxymorphone preparation Co-codAPAP (P.EN}-pamcetamol and codeine ~phatc 5. Beasley R, t1 ol. tSAAC Phase Three S1udy Group. Assotiuiion
(/Vumorphan ln}«tion and supposllories; EJ>da, ~)only rec- • Co-dydramol (BAN)--<lihydrocodeine tannite I part and pa- between ~ra«tamo) UJC i11 infancy a.nd childhood. and risk of
asthma, rhinoconjunctivi1is., and eaema in children aged 6--7
ommends caution in hepatic disease although lower dooes (un- raceiamol SO perts (w/w) years: 1n1lysis from Phase Three of 1he ISAAC programme.
specified) are advised in those patienu with se•·cre impairment • Co-hycodAPAP (PEN}-hydrocodone tattratc and paraceta- Lancet 2008; 372: t039-'18.
mol 6. MHRAICHM. Parxetamol use in infancy: np strong evidenc-e
Administration in r enal impairment. In patients with mod- for osthma link. Dn.g Safery Updatt 200l; 2 (4): 9. Available al:
erate to severe renal impoirmen~ the bioavailability ofoxymor· • Co-methiamol xly (BAN}-where x and y are the strengths in http://www. mh ra. gov.uk/P ubl i Cl Iions/Sa (et y au j dance/
phone was found to inc:ttase by over 50'~; consequently, it is milligrams of DL-methionine and pat&Cetamcll, respectively DniaSafetyUpda1elCON030923 (1cccssc<l l3/IOI09)
reco11Unendcd that oxymorphone is given with caution and in"" • Co-ox~AP (PE/V)--Oxy<:odone and paracetamol Hypersens;tivlty. Reactions cbarllctcrised by urticaria, dysp-
duccd doses (unspecified) to those widi a cn:atininc clearance of noea, and hypotension ban occurred after use of parxetamOI in
less than 50 ml/minute. • Co-proxamol (BAN}-<lextropropoxyphcne hydrochloride I
part and pwacetamol 10 parts (w/w) adults'"' and c:hildren.u Angjocdema has also been reported.'
Preparations Fixed ~ cruptioos, conflt!Tled by rcchallengc, have been de·
• Co-proxAPAP (/'£N)-dcxtropropoxyphenc napsilate and scribed,"' and toxic epidcnnal nccrolysis has occwred.12
USP 33: ~ H)<ito<Norido tnjectiott ~ H)-<lro· paracetamol
dilondo~ I. Stricker BHC, et al. Aculc hypcncnsicivicy reectiuns 10 para·
Pharmacopoeias. In Chin., Eur. (sec p.vii), 1111.. Jpn, US. and cc1amol. BMJ t 985; 291: 931-9.
Proprittary Preparations (dc'lails m given in Volume B) 2. V.n Diem I.. Grilli>< JP. Anaphylac<ic 5hoek induced by P'""'
!'kl
USA: l'UT1o•phar>; Opon~ cc1amol. £•r J Oin Phonnocol 1990: 38: 389-!IO.
Ph. Eur. 6.8 (Paracela'nOI). A while or almost while, Q)Slalline
3. Kumar RK, Byerd I. P1racct.amol u 1 eaUK of anaphylaxis.
powder. Sp3ringly soluble in water; freely soluble in alcohol; Hosp /.kd t999; 60: 66-1.
very slightly soluble in dichloromethane. Protect from light.
USP 33 (Acetaminophen). A white odourless crystalline pow- ~. ~;::~~~~{·i.,~,i·~:;ioroo"i. <w;;:.68.l)-ind11ccd an-
Oxyphenbutazone (8AN. rfNN)
der. Soluble l in 20 of boiling water, I in 10 of alcohol, and I in s. Ellis M. et ol. Jmmedi1tt advcrSC ttaction1 to aceuminophen in
G-27202; ~enylbutuone: Olcslenbutatsoni: OxifenJ>. 15 of l/V sodium hydroxide. Siem in ainight containers. Protect children: evaluation o( histamine relclSC and .spiromctry. J
U1aZon: Oxifenbutazona;' Ox)-phenbulazonum. 4·But)+ 1-(4./>y· Ptdio11· J989; 114: 6~
from light. Protect from moiStUre and heat. 6. Be>uscua K. d al HypeJ1cnsilivi1y reactions &O ~Cd3mol in
ct'Oxyphenyl)-2-p~3.5-dione m~. childr<n: utudy of:ZS cam. All•-:r 2005; 60: 1114-7.
0Ko..j>eH6yTa'!OH Adverse Effects and Treabnent 7. ldok.o JA, ti ol. Angionturotic oedema foltowin,1 ingcs1ion or
pil13••tamot. Trans R Sac Trop Md Hyg 1986; 80: 175.
C19H1DN201.H20 342.~- = Adverse effects of paracetamol are rare and usually 8. lhonias RHM. MYntO DD. Fixed dfug erup1ion dut 10 parace-ta-
mol. BrJ n,,..,,,,.,11986; us: 357-9.
CAS - I 19-10-4 (onhydrovs oxyphenbucozone); 7081- mild, although haematological reaclions including
38- I (oxyphenbu1ozone monohydrote). 9. Cohen H.'\, ti ol. fixed drug eruplion caused by acdllftuq>hen.
thrombocytopenia, Jeucopenia, pancytopenia, neutro- A"n Plt0-h<r 1992; 26: 1596-7.
ATC -MOIAAOJ; M02M04; S018C01.
ATC Ver - QMOIAAOJ; QM01AA04; QSOl8C01.
penia, and agJ110ulocytosis have been reported. Skin I0. Harris A Buige SM. Vasculilis in 11 fixed dnlg eruption due lo
1
pancc1amol. SrJ D1l'mo10/ 1995; I": 190-1.
UNI/ - H806H8JN5 (oxyphenbutozonc): A70845 I 3GV rashes and other hypersensitivity react.ions occur occa- IJ. Hem S, <I al. BuUous fixed drug: truptiotl due to p;irac:et.omol
(onl>ydrous oxyphenbutozone). sionally. Hypotension has been reported rarely with with 1n unusual immu.noOUOJcsceocc panem. Br J /Nrmotol
1998; 139: 1129-3 1.
parenteral use. 12. Halevi A, ~' ol. Toxic cpidcm1al nccrolysis usocia1ed with
Overdosage with paracetamol can result in severe liver acetaminophtn ingestion. A,,n Pbomiocot~r 2000; J•: 32-4.
damage and sometimes acute renal tubular necrosis. Overdosage. Acute oral ovcrdosage with paracetamol, wheth·
Ct' aa:idenlal or deliber11te, is relath-cly common and can be ex·
Prompt treatment with acetylcysteine or methionine is
tremcly serious because ofthe nlJTO\v margin between lher•peu·
essential and is discussed under Overdosage, below. tic and toxic doses. Adults taking a~ little as 10 to 15g of
0 References. paracetamol within 24 hours may develop m-cre hepatoccllulor
I. Gr.>ham GG, ., al. Totenbili1y of paraccumol. Drwg Sof<ty necrosis and, less often, renal lllbular necrosis. Patients should be
2005; 28: 227-40. considered at risk of severe liver damage if Ibey have ingested
Effects on the kidneys. For reference to evidence !hat abuse more than 150 mglkg of paracetamol or 12 g or more in tru~
or prolonged excessive use ofanalgesics, including paracetaninl, whichever is the smaller. The risk of severe loxfoity afler 1cute
tan produce nephropathy, soc under NSAIDs, p. I 02. par11cetamol overdose appears 10 be less in cWJdreo man in adu Its
Profile ot comparable closes; however. chronic use of supratherapeutic
See also under O\•crdo$agc, !><low. doses in children has resulled in unintentional overdoses and se-
Oxyphenbutazonc, a metabolite ofphcnyibutazonc (p.121),is3ll
NSAl.D (p.100). It has been applied topically to the eye as an Effects on metabolism. Use of por11cemmol, alone or with vcte hepatotoxicity. 1.2
anti·inOan1matory ointment in conditions such as episcleritis. other drugs (see under Flucloxacilli°' p.30 I), has been associated Patients receiving enzyme,inducingdfu&s or those with o history
OxyphenbulalOne was used systemically in disordes such as an- with 1ecumulation of pyroglutamic acid, rcsuhing in pyro- of alcohol abuse arc at high rislc of hepatic damage, os moy be
1.-ylosing spondylitis, ostcoanhritis, and rhewna1oid arthritis bul glutamic 1ciduria (5·axoprolinuria) and high-anion gap mel1bol- patients suffering 6om malnutrition such as those with anorexia.
such use is no longer considered justified because of the risk of ic acidosis.1-l AIDS, or l')'stic fibrosis. Those who have not eaten for a few
severe haematological ad\'C!SC eff'ects (sec also Effects on the I . Jlumphrcys BO. d al. Accuminophcn-induced 11nioo g3p mct:1.- days are also predisposed to hepatotoxicity. Such high-risk pa-
Olood, under Phenylbutazonc, p.121). bo)je acidos•S and 5-~xopro l inuria {pyr~lulltnic aciduria) :SC• tients may develop hepatoloxic.ity widi as tittle as 75 mg/kg of
quired in bosp11~1 . .4m J Kidney Dis 2005; 46: 143-6.
'The pipe:;uine salt has also been used. 2. Fenves AZ, 11 tr/. Increased inion gap mctaboHe :i.cidosis as a paracetamol (equivalent to about 5 gin a patient who weighs
result of S-.oxoproline (pyrog)ulamic acid): a role ror aecaami9
10 kg) ingested within 24 hours.
Porphyria. Oxyphcnbutazone has been associaled with acute nophcn. Cli11J Anr Soc N•pbrol 2006; I : 441-7. Early signs ofovcrdosage (very commonly nousea and vomiting
attacks of porphyria and is considered unsafe in porphyric pa- 3. Alados Arbolcdas FJ. ~' ol. Acidosis piroglutimiel uoc1ada a although lhcy may also include leUwgy and sw~aring) usually
tients. pancctarnol. An P~tl101r (Borr) 2007: 67: S82~. settle within 24 hou11. Abdominal pain may be the firSl indica-
Preparations Effects on the respiratory tract. lbc results of a case-con- tion oflivu damage, which is no1 usually apparent for 24 to 48
trol study1have suggl'Sled Oiat the frequent (daily or weekly) use hours and sometimes may be delayed for up to 4 to 6 days after
Propri<>tary Preparations (deaails are given in Volume B) of paracetamol may be associated with asthma. Howe,..,., the ingestion. Liver damage is generally at a maximum 72 to 96
Ind'...: Siotil Mu.: Edefet>t: Redolelt UK CSM has commented that the results of this Sllldy do not hours after ingestion. Hepatic failure, encephalopathy, coma, and
M<ilti-lngredlenc lltaz.: >~ ~ Afijllamri: Motrixf; fd>JjlCt'C alter any advice regarding the use of pwacetamol and tha1 it rc- death may result. Complications ofhepatic failure include ocido-
Fta,,,.,..,n; Reumamet. Mex.: Dannion. inainsa safe and effective pain killer for many patients including sis, cerebral oedema, haemorrhage, hypoglycaemia, hypo1en·
asthmatics. sion. infection, and renal failure. Prothrombin time increoses
All crms-references refer lo entries in Volume A
 Oxyphenbutazone/Paracetamol 113
Figure 1. A semi-logarith mic plo1 of plasma-paracetamol concentration against Figure 2. A linear plo1 of plasma-paracetamol concentration against hours
hours after ingestion. after ingestion .

r-
500 200 -··-- ·· ... ·- ---·--
190 r
J
13

180 r· 1.1

170
i
200
I.I
i

...,..,,
150 100
;;-

~
ISO -l ·- 1
3
5c: 140 -
i .,
-0
Probable hepatic toxicity Nom1al lr~lment line
I- 0.9
ts
.2
e..,c
130
I 0
<>
;;;
u
c
120
r 0.8 3
52..

..:a8
8 110
0.7 ::>

r
(')
0
E JOO I
I
.,
~
90 I
0.6 ~
ea.
~
5·
80 [ ::>
3
..'" 0.5
3

l
E 70 0

ii: 60 0.4 ~
5 50
~
...j
0.3
40
l
30
~J 0.2

20
I
~I r
High-risk 1rea1men1 line 0.1
10

0 ...,...,.
I
I I I I
' ! 1-r-r--r-·i 0
4 8 16 20 24 0 2 4 6 8 10 12 14 16 18 22

Time (hours) Time (hours)

Adopted from Rumock BH, M~11hcw I JJ. Acetaminophen poiso11in11. and toxicity. Conncsy of P A Routledge.
P'di<1tric.r 1975; SS: 871~.
Notes for the use of this chart:
No1cs forthe use of this cha11: I. The lime coordinates refer to lime a(\er ingestion.
I. The tim' coordinates refer to time after ingtJlion. 2. Plasma-paracetamol concentra1i,>oi. drawn before 4 hows may 1101 represent peak
2. Plasma-paracelamol eo11ccntm1ions drawn before 4 hours moy 1101 repr<scnl peak conoen1ra1ions.
c:oncentra1ion:s. 3. The graph should be used only in relation 10 a single ~cute ingestion.
3. ·n1e ~ra1lh should be used only in relation to a single acute ingestion. ·· 4. Pa1ie111s whose plasmn-paracclnmol 0011cen1ra1ions ar< abovo the nonnal 1rc-Jtme111 line
4. The solid line 25% below the ~tan~rd nomogram is included 10 allow for possible should be treated.
crTOr$ in plasma ass:lys and estimated time from ingestion of an overdose. 5. P11ien1S on cntymc-inducing drugs. with malnutrition or a history of "lcohoJ abuse, or
5. The solid line 50% below the standard nomogram is to assess the possible hepatic who have nol eaicn for a f<w diys should be lreoicd if their plasnu-paroccl3onol
toxicity in pa1ienu receiving entyme-inducing drugs. with malnutrition or a history or concen1rations are above the hi:;h-risk treatment line.
alcohol abuse. or who have not Colen for a few days. 6. The value of such charts is uncertain if the p.•tienl is first seen 15 hours or more after
6. The Yllluc of ~uch charts is uncertain if the patient is first seen 15 hours or more after ingestion. or has taken modified relc= pr<par•lions ufparncc1a1nol.
ingestion, or has taken mudificd release prepar3tions ofpnracttomol.

with d<1eriora1ing liver funcllun and surne l'<>eomnl<!nd 1ha1 ii be been 1hc snbj<.-ct of many reviews.~ 13 Guidelines have also b<en - Patienls rooci\ing cnzyme·inducing drugs ~h as car·
measured regulorly. However. as both paracetamol) Md issued in the UK by Ille Paracctomol lnfonnation Centre."~ bmnszepinc. phcnytoin. phenobarbital, rifampicin. anJ SI
ae.-tykysteine-1 ClJ1 indcpcndemly aftea proihrombin 1ime in the am1e consensus guidelines h3't been issued by clinical toxicol- John's won, those with mnlnu1ri1ioo or a history of alcohol
absence ofhcpolic injury, 1he use of prOlhrombin time a< a niork- ogists in Australia and New Zcalund. rs Abuse, or 01ose who have not eaten for a few days nre consid-
cr for hepototo>idly has been questiMed and ii has been recom- Prnm/'>I trenrmau is ~uen1i<1/, even \\then 1here are no obvious
ered al high risk. •nd should receive an antidote if their pla,.,.
111c11Jtd 1h:1t 1rc:11mcn1 decisions are b•sc.-d on the entire liver '1)'111ptoms, and all patients sl10Uld be •dmined 10 hospital: full ma·paraccuunol concenlrations an: up 10 SO% below the
biochcmistry.5 ~lpflOrli•-.: meMurcs shoukl olso be ins1itu1ed.
standard reference line.
Acute renal failure with acute lllbulor necrosis may develop. • Plasma-i>arace1an1ol concentralions measured more than IS
eveo in the 1bscnec of sevcr'C liver oom<1gc. Other non-hep:uic • Activated chao-.:oal may he u.<ed 10 reduce gas1roi111c-stinal ab- hours after ingestion are not reliable indicators ofhcpoloto.~­
symptoms 1ba1 l~v.: been repo11ed following paracetamol ovcr- sorp1ion, if it cnn be given wilhin I hour of1hc overdose, and icity. F\111hen11ore, the nomugram may not be suirabte for use
dosage indude myocardial abnonnalities and pancrca1i1is. if more than 150 mg/kg or 12 g of paracetamol (whichever is \\~ICll patients have taken modified-relcaseprepam1ionsof1'3-
smaller) has been ingCSled. However. i(accl)1cystcine or me·
The meehonlsm ~f 1oxicily in uvcrdosage with paracetamol is 1hioninc is 10 be gil'Cll ornlly the charcool is best cleared from
r:'°"1amol. '"1s SonlC suggestions for modified slral<>gies for
d10Ught 10 be the production of a mi1w but highly reoctM: me- 1he use of the Rumack-Mauhew 110mogram in 1ht face of
the stomach 10 prevent rt reducing the absorption o( ~lC onti- overdosaite w11h niodified-releasc prc1'3rations hove been
1aboli1c. N-acotyl-p·l>cnzoquinoneimine (NABQI) by cyto· dole.
du·onlC P450 isocrrl)I~ (mainly CYP2EI •nd CYP3A4)' in made. 19-2r
the liver 3nd kidney. TI1c amount nfNAllQI produced ofter nor- • Tiierc is linte evidence 1ha1goS1ric lavaae is of benefit in those • Pl3sma-paracctamol concentrations and the Rumaclc-M•t-
mal doses of pamcctamol is USt<rlly complelely dclOxified by who ha"e O\'crdo.<ed solely with paracetamol thcw nomog:un are also o( linle \"3luc in pa1ie111S who have
conjugation with gluialbionc and ~xcre1ed as mercaptopurine • Tiie plasma-paracetamol concc111ra1ion should be determined taken repeated supradterapculic doses or mulliple overdoses
and cysteine conjugates. In paracetamol overdosage, tissue as wou as possible. but not within 4 houo~ of ingestion, 1oco- of paracetamol over o shoot period of tinie: such po1icn1s
stor.~s ofslo1A1hione become depicted. allowing NABQI 10 3CCU· surc 11..1 pc-Jk conce11tnu1ons are recoroed. The risk o( lhcr should be considered al serious risk and given antidote ~al­
mula1e and bind 10 sulH1ydl)·l 11ro11ps "ilhin heµatocytcs causing dalTJ<l&C is dctcnnined by oomparison with a nomogr.nn refer- mem.
cell damAge. Subslanccs cap:iblc of replenishing depleled s1ores ence tine on a plot of plasma-paracemnol conccn1ra1ion • Deaths from liver failure haYC occurred m po1ien1s presenting
of ghuathione. such as :ll"t'tykystcinc or mcihionine. arc there· ago inst hours afier mgcs1ion. A semi-logarithmic plot or a lin- with plasma-paracetamol conccnm>tions below the 1rca1meo1
fore nst.-d ns an1ido1es in p.i....,ctamol overdosnse. A<:ctylcystcinc ear plot may be used. Stt Figure I (above) and figure 2 line: suggested cxplaruitions include inadequa1e,_pa1iem histo·
may also be involved in the rqxiir of d3onased Iissue. (Obo\'C). Generally. •ntidole 1reo1mc111 is required if 1ht pa- ries and a need for a lower ~·ca1me1111hr<:shold.--
Trto(ment or oral paracetamol O\.erdosagt. Tite 1mmagemen1 tient's plasma-paracetamol oonccn1ra1io11 is higher than the • If there is any doubt abitut 1im1ns or the need to 1rea1, then a
of pan1ce1amol OVCfdosn!!'e as pmctised in the UK and USA has OPf>rOprillte lint (but sec below). patient should be treated with >n antidote. In some ccnttts.
The symbol t denotes a preparation no longer actively marketed
114 Analgesics Anti-inflammatory Drugs and Antipyretics
patients wbohave ingested I SO mg/kg or more ofpancetamol Se1'•ice recommends the use of acetylcysteinc if clinically indi· 34. Kaufcftkr& AJ, Shepherd MF. Role o( cimetidine in the 1rc.11·
arc treated regardless of plasma-paracetamol concentra- cated. mun of 1ut1minophcn potson1ng. Am J Heulth·S.v11 Pltorm
1998; 55: ISICH9.
tions." · 1llC standard nomogrnm may not be appropriate in determining JS. Wilkes JM. ti ol. Acc:uminophc:n O\c:rdost. in preariancy. $01111'
• Antidote treatment should be swtcd as soon as pos.~ible after trcannent from pl:isma-p:iraoetamol concentrations 11\er ovcr- Med J2005; 98: 1ll&-22.
suspected paracetamol ingestion and should not be delayed dosage by intravenous infusion, as it is based on data from acute Pancre.atitis. Orua· induced pancreatitis associated ,.;th para-
while awaiting the rc:sulu of plasma assays. Oooe tlic results paracetamol ingestion rather than intravenous administration. cetamol was reported' to be a rare rcac1ion only oocurring in pa-
become available, treatment may be stopped iflhe initial con· Plasma-paracetamol eoncentratioDs more than 4 hours after in- tients talting more than recornrncndcd doses. In a retrospective
ccntration wu below the nomogram refeience line. However, lravcnous injcctioo arc usually Iowa-than those predicted for the srudy ofdata from 814 patients wbo had taken paracetamol over-
iftbe initial concentration is above the reference line, the full same oral dose at the same time-point after ingestion. Funhcr- doses, hyperamylasaemia was detected in 246, and was more
course of antidote must be given and should not be stopped more, patients receiving intravenous paracct•mol are lil<cly to common and more severe in patients transferred to a specialist
when subsequent plasma concentrations fall below the refer- have an increased risk of hepatotoxicity due to poor nutrition wiit because of more severe poisoning.1 Howc:111...-, acute pancre-
ence line. from acute fasting. lbc UK Natio11al Poisons lt(onnarion Se•,,. atitis was dia~d only in 33 cases.
Choice ofantidote. Aeclylcysteine (p.1687) is usually the anti- ice recommends antidote treatment with in11avenous occtyl- I. Underwood TW, Frye CB. Drvi·•nduc:cd pancrcalitis. Clin
dote ofchoice but the route of adminiSU'ation vories, and tl1e best cysceine (see above for doses) when 60 niglkg or more of para- Phm., 1993; 12: 440-ll.
protocol bas yet to he determined.S2A lntnvcnous use has been cetamol in total has been given intravenously to adults and 2. S~hmid t LE. Oalho(f K. Hypenmylasacmia and acute p&l'"IC"ati-
associated with anaphylt>Ctic reactions but is the preferred route children within 24 hours. Ifthere is uncertainty about the actual cis in paracetamol poisoning,. Alfmelll Pl1ormocol n.,,. 20CM; 20:
dose ofparacetamol given. the standard non10@Tain may be used 1 7~9.
in some countries including Australia, New Zealand, and the UK
because of fears that cnl abso<prion might be reduced by vomit- 10 detennine the risk of liver damage. Antidote tmitment (see
ing or activated ehan:oal. However, in the USA the oral route is above) is required if pll!l>ma·patacctamol concentrations, meas- Precautions
also licemed, and is clearly effective. The use of methionine ured at least 4 hours after adminis1I11tion, arc up to 50% below the Paracetamol should be given with care to patients with
(p.1591) orally is licensed in thc UK, despite the same risks of refcrentt line for high-risk patients (for examplc-lrcat if the
concentration is above 50 mgll. at 4 hows)(see Figure I, p.113
impaired kidney or liver function; the BNF 59 recom·
impaired absorption due to vomiting or activated chateoal. ll is
cheaper and easier to give than intravenous aoetyk:ysteinc and and Figure2,p.113). mends tha.t large doses should be avoided in patients
may be used in situatioru where a patient cannot be transferred t. M1l~s fK. ~' ol. AC'cidencat ~race1a.mol ovcrdosini and fufmi- with hepatic impainnent. It should also be given with
to hospital,provi<led it is given within 10 to 12 hours ofthe over- na.nt hepatic (-aifurc in children. MttlJ Atut 1999; 111: -472-S. care to patients with alcohol dependence.
~=:. ~~~~~;rn °{hfi~~!~~;:J;,~,:·2~~1 ~8:,.02~~~a-
2
dose and the patient is not vomiting. · Brea.lt fe eding. No advasc effects have beCll seen in breast-
Acel}1C)"teine is most effective when given during the lirSl 8 J. Whyte JM, er al. Acetaminophen causes an incrcast'd lntcma- fed infants v.hosc mothers wete receiving paracewnol, and the
hours after laking the overdose and tbe effect diminishes pro- ~:~l ~:~r,~= ~~i;:{_aducing func1ional factor VU 11tu American Academy of Pediatrics considers' that it is therefore
gressively thereafter. It used to be believed that starting treatment 4. Schmidt LE. no/.. Effect of11ccty&cystcint on prochrombin in · usuallycompat.ible with hrcast feeding. ThcBNF 59alsoconsid-
more than IS hours after ovcrdosage was ofno benelit and might
aggravate the risk of hepatic encephalopathy. However, !ale 1
~f;,~~:::o: ~~~2.nina without ~ioullular injury. crs that the amount of par~cetamol distributed into breast milk is
Joo small to be hannful 10 a hreast-fed infant.
treatment was subsequently shown to be safe,?' and studies of
patients treated up to 36 hours after ingestion suggest that benefit
s. !~~s:~. ~~a'1l!bi;cr~'~ ~~~;:~a~:~}ns;:i~~~~~ Pharmacokinctic studies in 12 nursing mothers gi•i:n a single
Reviews; Jssue: 2. Chichester: John Wiley; 2006 (accessed dose of paracetamol showed that peak paracetamol concenll"a·
m•y be obtained up 10 and possibly beyond 24 hours.26.2 1 Fur- 23110/06). 1ions in breast m1lkof!Oto 15 micro~s/mLwereachicvcd in
thermore, giving in!l"llvcnous acetylcysteine to patients who had 6. Whitco1nb DC.~' ol Auocia1ion <'f acetaminophen hcraaoc.ox· I to 2 hours. Plasma concentrations were determined in 2 moth-
already developed fulrninont h°Eatic failure has bee1I shovm to ici~ 1<ith fasti:1.
ind ethanol use. JAMA 1994; 2n: 184$- $0.
cn; a breast milk coplusma ratio ofabout I was reported.2 Simi-
redoce moibidity and mortality. 1. ~~r~~~-~8,~j ~:;;,'J:;)t~~°J; ~;~3;'~ of par:u:etamol lar findings have boen reported from other studics.1·'
• An initi1l dose of 150 mglkg(maximum of 16.5 g) ofacetyl· 8. V.le JA. Proudfoot AT. Paracetamol (•i:ctaininophcn) poiscin· I. Amcrlcan Ae:ademy of Pediatrics. The 1ranJ1fer of drup ind olh..
cysteine in 200 mL ofglucose 5% is given iniravenously over ing. Lanell 1995; 346: 50- 52. er chcmic1ls into human milk. P#<liotrk1 2001; 118: 716-99.
IS minutes in the UK. or over 60 minutes in the USA. This is 9. Prcscon LF. Paracetamol overdose. In: Puratttamol (ocrloml· (Retired May 2010) Correction. ;bid; 1029. Also avail•blc ot:
followed by an intravenous infusion of 50 ms/l<i: (maximum nophen): a critical bibllo1.raphk re'·icw. London: Taylor & hl1 p://11_p pol icy. n pp u b I ic at ions. ora./ c ai/con tc n tlfu 11/
Froncis, t996 401-73. pcdiatrics%.lb108/3/776 (acccs<ed 19/ tM>6)
of 5.5 g) in 500 tnL of glucose 5% over the nat 4 hours and 10. RoutJcdsc P. ~r al. Pardcc11mol (acclaminophcn) poisonil1g,
then I00 mo.,lkg (maximum of 11 g) in one litre over the next 2. Bc:rlin CM, <JI of. OispoSi1ion of 1cc:b.minophtn in milk. '3Jiv1,
BW 1993; 3 t 7: 1609-10. and plasma of lacla1ing '9''0IMf\. P«liotr Phnrmocol 1980: I:
16 hours. Sodium chloride 0.9% may be used where glucose JI . Zed PJ. Krcnulok EP. TreatmcM o( acetaminophen overdose.
135-41.
5% is unsuitable. The volume of intravenous fluids should be Am J Heolth-S)'Sf }'hafWt 1999; S6: 1081-91.
3. Hurden EL, a ol. Ucrction of ptraet-tomo1 in human breasl
modified for children. If an anaphylactoid reaction develops. 12. ~~~~o~~~,:,~~ ~~J;;~~~f;o~~c~~T~b~'-erdosc: eut- milk. Arch o,,
Ch.id 1980; 55: 969- 72.
the infusion sbould be stopped and an antihiswninc given; it '3. Dan RC, ~ ol. Acet1min0J>hcn poisonins: •n cw-idence b1scd 0
4. Bitztn P..O, n al. Excretion of pan«tar.nol in human breast
may be possible to oontinue the acetylcystcinc infusion at a consensus guideline for OUH>f·hospit.al management. Clln To.f"- milk. E•rJ CUn Phormuwl 1981; 20: 123-5.
slower rate. icol 2006; 44: 1-18. Hepatic impairment. Reviews'.? have concluded that there is
14. Pa~t1mol Information Ccnltc. Guidtlints fo,. 1/'C ma11age-
• In the USA, acetylcys1einc may also be given orally as an al- 111~nl of llCUltt porocttamol owrrlosogt (1•e111scd 1001). Also evidence that paraoetamol could be and had been used $1fely in
ternative tO parenteral trcatmenL It is given IS an iniliaJ dose available at: http:/bA•ww.ph1rmweb.ne1/pwmirror/ J1wy/ patients with liYCr disease. Studies had also sho"n that although
of 140 mg/kg as1 5%solution followed by 70 mglkgevay4 parocetamoVchart.html (oceessed 23/07/08) the half-life of paracetamol was prolonged in such patients, glu-
hours for an additi<lnal 17 doses. Some:N have suggested in- IS. Daly FFS. d ol Panel of Auoitrolion and Ntw Z~bnd clinical tathioneconccntrarions in those taking recommended doses were
toxic0Jot.1su. Guidelines for the m:uu.gcmt'nl nr riuacctamo1
creasing the loading dose of oral acctylcysteine when it is g;,.. poisot1ing in Au&iralia and New ZufamJ-eJ.plana1ion and not depleted to the critical le\'CIS that would enable accu!nulation
en al\a activated charcoal, whereas others'° have found that ctaborarion: a corucnsus statement rro.n cJinic:il toxicolog.Lus ofparacetamol's hcpatoioxic metabolite.
the efficacy of acclylcysieinc is nDI reduced by use ofactivat· consuh~ng to the Aut:iJ11asian pcusoM information ccn1rcs. Uetl I . Ben.son GD.~' o/. The therapeutic u~c of acetaminophen in pil)-
ed charcoal beforehand and consider a larger acetylcystcinc J A11112008; 188: 2%-301. Also ovoil•ble at: 1icnu. with liver dtscas.e. ...fmJ Th~1· 200S; 11: 133-41.
http://www.mja.com.ou/pu blie1is.1ucs/l 8&_0S _030308/ 2. Chondok N~ W.ut KOS. Pain m•n:ig.cme-nt in the cirThoc.ic pa·
dose unnecessary. dall 0916_fm.ldml (accessed l 3108/08) ticn1'. lhe clinic-al challenge. Mayo Clu• Proe 20Ht. 85: 451- 8.
Methionine, like acctylcysleinc, is most effective when given as 16. Graudins A. '' al. 0Y1:rdosc of ext~cd-reka.se aceta1ni·
early as possible after paracetamol ovcrdosage. However, it is noplten.11 Eng/ J M•d 1995; 333: 196. Pregnancy. Paracetamol is generally considered lo be the
not as cfli:ctive if 1teatmen1 is delayed""' and hepatic d&nage is 17. VassllloS, 110/. Use of the RuMadc·Manhew nomog1an1 in cas- analgesic of choice in pn:gnant patients. However, lhc frequent
es or CXtcnded-.re1Ca$e acetaminophen lo;icicity. lfnn /nr~m Med use of paracetamol (defined as most ~ys or daily use) in late
more fiequent and severe if treatment with mcthioi1ine is s1artod 1996; 125: 940.
more than 10 hours ancr ingestion; it may also precipitate hepatic 18. Dart RC. et al. TM safety profile of sustained rtlcasc puxcta- pregnancy may be associated with an increased risk ofpersistent
encephalopathy. mol during thc:tapt\ltic use and foll<>wing ovcrdoa. Dntg Saf~ty wheezing in the lnfant 1 which may persist into childhood1 (but
200S; 28: 104S-S6. see also Effccu on the Rcspirat()()' Tiact. ~bove). The authors
• TI1e usual oral dose of methionine in adults and children agt'<l
ovcr6years is2.5 gcvety4 hours for4doscs starting less 1han
19. Temple AR. Mr12~k TJ. More on cucndcd·rt:lcase tc\!tami·
nophcn. N Engl J Macl 199$; l33: I508.
emphasised that the number ofpreanant women taking frequent
IOto 12 hours after ingestion of the poraCC1amoland provided 20. Gra!Jdins A, 61 ol. More OJ• cx1t'ndcd releue acet>\minorhcn. N
0
doses was very <mall ind they recommended th~t infrequent pa·
the patient is not vomiting. Children aged Wider 6 ycors Engl J M•cl 199S; 3": I 508-9. rac:ctamol should remain the analgesic of choice in pregnancy.
should be given I g CVety 4 hoors for 4 doses. It has also been 2J. Ceum1k EW. ei al. Ext.uMkd·rc-lcasc;. acc1ominophcn oveYdose. 1. Shahten SO. d ol. Parac:e1amol use in pregnancy and wh«Zing:
JAMA 1996; 275: 686. in cotly childhood. Thorax 2002; 57: 958-63.
given in1n1vcnously.
22. :~~9:g:C'j,';'; ~;t,~_<rorn Jow dose pu.accumol poisonin:, 2. Shahttn SO. d ol. Pre~t•I p:a.racdtunof u:poS"urc: and riik of
The literature relating to the use of methionine 1n paracetamol Ulhma ind c:lc:,•:ued imm\u\oglobuliti E in chilJhood. Clin Exp
poisoning is, in general, imprecise as 10 tbc fonn of methionine 23. Aujb KS. #I al. Nomogram dots not show absnlute conecntr1· All"ll)' 200S; 35: 18-H.
used In the UK, the doses quotod above refer to 01.-mcthioninc.
Preparations containing both methionine and paracetamol (co-
2'·cion for creatment. BMJ 1998; l17: 16$5.
1
~:~!~e~,z~r::z:~fn:te:ns!oi::~i~&~5~ c;·'lt~:;,~~':,
Re nal Impair ment. Caution is recommended "hen gi>ing pe·
r:1cctamol to peticnts with renal imJlllim1cnt. Plasma concenlnl-
methiamol) have been formulated ror use in situatiM~ where Pl.arm 2006; 63: 1821-7. tions of pancctamol and its glucuronide and sulfate conjugates
overdosagc may occw. However, the issue of whether mcthi<>-
nine should be routinely added to paracetamol inparalions is
2s.:;:~:~o;:;!;~,'j7,,,~~;~cr:,cz~·~~~~· in para- arc increased in patients with moderate renal failure and in pa-
26. Smilkstcin MJ. e1 ol, Efficacy or oral N-aecctylcysteinc in tht tients on dialysis.'" ll has hcoi sugacslcd thal paracetamol itself
content»us for medical and ethical reasons. trcalmcnt of acc1aminophcn overdose: analysis of the National may be regenerated from these metabolites. •.i There are conflict-
Histamine Hranlogonists. lt has been suggested tlu!t since cime- Mu~ieentcr Study (1976 to 19U). N E111/ J Med 1983; 319: ing data on whether the conjugates of paracetamol accumulate in
1$$7-62.
tidiric blocks the hepatic c)'IOChrome P450 mixed function ox1- patients with renal impairment receiving multiple ~.l.l
• ~~~it::"r~ei:.'t! }~t::':/1!::~~~f~!~';i~~~1~
21
~sc system, it misht be of use as an adjunct toacetylcystcinc for I. Prescou LF. ~'al. Paracet.amol disposition and mc:cabolite kinet-
patients wh05C p<Od11ction ofthc toxic metabolite of paracetamol cysceine. Lanc•t 199<1; 335: 1572-l. ics in pa1ecnts with chronic: renal (aihm. Eur J CUn Pbonuacol
is increased due to enzyme induction. Although there have been 29. Knys R. n of. Jnlr1.vcnous acctyky'1eine in p<1l'OCc.tamC\I in· 1989; 36: 291-7.
several anccdolal n:ports clain1ing benefit for cimetidinc in pa- duccd fulminant hepatic feilurc: a prospcaivc controlled trial. l . Martin U. ti al. The disposi1ion or parxctamol and the accumu-
tients with paracetamol 1'8isoning. lhcre is no current evidence to BM/ 1991; 303: 1026-9. l31ion of its s'ucuronide and wlphalt! conjug:atct d11nng multiple
29. Ch::ambcrlain JM, ti ol. Use of acti\'tted ch3rcoal in a Mmubtcd dosing jn p1titnts with chronic renal fai)urc. Eur JC/in Phonna·
support tl1cse claims.5·0• i.u pnisoning with acetaminophen: a new loading dose (Of' N--ace· ,.,,11991; •1 : o~.
liver tronsplanration moy be considered as a last n:cour.e in tylcysteine? Ann Em"I M'<I 1993; 22: 1398-1402.
nr
30. Spiller HA, et ol. A prospective cvalua1ion of the cff'«t acti·
J . Manin U. et of. The disposition or pancetamol and its conju·
a11e:sduring ln\llliple dosiiig in pa1ients with end.stage renal fail~
some patients.
\"ated charcoal before oral N-ac:e1.ylcystc1nc in aoct3minophcn Urt'main1aincd on hacroo(foJlysis. Eur J Clin Pharmocol J993;
After maternal overdosagc during pregnancy fetal metabolism OY<rdose. Ann Emtrg M<d 1994; 23: 519--2J. 45: 1•1-$.
of paracetamol that crosses the placenta can produce sufficient 31. Vale JA, t!I ol. lntriwnous N-acetylcysteint: the treatment or
hq>atotoxic melllbolitcs 10 cause fetal hepatoloxicily. Limited choice in p1racet.1mol poisoniag? BMJ 1979; 2: 143$-6.
~ta from case rcporu and a case series suggest that early treat·
or
32. Vale JA, el al. Treatment •~etaminophen poisoning: the use Interactions
ofonl me1hionine..Al'('lt/n1crn Med 1981: 141: 394-6. The risk of paracetamol 1oxicity may be increased in
mcnt with oral or intravenous acetylcystcinc can be safe and ef- 33. Tee LG8. #I al. N·Ace1ylcystcinc for puace11mol O\'trdosc.
fective in such cases;» the UK Norio11oJ Teratology lnfonnario11 Lanen 19$6, i: 331- 2. patients receiving other po.tentially hepatotoxic dru~
A II cross-references refer to entries in Volume A
 Parace-..amol I 15
or drugs that induce liver microsomal enzymes. The often die analgesic or anlipyretic of choice, especiall:y from 33 to 50 kg: single doses of 15 mg/kg every 4 or m01e
abso11>tion ofparacetamol may be accelerated by drugs in the elderly and in paticnls in whom salicylates or c
hours. to a maximum of 60 mg/kg or 3 dllily (\\iiichever l$
less)
such as mcloclopramide. Excretion may be affected other NSAIDs are contra-indicated. Such patients in· • over 50 kg: usual adult doses (see above)
and plasma concentrations altered when given with elude asthmatics, those with a history of peptic ulcer, Tiie intravenous solution moy be diluted 10 • minimiw strength
probenccid. Colestyramine reduces the absorption of and chi ldren. of one-1cn1h of its original cooccniration in sodium chloride
paracetamol if given within l hour of paracetamol. The usual oral dose is 0.5 to I g every 4 to 6 hours up 0.9% or glucose 5%; the diluted solution should be used within
OReviews. to a maximum of 4 g daily. Paracetamol may also be I hour of preparation.
I. Toes MJ. ct al. Drua in1crttlions with p11ruce1amol. Am J Thu given as suppositories in a rectal dose of0.5 to I g eve- For past-immunisation pyrexia, •n oral or recta) dose of60 mg
2005: 12: 56-66. has been recommended for child1-cn 2 to 3 months of age Jfnec·
ry 4 to 6 hours, up to 4 times da iiy. essary a second dose may be given after six hours; iflhe pyrcxia
Andbacterials. The plasma-paraoc11mol concentrations con-
sidered an indic:nion for antidote 1rca1mcnt (see Overdosage,
Paracetamol is given by intravenous infusion over 15 persists after that dose, medical advice should be sought
above) should be halved in patienlS receiving enzyme-inducing minutes; dosage may be calculated by body-weight as It has been suggested 1 that the recommended doses of paraceta-
dn1gs such as rifampidn. Severe hepatotoxicity at lhetapeutic follows: mol for children may result in sub!hetapeutic blood conecntra·
doses or moderate overdoses ofparacetamol has been reported in rions, and that an initial loading dose should be given, followed
• patients weighing over 50 kg, single doses of I g by regular doses up to the recommendod maximwn daily dose.
patients receiving isonio:id, alorie 1·3 or with other drugs for ru-
berculosis.• every 4 or more hours, to a maximum of 4 g daily However, the appropriate niaximum daily dose remains contre>-
• fiom 33 to 50 kg, single doses of 15 mg/kg every 4 versial, and tl1erc is obvious conccm given 1he risks ofollerdos-
For the cffocu of paracetamol on ch/orompl-icol, sec p.262. agc.
For reporu of metabolic elTccts when paraoctinnol is given with or more hours, to a maximum of 60 mg.lkg or 3 g I. Zacluri3$ M, Wons D. Pain n:licf in dlild-. OW 1998: 316:
jlucloxocillin, see under Ad,-crsc EffcclS and Precautions ofFlu- daily (whichever is less) tSS2.
cloxacillin, p.301 .
For doses in children or in renal impaim1ent, see below. Administration in renal impairment. Jn p11ienrs with a crc-
1. ~~i!n~rl~ s;;~r~1::~:~!=. '~i~~~~ 4or,•tcnt n:· O References.
atinine clearance of30 mllminute or less i1 is recommended that
2. Moulding TS. "ol. Ac::etaminophen. isoni:Wd. and hepa1ic 10s:· the interval bcrwcen each intravenous parnceramol dose is in-
I , Prescou LF. Par«e1m11of (ncetnmi11oplwnJ• o rrltlcuf bihlio- creased to 6 hours.
ici1y. Ann/,,r~rnMN1991~ 114: 431 .
gruphic rrv1t"t~ London: Taylor & fra.n<:is., 1996.
3. Crippin JS. AcC"larninophcn Mp:atotoxkity: potcn1i1tion by iJo.. Headache. Non-opioid analgesics such IS parace1amol, aspi-
nia·zid. Am J G0-,·trwnttrol 199l~ 88: 59()..l. 2. Oannw:u1h 8, PChouccq F. Oases pharmacOIQSiques de l'cmploi
4. 'Nolan CM. e1of, Hcpatotoxicity assodated wi1h 11cc.1aminophen du paroc.!l3mol: Hp«ts pbnnacocinCtiqucs c1 pharmacodv- rin, and u1hcr NSAIDs are often tried firs< for the S)1llpt01natic
namiques. Drugs 200;: 63 (fllppl 2): 5- ll . • trt:atmcnt of various typeS of headache including mipine (see
usage in patients receiving multiple dni& O~rapy for IUbcrtulo•
sis. Chat 1994; IOS: 403-l l. J. PrC'SCO(t Lf. Nou\'cllcs pcrspec1ives nee le p.iracClamol. Dn1gs p.670) and tension·l)'J)C headache (see p.671}. These drugsgjven
200J: 63 (S<lppl 2): 5 HI.
Anticoagulants. For the effects ofparaeetamol on oral antico- at the onset of symptoms can successf\Jlly11Cat an acute attack of
4. Ouwn ST. Sco1l U. lnuavenous p~racrtamol (accta1ntnuphen).
agulants, see under \\larfarin, p.1 565. Dmp 2009; 69: tOl-13. migraine. However, absorprion ml)' be poor due to gastric stasis
which is commonly present in migraine. For lh1s reason dispers·
Antiepileptics. The plasma-parac:elamol concenlrations con- Administration in children. In the UK, the licensed oral dos· iblc and cffel"\'CSCent preparations 3nd compound preparations
s1deted an indication for antidote treatment (sec ()verdosage, cs of paracetamol for pain and fever in children, gi\"en a=irding containing dnigs such as melOClopramidc which relie\.e gastric
above) should be halved in patients receiving enzyme-inducing to age.are: stasis have been advocated.
drugs such as CDrb<Jmaupi11e, phenobarbital. phenytoi11, or • 3 months to I year: 60 to I"O mg
primidon~.
Pain. Paracetamol is used in the man1gcm.nt of mild to moder-
•I to Syears: 120to2S0mg ate pain (see Choice of Analgesic, p.2). II is ofsimil3r potency to
for the clTccls of paracetamol on /omotriglue, see p.530. • 6 to 12 ycaIS: 250 to soo mg aspirin, but with weak anti-inflammatory activity. Paroec1amol
Antivirals. For reports of adverse effects on the liver associated These doses may be iiven C\'Ct)' 4 to6 hours if necessary up to a may also he used as an adjun.:t to opioids in the management of
wilh use ofparacetamol with antiviral drug$, sec Wldcr Interferon maximum of 4 doses in 24 hours. severe pain such as cancer pain (p.5). Paracctllmol is the pre·
Alfa, p.980 and Zidovudinc, p.JO l I. In younger children the BNFC 1010/11 suggests the following fcrrcd choice for paiu in children (p.3) because of tlic association
doses: of aspirin ""ith Reye ·s syndrome in lhis age group (see p.23). In
Probcnecid. Prc~tment with probcnocid can clc:ctc:isc para·
the treatment of rhe:wnatic disorders. a '4"eak 1nti·inflamm~tory
octamol clearance and inerea.sc its plasma half-lifc. 1 Although • neonates 28 to 32 weclc.s po:.1mens11Ual age (gestational age al
elTcct limits the role of paraoclamol. Ho"'cvcr, it may be ofbcn·
urin•ry excretion of1hc sulfate and gluwronidc conjugatcsofpa- birth plus chronological age): 20 mg/kg as a single dose rhen
!Oto IS mg/kg every 8 to 12 hours if necessary up toa maxi· elil for simple pain control in rheumatoid l\rthrilis (p.12) 3nd on-
racciamol are reduced. I hat of paracctimol is unchauged.
mum of30 mg/kg daily kylosingspondylitis (see under Spondyloo1thropathies. p.14), al·
I. Kamali F. Tht effect or prob<nccid on paracc:lamol mcubol i~m though these paticnc.s usually require the additional anti·
:.ind phann;,eokinttics. E11rJ ~/hr f'fmrmm:ol 1993; 45: SSl-3. • n<0natcs over 32 weeks post menstrual age: 20 mg/kg as a sin· intlllll\matory effects providod by NSAJOs. Synovial inflamma-
glc dose then 10 10 IS mglkg every 6 10 8 houls ifneecssary uon is usually ooly 3 minor component of osteoarthritis (p.1 1),
Pharmacokinetics up to a maximum of6Q mg/kg daily and paracc.tamol is generally recommcnd.!d as fin;t choice of
Paracetamol is readily absorbed fiom the gastrointesti- • I to 3 months of age: 30 to 60 mg every 8 hours if necessary treatment before NSAIDs arc tried. Paracetamol is useful for the
nal tract and peak plasma concentrations occur about The BNFC 1010/// also suggests higher oral doses for use in relief of acule low bock pain (p.8).
I0 to 60 minutes after oral doses. Paracetamol is dis- children v.ith moresea.'E're symploms: Dependence and loler.incc are not a problem with non-opioid an·
tributed into most body tissues. It crosses the placenlll • 1 to 3 months: 20 to JO m&'ks as a single do.1e foUow"d by 15 algcsics sudl •> paracetamol. but !here is a ceili11g of cflicacy,
lo 20 mg/kg e,·ery 6 10 8 hours if necessary up to a rr.aximum above which inaeasing the dose has no funher lhcrapeulic ef-
and is present in breas1 milk. Plasma-protein binding is of 60 mg/kg daily foct ..
negligible al usual therapeutic concentrations but in· • olduchildrcn: 20 to 30 nigll(gasasinglc dose followed by IS
1.-reases with increasing concentrations. The elimina- lo 20 n1glkg cvety 6 10 8 hours if necewry to a mo.xi mum of
tion half-life of paracetamol va1ies fiom about I to 3 90 mg/kg daily. Usual adult mo., imum single and daily doses
hours. (sec abo\'C) should nOI be cxcecdod
Paraceramol is metabolisetl mainly in the liver and ex- UK licensed rectal doses. which may be given tochildn:nevcry
4 to 6 hours ifoccessary, up lo 4 limes daily arc:
creted in the urine mainly as die glucuronide a11d sul-
• 3 moouhs 10 I yc•r: 60 to 12S 1ng
fate conjugates. Less than 5% is excreted as unchanged • I 10 5 years· 125 to 250 mg
paraceramol. A minor hydroxylated metabolite (N-
• 610 l'.!~rs: 2S010500mg
acctyl·p·benzoquinoneimine), is usually produced in The BNFC 20/0111 suggests rhe following rectal doses in
very small amounts by cytochrome P450 isoenzymes younger children:
(mainly CYP2EI and CYP3A4) in the liver and kid- • neonates 28 10 32 week$ po:.1menstrual age: 20 mg/kgasa sin-
ney. It is usually detoxified by conjugation with glu- gle dose then 15 niiiJkg every 12 hours if necessary 10 a max-
rathione but may accumulate afier paracetamol over· imum uf30 mg/kg daily
dosage and cause tissue damage. • neonates O\'Cr 32 wed<s postmcnslrual age: 30 mg/kg as a sin-
gle dose then 20 ms/k& every 8 ho1~s if necessary to a maxi-
0 References. mum of60 ms/kg daily
I. van der M:tttl CD. ~I ul. P;,ra<.'clot1nol and mcubolite: phtttmact.ik·
int.tics i11 mfants. Eur J Clin Phnrmocol 200.i; S9: 2.. 3-S I. - I to 3 months of age: 30 to 60 mg every 8 hours if nccc,;."1lry
l. Palm~r GM, ti ol. I.\'. attcominophen ph11rm:.cokiMtin in nc- The BNFC 1010/11 lllso suggests higher rectal doses for use in
onatc.s after muhiplc dOKi:. Br J A11aes1h 2008.! I0 I: S23-30. children with more U>'f!re symploms:
Absorpt ion. ·me absorption of parncciamol was slow and • I to 3 monlhs: 30 mg/kg as a single dose followed by 15 to
incomplete in vegetarian subjectscornpan:d wid1 non-vegetarian 20 mg/kg c,·cry 6 10 8 hours to a maximum of60 mg/kg daily
subjects.' • older children: 30 to 40 mg/kg as asingle dose follo\\<ed by 15
I. Pl'CSCOll LF, d of~ lmpaired ~bsarpli on or paraceu~ in \IC&f> to 20 mglltg every 6 to 8 hours lo • maximum of 90 mg/kg
!Orl•ns. BrJC/i,, Pltann«ot 1993; 36: 237-40. daily. Usual 1dull maximum single and daily doses (sec
aboveJ should not be exceeded
Uses and Administration Doses by intravenous infusion in children, aivcn, acc;:ording 10
Paracetamol, a para-aminophenol derivative, has analg· l>ody-wciglu, O\'Cr IS minut.::s. are:
esic and antipyretic properties and weak ~nti-inOam· • f\Jll.1crm nC<lftates and other children below 10 kg: single dos-
matory activity. Paracetamol is given orally or as a rec- es of 7.S mgikg every 4 or more hours, to a maximum of
tal suppository for mild to moderate pain (below) and 30 msikg d~ily, intravenous paracetamol has not been s111died
in rrcmaiurc neonates
for fover (p. I0). It may also be given by intravenous • between 10 and 33 l:g; single doses of 15 mg/kg every 4 cw
infusion for the short-term treatment of moderate pain, m0«_ hours, to • maximum of 60 mgll;g or 2 g daily (which-
panicularly after surgery, and of fever. Paracetamol is C\<tr 1SlC$$)

The symbol t denotes a preparation no longer actively marketed

116 Analgesics Anti-inflammat ory Drugs and Antipyretics
with the noirsclective inhibition of the traditional NSAIOs.
However, licensed product infonnahon reports that upper gas-
troin1cstinal perforation, ulceration, and bleeds have occurred
with parecoxib treatment and therefore it should be used wi1h
caution in patients with a history of such e\""1ls.
Effects on the kidneys. Increasing evidence of the rcnal tOX·
icily of the selective cyclo-oxygcnasc-2 (COX·2) inhibitors such
Parecoxib So dium (IWL"l IJS.<\N. lff'JNM) as parceoxib suggests that such NSAIDs appear to have cffectS
i'.av;i Parec<lO<iburn; Pareccoob s6dico; Pa~oxib Sodoqve: SC· on renal function similar 10 those of the non-selective NSAIDs
691 24A N-f[/>·(S·Mcihyf· 3-phenyl-4.tsoxazolyl)pn.ry!]s...ironyl)· <= p.102).
propoonamide sodi<m Up to June 2004, the Australian Adverse Drug Reactions Ad vi·
HaT;:><->'1 n.p...Ot<cM6 sory Commiuee had received 20 repol1S of adverse reactions as-
sociated with parecoxib.1 Of these, 13 mentioned renal impair·
C,.H.,NiNaO,S = 392 4. mcnl with raised creatininc le\'cls and/or oliguria; acute renal
CA$ 198470-84·7 (parecoxib): t 97502·82·2
failure was rcpo11cd in 4 of the 13 cases and multiple doses of
(porecoxib sodium).
parccoxib had been gh'CO in 6 c3scs. (In Australia, parecoxib was
ATC - MDIAH04. approved for single-dose use only because of safety concerns
ATC Vet - Q/>40 IAH04. about multiple doses.)
UNI/ - E887433V6F. I. Advcf$t Dn.11 Reactioras Ad\•isory Cocnmiuec CADRAC).
Parecoxib-one 1ho1 only. A111t A<fv-eru Dr11g Reot:t 81111200~~
13: 10-11. AIJO G\':Ailable al: h11p•l/www.1g-a.gov.aWldr/aadrb/
..dr11406.pdf(accused 08111/07)
In teractions
For intc-ractions associated with NSAI Os, see p.103.
Parcooxib is r:ipidly hydrolysed to its ac1i~ metabolite, val·
decoxib; the metabolism ofvald•coxib is mainly mediated by the
cytochrome P450 isocnzymcs CYP3A4 and CYP2C<J. Conse·
qucntly, caution is recommended when using parecoxib witlt in-
hibitors of such isoenzymcs. l.Jccnsed product information ad-
vises lhal the dose of pamc:oxib should be reduced if gjvcn with
fl uconazofe, a CYP2C9 inhibitor; however, dose adjustment of
(porecoxib) parccoxib is not generally neccssaty when giving with ketocona·
:tole, a CYP3A4 inhibitor, dcspiie increased plasma concattoa·
Incompatibility. Pareco~ib sodium should not be mixed with tions of valdecoxib. ThecfTectsofenzyme inducers such as Cllr·
products other than those reoommc.nded in licensed product in· bamazepinc, dcxamethasonc, phenytoin, and rifampicin have
fonnation (sec Uses and Administration, below). In p011icular, not been studied; theoretically, the metabolism of valdecoxib
the use of glucose S% in lacllltcd Ringer's solulion will cause may be increased by 1hesc drugio.
parecoxib 10 prccipi!Jlle. Parecoxib should also not be given in Valdccoxib has been noted 10 increase the plasma levels of dcx-
1he same syringe as opioid.._ The use of Slerile water for injection tromethorphan, a CYP2D6 substrate, and therefore caution is
is not recommended as the rcsulling solution is JlOI isotonic. rccnmn>cndcd when giving porccol<ib with drugs thal arc metab-
Adverse Effects, Treatment, a nd Precautions olised via CYP2D6 Ind that ha\'C • 1131TOW thC111jlQ!tic index.
As for NSA!Ds in genctal, p.100. Such ctruas include flccninidc, nietoprolol, and propafenonc.
Valdecoxib may also affCCI the plasma levels of drugs that arc
Hypersensitivity reactions, including anaphylaxis •nd angioedc- metabolised via CYP2Cl9: an increase in Ilic plasma le,'Cls of
ma a.nd serious skin reactions, ha\'e been reported witb valdccox· omeprazolc was seen in p<tticnts using 'lldecoxib.
ib and may thefefore oc.;ur with parccoxib, a prodrug or \'al•
deco•ib (see also Effects on the Skin. p.138) Parccoxib should Pharmacokinetics
be stopped al the first signs of hypc:raensitivity. Some of these On intravenous or intrnniuscul>r injection, pMecoxib is rapidly
reaction• occurred in p:1tients with n hiSIOry of allergic reactions hydrolysed in the liver 10 its active mc1abolitc, valdecoxib, and
10 sulfonamides and the use of parcet1~ib is contra·indicatcd in J)IOl>ionic acid; the plasma h1lf-fife of parecoxib is about 22 n1in·
such patients. ures. Plasma protein binding is about 98%. Valdeooxib is also
Parccoxib should be ftvoidcd in patients with SC\ ere hepatic im- extensively metabolised in lhe li\'Ct; pathways involved include
pairment (Child-Pu&h scorcof IO or more). inOammatorybowcl those via the cytochrome P4SO isoenzymes CYP3A4 and
disease, and moderate to severe heart failure (N YHA class JI ro CYP2C9, and glucuronidation. Another &dive metabolilc has
!VJ. It should n<>t be used in patients with ischoemic heart dis· been identified but it is not considered to contribute a significant
ease, peripheral arterial disease. or ccrebrovascular disease. It clinical effect. Excretion is mainly via the urine with about 70%
should olso not be used after coronary artery byp~ graft suri:ery of a dose appearing as inactive metabolites. Less titan 5% of a
as dicrc may be an increased risk of ad,"Crsc effects such :is my· dose appears as unchanged \'aldccoxib in ll1e urine. No un-
ocardial infarction, dee!>'vein thrombosis, pulmonary embolism, changed parecoxib is found in the urine with only tl"dCC amounts
stroke, renal impainnent, deep surgical infections. and sternal in 1he focccs The climinolion half-life of,':lldecoxib is about 8
wound complications. l11is may apply especially to obese pa- hours.
ricntSor those with a historyofccrebrovascubrdiscasc. Partco>.· ¢ Reftn:nces.
ib should be used with caution in patients wilh significant risk I. Karim A, et ol.. A phaml1tokinctic t1tudy of inuamuscular (IM)
factors for cardiovascular disease such as hypertension, hypcrli- parecoxib sodium in JlOfmal subjccls. J CHn Phnrmncol 2001;
pidaemia, and diabetes mellitus. Calllion is also rteommcnded 4t; 1111-19,
when using parccoxib in deh)'<lrated patients: rehydration inay
be advisable before giving pal'C<Xlxib. Patici11S with severe renal Uses and Administration
impainncnt (creatinine clearance less than 30 mUmin) or those Pareco~ib is an NSAID (p. I03) rcp011cd to be a selccli"e inhibi·
who m•y be predisposed to fluid retention should be started al tor of cyclo.-0xygcnasc-2 (C'OX·2). It is a prodrug ofvaldccoxib
the lowest recommended do.o;e and renal function closely moni· (p.138) and is used for the sltOfHerm trcollnem ofpostoperativc
torcd. pain in patienlS aged 18 years and over. l':ln:coxib is given as lhe
sodium salt although doses an: expressed as the bosc; 42.4 mg of
Effects on the cardiovascular system. There have been parccoxib sodium is cquivalcnllo aboul 40 nig ofparecoxib. The
concems about the ad,,ersccardiovasculareffect~ of sclecti\e cy· recommended dose is 40 mg given by inlravc:notJs or slow intra·
clo-oxygcnase-2 (COX·2) inhibitors after the general worldwide muscular injection; this may be follow"d by 20 or 40 mg every 6
withdrawal of rofccoxib (sec p. I 2S). The shon-term u•e of 10 12 hours as required. The maximum daily dose is 80 ms. Eld·
parecoxib after coronary artery bypass gr.ill ~· h~s been :is- <rly patients weighing less than SO kg should begin trcauncnt
sociated with an increased risk of adverse effects such as n•yo- with half the usual do6c, repeated toa maximumof40 mg daily.
C3rdial infarction, deep-vein thrombosis, pulmonary embolism, Dose$ may need to be mluced in hepmic impainnenl, sec below.
and strol<e.1 When compertd with patients in the placebo group,
Parccoxib should be roconstiluled with either sodium chloride
the risk of such effects was almost 4 limes greater in those given 0.9%, glucose 5o/o, or sodium chloride 0.4S% wilh glucose 5%;
intr.1\enous parocoxib for 3 d•ys followed by oral valdeco.xib for no Olhcr solvents 3tC recommended in ~ccnsed product in ronno-
die OC'1 7 days.
tion. In addition tltc rcconstiluled solulion may only be inj«ted
For discussion and advice on the use of sdective COX-2 inhibi- into inm1venous lines delivering sodium chloride 0.9%, glucose
tors in palicnt<; with cardiovascular or ccrebro"ascular disease, 5%, sodium chloride 0.4S% with glucose 5%, or lactated RJng·
see under Cclccoxih, p.3S. cr's solution. (See above for details on incompatibilities.)
I Nussincitt NA. t1 ol. Complita1ions C>( the COX·2 inhibi\Ors
pt'recoxib •nd valdecoxib afM!r cardiac surgery. N Engl J Mtd () RelC:rences.
200S; 352: tOSt-91. I. Chttt SM. Goa KL. l'nccoxih (p:m:~oxib sodium). Dn1gs 2001;
61: ltl)-41.
Effects on the gastrointestinal tnct. h is generally acccp<·
2. Atnabik CM. Spencer AP. Par~co:cib fOt pucnteral analgesia in
cd that the inhibition of cydo-0xygcnasc- I (COX-I) plays a role postsurgical patientS. ·""" 11/UJrm«olW,. 2004: 38: Ul..-6.
in the adverse gilSU'Ointeslinal effects oftho NSAIDs, and that the 3. Mchlisch DR. tt ol. lli(' ""'IJnk: efficacy of in:ramuscular
sclcetive inhibition of the other isofonn.. COX-2, by NSAIDs parecoxib sOOhnn u'I postopr:rall\c dental pain. J An1 Dt'nt A11oc
s11ch as parecoxib n11y cause less ~Strolo•icily d1an 1hat seen 2004: 135: IS78-90.
 Parecoxib Sodium/Pentazocine 11 7
4. M:dan TP. ~' "'· 111c cycloc.b.yg~-1-spccific inhitii1or Pentazocine Lactate t-Wi.\\ us.w. .WNMJ ® Effects on the CNS. Oculogyric crisis has bccit associated
J»re'COX1b sodium lr. U cffec1ivc :a.s I~ mg of morphine ad minis· with lhc\lsc ofpentazocinc.1
•crcd inlDmuscularly IOr lfl!itling r;iin ::ifler arnccoq;ic lap;ir<'lt• l..utato de pentazOCina: P!.ntatSOSltnilalclaat Penta;;oc:ine. lac·
Olt1)' $Urb"C'Y- .i11at/t •.f,tulg :?OOS: 100: 45-4-60. tale de: ""'1".uoc.n lactas: Pent220cinl~1; Penta=ir.-laktat I. Burstein AH, Full<no11 T. Oculoi-.;yric: crisu. 1')0¥.$lbly r<-latcd 10
pent:u.oc:ine. Ann Phurmt~11hf!,· 1993: 27: 874.
Uca1.moier M. t!I al A n111Mbniud, double-blind compari~ h(... Pentazocino !a'<W.ls.
rwetn parcco="ih sodium and prop3Cccamol for parcnt~I pos&· Effects on the skin. Toxic epidennal necrolysis in a 62-yeor-
ncHTMoiJ,:.,Ha J\a.-T(fT
oper:ti"e analscsi1 anu inguinal hernia rr:p.:1ir in adult pabcnts.. old nian was attributed to penlazoeinc:1 ho hodtaken50to75 mg
Aneidr Analz 2005: I 00: J;~I S. C,~27NO.C3H60l = 375.5. every 4 hours for 8 days. His severe uraemia was allribuled lo
6. Sindh\.U~n&I w. ti ol. PilJ'C'COX1b \U'SUS tramado) ror pon-1p- CAS-17146-95-1. fluid loss dvough the skin.
p"'1dcc1omy poin. J M•d A.\.TOC rho/ 200S: 83: I SS7-62. UN•/- IP2XIB5/00.
I. Hunter JAA. O:;wison AM. To,.ic cp.idcrm::d nccrolysis a.s:sodet·
7. Gajraj NM. COX-2 inhibilors celccoxib and parcc:Oll.ib: va!uable Pharmacopoeias. In £111: (sec p.vii). US includes only Penta- ed with ~nluocine 1hcr~py •nd U:\'Ctt revcrsiblt l'tnol rJifurc.
optionJ forpoMopc:rat.ive pain m!'nagement. C11"TopMMChem zocine Lacu.1e Injection. Br J o.tnltatoJ 1973: 88: 287-W.
2007: 7: 23S-l9. Ph. Eur. 6.11 (Pcnlazociie Lactate}. A while or almost white
S. Lloyd Fl. et nl. lnrrav-c~ 0t intramu:;cuh1r percc.oxib foe aaite Treatment of Adverse !Effects
P'O''°pc:rative pain in •dultt. .A.;.il:ible in The Cochrane 0.Jta•
powder. Sparingly soluble in wa1cr; slightly soluble in dichlo- As for Opioid Analgesics in general, p.107.
base or Systematic ll.C\'iC\\'S: luuc 2. Chichester. Jo hn Wiley; romethanc; freely soluble in 1nc01yl alcohol. A I% solution in As penlllzocine has both opioid agonist and anlllgonist ae1iYity its
1009 (--.:cl 21/09/09). water lus a pH of 5.5 to 6.S. Pru<cct from light effects may not be completely reversed by naloxone, bu! IM of
BP 2010 (Pentazocc>e La<.1ate). A white to pale cream powder. the latler is still recommended in pcn1a1ocine overdosagc.
Adminimatlon In hepatic impalrme<>t. Licensed product Sparin&ly soluble in water, in alcohol, and in chlorofonn; freely
infonnation in the UK sutes C.a1 no dosage adjustment is gener- soluble in mc1hyl alcohol. A 1% solutioo in water has a pH of 5.5 Precautions
ally necessary for pareooxib in p;nients with mi/dbcparic impair- to6.S. As for Opioid Analgesics in gcneni~ p.107.
1?>Cnt (Child-Pugh score 5 or 6) and for those with moderate im- PenlV.ocine has weak opioid antagonist acrions 2nd may precip-
painnenl (Child-Pugh score 7 to 9) parecoxib should be gi\'en at Incompatibility. Commercial injections of pentazocinc lactate itate witl1drawal symptoms ifgiven to palicnts who arc physical-
half the usual do5e (see obovc~ repeated to a maximum dose of ;a.., reported to be inoompaublc'>ilh soluble ll<lrbiturates and oJh..
ly dcpe11den1 on opioids. It should generally be avoided after
40 m&daily. Use in patients wilhs....,,...impairmcnt (Child-Pugh cr alkaJine substnnces including sodium bicarbonate. Diazcpam myocardial infarction and in polients wiU1 hean failure or arterial
score JO and OVCt) is no1 recommended as there is no clinical and chlM!iazcpoxide have also been reported to be incompati· or pulmonary hypenension.
experience in s\leh p11ients. ble. as have gl)'COPytronium bromide' and nafcillin sodium.!
When f~I injections arc needed, pentazocinc should be giv-
J. lngallincni TS. ~I al. Comp~libi!hy of glyooP)TTolalt iajection
Preparations with commonly USc!"d inl\l.sion solutions .and add1tiv~$. Am J en in1ramuscularly rathc1· than subculaneously and Uie injeclicm
Hosp l'ltarm 1979; 36: 508-10. si1es should be varied.
Proprietary Preparations (details an: given rn Volume B) 2. Jesluin EL, e1 cl. NaftiHin sodium incomp~tlbi l icy wilh actdic
Aurtml.: ~n•t Aunria: D)nasttt 8d1~ D,nasta1: Chilo: f'ro·Bex-.r.: solutions.AmJ Hrup Phorwi 1981: 18: 462. 464.
Abuse. Sec undOI Dcpendena: and Wi1hdrawal, above.
CL: Dyn\SUt: O.nm.: D;-nasUt Fin~ [)yNNt rr~ Dinast>t: Grr.: Din· Porphyria. Pcntazocine has been ossocioted with acute aoacks
amt Gr.: 0,....1"1: Hong Konr: Dynast•t Hu11i.: D,nas<tt India: e;o. Dependence and Withdrawal
v.il·P: Vil«•< Vlllci>c< Valdonc·P: V•IUS·P: \IQ<di.f'. lndon.: D)nosl.it: lrl.: As for Opioid Analgesics, p.105. ofporphyria and is considc1ed unsafe in porphyric paricn!s.
Oi<>•nal: ltoL: o,na,,.1. Molo~o:
C>1"'5l3t Mu~ ~ Neth.: Pcntazocinc is subjec1 to abuse. Inte ractions
()y-i•SUt Norw.: D)NSl.JC HZ: t Phlllpp.: ()ynosm: PorL! Dyn-
for in1craetions associated with opioid analgesics, sec p. 107.
• ,..~Rut.: Drnastai ~n): r.: Roymn: Spoln: ~SM<!.: <> Pent;izocine docs produce physical dependence, but withdraw-
°"'"SW: SwltL: ee.-,..t. Tllol.: 1>""""1;
(Al<o«T•rt. VeneL: D;<>anot1'
UK: Dynaslat Ulcr.: D)'OUUl al symptoms arc oobstan1ially less severe tllan with morphine. 1t Tobacco s moking. Smokers melaboliscd ahoul 40"1• more .
docs no11ypially produce dtug-S«king behaviour oflhc same pen11ioeine than non-smokctS. allhoush 1herc was large i111cr-
dcptt or intensity as motphine or other proto1ypic µ agonist<, subjcct \l3ria1ion;1 1obotcco smoking mi&ht induce liver enzymes
nor does it substitute for moiphinc in dependent subjects.' Pen- responsible for drug oxidation.
tazocine injcctioo bas been abused,' but sn.:et abuse, especially I. V:1uzhan DP.*' nl. The influence of smoking on lhe inh:r~"1bjec1
Pentazocine (!Ill( UW-t ll'IN) ® \r::triat\on Jn penlnzocinc climin11i0f\, Br J Clir. Plron11acol l4>16;
in 1he USA, has more often involved 1he inuavenous use of
NIH-7958: NSC-107430: f'cntaUOSIMlC Pentazocin: Penuzocina; c111shed tablets of pcn!llioeine and lripelennaminc ('T's and J: 279-83.
?entazocio<u: Pentazocinum: Win-2022a (2R".6R".l JR')- Blues').i-' A decteascd incidence of pentazocine obusc in 1hc Pharmacokinetics
l,2.3.~.S 6-He~ahydro·6. 11 -dimetll)'l-3-<3-m~hytbot-2-enyl)· USA appeared 10 eomcide \~ilh the introduc1ion of oml tDblets Pen1azocine is well absofbcd from the gastroinlestinal lrllCI and
2.6-methano-3-benza1ocin·8·ol inc.>rpon1ting n~loxone, 1 the rationale being that 11aloxoncanlllg- peak plasma co11cc111rations occur in I lo 3 hours after an oral
onises lhc effe<:t of penlazocine if illidtly injected, but has no dose; the half-life is reporled to be abou1210 3 hours. Afitl' in1111-
ncttTa3()Us1H
effect when taken orally. Some continued 10 abuse the new pen- mu5e\llar injection, peak plasma conccnttalions occur in 15 min-
C19H21NO = 285.4. tazocine/naloxonc forn1ulation:f intmvenous abuse in one wom· utes 10 I hour and the half-life rs 2bou12 to S hour.. Aboul 50 to
CAS - 159·83· I. on, who wos """"""' of 1hc reformulation, resuhed in opioid 75% has bcc<l reported 10 be bound to plasma irotcins. Pcnla:lo-
ATC - N02ADO I. withdrawal symptoms and sewre hypcncnsion.l A 1989 rcpon cine undergoes extensive lirs1-pass 111c1abolism in the livu; ornl
ATC Ve1 - QN02ADOI . from 1hc WHO committee' rated the likelihood of nbLISC ofpcn- bioa\'3ilability is low with only :>bout halfof a dose read>ing the
lazocinc as moderate, based on its phan113cologial profile, de- sys1cmie circulotion. Metabolites and a small omounl of un-
UN/I - RP4A60026L. changed druiiare excreted in tlic urine. It crosses 1he placenia and
pendence polcntiol, ond ac1ual abuse. The commiucc considered
thot it should continue to be scheduled as a psydioiropic sub· .is distributed into breasl milk.
stance rather lhan a narco1ic drug. H epatic impairment. Cleurancc of pent.uocine was signifi·
H CH
~3
I. WHO. WHO c'tpen cummiucc on dru:, d..:.pcndcncc: twtnty· can1ly reduced and 1crminol half-lite and mil bioavailabilil)' in-
: fifth report W/10 Tttlt RqJ s~,. 77S 1989. Also 1v11bblc ac

~':' http:llhlJdoc ,\\'ho.in1hrs!WHO_TRS_ 7i5.pdf(•cc•ssed l7J06JOS) creased in cirrhotic poli"11ts wht:n compared \\ith healthy sulr
P' CH3 1. Hum.tr R, tnarnm IM. lnlra,c.nous pcnruocln~ :il'msc b)'I nurse. jccts.1
La."""' 1983: ii: 227. I. 'lcal EA. f!I nl. Enh111H.'t'd bic»uil~h•hlY 111d c1ecrcased clcar-

HO~ .>. Poir.hs A, Why.rot PL. Cumnl trends in 1bc abux of pcnt;:izocinc
and tripclcranamine: lhe metropo1ilM St. Louts expcrien«:. J Fo·
1w1Slc Sci 19&0: 15: 72-8.
~nc:c or a11alt;csi..:s in pa1icnl1 "ith <itT~is. Gas1rt)1m1arology
1919; n: 96-102.
4. Sen1y EC. Clin~I experience with T ..J 111d B's. Dntt Akohol Uses and Administration
V.pe11d 19&S: 14: 305-11. Pcn1:12.0Ci1.e, a bcnzomorph.:m derivative., is ~n opioid anaJs,esic
Pharmacopoeias. In Eur. (seep.vii). Jpn. and US. .S. JKkson C. tr al. F:m1I inttttr.lnitl be1nonhage associ:lted w11h (p.IOR)that has mixed opioid ogonis1 nnd antagoi11st actioi.s. Ag·
Ph. Eur. 6.8 (Pentuo<:iie). A white or 2lmost while powder. It phcnylprop.anol;,n1ine. pcnla~odnt-. and lriptlcnnam1ne O\'t'f· onis1 actil'ity is thought to be mainly al < opioid rcccptoJS(with
tlo!.<.J Em•ra Med 1985: 3: 127-32. ilOl!Sibly some a rcc<ptor acti• ily); it octs as n we.1k antagonist or
shows polymorphism. Proclically insoluble on water; soluble in 6. Reed OA. Schooll SH. Abuse o( pcn4iz.ocinit-nak>xonc con1bi111- partial 1tgonist atµ receptors. Pentnoeine is used for lhc relief of
nlcohol; freely soluble in dichloromcthone. Proted from liglll. 1ion. JAMA 1986; 156: 2562-4. moderate to severe pain including the pain of labour. Coinbined
USP 33 (Penlazocine). A while or very ~le, tan-coloured pow- 7. Reinhart S. Bandt SM. An acute hypc-rtensi"t: rapunse 10tr in· ·
travcnous use ofa newpc.ntazocint: fornn1huion. Ann £111,rg Med preparations with parncclamol or aspirin may also be used in lhe
der. Praclically insoluble in water; soluble I in I I ofalcohul, I in 1985: 14: S91-3. lrcaunent ofmoderate pain. It may also be used for prc·opcralivc
2 ofchloroform, ~nd I in 42 ofether; soluble in acc1011e; Sjllring- seda1ion and as an adjunct to ana<Sthcsia. Its ano.Jgesic cll'ect de-
ly soluble in ethyl acc1ate and in benzene. Store in ainight con- Adverse !Effects
As for Opioid An•lgcsies in general, p.106. clines more rapidly than thal of ntO'l'hine.
1a.iners. Prolect from lighl. Pentaioeinc is gh"Cn orally as the hydrochloride; d0$C$ may be
Pemazocinc may e2usc hallucinalioos and Oilier psychotomi1nct·
ic effects such as 11igh1mares and thought diSlucbanccs. B igh dos- expn:sscd as either lhe base or the sail P<ntazociuc is •lso gi"cn
Pentazocine Hydrochloride (SAN.\\ IJW( IH<MJ ® es may resuh in hypertension and lachycardia; incr~ ao11ic parcntcr.illy as the Joctale; closes m exprC$5Cd in lcnns of tl1e
Hodrocloruro de pentazocina; Pentaoosii1 hydrol<loridi: A=owo- and pulmona1y artery pressure with an increase in =diac work base. Pemo:iocine JOO 11111 is equivalent 10 abou1 I 12.8 mg of
has followed intravenous use in patients with myocardial inflrc- pentazocinc hydrochloride or 131.6 mg ofpen1:izocine lacia1c.
ooe. chlcr11)'drate de: Fen1aiocin-Ndro:d<lrid: Pentatocin-hydro-
chlond: P.:ntazocinhydroldorid: ~wocini hydrochlorid._m, lion. Like morphine ii causes respiratory depression, but pcrila- A usual oral dose is tlic cq11ivalen1of5010 100 mg of pcnbO.OC·
zocia< ts ~id lo have a 'ceiling' c!!'CCI and the depth ofn:spira- ine or pentazocinc hydrochloride e•-cry 3 to 4 hours after food, to
Perrtazocino hidtod'>loridas. a inaximum of 600 mi daily.
tory depression does not increase proportionately witl1 higher
neHTa30U"''3 f 11APOXAOP'<A doses. The usual initial dose by subcutaneous. intmmuscular. or intral'e·
C,.HnNO.HCI = 321.9. Rnrc od\'Crsc cll'CC1$ with pcniazoeine h.--c included ;\glanuloey· nous injection is the cquivol<m of pentaiocinc 30 mg as a single
CAS - 2276-52·0: 64024-15 -3. tosis and serious •kin rcoctions such a.s crytheina mullifonne and dose. Thercofler, 1hc dose moy be adjusted according to re·
UNll - A36BX041'PX. toxic cprdennol nccrolysis. sponse; licensed product informa1ion recommends that single
Pen1azocinc injections may be poinful. Local tissue damage 1noy doses should not usually exceed 30 ms (500 micrograms/kg) in-
Pharma<0poeias. Jn £111: (seep.vii) and US.
occur a1 injection sites pattic:ularly afttr subculaneous injection navcnously, or 60mg (I mg/kg) intramuscularly or subailanc-
Ph. Eur. 6.8 (Pentazocine Hydrochloride~ A white or almost or multiple~; there have been l\lports of muscle librosis as- ously. Doses moy be repeated every 3 to 4 hours; it should not be
whiie powder. It $hows polymorphism. Spa1ingly soluble in wa- soclaled wi1h it1tramuscu1ar injcc1ions. ne«ssary 10 exceed 360 mg daily. Also if frcqu~nt injoctioos arc
ler and in dichforonic1hane; soluble in •lcohol. A 1% solution in needed, the intramuscular route should be used rather than the
water has a pH of 4.0 to 6.0. 1'1-0lecl from light. Effects on the blood. There ha\'e been reportS of agranulocy- subcutaneous route, and the injcc1ion sites should be va;kd. Jn
USP 33 (Pcnwoc:ine ~) . A while crystalline pow- tosis associ31ed with peruaz.ocine. '·' ohslctric analgesia 30 mg may be g.ivcn tlS a single d\J01C by inlra-
der. It c><hibits polymorphism, OllC form nic!ting at about 254° I. Muks A. Abr3mson N. Pc-ntatocin< and aan11ulocyt("$iS. Ann muscular injection during labout~ allcmatively, 20 mg may be
and the other at about 218°. Soluble I in 30 of water, I in 20 of h•m1Mw 1980: 92: 433. given by intravenous injcctioo as soon as cuntractions occur at
2. Haib.-Kh H. tr al. Pcnloz.ocinc·induc:C'CI 1sr1nulocyluNis. Co11 t'l:gular intervals and repealed 2 or 3 limes al intervals of2 IO 3
alcohol. and I in 4 ofchh>rofonn; ,.cry slightly soluble in acotone M•dAu«J 1984: 130: 11 65~.
and in ether: praaically insoluble in benzene. s~ in airtight 3. Sheehan M. rt ol Pcnc3tocinc-induced ayantJ&oc:ytosis. Ctm hows if nccc:ssary.
coillainers. PrOlecl from ligJu. Med.foocJ 1985.132: 1401 . For details of do.•cs in children, see below.
The S) mbol t denotes a prepara1io11 no longer ac1ively mnrkctcd The symbol® dcnOles a substance whose use may be restricted in cettain sports (sec p.vii)
l I 8 Analgesics Anti-inflammatory Drugs and Antipyretics
Penlazocine lactate has also bttn given rCCllllly as suppositories. 3. Pug.h CB.~ ol. Vis.ual comp~11ibilhy of morrh1nc sulfate and of 10 given morphine and none of those receiving fentanyl or
mcpcridine hydroc:hloridc with Olher i.nje:ublc dru;s during
As a dclcrrent 10 Dbusc a combined oral ptcparalicn of pcntazo- simulated Y-sire injection. A.111J HOJpPhorm 1991: 48: J23-S.
sufentanil showed evidence of hilWlmine release. A II of lhc his-
cinc hydrochloride ~nd naloxone hydrochloride is available in 4·. Trissel LA . ~' al. Compalil>ility of do>.orubicin hydrochlortdc li- tamine relc:lSers were young women.
some counlrics. posome injcc1ion \\ ilh sdcctcd other druss d1.1ring s;mutattd Y-
0 l . Flackc JW, n ol. Histamfoc relcHe by four natc0tics; a doublc-
site "dministrarion.A•J Htofth ..Sy11 P/iorm 1997: 54: 270&-I:>. blind <tudy in humans. Anesth A11olg J987; 66: 723-30.
Adminl•tratlon in children. In the UK, pentazocille rs Ii· S. Turowski RC~ Dutlhalcr JM. Visual compMJbility or idarubicin
censed for the relief of modcrote to severe pain in chi~n Md Etrects on the nervous syrten\. CNS excitatory cff'ccts of
hydrochlondc with selected drugs during simulated Y·si1e injcc· pethidine such as 1remors, muscle rwilches, and convulsions
doses may be repeated every 3 to 4 how's if necessary. Those lion.A•) Hosp Pha'm 1991; 48: 2131-4.
a&ed 6 to 12 yeazs may be given a usual onil dose of25 mg. Chil- 6. Ltt DKT, ~' ol. Stability of ccflzoUn sodium i nd mepcridine have been associated with 1oxic doses and hove been anributed
drauged I to 12 years may be given doses of up to I mg/kg by hydrochlorlde.AmJHeol1lt-S,71Phorm 1996;53: 160S-JO. to the metabolite norpethidine. Accumulation of norpahidine
intravenous injection. may occur if large doses of pethidine aIC repeated al short inter·
Stability. Pethidin< hydrochloride injection 100 mgtmL was vals (including for patient-controlled analj:esia) and is especially
stable' for at least 24 hours at room tempel3!urC when diluted to
P reparations likely when renal function is impaired.1"1'
a concentration of300 m!?/}ilre in glucose 5% and 4% and in so-
BP 2010: ~ UpslAes: Per<azocine ~ Penwoet>e Str~­ I Kaiko Rf, • f al. Central nctYOUS system excitatory cffuts of
positonos: l'mwo:irle Tillleu; dium chloride injee1ion (0.9%) and sodium chloride injeclion meperidinc in cancer patients. Ann"''""'/ 1983; lJ: l&G-5.
USP 33: A=ntizocine and Aspirin Tablets; - ard NalOO<One Tot>- (0.9'.4) diluted 1 in S. 2. Lie~ nnan AN, Gokhtei~ M. Reversible parkin$0nism rdued
l<ls: f'WUJacne lri•cti::n Accclc\'8ted stability studies using elevated temperatures and hu· 10 mepcriditt<..N £n1/J Med t98S; 311 : S09.
Proprietary P reparations (details'"' given in Volume 8) midities lO simulate tropical conditions classified pethidine hy- 3. Mauro VF, a ol. Mcpcridine-induccd seizure in a ~tiene with-
out renal dysfi.Jnction or sickle cell anemia. Oin Pho''" 1986: S:
Auwol.: F~t: Aunri<r JV1ra1t: Belg.: forut: Conod.: T-..: c.,, drochlorid< IS a ' less stable drug substatice'.1 It was suggested 837-9.
Fortrat Oenm" fonralt Gor.: Fonnlt: Gr.: Fo'u! Indio: fortwin; Pen· thal during quality assurance of prepmations containing pelhi· 4. Morisy L, Plan D. HU>rds of hiJh~ost meperidine. JAMA
uwW-< lsr°"t 1iM.n NXt. Taiw>ot; lcol" T - Jt- filllwori: Pentagin: dine hydrochloride particular anention should be paid to their 1986; 255: 467-8.
Sostpt ~ Fortnll: Norw.: Forlr>lllt: NZ: Fonrolt; Port..: Sosegpnt: S. Annsrrong PJ. Ber$lrn A. Normc-pcridinc toxicity. Anu1ltAnol1
s.A(f~ ~;r. Sosenot Slnropo.-.: T.lwn Spain: Sosegon~Switz.: stability.
1986; 65:SJ6--8. .
~ Thai.: Ponp; UK: Fonnt USA: T>lwin: Talwin l\IX 1• I. Rudd L, Simpson P. Pethidin~ st1bih1y in intra.venous solutioris.
Med J Ausr I 978: l: 34.
6. Eisendralh SJ."ol. Meperidinc·induccd dctiriom. AmJ Psy,;hi·
Olry 1987; 144: 1~2~ S.
Multl·fnJn.<lient: Indio: ~ Fo.-.cet: USA: E"*ltnt.£2: Tilll·
cent: TutwnC~ 2. WHO. WHO expert committee on spccir.catM>ns for pharmoccu- 1. Kyff JV, Rice TL.. Mcpcridinf•ISSOCil>kd seltut~ in a child.
lical prepualions: 1hirty·fi1S1 rcpon. WHO Tech R.ep S" 790 Clin Pbartn 1990: 9: 337-41. '
J990. Also availab le at: htlp://li bdoc .who,int/trs/ I. Prylc BJ. eta/. Toxicityofnorpethidine in sickle cell crisis.BM./
WHO_TRS_790.pdf (accessed 26/06/08) 1992; 304: 1478-9.
9. Haameyer KO, ti of Meperidine-rch11cd sc~:z.urcs a.ssoc:i.11cd
Pe thidine Hydrochloride {BANM. rlNNMJ D ep endence and Withdrawal
wi1h p1.ticnt-conlrollcd analgesia pumps. A11n Phormocother
199J;l7;29-32.
® As for Opioid Analgesics, p. l 05. J0. Stone PA.do/. Norpcthidinc toxicicy and patient controlled •n-
algesi•. 8,J AnoeSlh 1993; 71: 73s.;.40.
HidroclonJro de pelidina: Meperid1ne H)'droc:hloride: Pethidine, Doses of ped1idine as large as 3 or 4 g daily have been 11. Marinella MA. Mepcridine-md~ocf gencreliz.cd seizures ~irh
chlorh)d-.te de: Fethidin./i)'drochlorict ~"" hydrochlori- taken by addicts. As tolerance to the CNS stimulant normal renal function. Sour• McJ J 1997: 90: S*-8.
dlm; f>elidiinihydrokloridi: Peticin Hodroldoriir: Petidin./iidroklor- 12. McHugh GJ. Notpethidinc M:C\lmll1ation and generalized sei·
and antimuscarinic effects is not complete with these rure during pe.thidinc p:lticnt·controllcd analgesia. Anoath Jn.
id; Pctidnhydroklorid: ~ hidrochlorid<:s; Petyd)<"!y chle>- very large doses, muscle twitching, tremor, mental tensfve 0tl'W 1999i 27: 289- 91.
n:modorek. Ethyl I ~+pheny!p;peridine-4-<atbol<ylate hy- J 3. Hubbard GP, Wolfe KR. Mcpcridinc misuse in a patient with
d'ochloride.
confusion, dilated pupils, and sometimes convulsions sphincter of Oddi dysfunction. Aftl'I Plwmocothcr 2003~ 37:
may be present. 5J4-7.
r
fleT>W1HA l<APOX110pHA
C 1sH11N01.HCI = "283.8. Withdrawal symptoms appear more rapidly than with Precau tion s
CAS - 57-42 I (pethidine); 50-1 3-5 (pethidine h}'dro- morphine and are of shoner dwation. As for Opioid Analgesics in general, p.107.
chloride). For the abuse of pethidine analogues, Stt under Pre- Pethidine should also be given cautiously to patients
ATC - N02A302. cautions, below. with a history of convulsive disorders or supra ventricu-
ATC Vet - QN02A802. lar tachycardias.
UNll - N8E7F7Q f 70. Adverse Effects and Treatment
Abuse . A syn1helic analogue of pc1hidine, MPPP (l·rncthyl-4·
As for Opioid Analgesics in general, p.106. phenyl-4-propionoxypipcridine), manufacnucd illicitly for rec-
The effects on smooth muscle may be relatively less reational use, achieved notoriety when it was accidcntully con-
intense than with morphine and constipation occurs taminated with MPTP ( 1-mclhyl-4-phenyl-1,2,3,6-tetrnhydropy-
less frequently. Local reactions often follow injection ridine) leading to an epidemic of parkinsonism among
intravenous drug abusetS.1 WHO has also identified another an-
of pethidine; general hypersensitivity reactions includ· alogue, PEPAP (l-phenylelhyl-4-phenyl-4-acetoxypipcridine)
ing anaphylaxis have been reported rarely. Pethidine as being liable to abuse.2
given intravenously may increase the hean rate. After 1. 8uch31l>lnJF, Brown CR. ' Dcsianc.rdrugs'; a problem in clinit:al
overdosage, symptoms are generally similar to those of IOxicology. MadTo.<icol 19SS: ): 1-17.
2. WHO. WHO expert commillc.: on mig dependence: 1wcn1y-
morphine poisoning. However, stimulation of the CNS founh report. WllO Tklr R.cp s,, 761 J98S. Al50 l\"lilable at:
and convulsions may also occur, especially in tolerant h11p://libdoc.who.in1/trs/WHO_TRS _76 J.pdf (1cccssed
26106108)
(pethidine)
individuals or after toxic oral doses; these have been
Breast feeding. No adverse cff'ccu ha\'C been seen in breast-
attributed mainly to the metabolite norpethidine. feeding infants whose mothers were given pethidine, and the
Incidence of adve~e etrects. The incidence of adverse ef· American Academy of J>ediatrlC$ considers' that it is therefore
Street names. The following terms have been used as ' street
names' (see p.vi) or slang names fC)( various fonns ofpethidine: fccts in hospitalised potients receiving pethidine was monitored usually compatible with breasl feeding.
Bam;Peth. by the Boston Collnbonltive Drug Surveillanoe Program.' Ad· I. American Aca«my of Pediatrics. The tral'lS(er o(dncs and oth ~
verse reactions lO onl pethidine were reported in 16 0066 pa- er chcmic:.lls in'o human milk. Pediatrics 2001: JOI: 776-89.
Phannacopoeias. ln Chin.• Eur. (seep.vii), Int., Jpn. US. and tients and mainly involved the gas1rointestinal lr.\CL After pethi- [Retired May 2010) CorrcClion. ibkt; 1029. AlllO available al:
Viel. h u p://a :a ppol Ic }'. • :> ppu bl i Cl t ions.orgies ifcon 1cnt/fu III
dine by injc<:tioo 102 of3268 patients had adverse effects. the
Ph. Eur. 6.8 (l\!1ldrie Hydrochloride). A white or almost while, pcdi•trics%3bl08.t'3n76(ae<'<SKd16/06/08)
CNS being involved in 38.
crystalline powder. Very soluble io water, freely soluble in alco- More recently, 20 adverse IQCIX>r>s were identified in a chart re- The elderly. Pethidine had a slower eliinination role in elderly
hol Store in airtighl containers. Protect from light. view of 141 patients given pethidine and considered lO be at high compared with young patients and a reduction in total daily dose
USP JJ (Mepcridine ~e). A fine white odourless risk of de'veloping toxicity;1 high·risk patients were defined ns might be neceswy in elderly patients n:ceiviog n:pc~ted doses
crystalline powder. Very soluble in waler; soluble in alcohol; those wilh renal impoinnent (crcatinine clearance 50 mlJminutc of pethidine.' Aoothcr study concluded that age:-related changes
sparingly soluble in clher. pH of n 5% solution in wai.:r is about or Jess), those receiving patient-controlled analgesia (PCA) with in disposition were not sufficient to warrant modification of
5. Protect liom light pethidine, and those given intravenous pethidine in doses of over pethidine dosage regimcns.1
200 mg dDily for several days. Tiie most common adverse rcac· I. Holmberg L.. 11 al. Compartt1vc dispo$itiOl'I orpt1hidinc and no,..
Incompatibility. Solulionsofpethidine hydrochloride :ue acid- pc1hidinc in old and )'OUfll p:rititn\.5. Eur J Clin Phtuwornl 1982;
ic. They are incompalible with harbitu11tesaltsand loss ofclarity lions were confusion and an.~iety; other reported advenc effects 22: 175-9.
was also seen in an early additive srudy 1 with other drugs inchxl- included nervousness, seixun:s, and hallucinations. Patients who 2. Herman RJ. ~t ol. EITcds or age on mcptridinc disposi1ion. CUn
ing aminophylline, heparin sodium, meticillio sodiurn, morph in< developed advasc reactions were signifteantlyoldcr, more likely Plrormccol Tltor J98S; 37: 19-24.
sulfate, nitrofiuantoin sodium, pheny1oin sodiwn, sodium io· to be taking a benzodiaupinc, and had longer hospital stays than Phaeochromocytoma. Pclhidinc provoked episodes of hy-
dide, sulfadiazine sodium, and sulti!f'uralOle diolaminc. Colour those wilbout adverse effects. Out of the 20 repo11s, 16 adverse pertension in a patient with phaeochromocytoma; the etfccJ was
change from pale yellow to light peen occurred when solutions effects were noted in the 123 patients who received pethidine via suppressed by labctalol.1 Like ocher his1amine-relcasing opioids,
ofminocyclinc hydrochloride or tetracycline hydrochloride"= a PCA pump; cumulative doses for palients using PCA were pethidine should be used with caulion in such pruients.
mixed with pc1hidinc hydrochloride in 5% glucose injcciion.2 ln found to be a significant risk factor in the d<velopment of adverse I. Lawttnc.c CA. Pc1hidine.induccd hypertension in phaeochromo-
the same study an immediate precipitate occurred on admixture effects. cytorn•. 8,\fJ 1978; I: 149-SO.
with ccfoperazone sodium or mcz.locillin sodium; with nafcillin I. Milla R.R.. J1ck H. Clinic~I tffecu of mtperidine in hospitalitcd
medical patien1$. J C/i11Pilonnoco/1978; 18: 180-9. Pregnancy and the neonate. Pethidine has been wid<ly used
sodium an immediate cloudy appearance cleared on agitation.
2. Seifert CF, Kennedy S. Meperictinc is ilivc and well in the new for analgesia during labour. It rapidly crosses the placenta and
Incompatibility has also been seen betw.:cn pethidine hydrochlo-
millennium: cvaluttion of meperidinc usage pa.ucm.s and fre· Iilee other opioid analgesics may cause rcspiratO<)' depression in
ride and aciclovir sodium. imipenem, furooemide.' liposotnal qucncy o f adverse dnt& rcaction!O. PJiormac.otlH!l'OP.'11 2004; 24: tl1e oconalc, although perhaps less so than morphine. RC$piratory
doxorubicln hydrochloride,' and idarubicin.' Solutions of cc- 77643. dep<cssioo varies according to the timing and size ofthe maternal
fazolin sodium• and pethidine hydrochloride mixed in 5% glu-
cose injection turned light yellow after storage for S days at 25°; Efl'ects o n the cardiovascular system. Histamine release dose.
the admixture was stable forat leasi 20days at 4°. was more frequent after pemidine than al\cr morphine. fentanyl, Fetal depression was DOI apparent when deli••c1y OCCUITed within
or sufcntanil given intravenously for the induction of anoeslhc> I hour of giving pethidine, but was present in 6 of 24 infants
I. Pace I JA, Phillips GI... A guide to physic-al compalibility of in1ra-
<wcnou.s drug admixlutt.."-A"'J HOlp Phorm 1966; 23: 409-11. sia.1 Increased plasma-histamine concentrations occurred in S of delivered I to3 hours after injection and in ell ors infants deliv-
2. Nieve~ordcro A ~ d ol Compatjbifity of narco1ic analgesic 16 palieots given pclhidinc in a mean dose of 4.3 mg/kg and ered 3 to6 h0UT1 after injectioo. 1 Ho><"C".'CI', higllcr blood concen-
solu1ion5 with various antibiotics durin& simu1a.ttd Y-$Jle: injt":c- were generally accompanied by hypotension, taehycardia, ery· trations of pc1hidine were seen m infants dehve1'ed within l hour
1ion. A•J Hosp Phom• 198S; 42: 1108-9. thema. and increased plasma-adrenaline coocentrations. Only I of.., intramu.,.,ular dose ofpethidine compared with those deli\'·
... II cross-references refer to entries in Volume A
 Pethidine Hydrochloride 1 J9
crcd I 1114 holrs after uvccto0t1. fhc role of pclhid1nc metabolites Hi1t1mine Hr antagonisu. Sec under Opioid Analg<::soe>. f!'
U..t.:bnil N. uf. lntr:t~ ck•ko..S. o: ~lutL·ut .:Mlin1n:tS1n1ton
w•s uncenain h hu also bc<11 rtponcd: that depressed neonalal J'.108. of ~ndUw dutms bto".' ..,,. J Olwet
llU-9
<;'"""'"'
19~ 140!
rc>ponses pm1<1cd for lhc lirst 2 days of life: dcprtssioo was
~rtlaacd be1n91.'JU- \\ILh 1i.., h1GhtSt ~ofpdlndioc(75 ,..aAOls. Soncc of the IT1QSI scriNIS IDl<l'llC'lions lf1\'C>lvingpelh1· f.nod Bl.~ .J SilC'-S4)K1f'it rh3t"SNCOLIQl(\ICJ a."WI phann~co·
dinc ha\"C been ";lh non-sekctivc MAO!s and ha•-c been man•· dyNnu~.J. af ...,..,,..usc.'llf.-r mcpcndinic u1 clckrty ['IOS:tOpCral1\·~
kl 150 m:: \\1lhlll 4 ll<\Ur'S of dch""'}) 1'1eonales appear able 10 palicm• .,,.. I~ 1997: 31: 13...g_
nicub<>lase pc1h1dinc. allhou~h pcobobly more slowly 1han ftst as enhanced dcptts.sa1• c~ or hypcr<~cillbolny (Stt ln-
ldufis.' n.. amcitJnlS of pe1h1d111• and norpcll11du1c cxcrc~ by laac:IJOll5. abo\"C). Hm\C\'CI'. 1 life-tlvcatcnint in1cract1011 has Hq>atlc lmpaim>ent. l1>c: tcnninal half· life of pdbadlllC was
•h< ~,IC tnc:ieasocd s1;n1focon1ly "-jth 1he nutcmal ~«liv· also been rtf1C"'\Cd bcrwttn pethidine and ul~ilil~. a scl«to~ prolon&cd IO about 7 hours in cinb<U poiicnls 00tnp;ircd wi1h 3
cty mcc" al for mtcf\,i, of.., IO 5 hour$ nnd l110SI of lhc placm· 1T100011nin< midase 1ypc B inhibitor.' Also, sympcorns •iaes- hours 1n healthy subJCCIS, which was allributed IO impa1rmcn1 of
tall) 1n111sfcrrcd pedndone should be ei.crclod by lhe Ihm! day. ti"c of a mild sorotonin syndrome dcvcloptd 1n 1 7).ycar-old 1ht drug·mecabolimg :>divity ofd.., li-. 1 Another srudy con-
Elurunationofpethid1nc lodl upl06 d:l)S m lhc11C0NltS in on- - . taking modo«rmdr (• ro•ersiblc inhibitor o( mclll03m- cluded that ah~ ompairtd hq'<ltic metabolism mtihl confei
Olhcr Sllldy•• inc midase typo Al. nor1nptylinc. and hlhaum ofter slcc "'IS CJY. relative protCClion from norpdbodino toxic~· an patlClllS willl ar·
Funh<rn:fcrencnon lhc lnnSplaccntal nnsfctof pechidine can
en pdhidinc intravcnoosly.' rllo6is. lhac n11;h1 be an incttased risk of cumulatrne to:'Ciacy
be fomd in Prqnancy under Pharmacok1n<ucs. below. Use: of !ht llll~I is011ia:lll 1'1lh pctlaidtnc ~to a drop in because ofslow elimina1ion of the mo1abolnc.l
"'<<ill>cr p!)'CllOloJPall ncw physical efl'cclS were found in S·ycat· blood prossurc and lclhargy in a S4·yoar-old man 1 Sorotonan I 1(Joa.U.He/ Tbt ~ffc-ctof c1rrhosi-1on&htd1ipositioA a.ndtlim·
Cllds born•<> m()(hcr1 who Md r=t>cd pethidine dunng labours syndromo devtloped in a 27-yw--old nian afler lhe '*of pclh1· 1N1.t0ft o( fM1)ttichnc nt min Clin PhantttN>I T1wr l974• 16:
66i-75. •
1't00a1al behaviour docs not oppcart0ti.w been alfcc1ed signaf.
icanrly ~ p:lhid111<. ahhouah i1 h>S been 1eknowledgcd 1ha1the
dine wi1h /i11r.olid-.' symporns rC$Olvcd whtn pethidmc was
stopped. The authors ofbolh studios attnbultd ~1e inlcraction to 2. '* SM.~ ul. Ptt1ysk'CUC: mw.:11boti.sm or mcpc:ndtnt 10
~pcridinc 1n nonnal and cirrllot1t subjuH. Cliu rl10l'fllllCol
rtla1ionsh1p be(v.«n ma1crnal anolecsaa 1n labour and su~· tho inhtbatory action of isoniazid and hllC2011d on monoa1n1nc Tlt<r 19RI; 30: 1 ~3-1.
quen1 inOlna bd\o\·1ow IS by no n\CQns simple.' TllC mules of oxidase.
arly snadics 1ha1sugSC'(ed an excess or ca~s c.f cancct in chil· I. Zombef1 GL. r:t ul $c:ftn: advtr1( ln1t rac11on hawun pedl~·
Precnancy. Some references•·> to 1he pharmacokinetic$ of
d mc and scl ~~ihPt. l.DM~t 1991~ 337: 246. C'N'tcc11on Jb;d ~ ptlhidinc dunna labour.
dr"1! whose mo~ 1crs received pclhtcltnc during. labour llll\t bocn
440. I. Tomson~ C1 pf M•tcma1 Lincti"s ::ind uansplxcn~I p&iS:ts.c or
r<l\ncd by 1 lalcr and larger study.1 potlh1di11c during J•bour. Br J Chn PhnrnuJc."ttl 1982; 13: 6Sl-9
?. Cilllnun PK. Possible StTOton•n syndrome wilh mock>bi:mii.k
I. Morrison JC. n nf. Mcu1horile; ol' n1fptnd1nt: nl011e.d lh ft t• I de· and p«hidu,., Mtd.I .fa<t IYY$: 162: $S4 l. Kuhnen BR. e11 <ti. Disrm•hon of mep:-ridi1\e aind nnrmcpend1ne
l'r<$$i{)Jl, AIHJ o~''" Ci,Wft,"(J/ 1973: ltS: 1ll2-7. (oltn" 1n1 n1ullipie do~s durini bhor.: I mother. Am J Ohctq/
l. liodgktnson R. rt nl. Ooub l~·h1•od comparison of 1M ncun:!be· 3. Gannon R.. ~' u/, boniazid , mcpcridine, •nd hypotcnsion. A1111
l111~n1 Mtd1983: 99: 41~. Coirtc1iol\. 1hkl.: 740, G)'H'<Ol 198S; IS i : ~ll<l-9.
h:avinur u( neontHH fol1<>""1n1 lhe adinini1tr11io11 o( different
doses of nwpc:r1dinc LU lhi.: mochtr, Con Auut1th .~cJ 1918; lS: 4. Das PK, ti of. Serotonin syndrome aflcr concomitant uutnltnt J. Kuhru:n DR. rt uf. OlspofiticJ11 of m cpmdine and n\lrm cpcridine
with line1.olid :md mcpcttd1nt. Cli'1 lef«I DJs 2008: 46: 264-S fClllo' ' ing mufople doses durins lahM: ti fetus and ntO.\JfC. A N1
-IOS-11
.l. llosa MIJ, ~'~' Urinary e\CttllCtn and 1nct.1bolisnl of pe1hidin<
J Oh.Vl.t c_,,,..
<011985; ISi: JIO- IS.
ond •"'l"lhodu,. in •ht newbom. Br J A_,th 1977: 49: 891 -9. Phenothiazines. Prochlnrpt!rt1Wlf! prolonged lhc respiratory Renal impairment. Plasma pro1cin bi tiding of pc1hidme was
4, Cooper l.V. <I al Eh1nln11lon urpe1h1d lne •nd buphlctlM ;,, the deprcss:mt effec1 of pclhidine in ~hhy subjccis.1 llnhal\ced rcpcncd robe dcc1~~scd in ronal discuo and ranged from 58.2%
nowhorn. A-ch Dlll C/1/hl 1977: ~2 : 638--11. CNS dcpttSSion and hype>lension werc ropor1cd when healthy in heallhysubjecu 10 31.8%in antiric paticncs. 1 The5'nie work-
S. BU<k C. Orvil' in P"'P"<Y C'"n A/NfAui11:J 1975, 112: 12&S. subject< were &i~ dtlorpron10:111t in acldi11011 to pcll1idinc;
6 ~nonymous.. To R•ca<i..re hft. L•IC'1 1981; ii: l9 1- l. ers also rCJ>Oncd proloogcd elimination of pdhidine in po1ie1111
lhctc was cvidenoc of i~ N-dcmtlhyln11on of pclhidnit.: wi1h renal dyst\Jnctl()fl.:
7 GoldlosJ • .,,, "' Childhood cane-er. •nt~nwKuJar "'iiorniri K, a.ltd
pcthidia< &•><• d•n•a labour /JA(l 1992: lOS: 341-4. I Steen SN, Yates M. EITccasofb<niqu1mnidond prochlorpcn· Sec also under P~ullons. obo•••
.tine, scpantcly and combmed with mcpuid1M. on the hum1"
Renal impairment. C1U11Qn is necessary "ben pethidine is r<SJWM°'l'C<tlttt. C/in Phn,..NO<OI 1'7>w 1972' 13: IH ('how K. ~I ul Plasma ~citl bindlrta or Pflhid inc in J'O:hcnll
gi\'on 10 p;ilil'lllS "11h ,.,,.111npoirme111; UK 1'""5Cd product on· 2. St:mbauth JE. Wainc.r IW. Drus inttr.inlOft ~ldmt AJ'ld
,.,,. rmal dtsasc. J Pl><•"' PlwnRacol 1913: 35: 94P.
fonNOlltl f\.'C.'Ommcnds Ihle II sllould !IC l\'(>fded in tholll: Wllh ct'ltorpmmnioc.. a IO'Ut combination J Clu• P~ol 1911: Chan K. "o/_ P'Urnl~U)elits of~ ietni\-cntlut pt1l'U·
ll: 140-6. dutc: 1n patecnu ""~ rt'fl•I dysfu1K.1i°"' J Cf;,, PJtat.oro/ 1987;
"""""1mpeinncn~ whtras US pmduct infmn.iion s~ IO 17: Sl6-:U.
uso reduced dosl:s. Evtdcncc nf CNS ei.citation, includanJ sei-
zures and iwilchcs. "' l p:11ion1s w11h rmal msutrocitncy given Pharmacokinetics Uses and Adm inistration
mulllpledoses or pethiclone was 81hibutcd loaccl.Cl>UbtlOll C>fthc Pethidine hydrochloride is absorbed from the gastroin·
mct~bol11e 1lCW'pCfh>d1nt. boell pGlh.~llS Md high no<ptlludino IO Pe1hidine, a phenylpiperid1nc derivative, is a synthetic
pclhadin<: ph<ma concl'fllr.ttlOll nllOS 1
tcstinal traet, but only about 50'/o of the drug reaches opioid analgesic (p.108) that acts mainly as a µ--Opioid
Stt 1t.o mdcr Ph~nnecol:inctin, below. the systemic circulation because of li~t-pass metabo- agonist. Pethidine is used for the relief of most types of
I ~HH nu/ Ac:.:umul~llOt'lofnormcpcnd•nc.•nxhwrnc..
lism. Absorp1ion after intramuscular injection is varia· moderate lo severe acute pain including the pain of la·
blc. Peak plasma concentrations have been reponcd I
,,m, ,,,,..,,, Nf'ltl ••a. N· 111-11
l0tbolnt ot ~UW, in p:Hi'l>l'KS "•1h tc1Q1 (at.hKl: or a1KC'f
to 2 hours after oral doses. It is about 60 IO 80% bound
boor. It is more lipid soluble than morphine and has a
less pOlcnt and shorter las1ing analgesic effect; analge-
Interaction:; 10 plasma proteins. sia usually lasts for 2 to 4 hours. Its sholt duration of
For interactions assoc1a1ed w11h opioid analgesics, see Pethidine is metabolised in the liver by hydrol)'Sis 10 action and accumulation of 11S potentially ncurotoxic
p.107. pethidinic acid (meperidimc acid) or dcmethylation to metabolite norpethidinc on repeated dosage make·it
Very severe reactions, 111ch1ding coma, severe respira· norpethidine (normeperidine) and hydrolysis 10 nor· unsuitable for 1he management of chrooic pain. Pethi·
1ory dcprcss1011, cyanosi:.. fl11ll hypo1ens1on have oc- pethidinic acid (nonneperidinic acid), followed by par· dine ha!> 11 weaker action on smooth muscle than mor-
curred in pa1ienls r~1vmg Ml\Ols (including mo- rial conjugation wilh glucuronic acid. Norpethidine is phine and ilS lower potential to increase biliary pres-
c!obcmide and selcgiline) and given pethidine. There pharmacologically ac11vc and ilS accumulation may rt· su\'e may make ii a more suitable opioid analgesic for
an: also repons of hyperexcitability. convulsions, tuch· suit in 1oxicity. Peth idine is reported to have a plasma pain associa1cd w11h biliary col ic and pancrca111is (bur
ycardia , hyperpyrcxio, and hypertension. Pe1hidine elimination half-life of about 3 to 6 hours in hea lthy see Biliary-tract Disorders, p.107). It is also used for
should no1 be gi,·cn IO patients receiving MAOls or subjects; the metabolite norpe1hid ine is elimi111He<.I premedicalion and as an adjunct 10 anaesthesia. It has
within 14 days of 1heir discon1inualion. Use of pethi· more slowly, with a half-life reported to be up to about hccn giYcn with phenothiazines such as promelhazine
dine with phen0thiazincs has produced severe hypo- 20 hours. Both pethidine and norpethidinc appear in 10 achieve basal narcosis. Pethidine has little eftCc;t on
tensive episodes and may prolong the respira10ty de· the CSE Al the usual values of urinary pl-I or if the cough or on diarrhoea.
prt.-s.~ion due 10 pethidine. urine is alkaline. only a small amount of pethidine is For the relief of pain, pc1hidine hydrochloride is given
excreted unchanged; urinary e.xcretioo ofpethidine ond in oral doses of 50 to I50 mg every 4 hours if noccs-
Plasma <.'Oncentrations of n01pCthidine ore increased by
norpethidine is enhanced by ncidificaiion of the urine. sary. h may also be given by intrnmusculac or subcuta·
ritonavir. wi1h a resultant nsk of toxicity: use toge1her Pethidine crosses the placenta and is distribulcd mto
should bt •~oided (see alro 1>.107). neous i1tjec1ion in doses of 25 to I00 mg and by slow
breast milk. inlravcnous injccti0tl in doses of25 to SO mg repeated
Antlbacterials. See MAOls Mlow lor 1nlcrn:tl0n$ bctweon
pechidlnt ftl\d /soni"1i<hnd lmedid. vRe•IC\\-s. after 4 hours. For posroperolm! pain, the BNF 59 sug-
Ed"-:i.rd$ OJ. rt al C\inial ptQrn~uM."ttt> of pcchl4111t 19Sl gests that the subcutaneous or intramuscular doses may
Anddepress.ants. For rtfettOCC 10 possible eases of serotonin CluoP/-"""'"''<'lil•O<t 1982; 7: 421-33.
S)'lldlom< assoctalcd" 1lh -ofpclhMlinc ~SS/Us,~ Opioid
be given every 2 to 3 hours if necessary.
t.toorc- RA. cl nl Opi::itc mcuhol•stn and ucrcUOt,, Bll•lfWt,~
A111l~ics under Interactions of FhlO\ttinc. p.•28. Sec also (7;,1A_,1bniol 19$7, I: ~5· In obstetric 0110/gesio SO to 100 mg may be given by
MAO!s. bck>\\· intr1muscular or subculaneous injec1ion as soon as
Administration. TllC ol11nano11on h:ilf·hft of pethidine \\l\S
Antiepilepd cs. OplOtd anolaosics and berb1Nrates can be CJt· prolo.,scd •nd plasma clc:nnc:c dccn:nscd "htn &i\'CI\ pmopcr· contracoons occur at regular intervals. This dose may
pttted IO have acld111'e C'1'IS dqnssanl ttfccis. Prolon!!Cd scct.- 31ively compared \\ilh poslOpmlliYO!y.1 be repeated :ifltr I to 3 hours ifneccssaiy up to a max-
1ic>n "Mh pcthtdin.! 111 1ho prrserocc of pheiobarl>i10Fhas also
bctn annb<ud IO 1nduc:1ioo ofN-<lcmdhylauon of pc1h1d1ne, rt· o...in& bbour lhc phanoucotintttcs ofpclhidino may depend on 1mun1 of 400 mg 111 24 hours.
suh1n: in the enhanced fooll81ion of the potentially ncuro1oxic hov. ~ issiv<n In 1compansonofintramuscular injcc:t10n 11 d1r- For premedicJlllon 25 to 100 mg may be g1~en inrra-
metabolite llOl'pclhid1,1c. u The hcpahe metabolism of pclhidino fcrcn1 siccs. absotpilOll of pclhidine from !ht g)uta.. muscle was
impaired and tllc dclloid muscl• was preferred.:
muscularly about I hour before surgery. II may also be
appc3rJ lo be enhanced by phml'lom: ~ 1ogc1hcr n:sullcd in giYen subcutaneously in similar doses. As an adj unct
r<dut:cd half.life and bioa•'lilabohry in hcahhy suh,.as; blood 1'10 s131istically s1rniricant daf!'C!rtnces were found '" pharmaco-
concentn1tions of norpc1h1dinc "cro incrc:ucd l kit1t:tic parameters for dcllNd and gla•cal 1n1namuscular UlJCC- to anaesth~ia 10 to 25 mg may be given by slow in·
I. St•mbwah JE. ., ol A pcll<n1l1ll1 to.<oc: ...... in1<rac1ion bc- lions in oldcrly pos1opcrali•• paticnis.> However, sub&an111I travcnoos injection.
l\\"\."tft pe:llh61tM: (meprridu~) lll\d phcnobttbtt0ne. Lont:1:11977; intap.tienl \'lriabilil)' w n$ no1t'd for both SlltS, • rid 1he 1u1hors
I: 308-0 For details or do~~s in children. sec below.
sugge.<lcd 1h>1 niorc rapid Ol\d predict:tble roulcs such u inllllVC-
2. Sc;unhaujth JE • .,., fll. 'The ctlttl nf1>twMbarti11al on Lhc llflellboo nous i1tjcc1ion may bt more appropriate for pos1opcra11ve use in Admmlst.ration. In ocldi1ioo 10 ~,. con>cntional roulos p:thi·
liJ•tl or 111i:1><ridi11c '" normal \·~IUf'UCCr1 .I Ct/11 P/wrtHut'OI
197S. 18: 482-QO, the oldcdy. d111c hiu been s•vcn tpic!urolly, 1-' inornpcritoneally...3nd inlralh·
f\11'1d S\tl. Krc1schinuir KM. Effect ufphcnyioin on 11lcpcridinc: I Tar.tSCil A. et ui P1Hent<On1rolled 1n~l3C1 1 c 1Mrapy. pan l.
ec31ly."' h hos 3Jso been given by various routes as lt poliml·
cltartnte and nonncrcric1ine form'lll(\41 Chn Pha1macol Tft:r plurtucokintocs of pelhidine: '" 1M per· 1.nd pos1o~ rnllve pt· conorolled sys1cm.1°'1l Howc\or, som" consider that 1hc use of
IQR l ;~O: (•80-(. nnd'.t. Qi,, Phftnt1Mokiur11 98J; 7: 149-6J pclhidin.- $hould be avoided for palicn1~1rollcd analgesia bt·
The symbol t denoau a prtparotion no long(r ~ct1\'ely marketed The symbol® denoits n subs1nncc whose use may be rcwicacd in cenain sports {sec p.vii)
120 Analgesics Anti-inflammatory Dn.Jgs and Antipyretics
cause of 1he increased risk of no1)l"thidine-induced seizures" 2. Diab FH. Cf ol. Efficacy and safety of combined mepcrtd1ne and Phe nazone {8AN.tlNNJ
(see also Incidence of Adverse Effects and Effects on the Nerv- midazolam for EGO sedation compared wilh midn.ol:am alone.
AmJGos"wnt<ro/ 1996; 91: 11 20-S. Analgesi'le; ,A.ntipyrin; Antipyrine; AzophetV.Jm: Fenatsoni; Fena-
ous System, above).
3. Wuna L. rt al. The compari.wn of micbwlam and top'cal lido· zon: Fenuona: Fenazonas; ~ Phenazonum; f'hen)okl·
I. Perrill SW. frtdunl pethidine in labour. a s1udy of dose re.. cunc s·p-ay versus the combination of miduolam. mcperidine,
quin:.menes. Ano"slhesio 1980: 35: 380-2. imethylpyrazolone. I .5-~2·ph!nyl+pyrazo'>n-J.one.
1nd topical lidoc.aine spray to sedate J)'tic:ntJ for lipper endosc~
2. Husemcytr RP. 4tf q/, A study ofpcthidi.nc kinetiC$ and 1nalgesia py. Gosir0;n1w End0tt 2001; 53: 289-93. <Dei-oa30><
~;;:~~d~i~::;!~';;'1_,1'~,;:~8,.~~=~~i~~:~~~:ui~,~ tYTIC COCKTAILS. Lytic eockla ils consisling of chlorpro- C11H ,1N20 = 188.2.
3·:f~~ii: ~~~:! 1:::fo~0;:t~~.c;~~!:~~d 11;W,t~~ m112.ine, perbidinc; and/or promethazine haloe been given in·
travenously in some countries for the management of pre-cc·
CAS- 60.80·0
ATC - N0i6801; S02DAOJ.
3S5-7. lampsia and imminent ecl:.mpsia. However, 1hc use of ATC Vee - QN028801: Q50WA03.
4. Blythe JG. e1 al. Continuous posto~li\.'t: t~dural analgesia phcnothiazines is generally not recommended late in preg· UN/I- TJCHAIBSIH
for &fO«Ologic oncology patients. Gyrttto/ Oncol 1990: 37: nancy, and other lteatments are preferred for hypertension
30?-10.
S. Colbert ST. ti o/. An assc.wncnc of th<: value of in~peritoneal {see Hypertension in Pregnancy, under Hypertension,
mcpcridine for analgesia postlaparoscopic tubnl liptK>n. Annth p. J290); the management of eclampsia, which is the convul-
.Anolg 2000; 91: 667-70. sive phase, is discussed on p.5 J2.
6. ~~J~:~~i~~· ,:,o~l~~~~~~'~he~~~d~=~~! ~':~:~: Lytic coclctails have also been used for sedation and analgesia in
tee1omy: randomiied trial. World J s,.,, 2002; 26: 1432~.
children, by intramuscular or occasionally intravenous injection.
7. Acalovsc:hi I,~' ol. Siddle block with pelhidtnc for pcrincel op.. However, there is a hig)l rate of therapeutic failure as well as se-
cntions.BrJAnowh 1986; 58: 1012-16. rious adverse effects wilh such combinations, and the American
8. Yu SC. tt al. Addi1k>n of mcpcridiM to bupiv~c:ainc for spinal Academy of Pediatrics' bad recommended lhat alternative seda-
1naosthcsia for ccc11reon section. Br J Anotsth 2002: 88: tives and analgesics should be considered. Lytic cocklails are nor
379-83. the most appropnate means of sedation for short procedures
9. Vrankcn JH, et al. Pl11ma conccnrra ti~ns of meperidine and since paticnlS must be inonitored for about J hour before the pro-
normeperidine following continuous intr3!heQll mcperidine in
patients whh nc\lropathic can«r p1in. Acta Anauthtsiol Scond cedure while the drugs lake clfect. and for even longer during the
recovery period.2 Pharmacopoeias. Jn Eur. (Jee p.vii).Jpn. and US.
200S; 49: 66S-70.
Ph. Eur. 6 .8 (Phena.rone). White or almost while Cl')'S!allinc
10. ~We! ~h~·~~:~·,~:~:l~=!~!~;~!°;;i~:aan~tif:i~~ I. American Academy of rcchatrics Commince on Drugs. Reap-
praisal or
lytic coclctaiVDemtrol, Phcnergan, Ind Thorazine powder or colourless crystals. Very soluble in water. in alcohol,
and in dicl!lororncthllle. Protect from lighL
Clin An.,th 1996; 8: 4-3. (DPT) for lhe sed11ion of ehHdren. J>ediotrlrs 199S: 9$:
11. Kee N, et al. Comparison of patient·con1rolled epidural a.nalae· 598-602. USP 33 {Antip)-rine). Colourless crystals or while crystalline
sla wilh patiui1-conttollcd inlravcnou.s analtesta us.ing pethj .. 2. Bar st SM, ff al. A comparison of propofoJ and Dcmcrc'PPhcner- po"-'der. ls odourless. Very soluble in waler; freely soluble in al-
dine o r fen1anyl. Anou11t /11rens ive Cor4 1'97; 25: 126-32. gan-lboruinc for brief, minor. painfUI pnxcdurd in a pediatric cohol and in chlorofonn; sparingly soluble in etJ1cr. Solutions arc
12. Sharm1 SK, ti al. Ccsart.11n dcliYcry: .a nndomiud trial of cf,;. hcma10Jogy-oncolo3y clinic. Jn1 J Ptdiolr Hemato/IOnco/ 1995;
dura1 vcnus p:iticnt-concrolled mcpc:ridint an1lgtti1 during a- I: S87- 91. neurral 10 litmus. Store in airtight containers.
bor. Antsth.,iD/ogy 1997; 87: 487-94.
n . Chen PP, ti al. Paticnt~lloltcd f>C'hidi ne oner major upper Shivering. For rcfc:rence to the use of pethidine in the manage·
P henazo ne and Caffeine Citrate
ment of shivering associated with anaesthesia, see Wlder Ad·
~:::_iX,'!~~=~ ~00~~ ic[6_~2~pidural and in1ravenous verse Effects ofGeneral AnaWhetics, p.1935. PClhidine has nlso Antipyrino-Coll'enm Citric:um; Fenuona y citrato de cafeina:
l~ . Hagmeytr KO. rt al. Mtpcridine·rtl1ted seizures associ~ tcd been used lo treat amphOlcricin B-induccd shaking chills.1 Migrenn
with pa1tent-coctrolled analgcsi11 pumps. Ann Pitomtoco1hcr I. Burts LC, ~~al. Meperidinc f'or the treatment or shaking chills
1993; 27: 2~)2. CDet<a30H M Ko<j>e1<11<1 lJ>iTpaT
and fe~. Arch Intern M ed I9SO; t40: 483-4.
UN/I - JZ4L017NPG.
Administration in chHdren. Pethidine is licensed for lhe re· P reparations
lief of moderate 10 severe acute pain and for prcmedication in Description. Phcnazonc and caffeine citr• te is a powder usual·
children. However, the BNFC 1010/JJ does not recommend its BP 1010: Pe1Jlicj;ne ~~.. T.ltilets: ly containing phena:z.one 90%, caffeine 9'Yo, and citric acid
use in this patient set. ~~';.."'::"~~-~O<\:~~ rnonohydratc I%.
For lhc relief of p2in, pethidine hydrochloride may be given Proprietary Preparations (details an: given in Volume B) Pharmacopoeias. In Jpn.
orally or by inll'llmuscular injeccion in doses of O.S lo 2 mg/kg, Air" Cltyc<; Mop..-ot Auttrlo: Alodao: &If-' Oolant"1c lmu.: Dolonti-
repeated after 4 hours if necessary. For postoper<1tiv~ pGin, the N: DolooaJ: Oom:>t Conod.: Dtmerot Chile: Oetncrott. Cz.: DolWc Ph e nazone Salicylate
BNF .S9 suggests that this dose 111J1Y be given intramuscularly Ger~ °"'"'1bn: Hung.: Dol"'l""' brock DofeSIJne: Philipp.: Demo. 0..
c'uy 2 to 3 hours if noccssary. mad: PoL: Oola~~ Spoln: Ool;in""1o: Tull<.: Aldclarc USA: Antipyrin Salicylate: Fenat.sonisalisylutti; Fenazona saf1c1lalo:
Demerol: v...u.: .~. Fenuonsafcylat: Phenazoni Salicylas: Saiipyrn
For prcmedic-•lion, the BNF .S9 suggcsL~ &iving 0.5 10 2 mg/kg Hulti·ingrediont: UK:~"" Pll)(), USk Mepmmo
intramuscularly about I hour before surgery. O:Oe11aJOHa ~T
See also Ly1ic Cocl<Wh. below. C 11 H 1zN 20.C 7H,Oi =
326.3.
CAS - 520-07-0.
Edampsja and pre-eclampsia. See Lytic Cocktails wider Se- Phenacetin (,1NN) ATC - NOZB801; S02DAOJ.
dation, below. ATC Vee - QS020AOJ.
Accto·p-phenetidide; Aatophenetidin; Acct)'fptoenetidir( Fen-
Pain. Pethidine produces prompt b<lt short·lasting analguia, and acetin; Fenaccli-la: fenase~lfl( Paracetophcnetidn: Phenacetine: Pharmacopoei;as. Jn Fr.
may be preforrc-d lo morjihinc when rapid control ofacute p1in is Phenacetinum. p.Acetophenetidide: 1'-E1hC»<)'Keunilide; N-{1·
required. It has been widely used in ob.o;tclrics to control 1hc pain E~acet.mide.
Adverse Effects, Treatment, and Precautions
oflabour (although the BNF .S9 nOICS thal l'l'lOlJlhine or other opi- Phcnazane is liable to ~ive rise to skin eruptions and in su=pti·
oidurc often p<efem:d for obstetric pain). and for postoperative
Cl>eHaueTMH ble individuals even small doses may have this effect. HyperseD-
pain reliefafter caesarean section or Oll>Ct swgieal procedures. CooHnNO; = 179.2. sitiviry reactions and ncphroloxiciry have been reported Large
CAS - 62-44·2. oral doses may cause nausea, drowsiness, melhacmoglobinao-
In a study of patients wilh intrac:cablc pain the minimum effecti'-c mia, coma, &nd convulsions. Allhough the benefit ofgastric de·
analgesic blood concentration ranged f rom 100 to
ATC - N028EOJ
ATC Vet - QNOZBEOJ. contamination is wiocrtain, acrivatt:<I charcoal may be given to
820 nanogramslmL (median 250 nanogramslmL) in JS of 16; adults or children who have ingested more than 20 mg/kg wilhin
the remaining pa1ien1 failed lo ohlain analgesia whh pethidine. UN/I - EROCTHO I H9.
l hour of presentation. Thereafter, symptomatic and supportive
Additional measures ,.-ere
considered rn:ccssary 1if the minimum thenpy should be given as appropriate.
effective c:onccntnllion exceeded 400 ~ms/ml..
Pethidine has traditionally been given b) intennittcnt intramU$- Effects on the blood. Phenazonc can cau<e hacmol~ie anae-
cutar injection in the lrcatment of acute pain. bur inconsislent mia in certain individuals with a deficiency ofG6PD. Episodes
pain relief can be cx,pectcd because of flucruating blood-pethi· of agranulocytOSis were rcported2 in 6 women ming a crcarn
dine concenirations;· eontiOUOU$ intravenous infusion might be containing phcnazonc; all recovered on withdrawal.
rnorc effective for acute pain. Fur reference lo use byothet routes I. Pranktfd TAJ. )lcmolytic cffccu or dru~ ~nd chemical agt:nts.
see Adminisuation, above. C/in J>hort111Jcol Tloco· 1963; 4: ))4-SO.
Adverse Effeds and Precautions 2. Dcl3nnoy A, Schmit J-C. Azranufocytosis after cU11neous C"On-
I. Malhtt LE. CHynn CJ. The minimu1n effecth~ analgesic blood tact with phcnu.C'lne. &r J Ho•"!atol 1993~ SO: 124.
concentnlion of pethidine in par~ts w1lh. intractable pain. Br J Phenacetin may C<'luse meUlaonogJobinnemia, sulfhaemo@lobi-
ClinJ>hormoco/ 1982; 14: J8s-90. nacinia, and haemolytic :111aemia. Effects on the kidneys. Phenaz.oue is considered nephroloxic
2. Edwards DJ, ~t al. Clinic.al pharmacokinc1ics of pethidine: l93l. Prolonged u.. of large doses of analgesic mix1Ure$ concaining but only limited clinical information on phenazone is availuble
Clln J>hurmocolrin<I 1982; 1: 421-33. phenacetin has been associated with !lie development of renal bo:cause it has been mainly used \vith phcoocctin. 1
soCKlE·CCLL CRISIS. Concern has been expressed over the con· papillary necrosis (see Effects on the Kidneys, p.102) and transi· I. Pn:scon LF. Ana1gca.ic ncphropa1hy. a reaws:sment of the role
tinued use of pethidine for analgesia in painful crises in sick· tional-ccll carcinoma of the renal pelvis. of phcn~c:ctin a.od oiher analgHics. Drugs I 9R2; 23: 75- 1'49.
le-cell disease. Control of pain may be inadequ.rc and doses Porphyria. Phenacetin is considcted to be Ufl.S<lfe in patients Effects on the skin. In a summary' of77 easeJ of fixed drug
commonly used to manage crises may lead 10 accumulation of eruption pheoazonc derivatives were considered to bt the C<'lusa·
with poiphyria because it has been shown 10 be porphyrinogenic
norpcrhidinc, the ncuroexcilltory metabolite of pethidine, ina11fma/s. tive agent in 9 of the 14 cases thal wm severe generalised reac·
and prccipilale sciwrcs. •.l Sec also Effects on the Nervous tioos.
Sys1em, above. Uses and Administration I. SwbbS.ttol. Fi•eddrug crupo;ons: 77u- from 198110198S.
I. Pryle BJ. ~I ol. Toxicity of norpethidine in sick.le cell c:risis. BMJ Phenacetin, • para-aminophenol derivati'"'• has 1na lgesic and Br J O.rmotol 1989; llO: 583.
1992; 304: 1413-9. antipyre11c p<operties.11 was usually given wilh aspirin, caffeine,
2. Hmis:on JFM. ~' al. Pcrhidine 1n .sickle cell CTisis. BMJ 1992: or codeine but is now linle used because of adverse haematolog- Hypersensitivity. lmmcdiace a\ICfl!iC rcacrioos to phcna:zonc
~:112. ical effects and nephrotoxiciry. have been repo<ted.'' In onepatienl leucopenia was detected 8
weeks latcr.1
Sedation. Some refcrcnces•·l to tho use of pethidine for cndo$· Preparations J. Kadar D. Kalow W. Acute and 1.. ten1 teukoptn;c rcxtion to anti-
copy. Propd etary Preparations (de1ails arc given in Volume B) pyrinc. Clin Phormocol Thtr 1980; 28: 820- 22.
I. Bahal·O'Mara N, ~
al. Scd:>1ion with meperidinc Ind mid 3~ Mult;.mgr~ont: C..: 0i">'1t. M>-unalf; Hunl-' Anl'-ralg«:•: Oolor. 2. MeCrn. J8, ~'of. Allergic reaction to antipyrinc. a marker of
iolam in ped111ric p21ients undergoing endoscopy. £11r J Clin hepatic cn.iymc activity. DJCP Ann Phormoco1/~,., 1989; 23:
rhormott>l t994; 41: 319-23. 38-40.
All cross-references refer to entries in Volume A
 Phenacetin/Pheny!butazone 12 l
Porphyria. Phenazonc is considcted IO be unsafe in paticms
with porpbyria because it has been shown to be porphyrinogcnic
innnimals.
Interactions
Phenarone atreas the metabolism of some other drugs and 1ts
own metabohsm is affected by other drugs thtt increase or re·
l?henylbutazone (&WINN)
duce the activity ofI i - enzymes. !Ma6one: Fenilbutazon: feni!llut.uona: Feni'butazonas; FC!\)'lt>-
uwon. fenylobu"..uon: fenyi.1ibutatsoni; Pl'i<!n)ibuWone: Phc-
Pharmacokinetics (phena zopyridir.e) l'l)b.n.aun.rT< '>·Butyi-1.2-diphenylpyruoliciine-3.5-0one.
Phcnaione is abso<bed from lhc gasll'Ointestinal tract and rcaJt
plasma ccncenlrations oocur wilhin I IO 2 hours of ingestion. h ~111M6yra!OH
Pharmacopoeias. In f'o/. and US.
is di:;tnbutcd llvou&hout the body fluids and concentrations in USP 33 (Phcnuopyridine H)'dnxNo.<ide). A li&hl or d•ri< red t0 c ,~H 2cN 20 1 =308.4.
the saliva and breut milk reach about the same le,.., ls as U>Ose in dark violct crystalline powder. Is odourless or with a slighc odour. CAS- 50-33·9 (phenylb~tozonej: 129- 18·0 (pllenylbuto-
plasma. Less than 10% is bound to plasma proteins ind it has an Soluble I in 300 of cold waler, I in 20 of boding water, I in 59 zone sodium); 4985-25-S (phentlbutozone piperozine).
elimination half-lifeofabout 12 hours. Phenazone iunetaboliscd of alcohol, I in 331 ofchloroform. and I in JOO of glycerol: very ATC -MOI MOI: M02AAOI.
in the liv<:r to 3 major metabolites 3-hydroxymcthylphenazone, sl igl1lly soluble in ether. Sloie in airrig)Jt containers. ATC Vee - QMOIMOI ; QM02AAOI .
4-hydroxyphenazone, and norphen:u.oue. Phenazone, 3-hy· UN/I - GN5P7K3T8S.
droxymedlylpbeouone, and glucuronidatcd metabolites are all Removal of stains. Phenazopyridine stains may be remo,.ed
excreted in the urine./\ small portion··may be eliminated via the from falxic by so.king in a 0.25% solution of sodiwn dithionite.
bile. Adverse Effects
Phenazopyridine hydrochloride has caused sasno1ntestinal ad-
Uses and Adm inistration verse effects, headache, and rashes. Hcpatotoxicity. hllCITlolytie
Phcnuone is an NSAID (p. 103)and has been given 01~lly; phcn- 1n1emia, methnemoglobinaemia, and acute renal failure have
azonc and catreinecitrnte and phcnazonc salicylatc have similar- also been reported, generally associated with overdosage or with
ly been given orally as analgesics. therapeutic dcses in patients with renal impeim1enl Cryslal de·
Solutions concaining about S%ofphenazone have been used top· posits of phcnazopyridinc have formed in dte urinary Inlet
ically as C2r drops in disorders such as-acute oriris media (bul see Abnormal color•tion of body tissues or Ouids may occur. Urine
below). is tinged either 0111nge or red and undercioU1cs arc apt to be
Phcnazone is used as a test for tbe ae1ivit)' of drug-metabolising sunned
enzyme.~ in the liver. Pharmacopoeias. In Eur. (sec p.vii),Jpn. and US.
Effects on the CNS. Aseptic meningitis, ,.;th dis1inc1episodes
of lever and confusion. was associated with the use of phenazo. Ph. Eur. 6.8 (Phc<iylbutaiooe). A whiteoralt00$t white, crystal·
Diagnosis and t esting. A review' of nonnal plasma-phena-
pyridine.' line powder. Practically insoluble in water; sparin!!IY soluble in
zonc phanrocokinetics, urinary metabolite disposition, aod total
I. Herlihy TE.. Phen.azopyrldinc: and aseptic mcnina;.itis. Ann llurm •lcohol; it dissolves in alkaline solutions. Protec1 from light.
body eleorances of phcnazone in the presence of ci1Thosis, fatty
~d t987: 106: 172-3. US P 33 (Pher¥butaz.onc). A while lo ofl~white, odourless. ays·
liver, hepatitis, and cholcstatis.
t«lline powder. Very slightly soluble in water; soluble in alcohol;
I. S1 Peter JV. Awni WM. Qu:.ntifyine hcpa1ic (unclion in the: pres· Overdosaae. A 2-year-old child dev<:loped cyanosis and mcth· freely soluble in accconc nnd iii ether. Store in airtight containers.
cncc of liver d1'1C'tk wi1h phcnntone (anlipyrine) and it$ mc11b- aemoglobinaemia after ingcs1ing at most three 200-mg tablets of
olitcs. CllnPltornu~lt~t 1991;20: 5MS. phcnuopyridinc hydrochloride;' she recovered after treatment Profile
with me1hyhhioninium chloride. Acute renal failure bas been re- Pitenylbutazone. a pym:oione dcrivnti1..,, is an NSAIO (p. I00).
Odtls media.. ll1cre appears to be no justification' for the in· ported in a 17-ycar-old HIV-positiv<: girl, with no previous histo- Howev<:r, becauseofos toxicity and in particular its adverse hac·
clus1on of phenazonc in topical prepanitions used in 1rea1ing ry of kidney disease, who took 1.2 g of phenazopyridine in a su- maiological renctio11s (sec Etrec1s on the Blood, below). it is not
acute otitis media (p.196). It is presumably included in such icide attempt' used as a general analgesic or antipyretic. Although phcnylbula·
preporations because it is belie,..,d to hove a local anti·inflamma- zone is effective in almost all musculoskcletal and joint disonlcrs
I, Gold NA. 81thoncy \VG. Mc1hemoglobinem11 dUit to ingcslion
tocy and, therefore. anal~c action. It would, howc=. seem of ot mo.st thrcf pill.$ ofpyridium in a 2·yca,..otd: case report and including anky105ing spondyihis, acute g0<1t. osteoa.1hritis, and
unlikely ~iat phcnozone would have any action on the skin of the «View. J £nitrt MrdlOOl: 2S: t43-8. rheumatoid a?1lvitis, it should only be used in acute conditions
intact t}mpanic membrane and, thcn:(ore, on the p•in which is 2. On<krAM.tln/. Acu1c: renal f1llure due 1ophcn11opyridine(Py· where less toxic drugs have failed. In 1he UK its use has been
due mainly co the stretching and distention of the m:mbrdne. ridiurn., overdose: ca~ repon and review of the lheraturc. P«IJ.. restrict~'<! to the hospital treatment of ankylosing spondyliris
otrNepltro/2006; 2t: 17611-4.
l. Carlin WV. '' there any justific:.lion (or usina phoM.'.>zonc in 1 wvesponsive to other drugs. Initial oral doses of up to 600 mg
lo~I opplication prCKnbed for 1hc 1rca1mcn1 of acute oc.i1i1 me- Precautions daily in divided J~ have been used in the treatment of rhm-
dia? 81>/J 1987; 294: 133;. Phenazopyridine hydrochloride is contra-indicated in patients matic disordets. After I to 3 days, the dose should be reduced to
Preparations with r~nal impainnelll or severe hepatitis and should be used ~ie minimum ctrecti'" amount, usually 100 to 300 mg daily;
with caution in those with G6PO deficiency. Treatment should tr""tment should be given for the shortest period possible, up to
USP 33: ~ at>d Beozoc.00• Ot.-c 5ou.ort Atlipymt. llM."Oc>.i,.., be stopped if the skin or sclerae become discolouml; this may a usLoal maximum of I week. lftreaunent is cxp~'Cled to continue
>nci "'-.-lopnme H)drocl-lo<idc Obc SoMiO<\ 111dicatc accumulation as a resole of impaired ~n~ l excretion. for more tluin 1 week, blood cell counts should be pcrfonned
Proprietary Preparations (detoils arc given in Votwne BJ Phenazopyrid1nc may interfere with urioolysis based on colour before and regularly during therapy; monitoring of hepatic ond
Austral: Eraso•t: Gor.: Eu.i-t.d. Mlr""·Krarit: Migr.i<Wl Pl>ena..'Or"C Mono reactions or ~'J)CCtl"OlllCtJY. renal fu.netlon is also reconuncnded. Reduced doses arc recom-
~-.nt; Honi Kong: Trope>: frf.: Tn;,pox: Pol.: Antotatr,n: S.Afr.: ""- Staining ofcontact lenses may oe<:ur. mended in elderly patients.
'"""' Olo.f'llent. Y•ne:.: DIA,,,.,.. In some 001111lrics phcnylbutazone has also !teen given as• rectal
Multi· inaredient "'r" Aquo lent Colinoc 8',umolt: Bi<l•on: Bideon
Pharmacokinetics suppository and applied t0pieaily formusculoskclcloi pain and in
free: C..-osporirc c . . _ CSt Clari sofl: Con Cr.sulomicina: ltix KA· Phen:i.zopyridine hydrochloride isabsod>ed from the gastrointcs· soft-tissue injury. lt has also been given intramuscularly as the
lopsi~ ll!f'O<dj: Ollllex G: Oloam. Biotic. Otomo~ Otocui: Otonorth- linal tract. It is exctelcd m.linly in Che llfinc; up to 65% may be
ia. Sotl<1rum Usuaix: VdM. Av"'o!: A.nl~n: Avstrio: AsllYN Efeumf;
sorlium salt Other sails of pl1enylbuU20tie thal how been used
excreted as unch&lged phenazopyridinc and 18% as paniccla- in musculoskekta~ joint. and soft-tissue disorders include the
Collo Seit: Ota;gan: 8 1lr~ Hemcrtn>t Otocalm;oe; O..rte 1-fomosa. moi.
tqirt T~ Braz.: Ane<tesiolf: e.p..m.!."<l<.t: Osmotolt. Ot"'"¢ calcium, meS'Jllatc. and piperazine •alls.
Conad.; ~ Cz.: ~ Otnm.: IC.c&ot Fr.: BnAt>c: H~C; Otp•x: Uses and Administration
Ger.: Cofrcemcd Nt: Otatgan: Gr.: Otit Hone Kone: Neo-Active Breast feeding. No odvcrse effects hal'c been seen in b<cast·
Antimeumatic: Huni.: Olipix Ind/a; Tyt;>: 1.,.,.1, ~ br[Jrops: Phen32Xlpyridinc ls an azo dye that exerts an anal~esic effect on fed infants whose mothers were @i""11 phcnrlhut~1.one. and the
Otidin: l ral.: Ota~ OtO<T'idotlt: Oto;>« Neth.: Spall Nt: Nor#" An· lite mucosa of the urinary trncl and is used to provide symptomal· American Academy of Pcdiotrics conslden Iha! it is therefore
ontu"1t;ca: fanalgin: NZ: Aun1pt f'Mfpp" !lur>lg.an: Port.: - A t ie relief of pain and irritability in conditions such as cystiris usually compatible wiU1 breast feeding. Ho""''er, UK licen~cd
Rus.: Woeap (<Jlcv,,,,..,,~ oq,.,c (OT~~ Ctn""" (01'.peMO<C);s.Afr" (p.2379), prostatitis (p.2382), and urethritis (p.215). Phenazopy· product infonnation stales that phenylbutazonc should be avoid-
Adco-Olised: Al.~alytt: Al.r11•Jl(t: "'1ron• Forte: Covanaine: th<<>t: ridine hydrochloride has been gi\..,n in usual oral doses of about
C1<>l'ntn Fort<t. U'Mrsal E•mlle °"'P't: s1neopore: HECt: Tt0peic ed during breast feeding as small amounts are distnbuted into
200 mi three times daily after food. If &iven with an antillacterial
Spoi"' ~ ~!: Otooedol: !'l:>mlda Heridlst: Qvin'>pedo<: T<I> Ina.st milk.
!etas Qu;mp.-: Swed.; Ooleront. Koffazon: Swru.: Ot..'g>n: Otipax; for the treatment of urii1ary-tract infections (see below), treat-
I. American 1\c:ad.:1ny of Pedi:urics. ~ 1ransrcr or dt'UI~ and oth·
Otos.ll; Otc.thticond. Ul<T" Otipax (0r""'1<cr, Otisol (Onoo.•~ USA: ment should usually not exceed 2 days. aithOtJO.,/t lower dose.5 er chcmials t1110 human milk. Pt1ditrtria 2001: 108: 776-89.
e..
A"'lll': All"'&<"C ~~Otoe Cy-Ge!ic; ,Gosoc: Ncalic
QI( Edgt. Otoc'*"o. l,.mpogesict V<nn: A.Jdocai,,.j:
Orirt OtodOnj: Olc(rir.j .
°'"'
0...-.itl;
have been ~iven u part of a combined preparation for at least a
week.
IR<tired M•y 20t0J Conection. Ibid.: 1029. lllso availoblc 01:
h 11 p :l!nn p po ltcy. I :a PP" b Iicn Ii o ns.or;/c Sil conccn llru 11I
pcdi:uric~%;bl08/3n76 (xccued 08/11/07)
Urinary-tract infections. There is no well-substantiated role
for pbenuopyridinc in the treatment of urinary-tract infections Effects on t he blood. Bo1b phenylbutazone•·l and
(p.215) and its odver.;e etr.cis arc pot"'1tially serious.' ox)'pbenbutlttOne'-' aJ'e well known for their ad\'e1~e elfeets on
Phenazopyl'idine Hydrochloride I. Zeh:ni1sky SA. Zh:.ncl GU Phe1l ~topyrid inc in urinary 1ruc1 in· the blood aod cspeciAlly for fatal a:;r.rnulocy10Sis and aplastic
fl:ctions. Atm Phor1mrt:01h<•r 1996~ 30: 866-S. anaemia. Lcucopenia, pancytopenia, haemolytic anocmia, and
~ uSAN. rlNNM) thrombocytopenia may also oocur. The UK CSM' noted that be·
Chloridrato de Fena::opiridina: Fenazopi1idll'I I idrd<lorur; fena-
Preparations IW«n July 1963 and January 1993 it had received 74 repons of
zopirydyny chlorowodol'd<: Hidrocloruro de fenazopiidina; USP ll: ~1dine Hyc;,..,,hloridt -lbltU agnnuloeytosis (39 facal) associated wiU1 phcnylbuta.zonc and
NC-150; NSC-1879: PMnazopyridiM, Chkl<h)'<hle de; Phena- Proprietary PNparations (det>1I• are :;iven in Volume BJ 40 reports ofnculropenia (4 focal). Up-to-date figures were not
ropyridini Hydrochlori<b'n; W. I655. 3-Pheni1a:zopyn<fne-2.0. Ati.: Cisulgina: llefr,: U1lpf''ln<O: &oz.: Pyridit.m: P)nscpc: Urologin: Co· provided 011 oxyphenbutaz.onc, but ii is considered lo be more
nod.: Phenno: Chllo; Nmnilt: Nordox; Pyri<jumj: Honi Koni; CP· loxic to the bone marrow than phenylbotazone.1
dlykiamine hydrochloride. !')Mine: PheNdiM: Phcn= ~ ~ Indio: i')<'Oi<.rn lndon.:
f')riciumt: Uo~ tlx: /sroe~ Se<l.r11; Mu.: ."1vena: Azofurf: Boorom.. Plr- I. SOuigcr LE, Wcstrr!1otm 0 Drug-induced blood dyscruiu in
<lle""'300"'PIW0Ha r11.t>p0X/\O)l4<A
om<-: 1nm< Philipp.: A>omirt. Pol.: Nei<d: S.Afr" Pyridium Sinp- Sweden. DMJ I9i3; 3: ))9-43.
C 1 ,H 11 N 1.HCI =2~9.7. P"'"' ~ Tl>oi.: Ammilazoc Anua ~ Su-ne<iunt U>one·
T: USA: l\z')-~ BatldU'n: P'°'""; l')ndoolet: f')ridium; Rc·ho:
2. Anonyinous. Phcnylbutnonc 3nd oxyphcnbutnonc: time to call
a halt. />nrg Tl:tr Bull 19S4; 22: S-6.
CAS - 94 -78·0 (phenozopyridinc): 136·40·3 (phenozo- l.ht>gesoc; Ycn•L: P)ri6umt 3. The lntctnalion:al Agrnnulocytosis ind Apfastic A1ltmi:1 Study.
pyridine hydrochloride) lfo;ks of ayanvlocylosis and aphutic annnia: a firs1 report of
Mu~l-lngredient: Al%.: 8ac...ui: Med>r'°" Ool: Nor2. Pr'po< PU; Uro-
AiC - G04 6X06. wm Oct: Broz.: Minuet Uro-Saxa;rlt; l.koctrim; Uroler.t \kcpac:Uq>- their rt-latio.n to dNg use with spcciril rcft~ncc t.o •~lge:sics.
AiC Vee - QG048X06. "'°"' Chile: 1.ko·Micino..o: Honr Kon(: U<obirw.; Indio: Ncpl-roicic:
Mu.: Azo.J..k<lnillrc Am·Wl1'C>m)'lon: Azcge>< """"": Moel•~ Nab·
4

JAMA 1986; 156: 17~9-S~.

4. t'SMJMCA. Drug-induced ncutropc-oia :md ngranutocytosis.
UN/I - OEWG668WI 7 one; N~ Norilcn: P11T,1r. Ura-. - . Spain: Micturol Se· C"r"'nr Problems 1993; 19: 10-t I.
The symbol t denotes a prcparAlion no longer actively marketed
122 Analgesics Anti-inflammatory Drugs and Antipyretics
Por phyria. Phen)'lbutawne has been associaled wilh acu1e at- Porphyria.. Piri1ramide is considered 10 be unsafe in pa1ients Effects on the kidneys. Acu1c nephtopalhy w11h chara,ieristic
U>Cks of porphyria and is considered unsafe in porphyric palicnts. wilh porphyria because ii has been sho"n lO be porphyrinogcnic features of llcnoch-Sch<inlein pu1pura.' acUle renal failure..'
Preparations in ommals or iff-''ifro systems. uraemia wilh hyperl<alaernia, and acute interslitial nephri1is>
Preparations have been associaled with systeonic ,.o;c ofpi roxicam. Ncphrotic
Proprietary Preparations (details illC given in Volwne 8 ) syndrome and inlcrstilial nephritis have followed lopical use of
&:lg.: &.Jwoloot:.&= BuwolOna: Butooont: llu:azona: 8.uzcnolt: Proprietary Preponotions (details arc aivcn in Volwnc 8) piroxicam gel'
Neo Butuol: Mtt,:;' &.Au"'6ne: Ger.: Amb<ne: eocrheu:lon OPT: Aunrlo: [).podclor: S.11.: 0.l'ddor: Ct.: ~: G•r.: Dp.dolQr; I. Coebtl KM. Mucllcr·Brodmann W. Reversible o vert nephropa·
=~~~~h-6:1;1!.t.L~~~~=~ Neth.: Oipdob;
thy wi1h Henoeh-Sth6nltin purpura due 10 piroxic1m. 6MJ
Neth.: l!ut>""6n. Po/" ~ p......., S . - t Rus.: Bvtadioo 1982: 28~ : 311-1 2.
(6yt.,...,.,): S.Afr.: lnBazone: Spoln: ButuoSdmt: Switz.: Butadion: 2. Frais MA. tt ol. Piroxkam.1nduced Tlm ii!I failure and hypcrble..
ThoL: Butartol: Butato<le: KB Tazone: l.eopNn: Nco.Pyruolt ~ mia. Amt btrun Med 1983: 99: 129- 30.
Pyruolone; Rruma~ Allummb: ~: Ukr.: But»on (~~ Piroxicam (BAN. USAN. rlNNJ 3. Mitnick PD. Klein WJ. Piro>:ic:tm·induoed ren~I d isease. Arch
Venez.: Pmmilenf': T~ fnt<FR .Wed 1984: 144: 63-4.
Muld ·ing,-edient Aurtrlo: Ambene N: A.Tber.et Bror.: Buuzilf: CP-16171: Pfroksiwmr. p·,roksil<am; Pirol<sikamas; Piroxicamum; 4 o·Callag.h:m CA. t!I nl. Rmal dis.use and use o f topical non-
Dorendt; l1loile>c ~t: Ra.mo¢ Chilo: &'wno Analgcsko con Fe· p,...,,.lcJn~ Pr oxikAm. 4·H)odroxy-2-me1hyl-N-(2·pyridyl}·2H- Slcroidal on1i-inflamma1ory drvp. BMJ 1994; 308: 110-11.
nibu°"20N: Esonf'ri>< Fr.: Dext,..rine pt.~ H ung.: RheOIOior<
lndon.: &Jomidon: ~rint ~ ~ Sl<a!L1: Mex.: But.,...... 1.2-benzolhiazinc-3-ca<t>oxamide 1.1-dooxid~. Effects on the live.r. Necrosis of the li\'CI, somclimes fatal, has
cot Bu-a t Dex.ad·.t.;t O~ ~t Zolidimof: Ru•~ Ambene n..po.C1<KaM been associaled wilh piroxicam. 1_:,
(AM6<He~ Spain: Mrodelmol &or.; Ooctolril Mti·n&mat; Switz.: 6'.o·
~ Hepa!Juzonef: Thai.:.All>Qnt: Asialax1: ~'°"t: ~. Tra· C 15H nN 10,s = 331 .3. l . IA~ SM. a al. Subacuu: hepatic necrosis induced by piroxicom.
BMJ 1984; 193: :141)-1.
bilt:Ukr.:~~"')f. CA5 - 36322-90-4. 2- Paterson 0, et t1l. Piroxica.m induced submusivc neerosis ohhe.
ATC - MOIACOI: M 02AA07: SOI BCQ6. liver. Gut 1992; 33; 1436-&.
ATC Vet - QMOIACOI: QMOZAA0 7: QSOl6C06. Effects on die skin. As with Olher NSAIOs, rash has occurred
Piketo profen ltfNI\? UNI/ - I 3T406VMAM. in palients iakina piroxic:am. Photoloxic n:adioos ha,.., been de-
Pi~toprof<n~ Pi<etoprofcno; Piketoprofcr<Jm. m-Bcnzoyf-N- scribed.' Serious skin reac1ions allributed 10 pitoxicam lherary
(4·rncthyl-2~hydratropamide. include lOXic epidermal necrolysis.' pemphigus wlgaris,l t:ry·
lh<ma multifonne,' and Ste...,ns-Jolinson syndrome..' Fixed drug
n.....eY~ eruptions ha"e also been reponcd.6
CnH20N202 344.4. = Concern by the EMEA over !he serious nallll'C of skin reaclions
CA5 - 60576-13-8. assncia1cd with piroxicam has led to restrictions on the sys1cmic
UNll - 3 6ZQ8C4NLO. u.~ of piroxicam in 1he EU (see Ui;cs and Administrntion, be-
low).
I. Skm RS. Phototoxie rtac1toDs to piro:t;cam Rnd o ther non.stttot.
dal an1;;nn1mon1tory • gents. N Engl J Mtd 1983; 309: ISc>-7.
2. Chosidow O. "ol. lnleStinal invoh•cment tn dru1·induted toxic
cpidemn l n<CTOlysos. Lanc.i 1991: 337: 928.
Phanna copoefas. In Chi11., Eui: (~ p.vii).Jp~ US. and Viet. 3. Marlin RL ~' nl. Fa1al p1:mphis,u1 ,. ,,,~ris in a pa1ien1 taking
Ph. Eur. 6.8 (f"oroxicam). A while or shghtly yellow, crys1ollinc piro.iaom. N E11gl J Med 1983: 309: 79~.
powder. h shows polymorphism. Practically insoluble in water; "· Prieto A, 11 cl. r iroxicam·induc:ed f'ryd)tma multiformt. Con-
sliglitly soluble in dehydrated alcohol; soluble in dichloromed>- 1ac1lkrmolifis2<MW: 50: 263.
anc. Store in air1ight conlaincrs. Protect from light 5. K atoh N. "'of. Piruxic11n induced Stevens· Johnson syndtomc. J
USP 33 (Plroxr.:am). An oft:while 10 lighl Ian or lighl yellow, Dermaio/ 1995; 22: 677- 80.
(), Cuerd~ Galindo E. ~' nl, Fixed drug crupeton from piraxicnm. J
Profile odourless po"'dcr· II forms a monohydralC Iha! is yellow. Very
£,,r A cod CNnnou1/ Vcnucol J:OCM: 18: S86-7.
Pikeloprofen isanNSAlD(p. 100) 1ha1has been used lopicallyas slighlly soluble in woler, in dilule acids, and in rnos1 organic sol-
lhe hydrochloride in concen1ra.lions of about 2°A in musculoskel- vents; slighlly $Olublc in alcohol and in aqueous alkaline solu- Overdosage. Delllils of 16 patient; who were considered 10
etal,joinl, peri-articular, ond soft-tissue disorders. tions. Store in airtigh1containers. Protect from light have taken an O\'crdosage of piroxicam alone were reported' to
1hc Na1ional Poisons lnfonno1ion Service of d1t: UK. Thirteen
Preparations palicnts (including 5 children) had no symptoms after doses esti-
Propr'i etary Preparadons (details arc g.ivc11 i11 Volume- B)
Piroxicam Betadex (USAN. rlNNMJ malcd 10 be up to 300 10 400 mg; 2 patients complained of dizri-
Port.: Plc.im: Zttr-*'< Spoln: Ulm>tel: T~""'"'" CHF-1 194: Piroxicam 8eUJ Cyclodc><trin: l'l'o>cicam Beta Cyclo- ness ind blurred vision • fter 200 10 300 mg; the last patient, who
de>drin Comple•: Piro><icam lieiAde>c: nrmcicamum Betadexum. claimed 10 have taken 600 mg presented in coma, regained con-
nl<poKCMM.lM 6e1 i\AeKC sciousness wilhin one hour. and had recovered fully wilhin 24
Piritram ide (8AN. rlNNJ . (C1 5H 13N30,S)i.(C,1H100i~)s =6337.6. hours. Severe mullisys1cm 1oxoci1y has been reported in a 2-year·
old child after ingestion of 100 mg of piroxicaon.>
Pirinitramide: Piritramid: Plritramida: Piritram;di; P'ntnmicbn: R· CAS ·- 96684-40-1.
I. Coun H~ Vobni GN. Poisoning afier overdose with non-steroi.
3365. 1 ·(3-Cyano-3,3-dipheny~~)-4-piperidinopoperidine-4· dal anli-inO:unm;nocy drugs. AJ,.,.,, Drug fte(Jct ,f(u/t Poison-
cart>oxam~. Adverse Effe cts and Treatment "''Rev 1984: J : 1-21.
As for NSA!Ds in gcnetal, p. I00. 2 MxDougall L.G. ~t nl Piroxican' puitoning in a 2-ye&r-old child;
n'1jl'<TpaMl1A a CUC rq>Gll. SAfr ~kd J 1984: 66: ) l- 3.
C,,H3 1 N 1 0 =4 30.6. Local inilation and occasionally bleeding may occur Pancreatitis. Poncre<'llilis has been associated with piroxicam
CAS - 302- 41 ~0. wi1h piroxicam suppositories and there may be pain use.I.!
ATC - NOZAC03. and occasionally tissue damage at the injection site on I. Haye: OL. Piroxiea1n and palk."Tatiti.s. Ann /111.:m Med 19S6;
ATC Vee - QN02AC03. intramuscular use. Application site reactions have also 10.I: S9S.
UNll - 4RP92LYZ2F. 2. Hctuwotrt F, t:r al. Pa.nctta11ce aigue av piroxicam. Gas.tr«nl'rol
occurred wi1h topical preparations of piroxicam. CUn Biol 2006: 30: 635-6.
Piroxicam is considered to be associaled with an inter-
mediate risk of ga~trointestinal effects although there is Pre cautions
some suggestion that the risk may be higher than for As for NSAJDs in general, p.102.
other inteJTTiediatc-risk NSAIDs (p.10 I). B reut feeding. No ad>use effects have been seen in breast-
0 A repon 1of1he ad•'Crse reactions associated wi1h piroxicam in fed infonts whose mothcB were given piroxicam. and the Amer-
Soulh Africa during 1981 lo 1986 included two r<aetion$, par- ican Acodcrny of Pediatrics considers 1Iha! it is 1hcrcforc usually
aeslhesia and hair loss, n<>I previously recorded in 1he li1eranore. compa1ible \\ilh brcasl feeding. The: BNF 59 also considers the
I. Gc:rbn" D. AdH:TSC rcactioni or piro."<icnm. Drug /J1tc:// Clin
amount cxcrelcd into breast milk 10 be IOO small to be hannful lo
Pi.on..1987; JI : 707- 10. • brcost-fcd infonl.
Piroxicam appears in~ milk in eoncentralions of aboul I%
Effects on the blood. DeClea-;es in haemoglobin and haemat·
of those in the maternal plasma .2 Similar data ore also included
ocri1no1 associa1ed •vilh obvious gas1roin1estinal bl«ding. have
Profile occurred in p:llicnts laking piroxicam. ·111rombocy1ope11ia,
in 1he licensed product infonnalion although ii does nol rccom·
PirilrJmide is an opioid analgcsic{p. I OS~ mend piro.,icam u~ during brtaS1 feeding as clinic;ol safety has
lhrombocytopenic purpurn,1and aplasiicanaemia2 have been de-
II is used fot the management of severe po in including P<>SIOJlCf· scribed in palients on piro~icam. nol been established.
alive pain, for premcdicalion, ond to provide analgesia during an- 1-.. Amerie:m Academy orPedi31r;a. The 1r111nsfer of drugs and otb·
I. Bjoms:11d H, Vik Q. Thrombocytoprnic purpura asscw;i.11ted v.•1t.h er thtmiCJtls in10 human milk. Pnfi111r les 2001; 108: 776-S9.
aesthesia. ll is given by inlramusailar, subcuuincous, or slow in- piroJCic"m. 81•J Clin Pr«l 1986; 40: 42.
lr.IV<:nous injection as the l:lllnlle in doses cquivalcnl of up 10 [Retired May 2010) Corr.c1io.1. ibid.; 1029. Also availoblc at:
2. Lee SH, ct ttl. Apb5tic 1nJ-elrti;i as~ocia1cd with pirox.icam. Lou· h up ://1 appo I ic y.a:i pp u bl i ca li ons.orsJc gi/con ten 1/fu11/
oboul 30 mg of the base. w 1 9~2; i : 1184. ped131ri<s%3bl08/31776 (•cocssed 08/111117)
ORcvicws. Effects on electrolytes. Reversible hyperkalacmic hypcrchlo· l. Ostcnsen M. Piroxicam "'human b~I rnilk. Eur J Clin Plutr-
macol 1983: 2~: 829- 30.
I. Ku1nar N. Rowhoth11m DJ. Piritramidf_Br J AnoeJtfr 1999; 81: raemic acidosis has been reponectl.l in patienls receiving piroxi-
3- S cam. Severe hyponalracmia and symptoms reseonblin& the S}'G: Po rphyria. Piroxicam bas been ossocialcd wi1h ocute anacks of
2. Bouillon T. Cf ol. The phann.acokittttics or piritramidt 1ftcr pro- dromc of inappropria1c aniidiurclic honnone scaelion have also porphyria and is considered unsafe in porpbyric patients.
longtd administration to intensi"·e care patients. Eitr J Anoatheo. been a.ssociated with piroxicam.>
sio/2004: 21: 673-8.
3. MOiier C, ~ IJ!. Phan nacokin( tics o f piri1r1midc in newborns. Sec olso Effects on 1he Kidneys, below. Interactions
infants 1nd you.n.g children in intensive ore un1t.J. Eur J Pedio11· 1. Grossman LA. Mol>s S. P1rox.ic:am and hyperkalernic icidosis. For interactions associated with NSAIDs, sec p.103.
2006: 165: 221)..39. A•• fn1trn Mt d 19&J: 99: 2&2.
11 ol. Ptos~c1ive cvaJo:a1ion of 1he ph3nnacody..
.t. HueMt:let C, l . Miller Kr. et ol. Severe hyperkalemia during, piroxlca.m 1herapy. Use of aspirin with piroxicam results in decreased plas-
namiC$ of plritramide. ln nronll'S 1nd infants. Em· J Pr<liatr Arch /n/"·n Med 19~: 144: 2~ 14-1 5 . ma concentrations of piroxicam to about 80% of nor-
200S; 167: 867- 72. 3. Pclersson J. t1 ol. W3tcr in1oxica1iau ::.ssoci21cd "'Hh non-steroi·
S. Rem.ane 0.d o/. Sllbihty of piri1.111midc in patient-conuollc.d 3n- d11I :mti-inOunmitory drug 1her11ly. AC'IO MtdS<-nnd 1987: 221:
mal. The UK licensed product infonnation for rito11avir
algc:ti1 {PCA) 50lu1ians. Phormn:it 200CI: M: 380-1 . 221-). suggests that use of piroxicam with ritonavir may re-
All cross-references refer 10 entries in Volume A
 Piketoprofen/Proglumetacin Maleate 123
suit in increased plasma concentrations of piroxicam Other sal!s or compounds that have also been used in- Pranoprofen (rfNNJ
and a11 increased 1isk of toxicity; it recommends that clude piroxieam cinnamatc (cinnollicam), piroxieam Pranoprofene; Pra~ Pranoprofen...n. a-MWif.·S.LJ.{ I;.
use together should be avoided. choline, and piroxicam pivalatc. ~2.3-b]pyr.Onc-7-acetic acid.
npat«>npocte>t
Pharmacokinetics
0 After a review' of the benelit-risk balance for piroxicam the
EME:A placed n:striaions on iis systemic use end stated that: =
C1sH131'.03 255.3.
CAS - 51549-17.4
Piroxicam is well absorbed from the gastrointestinal • its m;~ in acme poinful and injlumm(llory co11ditl01?S should ha ATC - SO I 8C09
tract and peak plasma concentrations occur 3 to 5 hours oball((Q11eJ ATC 'lei - QSO I 8C09.
after an oral dose. It is more rapidly absorbed after in- • Its ~ sho11/d be //111/ted 011/y 10 the s_m1p1umatic rel/a/ofoste-
UNJ/- 2R701ET613.
tramuscular use and is also absorbed to some degree oarlhritis. d1e111n01oi<f ''rt/rritis. and an!Q.fosing spomlyliti.r
after topical application. Piroxicam is 99"/o bound to • it $hould 1101 ~ usttl as o first·lln, t1Y!atment
plasma proteins. It has been detected in breast milk.
• the doso should~ limit.Oto 20 mg doil)•
P1r0Aicam has a long plasma elimination half-life of
about 50 hours and steady-state concentrations are not • treo/lf1'111 shmtld be reo·ir.wd wilhin 14 do.11 ofs1a,-tlng
reached for 7 10 12 days. It is metabolised in the liver • II should on{v be suwted by doclors experienced In treating
by hydroxylation and conjugation with glucuronic acid C'hrome painful trnd inflammatory C01Klitiom
and excreted mainly in the urine wirh smaller amounts • 11se wilh o ga<tmprotect/ve drug should be IXJluidered
in the faeces. Enterohepatic recycling occurs. Less than • ii ~lwuld not be gf~11 to putie11tJ at ri.<k nfgosrrointestinol dis- Pharmacopoeias. lo Jpn.
5% of the dose is excreted unchanged in the urine and ortkrs ossocio1edwith blttding or 10 those who,,,,..,, had1J;;n Profile
facecS. rttJCJiOnl· 10 Oflrer drugs Pranoprofcn, a propionic acid derivative, is on NSAlD (p.100). lt
is used as eye drops in a concen1ration of0.1% for ocularinflam·
• it should not be 11.<ed"'''"another NSAJD or mt 0111icong11lont
Piroxicam betadcx dissociates in the gastroimestinal mauon Pranoprofen has also been gi'°tn orally for the 1rca1ment
I. EMEA. Quitsdons ::ind 111swen \Jn 1he ttYicw of piroxicam (is- of pein, infbmmation, and fever.
tract lo its componen ts piroxicam and bctadcx sued 2 lst June. 2007). Available at: hnp:li\\"\\-w.cmea.europa.eu/
(p.2217). Piroxieam absorption from piroxieam bcta- pdfslhmn11n/pres.sipr/pi,oxic1m_264S7807cn.pd( (1cccsscd 0 References.
dex is more rapid than that of unmodified piroxicam; 08/11107) 1. Notivol R, ~o/. Treatment of chro1lic nonbac:tcrial conjuncdvi1is
with a cyclo-oxygtnue inhibitor Of' a corlicosteroid. A"' J Oplt-
peak plasma concentrations of pirox.ieam occur 30 to Admlnlstntion In children. Piroxicam hos been usod in elul- tholmol J994: 117• 63t~.
60 minutes after an oral dose. Betadex is not absorbed drcn with juvenile idiopathic ruthrilis. The following doses, giv- Preparations
but is metabolised in the colon to various sugars. en according to body-weight, arc recommended i11 the
Proprietary Preparations (d<tlils are i;ivcn in Volume B)
BNFC 1009 for children aged 6 years and o-= &Ir,: Ptw>OO< Broz.: DifetlC Gr.: Pt-anolen: Ital: Olblar: PranolloJ< Jpn:
O Rtrercnces. Ni011"( Mu.: Nil2rc Pon.: Ofialo1': Spain' ()Ur. Turlc.: Ofuhr.
• less than IS kg: S mg once daily
I. Rk"-'rdson CJ. erol. Piro,ic.:;am and Y·hydroxypiroxicam kJDf1·
• 16to2Skg: IOmgooce daily
c:,!~~o;!~~ll1'~K~~ ~~~~~ni$1n1ion or piroxicam. Eur J
• 2610 4Skg: I5 mg once daily Proglumetacin MaJeate (IWl.\t 1NN/\1j
2. Mikc:!J A-L. ~I ol. Sl~ ady Slal.: ph.ann:kXILinc:liC$ or pirosic:sm
inchildren -v.•1\b rhcum.3ii.:distasu. Eur JC/in Plt0rrn0e<>I 199 1: • 46 kg or O\'Cr. 20 mg once daily
CR-W4; Maleato d! progk.metao->a; Proglumetacine. MalC.:e
..:1 : 79-81 (higher dearan..-e a11tl shorter tiaf(..life in chiJdrcn). Preparations de: ~·""m M<.leas; Protaconc Maleate. 3·{4·(2-(l·p·
3. Rudy AC, N nl. Th~ pharmxoJcinttics ofpiroxicam in ddcrly Chloroberuioyl-5-methoxy-2·methymdol·3-yiacctoxy)et'1yl]pip-
pcr$ons wiclt and witlloul rtn1l 1n1pnirmCllt. Br J CHn Phonnocol BP 20 I0: Pwo>OCUn Copsu°e<: l'Woxkam G•t
1994. 31: t-S. USP 33: l'l:oxicam ~ l'lroxamOo;m. erazin· 1-yl}propyl 4-bcnzamido-N.N4propytglularamare di-
~i~ X. et of, Oral hfonailabili1y ofCllF I 194, an inc:lu· Prof""ietary Pre parations (dellits arc given in Voluar.c 8)
malcate.
sKm complex of piru~ktun and O<yclodc-xuin. in hcallhy sub· MaMaT
npor11)'MCTaU)1Ha
~ Bcnisv>c llnon01: F•bopxic;mt Feldenot: llogos<>e: Hon>ocolmef,bac
j«ll u.nikr sio.;le dOIC' oncl sicady·~tatc conditions. E,,r J Clln
Phrtrmn=/ 199S; 47: S3l -6. Ke--"""f; Miloot Nicar. Nae Nali<>C O>t~ Pl-oolgint: Samorue C,,HsaCINs0a.2C,H,O, 1076.6. =
CAS - 57 i 32-53·3 (progl~merocm): 59209-40-4 (prc-
Solc>co1m: T.......t Tri>ciwr< Trux• Rt: Truxaf: ~ Austro/, Feldene:
S. Karim A. et ul. O~aprot.in and piroxicam, nons;icn>icbl a.ntiin- Mobifis: ~--Cf: Aumio: 8,...ldolf: arexrc felden: Plrocolf: Pirocam: glvmetocin moleore).
n11mmntory dMJp with kmg. half-liws: err~ct of protcin·btndlng Parortieum: Piroxt Plroxist.od. Tonimedt: 8 tlf.: ~ Oocpiroxi: l<TC-MOl/\8 14.
differtncts on st~:1dy-Mak: pharmacokinc1ics. J Cliu Phw'ln«ol fodc"le; Piromed: n-oxt.ep; Pi<co<ymedt: Pol~ne: Sokam: Braz.: A..,.,.. ATC Ver - QMOIA814.
1997: 37: ~67-78. imt: An.1one: Brem Ciclodat ~ Feldlnax: rcldcne: feldo>rt:
6. \\-...ng 0. ~, ul. Compartlli\-C populauon ph:.tr-maec1kinetlc·phar- fdc!nnt i•omosta~ Flogl!NI: RooOam ~e: innanan: t"°3><: U!<dt·
macodynamit analysis for pirOA•tanH~-cycfoc:Jc:urin •nd pitoxi- 'Nf: f'iqrten: Plr<locamt: Piro...,., Pn:»ofor: F'vc><•lonf: Pirol<il: p...,.,...
cam, J Chtt Pft.nrnu.rcYJI 20(J0: 46: 1~~7-66. PltoUw1 FYooc¢.is~xidl: Canoe!.: ~ N u.f'lro><: Chf/e:
F•budol: ~...., : Pomar: Pri<om: Cz.: Mlnmint: feldenet:
Flammn: ~ Plrotamf. l'lroxt: Pro-RoxJwnt: R.........oort: O•nm.:
Uses and Administration Felden: Pl'°"' Fin.: t!ro>odc.'t. Fetdcn: PlrOXAlt f'lmxirt Fr" tlrtlOl"< Cycla-
Piroxicam, an oxicam derivative, and piroxieam bcta- dol: F•ldene; Gddo"O: lnCac<4 PIO><ll'/O(: Zofcn: Ger" 8rtoOdct c'ini<f:
cunJ>r<»<t: Feldenf: flexase. ~ Mobi~t Aleut Plro""""1: Piro
dcx are NSAIDs (p. I03). Piroxicam bctadex m~y have KOf: Po'Dt, Plrcbl't>: P""9.wn: f'w'o""'"'f; Plro.-lleumAj: Piro>< ~
a more rapid onset of therapeutic effect due to its en- Int, Gr.: lkOJrart B•-ex'"' ca~ Conzlo: Fel:l<o0< F•dinor: F1odeneJ;
Gro<Oleno:lnl'..,.,,.,.·N: N eo~NM:~Pamlipt-O;l'<d(~
hanced solubility (see Phannacokinetics above). Both Propanot f'ior<o<I; Reu:-naplu• Rworncd: ~ ~ ZerospMn~
have been used in musculosk·e letal and joint disorders Zoumex: Hong Koni; CP·Plrco<: FeldeM: Mobis; Fr.om-0: l'Woocicaf: Se·
such as ankylosing spondylitis, osteoarthritis, rheuma- Ide""' SyncxiGamf: Vldlproc:amt: Hun1.: 8tt>on; En>ont: fttdene:
Floroeo<in: Hoterrin: Huma.flrocamf; Pkorhtumf: Indio: &-= Oololcam:
toid arthritis including juvenile idiopathic arthritis, in Dolonex: Mob1am: "''°'°"'Plrcc Supnti~ lndon.: Fl>Odcnf: ftlam:
soft-tissue disorders. in acute gout, and in postopera- Fe'dene: lnlold: Kil•dene: Ll...-...mo; l.Jco(et Maxi<.amf: Protom: flro.
dene1: Plrole~ Rc><icam: Rex~ P.osict Rocidene. Scandene: Sddt!tt. T"'P-
tive pain but systemic usage in the EU is now restricted dme: ltf.: ~- Peric<1mt Israel:~ f»:>an: Fdcren•. Ital.: Algae·
(sec below) toChronic painli.il and inflammatory con- •"'t. Al1lq Mroo<ic.m: Broxin; Btt"« &uxium G:ladol: C•clafastt:
ditions. '""'"' O.Xc:im: faekamt Eurco<1 Ftldene flodot lpscltoi; 1.amponex:
Oxicam I: P".rcb<c Plroh.t Polipii'O><t: Rax:•mf: Reurnoet ~ent: Rox·
Jn rheumatic disorders the usua l maximum recom- ""': Roo<cnll: lloxiderc SiNnrot Spiroxt: Zelis; Jpn: Sa"°' Maloy>io: 6ttx·
,,,. Foldeno- ftl•<>mt. PNmictt t.%>Nxiam: Mu.: Air.c'¢ /\ndn:Ncamt.
mended oro Idose ofpiroxicom is 20 mg daily as a sin- >.po:.nnt. Arlexiw" Anrot. MyCMrc ASOl)onj: A>dtim: ~ &-
gle dose; divided doses may be used if nccessa1y. ........._ llre".OC.m; 9'-.><o:!On: Si'-""'"'~"" C"oken T: DO<orut Dolz)-
CM"'C Ec:eamt: F.iciwlt ftldc..,., ~-ot. Qondic;,.,; Ostcral Q,..11.t\ll
Piroxicam has been given in similar doses as a rectal O>O<onct, fTodax; Plrox: Pl""'2nt: ~Tyl".....t, ~ Revtricom: Ripox
supposilory or on a short-term basis by intramuscular Serpicom: Tn;>"Ot Vurem: Neth.: Sr""""': NorN.: S.'Coodot Ftldenf:
injection.
For dosage in children, see below.
,,.M
Plroxt: NZ' Cand)t l'W>tn-0: Plroh•""-'D!. Philipp" FtlOene: Floma.-.at
flaxi..,e; Ma:.ro=<am: Nt;>e:r'.ant:
icam:
Pari>:arr.: Pitostadt: Prooomax: f\ax.
Pol.: f<-lotnr: Ha.,,.... Hottmr>f: Port..: 8re><i't F<ldenl!: Fioxa<; Profile
(proclumetocin)

floiOo•. Rcmi<~ ReU"l>:>xicon: 11.ocazn Ru<.: Erazon t3i»JOH~ Malgel Proglumetacin malea1c, an indokace1ic acid derivative n:lared 10
Piroxieam is also used in the local treatment of a vari- (--~ $.Afr.: i>'C><K••• feldtret P"oocam: i'yroca?<: Rht<Jteiic;
Y)'U"'I\ Sfn,oporc: Feldtn~: RoSIOe>i: ~ 'VftlX•carri: Spain: !Yex.nt
indomclJlcin (p.69), is an NSAID (p. 100). II has been used in
ety of painful or inflammatory conditions as a topical Ci<ladcl. C>cltb3nj: felti<g•I: Folden<: ~ SWmn-c Sasule.v, V> musculoskcletol andjoinl disorders in onil doses of up to 600 mg
gel in a concentration of 0.5% applied three or four l.t>.11.•ln. S~.: Brexdot Swh:z.: Fekiett P1'ocam,: FWo$OI: Thai.: AmMI· daily, in divided doses. Proglumetacin m•teatc has also been giv-
dc<lC< a.-._ Bu:aanon. C)dodcx: Oexa'in. Fclco<rc ~ Fftam: Fol· en as recal S1Jpposi1orics and topocally as a S~~ cream.
times daily: rreatment should be reviewed after 4 l'K>.x. Felpac: ::elrox: Febcom. Flamic: Heropedd: lfetned; KobUc.an"(
weeks. A I% gel is also available. Piroxieam has been v ..noxi<a'1': 11.>sv...n; l"1oiaamt: ~ Neotiu: N - PC·2ll: f'hera. 0 References.
used in some countries as a 0.5 or I% cream and as eye ""e; Pi-.-ock PiWowm: P'.- IYO>C Praxit Pwum: Pk00<: l'irolc>I: """"'"' L Appclboom T. Franch1t-nont P. ProgJumetacin wrsus i.ndo1ne1-
oro.cin. Pirco<cn: Pi"""'1on: P ' - PWooc>il. Polyxi<am: f'ooed<ncj: Py- ncin in rheumatoid arthriliJ: a douhlc·blind mult1ccn1a s.tud)..
drops in a concentration of0.5%. "*Yt: Roc:.,oot !lodO: P.oxicam: Roio!tn: ~ ll<>")'<•m. ~ Ad• Therapy 1994; It: 128-34.
~~Um: Setaro>< Sotilenf: Spo.Tic: Xicam: Turk.: C)<Cl.adot 2. M1rttns M. Doub1c·blind ratldo:nized c-om1>ari~on orprogluJnct•
Doses of piroxieam betadex are expressed in tem1s of rclden: ~'.bmcJC: O~ik.am: UK: 8rex1dot Fe~ UJcr.: Fina Igel acin and napro:<cn sodium in the t.rt:a.mcnt oJ"p;ilit'ntS wi1h ankle
the equivalent amount of piroxicam. Piroxicam bcta- (lll•"'.wt""): USA: F~ Y•ner.: llior*oxt: Cdolant. feldene: Feklcn· >pni,,._ Om Th<1· Res 1995; 56: 6.l9-48.
ed<' fl>malit lepe><Jlr. M»tpircc Piroamt: Prom>xt; "-nit IV.end
d~x 19 l.3 mg is equivalent to about 20 mg of piroxi- Pre parations
cam. In rheumatic disorders piroxicom betodex is giv- Multi·insrcadient Ari.: >4'o-lr..aut &..1~ P.ut 812: f~ fit'» Pro pri ~tary Preparations (details ore given in Volume 8)

en in an oral dose equivalent to 20 rug of piroxicam

Camon A 11exa,,,;,, 812; Re"""""'
eren....t: Floi•trin: ~"'· 812: Arg.: Ehno:t 8•1f.: lOlr_>dot Gv" ~ Hong Koor- A5o>ar"< ltaJ.:
~ Ri.rn-.edan: R.lm1Stdon fuoclei; Soloufrn Pluo; SoloaJm.6( Solo- Al\ooQnt; Prooci: Jpn: Miridic<rc Pftfl•PP.' Allo"3rc Port..: Prow.ii; Spo.n'
daily as a single dose. This dose may be reduced to <.irwtcx: lndon.: Count..-pl', ·PX!'t n..,;.: Cocnteo-p.>n Plus. Prodamooc; Thal.:~
I0 mg daily in elderly patients.
The symbol t dcno1es a pttpar3tion 110 longer actively marketed
I 24 Analgesics Anti-inflammatory Drugs and Antipyretics
Propacetamol Hydrochloride (61\NM. rlNnll) Propyphenazone (aAN. riNN) Preparations
rii<lroclor\Jt'O de p<epa{etan\OI: Propacetamol chlori'l)'drate de: lsopropylarttipyrine: lsopropylantipyrirun; lsopropylphenazone: Proprieary Pr.,paratlons (details an: given in Volume B)
Propaceiamol-hidrol:lorid: Propacetamol-llydrochlorid; Propa- Propilenazon; Propifenazona; Prop<~ Propyfenatsonc Huni.: 1Nnsont; Turk.: lliariOOI\
cet.amolh)<droldorid: Propacetamoli hydrocNoridum: Propace;a- Propyfena2on; Propyphenarone: ~azor-.rn. 4-lsopro-
molio hidtOcNoridas: Propasetamolti)'droldondi The hydrocnlo- py!-lJ-dirrethyl- 1 -phenyl-~S.one.
ride of NN-doelhy1glycine ester with 1W3Cetamol: 4-Acewn:OO- npon11cj»<a'IOK Ramifenazone (IWNJ
pl>en)'! diethylaminoacetate hydrochloride. C 14H 18N 1 0 =230.3. lsopropyiaminophenazone; lsopyrin: R.nifenazooa; Ramifena-
nponaueTa"°"' f~'<A CAS - 479-92-5. zone; Rami'.enaz«un. -4-lsopropyiami>o-2.3-dimeth)l-I -phenyl-
C14H20N20J.HCI 300.8. = ATC - N028804.
ATC Vet - QN02BB04.
3~5-one.
CAS - 66532-85-2 (prapocetomol). Pa....Ha'IOH
UNI/ - OEDBFV7 5PY.
ATC - N028£05. C 14H ,, N JO = 2-45.3.
ATC Ve1 - QN02B£05. CAS - 3615-2-4-5
UNll - GKH2KOV2RF.

(propocetomol)

Pharmacopoeias. In Eur. (sec p.vii). Phannacopoeias. In Eur. (seep.vii) and Jpn.

Ph. Eur. 6.8 (Propacetamol 1-fydrochloride). A white or almost Ph. Eur. 6.8 (~)- A white or slightly yellowish
white crySllllline powder. fra:ly soluble in water; slightly solu- crystalline powder. Slightly soluble in water; freely soluble in a.1-
ble in dehydrated alcohol; prxtic:ally insoluble in ace1onc. Pro- NOTE. The name lsopyrin has also been applied to isoni~id.
cohol and in dichloromethane. Protect from lighl.
1ec1 from moisture. Profile
Profile
Profile Ramifcnaz.onc is an NSA ID (p. I00) tliat bas been used in ~
Propyphenazone, a pyrazolone derivative related 10 phcnazone rations for painful and inflammatO<y condi1ions; it has also been
Propaceramol hydrochloride, 1 pata-aminophenol derivative, is (p.120), has analgesic and antipyrclic propenies. lt bas been sjv-
hydrolysed lo paracetamol (p.112) in the plasma; I g of propa- used in veicrioaiy medicine. Ramifenazone has been given as lhc
cn orally and :lS a rectal suppository in the 1rea1ment ofpo in and hydrochloride and the salicylate.
cetamol hydrochloride is hydrolysed to release abou1 500 mg of fever. ll1e usual oral clo5e is 0.5 to l g up to four times dally.
parace1amol. 11 has been given inll'3muscularly or in1nvenously There have been some repons of severe hypersensitivity reac-
for lhe trealmcnt of pain and re.,., . . tions in patients receiving propyphenazone.
0 Rcfcn:noes. Porphyria. Propyphenazonc has been associalcd with acute at- Remifentanil Hydrochloride
l . AIJtpen K. et al. Phannacokincties or sin4le dose. intravenous tacksofporphyria and is considered unsafe in porphyric patients.
propactwnol in neonates: effect of ge:sut1on11 age. Arch Dis
Preparations
(6ANM. USAN. r!NNM) ®
CJil/d Fttol Neonotol Ed 200.; 89: F2S-F21l.
2. W:llson PD. el al. Antipyret1c dfscacy and tolerability oh single ProprietAry Preparadons (deiails arc ~iven in ~lume 8) Gl-8708-4& 1-Gdrodor~o de remifentarulo: Rem!cnt.ml. Chlo-
intravenous dose of the acctamlnophcn prodrug prop&cctamol in Auntio: Oim-Antost. Ci«" Dtmex. rtiydrate de: Remifentanili Hydrochloricbn. 1-Cattoxyl-4-(N-
children: e randomized. double--blind, placebc>-coritrolkd 1riat. phenylpropionamido)- 1-~endine propionic aci<l dirnclhyl ester
Clin T>icr 2006; 21, 762-9.
Multl-inpd"oent A,,.: ~l; Espasmo Cbo1<r1i< Satidon: Au•·
trio: Adolcrin; APAt: Avamiar.m: Colda~ Eu-Medt,_G""-adll; monohydrate.
3. Prins SA. et ol. Ph.armacokinctict a.nd analg,Hic effects o( intra·
Yen<:IU$ prOf16CClamol \'S rectal p1recctamol in c.hildrcn after m11.~ = -~~=~~t.s=im= PCMl1¢et<TaH•,.. r~P"A
jo<craniofxiol llUrJCry. Poediotr Anoath 2008; 18: 582-92. -Mt: Belg.' Krri No-at. ~ Broz.: Saridon; 10nopon:
Chlle: Ab1Jgin: Oroo<et Espostno ~ Espumo O..lfn> Compues-
C20H28N20s.HCI =
-412.9.
Adverse effects. Oceupational contact dermatitis has been re- taf; Gripasan ~a ~ COl1l>UostO ON; SAC C..: S.ridon; CAS - I 32539-07- 2.
puned in healthcare professionals after preparing injections of ~ Noof; v.retot Oe1'm.:.Kodarrici; Ger" Cbljpl C<>mpo!i· ATC - NOIAH06.
propace1amol.1· 3 ,._.,, Nt: ~St. Opladon N: Salidon: Sct,....,.rg~~~
g'ri St. Tltmta St: Hon1 K~ng: ~ Huni-: Saridcr< Tmell Pro; /n- ATC Vtt - QNOI AH06.
Propacetamol is lhc hydrochloride of N,11'-diethylglycine es1er do"-' BodrexH..,-.: l!uWnidoo; Cet-mt:~ t-V>r.t; Oskodon UNI/ - 5V444H5WIC.
with paDCCtamol and lhe resulls of a study' have suggested tha1 ~ ~: S.ridon: ltoL: ~ irANt Neo-QPtalid0<1; Odon-
allergic reactions to propacetamol arc related to sensirisation to ..i;to Or. i<naw <0<1 Vit. Bl, Opu'"odr:>rt Sandor< Sedol; ~I.Mi­
the activaled ester rather than to paraec1amol itself. ~~on; M u.: e..,.,,,,.. Gbaigr.a: 10nopar< N eth.: Oro Hoold.?-
jnpoeckr<: Kruodv•t Kruodv.t PPC: Para-don; S.n&li)r< Saridot>; Po).:
I. Barbaud A. et ol. Occupational al?uay 10 propacc11mol. Lanen Anal&et Ctf;/£W. Gudln Pt. Kn:>pe Zolodkaw<: P = P f Satidon: ;
1995; 346: 902. Por1-: AvafTli&Rrrl: OpWdon: Sandell N; Rus.: Calfd.n . ): Cof-
2. Sz.czu,ko C. et t1I. Occupational con111c1 demutllis fro:n propa· fedon (~AO•}t: Gewadal (f•taA••): Kof•n •}: Sar;don
cc1amol. C<>nlocJ !HrmaMis 1996; 35: 299-lOI . (~OH); S. A(r.: !Mcot Spain: AWominot c.tmople><; Oolo<lens:
3. Oidcn K. n ol. Occup:ttional allergic: COlltact dc:n:natitis from Mdabo<'c ~ Q\?ulidon; Qu~ s.rido<i; Sedamertkf; 51.*nerin
drua- in hea11bc-ate WOiken. CunlOCI o~""ultis 2001; 4$: I'""""' Tolllet.. Quimpe; Tonop1n: Slriu.: Dia:g;nc fo11tf: Esc:og<W
273-9. ..,. cod•"'et. Sposmo-Clbalg<> «>•'1't: Spasmo:C;ootgW>t. Tonoponf:
Turk.: Alj;t, 8iop-..,,t: t-'ino..i Plus; OpWidO.">: PanalgCie; Ukr.: Kclan
4 , Octl V, ct ol. Mcch:mism of :.llcr;ic cont.1cl dermatitis from
(I<.....); ~n ~t,Noval&in (HOOMl•M)c l rincll(T-)>
propacctamol: scmi1iz:a1ion lO 1clivated N.N-diclhyl&.lycine.
Cuntoct Dtrmo1;/i1 1998: 38: I SS-8. (remlfentonil)
Preparations
Proprietary Preparations (details arc givtn in ~lume B)
Proquazone (BAN. IMN.rlNN) Incompatibility. Rcmifcntanil hydrochloride should not be
llel1.: f'ro.Olf>lgOl\t, Oonm.: Pro-D.<~t; Fi"-' Fl'o-Oafalg•nt. Gr.: -43-71S: Prcx:uazona: Prolwazorc Prokvatsoni: Prokvazon; Pro- mixed in the samt intravenous solution as blood products. UK
Pro-Oalolp.i: lsrotl: Pro-0.f•lganf: llOI.: l'rO-Efer>Jgant M • • .: T~ quozO<lUm; RU-43-7 1S-n. 1-lsop<opyl-7-melhyl--4·~­ licensed product infonmllion states 1ha1 ii should DOI be mixed
Norw.: Fto-Da!'alg•nt: Swed, J>ro-Oalalpnt. • ufu-2(1H)-one. with lac1ated Ringer'$ iojcclion with or without 5% glucose;
npoKSi!30H however, in lhe USA the producl lileratute states !hat remifcn-
C, 8H 18 N20 = 278.3. tanil hydrochloride is slablc for 4 hours at room tcmperalurc after
Propyl Nicotinate CAS - 22760-18-5. reconstitulion and dilution 10 20 lo 250 micrognuns/mL with lac-
ATC - MOl~Xl3. tated Ringer's injcclion and for 24 hours iflaclaltd Ringer's with
Nicoti:loto de propilo. 5% glucose is used. lncompa1ibili1ics have been reported be·
ATC Vei - QMOIAXl3.
nponow-o......a1· UNI/ - 42VPJ2980S.
tween chlorpromlttine hydrochloride 2 rtlj!/mL and rcmifentanil
C,H 11 N01 = 16S. 2. 25 microgran1s/mL (as rhe hydrochloride) in So/e glucose and ce-
CAS -7681 - 15-4 . fo pcra zon e sodium 40 mg/mL or ampholeric ln B
600 miaognms/mL Bnd rcmifentanil 250 micrograms/mL (as
lhc hydrochloride) in 5% glucose.'

fu
I. TtiS5CI LA, et ol. Compotibility of rcmi(cntlnil hydtochlondc
.# wi1h selected drugs during svnuJared Y-site adminis1r1tion.A1r1J
Hea/1/t-S)'.<I Phorm 1991; 54: 2192-6.

N Dependence and Withdrawal

As for Opioid Analgesics, p. I05.

Profile
OAN
~
CH
3 Adverse Effects and Treatme nt
Propyl nicotinatc is used in lopical preparahoos as a rubefacienl As for Opioid Analgesics in general, p.106 and for
H3C CH3
Preparations Fentanyl, p.58.
Proprietary Preparations (detail• are given in \tlume 8) Profile
Ger.: Elacur: N<odonf: Ula, Ana<ios (A>1Woc)t- Precautions
Proquazonc is an NSA IO (p.100) thal has been used orally and
rectally in musculoskclcral and joint disordel$. As for Opioid Analgesics in general, p. l 07.
All cross-references refer to enlries in Volume A
 Propacetamol t-:lydrochloiide/Rofecoxib 125
Administration. Rcmifenlanil h}d~hloride i11j«:lio11s oon· 1n 1he BNFC' 111119 for use on ncona1es ahhoush in the UK
tuinin; gtycinl! should not be given by lhc epidural or introlhecal
rnuleS-.
For provision of analgesia during maintenance of an-
aesthesia in vcntilaled patienls, usual infusion doses reonifen1anil is no• licen.<ed for
cg_e.
=
in childrc11 under I year of
range from 50 nanogramslkg to 2 micrograms/kg per
Hepatic impairment. Althoush the ph•m1acokinetics of minute depending on the anaesthetic drug employed Preparations
m11ife'1lanil ore not changed in patients wilh sevcl'C hepatic in>- and adjusted according to response. Supplemental Proprietary Preparations (dcl3ils arc ~iven io \i>lum~ 8)
paimlCnt, such patiems lllay be more sensitive to the respiratOI)' Ari" Remcit; Uhiva; AunlOI.: ""'2: Austria: Ulti,.: &11.: \Jl".NO; 8-:
dcprcssanl eft"ects and shonld be monitored with do.~ titrated 10 intravenous boluses of 500 nanogram s/kg to un.,.. CAnod.; Ulliva; Chllr. ui;,z C..: '-""""' O•nm.: U~ova: Fin.: UW.:
individual ~uiremenis. I microgram/kg may be given every 2 to 5 minutes in fr.: U",Jlq' G•r.: Ulttvit: Gr.: l#tiv11C Honi Kon~ uiv..a; Huni.: U~t: Jtl.:
response to lighr anaesthesia or in1cnse surgical stress. -UMM: luoel: t.Jtwa. Ito/" Ulfrn: Mu.: Ut>Ya. Neth" U!Wo: N<VW.: L'lti·
Renal Impairment. The phannacoki11e1ic• ofrcmifentnnil are VA; NZ: Ulliva. Pol.: utt;vo. Port.: u~;,.. Ru'" L~ (YA.,.,..); S.A(r.: Lil·
,..,. changed in pa1icn1s wi1h SC>'tn: renal impaim1cn1 (a cseali· The infusion dosage in spontaneous respiration is ini- 1lv1: Sfrtgopore: Ut""-a: Spojn; Ultva: Swed.; lJltiv.l; Swrtz..: ltM: Turk.:
nine clearance of less 1han 10 m!Jminutd and licensed product tially 40 nanogramslkg per minute adjusted according U/liva; UK: Uhil-11: USA:~ Ven.." Ult"".
information states 1h•1 lhe carboxylie acid metabolite is unlikely to response within a usual ra nge of 25 to
to uccumula1e to clinically active concentra1ions in such patients 100 nanogramslkg per minute. Bolus doses are not rec-
nfier remifenianil infusions given for up 10 3 days. Dosage ad- Rofecoxib (5AN. uSAN. ,INN)
jus1mcn1 is eonsidet~ 10 be w1ncccssa1y. This is supported by ommended during spontaneous ventilation.
MK-966; MK-0966; Rolo!coxib: Rofeco><W"n: Rofo?tdsibi: Rofe.
phamiacokinetic studies'.! in in1ensive care patients ~ith tc1'31 For continuation of analgesia into the immedia1e post-
impaimient given remifenlanil infusions at a rate of 100 10 koxi!J. 1·fp-(Metll)'!s.Afootl)pher.y!}3·phenyl-2(5H)-f..nnone.
operative period typical doses by intravenous infusion
ISO ~nograms.'kg per minule for up to 3 day$. Po+e<OKCH6
have ranged from I 00 to 200 nanograms/kg per c.,H..o.s = 311 .~.
I. Breen 0. ~I al. Offiel o( pharrnacodynamjc cfrect.s and sartry or
r-:mircntanil in intt.l\live Cllf( uni1 p:11ictus with "ariaus dcvccs minute; suwlemental intravenous bolus doses are not CAS - 1610/1 . 90-7.
or renal impairment. Crit Can!' 2004: 8: R2t-JUO. recommended during the postoperative period. ATC - MOIAHOl.
! . Pitsiu ~. ttt 111. Ph:innaeokinetics orremifentani l :ind hs major ATC Ver - Q,MO I AH02.
met1holite. r!mifen1anil acid. in ICU p:11icni:1 wilh rtnol imp3ir· To provide analgesia and sedation in ventilated pa· UNIJ - OQTW8Z7MCFI..
mcn1. Br J A""""'' 2004: 92: 493-50}. tients under intensive care. remifentanil is given as an
intravenous infusion at an initial rate of I 00 to
Interactions 150 nanogramslkg per minute. Doses should then be
For in1eractions associated with opioid analgesics, see titrated to provide adequate analgesia and sedation; a
p.107. period of 5 minutes should be allowed between dose
adjustments. Additional sedative drugs should be giv-
Pharmacoi<inetics en to those patients inadequately sedated with remifen-
After parenteral doses remifentanil hydrochloride has a tanil infusionsof200 nanograms!kgpeiminute. An in-
rapid onset and short duration of action. Its effective crease in the rate of remifentanil infusion may be
biological half-life is about 3 to 10 minutes and is inde- nec:essa1y if additional analgesia is required to cover
pendent of dose. Remifcntanil is about 70% bound ro stimulating or painful procedures such as wound dress· H3C-s
plasma proteins. mainly to a 1-acid glycoprotein. It is ,,~
ing. Doses of up to 750 nanogramslkg per minute have 0 0
hydrolysed by non-specific esterascs in blood and tis- been given to some patients. Bolus doses of remifen·
sues 10 an essentially inactive carboxylic acid metabo- tanil are not recommended in in{cnsive care.
lite. About 95% of a doseofremifentaoil is excreted in ll"rollle
Remifentanil is also used as an analgesic in patients re- Rofecoxib is on NS.-.10 (p.100) reported 10 be a sck"Clive inhil>-
the urine as the metabolite. Studies in animals suggest i1or of cyclo-oxyge11ose-2 (COX-2). II was given orally for
ceiving monitored anaesthesia care. In the USA, it may
that remifenranil may cross the placenta and is distri b- symp1oma1ic rtlicf i111hc irea1111en1 ofos1C<X1rthri1is and rt1cu011·
be given intrave nously in a single dos e of
uted into breast milk. 1oid arthritis. and in 1hc mMagcmenl of acule pain. dysn1cno1'
I microgram/kg 90 seconds before the local anaesthet· rhoe:i, and n1igr.iinc but was generally "ilhdrawn worldwide uf-
O Licensed produc1 infonnatoon for remiten1;u1il gives values for ic; altema1ively. a dose of JOO nanograms,'kg per ter repo11s ofcardio\'UCt1lar adverse elfec1s (sec below).
a 1hree-<l0mpa11menl phom1acok1nctic model wi1h a r•pid distri· minute may be given as an intravenous infusion, sta1t·
bution half-life of I minu1e. a slower distribution half-life <>f 6 Rofecoxib has been a1iplied lopically in some countries.
minu1cs. aoid •terminal elin1ina1ion half-lifeoflO to 20 minutos. ing 5 minutes before the local anaesthetic, which Effects on the cardiovascular system. As ofFchlllM)' 2001.
Reforenc<s..
should be reduced to 50 nanogramslkg per minute after 1he 1.JKCSM had rec•ivedasmall nu1nbtrofreporuofn~vocar­
I. Et1:~n TO. N:einifon1anil phannacotirwric1 anJ phnrmacodynam· the loca l anaesthetic. Subsequent adjus1ments of di<1I i1ifarctio11 or ischnemia a<socia1ed wilh tho! selective cyclo-
ici: o prclin1inary :mprais:JI. <:1111 Phormacokinc.>1 199S: 29! 25 nanogramslkg per minute at 5-minute intervals may oxygenase-2 1COX-'.?) inhibilors.1 Al lhar lime ir noted lhal
80 9~. . COX-2 inhibium such as rofecoxib did nol possess the intrinsic
be made to maintain a balanced analgesia. an1iplatcle1 activily associa1ed "'ilh aspirin. J11d consequenlly did
~. E¥an TO. PhatmA<o'-in.:tictt and ph:un1.11t:od~-narnf<.s ofNlllifCn~
tnml: ;in upd:Kc ln 11'c )'<ar2000. C1m Opi11A11~11>c-.~1200IJ: Rcmifentanil has a very rapid offset of action and no not pro"ide t}(()teciion :lgainst ischacmic c.ardiac events. Data
IJ: 449-SS. rt:Sidual opioid action remains 5 to 10 minutes after from a tarae. randomised s111dyalso showed U1e incidence ofmy-
J. Ross Al\.,('/ <d. Ph3rmarokinctiCI urr<mifotrnnil in !'ll"C$lhC1iud oe<1rdinl infarc1ion to be g11:alcr in pa1icn1s iaking rofecoxib 1han
p..-di.atttc; poilicnls und crs(\in~ clttli\·~ su~..:ry or Ji11i;n0$'.lic prO- stopping an infusion. When appropriate, alternative an-
in 1hose laking naproxen.l Poslmarketing surveillance of ro-
Ct..-durcJ Aue11h .411nlg 2001: 93: 1393- 1401 . algesics shou ld be given before stopping remifentanil, fecoxib con1inued 10 provide further CllSO r~ns ofadve"" car-
in sufficient Lime to provide con1inuous and more pro· diovasc<1lar elfo:1s. In addition, resul~ of 1h~ 1hen unpublished
Uses and Administrat ion longed pain relief. APPROVe sllidy of rofCcoxih for l'""'tntion of ndenomatous
Remifcntanil, an anilidopiperidine derivative, is an polyposis indic<11<:d 1ha1 lhe risk of myocardial infarclion nrtd
0 References and reviews. stroke was mar1<edly increased in potienls receiving the drug
opioid analgesic (p. l 08) related to lentanyl (p.60). It is
1. Davi' PJ. Cfodi$ fr. The \l!SIC or uhr;·shon-.ac1ing opioids in~- compared wi•h 1hosc on plac:d>o; however. this diffc~OC'e' wos
a short-acting µ-receptor opioid agon ist used for analg- d1:uric a:1:a~ill'4!slo: lhe roleof ttinifcnc:tnil. Clin Pht,rmocokiuet only apparent after 18 month.softreaune.111. As 0 result.. rhcstudy
esia during induction and/or maintenance of geneml ~OOS: 4~: 787-96. d I d · "· .__ 2004 I '
2. ScoH U. Perr) CM. Rcmi((1ll~nil: n rn"i<w o( its use during the was stoppe car y an • in oX"ptcmU\,.. • t l~ manu1:telUl'C'I'
an~esthesia. It is also used to provide analgesia into the indv<.'1ion :.nd m.:1intenance ar gcnu..I anatAMs 11 • Dn;gs 200S: generally withdrew rofoccudb worldwide. The cardiovascular
immediate postoperative period. and may be used as 65: 1793-llnJ. t"onttti0<1. ibfr(; 1286. findinp from the APPROVe siudy were published in 200S;l the
lhe analgesic component of local or regio11al anaesthe- 3. O:ith:.,hill AJ. ~ea1ITTz. (iM. Re1nifenttinil: a ~view or iu anaf· rcsulL~ showed 3 twofold incre.ise in the risk of adverse cardio-
!>"C,tc and K"dativc: ...,.~in the intc:nsivc coirc t111i1. Drrtgs 2006: 66: vascular C\'ents in pnticntsrcociving rolCcoxib 25 mg daily when
sia with or without benzodiaz.epine sedation. Remifcn- 36S-S5 . conip:irtd wilh those on placebo. More recen1ly. da1a for patients
tanil is also used to provide analgesia and sedation in 4. W<liin~ L. Ro1h tl. E>Jl<ricn« w;1h r<mifentonil in neo11>1c1 and in the APPROVe Sllld)' ha,·e been re-analysed to include extcnd-
infon1s Drag,.\ 1006: ~ti; 1339-SO .i •
mechanically ventilated patients under intensive care. .s. Rom&IS-l! R. f'I ol. l~emifi:nt:inil for w~neral an~c-sthr:si1: " ~ys- cd follow-up findings. Overall. 1his 3Mlysis confim1ed the in-
Ir has also been tned in labour pain. 1cn1t11ic review. A1tMs1/tt:si(l 100i: 62: I 2(i.6-.SO. creased risk of eordiova.scular cv..:nls such as myocardial infatc-
6. Hill 0. Remif~nu:mil in obst<ltics.. C11n·OpinAuuet1lwsiol'.!008: tion and Slrokc in p:.uicnts 1a~in~ rofecoxibwhcn compared wi1h
Remifenrani l is given intravenously as tl1e hydrochlo- 11: 21c1-1 those given pl:io:bo~ there \\·as also a non-siiri:n1ficanl ~in
ride, usually by infusion. Its onset of action is within 1 7. Wilhelm W. Krcuer $.The pl:cot for short-ac;lina opioids: special the risk of soch e\'cnts in the year afkr rolCco>..ib was slopped.
minute and the duration of action is 5 to I0 minutes. cmphuis 011 r~mifrnt:m1I. Cru c"~ 2008. 12 (suppl 3): SS. Small p:uicnt num~rs mode ildirrtCUlt lO¥iven any more precise
Doses arc expressed in terms of the base; remifentnnil t;;.t~~~3~11c2~,,:~:C:~,~~l:~f;!~;~~;t;tcf1~r~~n,c.'articlc$/ details abou1 when 1hc increu~ risk bepel or ended: however.
hydrochloride 1.1 mg is equivalent to about I mg of 8. Mal'\h OF. Hodl;inwn Ii. Kt':mifcntnml m poitd•atric: an1eMMlic 1hc dat11 suggested au early incrco1sc in risk lh:3t persists for abou1
prnc1ic<. .~'""'"h•.•ia ~009: 64: 301-8. I year after 3 )'l'O<S ol'lt<•tmcm. Similur da1a. suggc.uinga 1.5·
remifen1anil. lni<ial closes for anaesthesia in elderly pa· 9. Hitt0\ 0 A. f-ernoindo R. SyMcmi< rcinifctuanil for labor 11nal1e· fold increasl! in rbk or lhrombotic tYCtllS wilh rofecoxih. were
1ients should be half the recommended adult doses and .... Ane"'' .4"u(~ 2009: 109: 192S· 9 reponcd from n >ludy of adjuv:inl use for t"Olorcc1al cancor.s A
then litrated to individual requirements. Obese patients Administration Jn children. Rcmifentanil hydrochloride. eumulali\'e rntt:Mmalvsis also indic:ncd an incrca~~d risk of
ma}' require doses based on their ideal (lean) body- give11 h)' continuous iruravenous infusion, is used for analgcsio myocardi•I intilmion in paticms 1ttei,·ing rolO!coxib.•
weight. For details of doses in children, see below. during mainlcn••icC of general anocs1hesia in children. Usual in· Subso.1ucn1 in\CStiga1ion by US and European regularory au·
fusion doses (expressed as lhe bascl for those aged from I to 12 lhotities has confimied l~ot otlier COX-2 inh1b11ors are also as·
When used to provide analgesia during i11d11c1io11 of ycors rdn~e from 50 nanOJlrains/kg 10 1.3 1nicrogramslkg per socia1cd with some increased cardiovascular risk (sec under
anaesthesia an intravenous infusion is given in doses of minu1e dcjX'ndi11g on the anaesthetic drug employed and adjus1- Celccoxib, p.35}. as al'c some non-scleclive NSA IOs (sec
0.5 to I micrograms/kg per minute. An additional ini- ed according to response; •upplcmental intra\enous boluses of Thrombotic E"ents. p. l(JO).
tial intravenous bolus of 1 microgram/kg may be given J microgr.1111/kg may be given over at lcasl 30 seconds. US Ii- A review'ofprospccti\'es1udie:;e\'lllua1ini;tbccfti:ctofselective
over 30 to 60 seconds pa1ticularly ifthe patient is 10 be cen.<ed prnduct infomwion also s1a1es that neonates and children COX-2 inhibit0t~ on blood pre.sure "'as ooable to detcnnine if
aged up 10 2 months may be given infusion doses of lhere was any associa1ioo bc:1wcen 1he use of these drugs and
intubated less than 8 minutes after the start of lhc infu- 400 nanograrns/kg to I microgrnml((g per minut~ wilh supple· blood pressure elevations. Of the srudies considered. a ran·
~ion. 1ncn1al boluses of I microW""ul/kg. Siniilar doses nrc suggested domised Sl\Jdy in elderly. hypcnensive pa1io11s with osteoarthri-
111e symbol t denotes a preparation no longer actively markeled The syinbol ®denotes a substance whose use may be rcslricted in cenain spons (seep.vii)
126 Analgesics Anti-inflammatory Drugs and Antipyretics
tis has suggested that the risk of developing i~ syrtolic or more. three or four times <faily for pain and f.--er, lower doses 4. Bitgcn C, ~t al. .Efficacy and aafcty of willow b1rk cxLract in the
blood pressure is peater in those patienlS receiving rofecoxib are used in combination preparations wilb other analsesics. Sal- 1.rcatmcn1 of osteoarthritis and rheumatoid 1rt1vilis: results of 2
than in those r=iving celecoxib.r However. the manufaC1urers icylamide has also been applied topically in various preparations randomized double-blind conttollcd trials. J Rht urnotoJ 2004;
31: 2121-30.
of rofecoxib have p0in1ed out that chc scudy used doses of~ in cooccntra1ions of up to 8.So-" for the relief of muscular and S. Anhrilis Rcsc1rd1 Camp¥ign. Complementary and 1frcma1ive
fccoxib greater than those recommended for elderly or hypcncn- rmuinatic p0in. medicines for lhc '1t1tmcnt of rheumatoid arthritis. osuoanhritis
sive patients. and fibromyalgia (issued February 2009),
I. CSMIMCA. COX-2 sel«tivc NSAIDs leek 1ntiplatelc1 activicy. Preparations Av1i11blc al: hup://w\\·w.arthritisrtscarchuk .org/pdf/
Current Probltms 2001; 27: 7.
2. 8ombl.rdic:.r C. ~t al. Comparison of upptr pstromtestinal toxic·
Proprietary Preparations (details arc given m Volume B) fto~f~fo;~;~;?~fc~~~~u7o)ive%20m•dlc in••-
AW1ria: W.ldheim Rheumo.0-. uiv, Cmon N (Ue$<•OK H~
:~.~~!;~x~~"to~&r;;;~ ~~~ts with rheumatoid anhri· Mutti·lngrtdlenc Arr.: F'"'V9t: f\n;;ogript: VcnU:r: Ausuia: Ri~
Preparations
3. Brcsaliet RS. et of. Cardiovasculv events anoci:t.tcd with ro- Rubriment Si~ S. fottet: ~ S, ohno Co'le.nf: Siw>'..in S,f: Propr ietary Preparations (details are given on ~hune B)
recoxib in o colorect1I adenoma chcmoprevcn1ion trial. N Engl J w-.., Sport· und Rheuml:f\Mlt: Belg.: Per- Broz.: Zortrioc Gt..: As.salix: A<•p"'"'f: Op:e>A; aa.ftc>c; PnWctiv; Rhcv-
Mod 200S; 3Sl: 1092-1102. Correclion. ibid. 2006: 355: 221.
Waldheim ~f:
cwlfine; Broz.: ConslN II; Nogripe; l\o:ip.a><: Vg G;>t: Oenm.: Koda· ma!Qpsj; RI'..........,
S.licist: Pol.: SoOc:tonex: Swnz.: AssalO<: Ukr.: Ass>b
4. Baron JA. ei al Cardio,·ascolar events associated v.ith rofccox· n>d: lCoft.al fT~ l't!rcvta'sine: Gr.: Myalgesc: HOtlt Koni: Antam;n: Ar·t> (At......:).
ib: final analysis or the APPROVe tri1I. Lon~ct 2008; 372: cot~fort~ Anl;fiu·N~ Co-flMtt Of Multi-Symptcmt: ft;
175~ . Correction. Ibid.; 1132. Zep: ~p: Neorep: Quomp; 1..-: Cold Cap; Core>eint: ~OP< ~~d..~~:.~~~t.!~1=
S. Kerr OJ. rt nl. Rofeooxib and c.atdiOV1scular adverSc events in ltoL: Anoconttaf: Mox.: Arrion: &.by.>o1tol: NZ: C.,-,,.V. Pol.: Ro... Aictt; N)11 Cold & Fl.i f'clller [)!y: N~I Cold & Au Fp.,. Ooy & Nigt1t:
adjuv:1n1 lrea1ment ofcolorecul canccr.N Engl J Med20-01; JS1: mosot: Scorbota,,,;d; Rut.: Cefecon N (Ue+t•o• H): l'ertut•l&ine Nyal COIJ&h. Col:j & Au Doy & l\lgtlc Nyal Ht.ad Colo FiJttt<.-Ooy& Night
Nya! Sinui Roiliot NyaJ S..US Retoel't4y & Niltrl: l'loa· It: Au.nrlo: CXie>to-
3~9.
6. JOni P, ~, of. Risk of cardiovas.cular evcnu and rorccoxib: cumu·
lative met1•1n1lysis. Lanett 2004; 36•: 2021-9.
(n•P"Y'"""''"')t: s.A(r.: Cobpst: Flutex Cold ond Au: Histamed Com·
P<M'<l: U.;cot: Spook Nerve f'aif, ~edyt. Sf>o/n: Contidrlt l'ncl,o: f\i.
~ Rlnomocine >cli"ada; Yend« Sw~ &cotrW sans .codeinet:
doron: &oz.; C*nan: Qlmipl"" Floriny:
no&.,~
""°"' fUc; P.1'si Cathaf; Ca-
Ho3kra<.1erTeo: Cz.:-<l<yCajt: Calmonalt: &1oil-
7. Johnson DI.., ti ol. Effe<::t of cycloo.xycenase--2 inhibitors on ~ "'t: 0.. Gel de denwon: Thai:~' fetol: Poinol: UAt'.: ""'i'!eef: llalolyl Neat: Fr.: At1<Dphytum: Ar\hr~isane: Arllvoftome;
blood pnssu~. Ann Pha<mocot,,, lOOl; 31: 442.-6. IUit Ukr.: Percutalsine (flell"l"-~ USA: Mahar; Be.flex l'l.o: a,.. ~t. Ploy1heol fan:e: S.-..... A,: Ger.: Disfstodorc»: Dr W~
8. Whchon A. tt al, Cyclooxygcnate-2•.spccHic inhibitors and car· MIC Combif'oc Ouraxin: l~ l.obKf; Paioaid: S&lflO< lM>-Bmh moms Rhc..,,.~ Gr.: Pusillorine: H ung,: Urohortx lndon.: OWn:
diorenal function: a nrMSoroiz;t:d, COtltrolled trial of cckxoxib.nd Vent.<.: Court:~ Ital.: Biothymus 05: ~ Oonatg 1n11...znc: lnl\c>d C; Ne>ril: Re·
rofccoxib in oldcrhype:nCASive osteoarthritis patie.l'ls.AMJ Tltr.r umaf0t1; Moloy*: Celery PIU>j: M ex.: I~ Pol.: £ntero.ot lnfelcto-
2001; 8: 8S-9S. ten; fYogt Revnxor: Revmosot Mnosol C: -~ Port.: Neuroc..--
dolt.$.Afr~ o;g..iodoront. Spain: Do1osJt: ~: Mt10~1f; Nit_,.
Preparations ~t: N.lt""" )iqueW<f: s.m..: Ong.cs anlimumatismale>t:
Propri"tary Preparations (dcl•ils are given in Volume B)
Salix SU.th Gouttes Rh-.osmq; r ...... MU!lo.matismale: UK: Bo-Stnlh
WillOw formula; Ge<..o House Re.nalex: Ho:rto1Pin Relet StjolYlswort
lndl« Roklabt: Roflbt; Ro6>oct. Roizt: \Aonatit; Turi<.: Eaooc ~ Corteu de sauce: Ecoo:e ~Sar.Ac: FOlfakereg; Gluosnit/ ~ Compound: Ukr.: ln<ti (kli)f: Vcnu.: Pas<ollot\.m
Rcox; Rofemaic: Romaryd; v..m_ Ukr.: Ooocbol GO.c:tte6ot.~ R.oko
(P....). Kora wierzby. Pajtriuori; Slilgbari<: Salicis cortex Saule. ecorce Homoeopattric: Conod.: Homcodel IS: c;.,.: ChcidonVn <OtllX UK:
de: Vlbov;I kin: Weic-enbaumrinde: White Willow Bari<: Willow Digestodoron.
Multi·l~grecfoenc Indio: Rofecip Plust: Ulu~ Oenebol Ce! ~
ftN>)t. Bark.
1-!aa
Salol
UNI/ - S883)9)DYX
Salamidacetic Acid Bel1zofenolsaf~~ Benzoph<!nol Salicylate: Fen,.tsakytat: Feny-
Cart>amoylphcnoxyacelle acid: Salamidacctico. acido: ~­ j,.r saJiqtM: feny)oflsabsylaatti; Phenyfi Sakylas; Phenylis Salicylas;

HOJ?
mide 0-acetic acid. (2-Carbamoylphenoxy)acetic acid. Salidato de fenilo. Phenyl salicylate.
Ha-rpKR CaAMU""""1<AOueTaT (sodium salamidacetate) ew,,..
C,H,NO, = 195.2. C 1)H1001 = 214.2.
CAS - 25395-22-6 (solom1docet1c ocid): 3785-32-8 (so- CAS - I 18·55-8.
dium solomidocetote). ATC - GO•BX12.
.'ITC Vet - QG046X I 2.
~oyo UNI/ - 28A)7T47QO.

HO HO'''"Y"'''OH
OH 0 0
~o~
OH

P~armacopoelas. ln Eur.
(solicin)

(S« p.vii).
Ph. Eur. 6.8 (y>/t'ktN B2ri<). The whole or .fragmented dried bark
v
Phar macopoeias. Jn Pol.
of young brulchcs or whole dried pieces ofcurrent~ twigs of Profile
various species of the genus Salix, including Sali.t p11rp111WI, S.
Profile Salol is a salicylic acid derivative (see Aspirin, p.21). II was for-
daphnoida, aod S.ji·ogilis. ltcontailU not less lban 1.5% of toe.al merly used as an intcSlinal antiseplic, but effective doses were
Salamidacctk acid is a salicylic acid dc:nvati\'e (see Aspirin,
salicylic derivatives, expressed os salicin (C 13 H,.o, • 286.3), toxic owing to the libcMion of phenol. II is used in oral prcpara-
p.21) that has also been used as lbe sodium and diethylamine
calcula1ed with reference to the dried dNg. Protect from light lions eontainingmethenaminc for the treatment of lower w'inary·
sallS for the lrcatment of musculoskelctal and joint disorders.
Pre parat ions Profile tract infcctiOClS.
Salix con1ains v:iriable amnunts of tannin and also of salicin. SaJol has been used 1opic1lly as a sumcrec".
Proprietary Preparations (details arc given in l.\lluinc B)
Aurcria: Akisti\. which has antipyretic and onalgcsk actions similar to those of Preparations
Muld·i.nl""edient: Auttri'.o: Ambenef: ~ser. Gtt.: Caye ~ aspirin (p.21 ). Salix has been used in a variety of herbal remedies Proprietary Preparatioos (details are givtn in Volume 8)
tna·Blls;omt; Rus.: llmbene (A--.tieHo~ Thok: Tr>t>itf. for painful and inflammatory conditiuns and for fever. It was Aunral.: Aussie 'r.ti 5uislickt.
once used as a biner. M ulti-ingredient: A..,.: Dermithon: Austria: car! Boder'S OMn;I: tlt11.:
~ &oz.: Talco Aliviot. Cono&., F~. Wall<ins Settelz;
Adverse effects. An anaphylactlc reaction developed in a 25- Chile: -.:pt Cz.: l'lltodon'.>I fSt: frJ Botostyrot Ocmqit.I lrder'C
Salicylamide (&AN.lfNN) ycar-old woman with asthma and • known allergy to aspirin. Niuulm1: Pot.: Salour.naf: Uroul: R us .: PHodontocide
Saldarnida: Sali<ytamid: Salicylam'du'n; Sa.'\sy)l><amidi 2-Hydroxy- within 15 minules of ingesting a dietary supplement eon1aining (lla?OAOHTOW<A): SwltL: ~ Nt; Dermoph'l lndier( QJ Eavf;
willow bark cxtract. 1 The link bctwcen salicylale and willow Penta: Turi<.: Saodolnt: USA: Atros~ D.vp>¢ Dolsec!j: ,.....JI< MSP.
benzamidc. !!lu: Prosed.OS: Trac 1m 2Xf: U."-A: UreC'e: U-.llOr< ~ MoQliedf;
bark allergy was also reported in a carpcnlct who developed o Vrimu·T: \.kWNx Uisodt. IJl'oseptic; VriSymj; ~ Uo lllrc: Urogosic
Ca...u"'"'"'l1A
C7H7N0 2 137.1.
CAS - 65-45-1
= widespread rash, similar 10 tha1 he had with aspirin, whe" work-
ing with willow wood.1
~ ~ 0-1.J:rona·C.

ATC - N028AOS. I. Boullala JI, et o l. Anaphyh1ctk rc.xlion lo a dictel')! aupplemc-n1

ATC Vet - QN026A05. containing willow bark.. AM Pltnrrnoe1Jthcr 200); 37: 832-S. Salsalate (BIW. USAN. 4-INJ
UNI/- EMBBM 710ZC. 2. Jennings A. Link bel~een ulicyl>te and willow ba.r1c Pita,.,,, J
2006; 276: 417. NSC-49171: Salicyl Saicyfate: Salicylosalicytic Aci<t Saiic)'fsalicytic
Acid: Salsalato: Salsalatum; Salysal; Sasapyrine. 0-(2-Hyd"Oxyben·
Pain. Preparations containing willow bark cxtrac1 h•ve been zoyl)salicy'.ic acid.
tticd with some success in 1he b'Calmenl of musculoskeletal dis- C~T
orders such llS low back pain 1•1 and osteoanhrilis.• A reports by
the Anhri1is Research Ca.mpaign in the UK concluded th•t, c ..H , 00.> = 2sa.2
l:ioscd on limited evidence, willow bark may have a moder.lie ef- CAS - . 552-94-3.
ATC - N028A06.
fect in treating pain di.JC 10 osteoarthritis and rhcwnatoid anbritis; ATC Vet - QN028A06.
however, it was not as effective as NSAIDs for pain relief in os- UNI/ - V9M0595C91.
teoerthritis. It appeared to be relatively safe when taken in the
Pharmacopoeias. In Pol. and US. recommended doses.
USP l l (Salicylarride). A white praclically odourless cryslallinc l. Chrubasik S. et al, Tra&mcnl of low back pain cxxtrl'l:ahons
powder. Sligh1ly soluble in water and in chloroform; soluble in with wiUow bwk e""Ctnct: 1 randomized double-blind sa\ldy. Am OH 0 ()

v~o~
alcohol and in propylene glycol; freely soluble in C1hcr and in so- J Medl<xll>; 18': 9-14.
lutions of alkahs. 2. Chrubactk S, et of. Tre»llnCnl or Jow back pain with a hc:tb~I or
Profile synthetic 1nti·rheuma1ic: a randomiud con1101lcd study. Willow
Salicylamide is a salicylic acid deriva1ivc (sec Aspirin, p.21) but
- ~;Sk~9~~Cl for low boc~ pain. RJ,,,.maro/ogy (0.iford) 200 I; 40: COOH
is no1 hydrolyi:cd to salicylate; ii is almost comple1cly metal» 3. Goagnier JJ. ~of. Hcrb3.I medicine for low back ~in. Available
liscd to inactive meaboliles during abi;oJlltion and on first poss in The Coc·hnnc O~tab..s~ of Sy~1cma1ie Reviews: Jssue 2. P harmacopa.iu. In Chin. and US.
through ~1eliver. It is gi'ml in usual oral dosesof325 to6!i0 mg, 01ichestcr. John Wiley: 2006 (1ce1:•1Cd OS!IQ./06). USP 33 (Salsalate). Store in ainight containers.
All cross-references refer Lo entries in Volume A
 Salamidacetic f>.cid/Sodium Aurothiomalate 127
Adverse Effects, Treatment, and P recautions l . Coblyn JS. et ul. (iofd-indu(ed 1hrombocytopcnia: n clinical and
As for Aspirin. p.21. immunogcnc.tic Sluc.Jy ur lwcn1y-thrtt patiC'f\LS Ami /11tcm Mt:d
The use of aspirin •nd OIOO acetylated salicylates is generally
not recommended for children because of die risk ofRc)'c's syn·
drome. unless specifically indicated. Some licensed product in·
Na··oDo J98t; 95: 17&· &1.
3. bcobs JC. •t al. Consumption C:03gu~thy aiOer gotd 1hernpy
ror JRA .J P•diurr 19$4; 105: 674-;.
Au Effects on the cardiovascular system . Vasomotor or nitri-
fonnation exicnds this precaution to salsalate. 's o- Na' toid reactions associat•d with gold compounds are usually tran-
Effects on the gastrointestinal tract. SalSJ>l•tc is associated sient and self-limiting und although they may be mild there have
with less faec•I blood loss than aspirin and hos been reponed to been isolated rqaorU of associated complications such as myo--
cause fewer gastric lesions than piroxicam.' However, small·
bowel ulccratH!ns were reported in a patient when salsalalc was
added to a regimen of ranitidinc and mc1ocloprnmidc which had
HODO cardial infarction. stroke, lrllnsient ischacmic •ttack. and tran·
sient monocular visual loss.1 Most reactions have been associat-
ed with sodium aurothiomalate (a reported incidence of 4. 7%)
been prescribed fot duodenal ulcer.2 Au, but they hove also ocCUJTed -.i1h auranoftn and sodium auroth1·
1. ro1To GS.~' ol. Salulatc in lhc lre.ttiunent or rhe~matoid ~nhri­
S o- Na' oglucosc. Tachyphylaxis usually occurs to lhc reactions and most
tis: a doublc-b1ind clinical and pstroscopic 1rial \<en.us pirox1- patiencs are ahie to continue treatment but petadoxically in some .
(~m: l l-cndoscopiccvah1aoon. J Im Med Rcts 1989; 17~ 32()-3. Pharmacopoeias. In £11r. (seep.vii). Jp11. and US. the severity increases with repeated doses; 2.8% of patients re:
" Souu Li1n1 MA. Ulcers of the su·tall ~~I assoc i:n~d with Ph. Eur. 6.8 (So<ium Aurol!1iornabte). A mixture of monoso- ccivina sodium aurodtiomalate may require a change of t.reat-
s.tomad•·bypusing salic)'l:11cs. Arc.h Int~,.,, Al~d 1985; 1 ~ 5: dium and disodium salts of (2RS)-2-{aurosulphanyl)butanedioic 1nen1 due 10 recum:nt reactions. II is important to distinguish
1139. 1
acid. It contains 44.5 10 46.0"/o of sold and 10.S lo 11.8% of so- such reactions from true anaphylactic reactions to gold. Patients
Effects on the kidneys. A case of minimal-<:hange nephrotic dium, calculated wilh reference 10 lhe dried substance. A fine, takin!fCE inhibitors may be at incrcucd risk of nilriloid reac-
syndrome associated w11h salsalate use. 1 pale yellow, hyi;roscopic powder. Very soluble in water; praeti· tions. Transfer ofdic patient 10 sodium aurolhioglucosc or re-
1. V.llb M. TovBr JL. Salsala1c and mininul-chanac ncphrolit
catly insoluble in alcohol :ind in dichloromethanc. A 10% soli>- ' duction of dic dose by SO%, irtjcction in the recumbent position,
taon in water has a pH of 6.0 to 7.0. Store in airtight containers. and observation for 20 minutes hoV<: been recommended for lhc
oynclrome. A1111 /n1erir M•d 19&1; 107: 116. 1
USP 33 (Gold Sodiuin Thiomalate). A mixture of the nJOOOSO- next few injections after a reaction.
Effects on ttae mouth. Ulcerated lesioos ou the lO!lb'UC of a dium and d1sodiwn sallS ofgold d•iomalic acid [(aurolbio)suocin- I. Ho M. Pullar T. Vasomotor reac1ions '~th sold. Dr J Rh~,,motol
77-ycar-old man were caused by laking salsalate IJ!blecs incor· ic acid) !C.H.AuNaO,S • 368.1 and C,lf,AuNa10,S z 390.1) 1997; J6: IS4-6.
rcclly. 1The patient had placed the tablclS undor his tongue ralher that has a gold content of 44.8 lo 49.6%. and 49.0 to 52.5% cal-
2..G.rthur AA, et ol. Niu-itoid rc~c1ioiu-: cue rcpotts.. rc\'icw, Md
th:in swallowing them whole. resulti11g in prolonged, direct con· rcc:ommcndllltions for managcincn1. J Rhn1ma1ol 2001; 28:
culated on the dried alcohol-free and glycerol-free material. pH 2209-12.
IJ!ct wilh the tongue. ofa 10% solution in water is between 5.8 and 6.5. Store in air- l. Nixon J , Pan dc I. Gold, nitrilotd reactions 0:nd angiutc:nsia<oo-
I. Rui=tin JM. Ascroth. JO. l.iog,ual Jcsions tcCOndary to prolonged tight containers at a temperature of:?5°, excursions pcnni1ted be· vtrtini entymc inhibi1ors. RhrHma1olog" (Oxf()lviJ 2006; 45:
contact w'ith S3lsala1e tablets. A11u PlJormacot/1rr 1998: 31: tween 1.s• and 30°. Protect from lighL llJ-19.
1248.
Effects on the gastrointe stinal tract. Entcrocolitis due to
Int eractions Adverse Effects sodium awolhionialatc has been reported' and 27 other caS<:s as·
For interactions as.o;ociated v.ith salicylates, sec Aspirin, p24. Reports show a wide range for the incidence of adverse sociatcd with gold Qierapy micwcd. For oohtis associated with
oral gold, sec also under Auranofan, p.27.
Pharmac:okinetics effects of sodium aurothiomalate. However, some con- I. Jac:: ks0n CW. et ol. Gold
1 indu~ fnlerocoluis. Gut 1986; 17:
Salsalalc is insoluble in acidic gastric fluids but is soluble in the sider that with careful treatment about one-third of pa- 4S2-S6.
small intestine. One molecule ofsalsa late is hydrolysed to 2 mol· tients will have adverse effects. It is also considered
ec:ulesofsalicylic acid; hydrolysis occurs both in the small intes- Effects on the Im mune system. Details ofa palicnl who de-
tine and after absorption of the parent compound. Additional de- that in about So/o of patients these will be severe and veloped nn immune deficiency syndrome that was attributed lo
tails on the pllarrnacokinctics of salicylic acid are provided in that some of the effects will be fatal. The most common gold therapy with sodium aurolhiomalnte.1
aspirin (sec p.24). Not all of the absorbed salsalatc is hydrolysed effects involve the skin and mucous membranes with I. Hask.ard DO. Macfarlane 0. Adult ,cquired combinC'd immune
dcfictmcy in :a pulicnt with rheumatoid arthritis<'n gold. J It Sot:
and about 13% of salsalatc is excreted as gluauonidc conjllglltcs prurirus (an early sign of intolerance) and stomatitis Mod 19!$; 81: S48-9.
in the urine; thus, the amount ofsalicylic acid available from sal- (often with a metallic taste) being the most prominent.
salate is less lhan that Crom aspirin when the two drugs arc given Eff'ects on the kidneys. PrOlcinuria developed in 21 patients
in cquimolar equivalenlS of solicylic acid. Rashes wi1h pmritus often occur after 2 to 6 months of while receiving a standard regimen of sodium aurothiomalale.1
intramuscular treatment and may require stopping The severity of the proteinuria varied greatly and in II it in-
U ses and Administration creased for 4 months after treauncnt was stopped. Eight patients
Salsalate is a salicylic acid derivative that has analgesic, anti-in·
therapy. Other reactions affecting the skin and mucous
were considered 10 have developed the nephrotic syndrome. The
flanuna1ory, aod anti~ic actions similar to those of ospirin membranes include erythema, maculopapular emp- ancdianduracionofproteinuoia was II monlhs,reso!vins inall 21
(see p.24). It is used for pain and fever and also in inflamanatory tions, erythema multifotn1e, urticaria, ecz.ema, sebor- patients when rrutmcnt was stopped; at 24 month$ 3 paticnlSstill
disorders such as ostcoanhritis and rheumatoid arthritis. lbc rhoeic dennatitis, lichenoid eruptions, alopecia, exfo- had proteinuria ond it was not u1nil 39 months that all were free
usual initial oral dose for inflammatory disorders is 3 g daily, giv- liative dermati tis, glossitis, pharyngitis, vaginitis, of the condition. Renal biopsy indicated several IYJlCS of kidney
en in 2 or 3 divided doses with food; the usual main!A!nonce dose damage.
i s~ 10 4 g daily, 9CIJusted according 10 response.
ph0tosensitivity reactions. and i/Teversible pigmenta-
tion (chrysiasis). See under Aunmofin (p.27) for a comparative incidence of pro-
Preparatio ns tcinuri3 in ~lients rcc~iving sodium aurothiomalatc or ou-
Toxic effects on the blood include eosinophilia, throm- nmofin.
USP 33: S.ls;\Jotc! Copsui..: S.lsalate Tal:leu.
bocytopenia, leucopenia, agranulocytosis, and aplastic I. Holl CL.~tnl. Tht nauntcourse of ioldncphroponhy: loftJ'c'm
P roprietary Pre.paratio ns (derails art given in Volume B) anaemia. Sludyof21 paa;cnts. BM.I t9S~: 295: 745-8.
USA: A-r.ii<>e hfe$'c-SA; ....lho·G: o;..w Mlrl......ic: S.:llex: s.isrtab.
Effects on the kidneys include mild transient proteinu- Effects o n the lungs. 'Gold 111113' is the t01m used 1odeseribc
symplOOlS of dyspnoea on cxcr1ion, weakness. dry cough, and
ria which may lead to l1eavy proteinuria, haematuria, malaise that ore seen rarely in patients on gpld rreatmcnt. 1Such
and nephrosis. symptoms usually develop some weeks or months ancr sll!rtinJI.
Sarrcicenia Purpurea
Other effects reported include pulmonary fibrosis, dys- ~old treo1mcn1 ond arc associated wilh cumulative doses of SCV·
Pitcher Plant pnoea, toxic hepatitis, cholestatic jaundiee, peripheral era! hundred milligrams ahhough. very rarely. they have been
Cappaue1<1<R r1ypr.ypt<an seen ,.;1h cumulative doses of less lhan 100 mg.1 Pulnionill')' in·
neuritis, encephalitis, psychoses, fever, and gastroin· stafficiency may evcnrually develop and there have bt..:n occa·
UN/I - FOPOBHl43P. tcstinal disorders including entcrocolitis. Gold deposits sional fotalities.1 nae pulanonary lesions usually sub~idc on stop·
Profile may occur in the eyes. Vasomotor or nitritoid reactions, ping of gold lherapy, although pcrsis1e111 symproms have been
The roots and leaves of Sarrocenio f"trp11rco (Samiccnincuc) with weakness, flushing, palpitations, and syncope. repo1tcd.
ha)•e been used in the form of an aqueous distillnte, giV<:n by lo- may occur after injection of sodium aurothiomalate. Non~ac1erial thrombotic cndocarditis associated with ~old­
cal injection, for neuromuscular or ncutalgic pain. induccd pulmonary disease has also been reported.' This was
Local irritation may also follow injection. considered 10 be a manifestation of gold-induced immune com-
Preparations Sometimes 1herc is an initial exacerbation of the ar- plex depositioo.
Proprietary Prepara t io ns (details ott gi\'en in Volume 8) thritic condition. L Sinha A. ct al. Gokl-iilid!Ked p~umonili$: c:ompulcd 1omog.m--
Conod" ~USA: Sa.-•pin. phy lindinas 1n a P').licnt • ·i«h rfic:um:itoid ar1hrit1J. Rhcumotulo -
Some adve1'3C effects of gold have a11 immunogenic gv (Oxford) 200t : 40: ill- 14.
HomoeopatNc Fr.:~ ere l'Abbc Cha.pitre no 8t. 2. Hafcjec A. Burke MJ. Aeulr pncumonitis startiil,S :! hour$ 1Aer
component.
in1ramvscolar g_old administration in a ~ttettl with t11cu010.101d
ORevicv.'$. arthritis. Ann Rlwum D/1 :!004; 63: 1~lS-6.
I. Tolman ECS. Goulid> NL. Adva$C: fe:1c1ions with oral :and 3. Soler MJ. c1al. fatal. S"kf.inducro pclcumonifis. Rlw11m"'ol Jut
2003; 23: 207-10.
Sod ium Auirothiomalate (rlNNJ 2.
p1rcnh:f'al gold prcpei-otions. Med Tf).:tlco/ 1981: 2 : 177-89.
Roon EN. Cl al. Pl\renlml sold ptt~rattons. Effiacy and
'\'a.A
.a. Kollcf M H, et al. NonbutcriaJ Uvo111botic endocardillS 1ssocia\-
Hf~y <d whh gold induced pulmonary d •~sc. Ann /uw,.,, M~d 19&8;
Aui'Oth.omalate de Sodiun; Aurotiomalato de s6d.o: Gold Sodi- of lhtnpy aOcJ' swi1chin1 fro:n aurothioslucosc to au-
IOI: 903-4.
roth1<Wnalate. J Rlitmnn10/ 200S: 31: 1026-lO.
um Th1omalate: Natrii aumthiomalas: Nat~omalat
Effects on the blood. Blood disorders stldl as cosinophili•, Effect:s on the nails. A 34·ycar-old woanan with severe rt.cu·
Natriumaurotiomalaattt Natn..naurotiomalat Sodium. ru"Othi· matoid arthn1is receiving intramuscular gold dc\·eloped yellow
omalate de: Sod'aum Aurothiosuccn<te: Sodu aurotojabla...: lcucopenia, sronulocyloJl"nia, and thrombocytopcnia ha\'C QC.
cum:d in potiencs receiving ¥Old therapy. Eosinophilia has been thickened toenails and lingcmailsafler2 years oftrcatntenL1 Al-
Sod)o.m Orot>yomalal
reported to be the most frequent haematological abnol1TIJllity.1It lhougb there was some ianprovcrncnt in nail growth on !topping
HaTpHR Aypon<O""""T has been ~t11na1t:d lhal thrombocytopenia develops in I 10 3% of trutmenl, sotne light yellow discoloration in all 20 nails persist'
CAS - I 22H-57-4 (cr l>ydrous xNo): 39377-38-3 (dao- patients r,-c.:i,;ng gold sales.' ed.
d1~m monohydro1e). Fatal consumption eOG1gulopathy occuned in 4 childn:n after lhe I. RcxA MAB. Ralnavct M.. VC"llow nails 3$$0Cia.ted "ilh £Old thcr·
itpy ror rbevmalo1d anhri1is. Br J D~nnoio/ 2001 ; 145: 8.SS-6.
ATC-MOICBOI . second injection of sodium aurothioglucose or sodium aurothi-
oonalate.> Effects on the nervous system. Newological complicatioos
ATC Ver - Q/1101(801. J. Foster RT. E®nophilit1-a mark~rofgokl toxicity. CauJ Hosp wilh gold sallS nrc infreqoent but may include peripheral ncurop-
UNI/ - E4768ZY6GM. Pham• 19&S: 85: ISO- I. alhy, Guillain·Barrt syndrome, myokymia (repeated involuntary
The symbol t denotes a preparation no longer actively marketed
128 Analgesics Anti-inflammatory Drugs and Antipyretics
contractions of muscle fibre). and enccphalop3lhy. Some throat or tongue, metallic taste, prurirus, rash, buccal nile idiopathic arthritis; they may also be beneficial in
reports,.. are given below. ulceration, easy bruising, purpura, epistaxis, bleeding psoriatic arthritis. (See Rheumatic Disorders, below).
I. Dick DJ. Raman 0. The Gui Ila in-Barre l)'ftdtom"' folJov.ina &Gld
lh<ropy. Sccmd J Rheumo1011982; II: 119-20. gums, unexplained bleeding, mcnorrhagia, pyrexia. in- They arc generally used as disease-modifying
2. Schlumpf U, t:t ol. Nt'\jroloik complic:itions illduccd by gotd digestion, diarrlioca, or unexp lained malaise. The de· antirheumatic drugs (DMARDs) in patients whose
trea1ment. Artltdtis RMu.m 1983: 26: 82S-3 I. velopment of breathlessness or cough should also be symptoms arc unresponsive to or inadequately control-
3. Ctrinic MM , ~' ol. Gold polyncuropa1hy in ju~k rheumatoid
arthri11". BW 1985: 290: 1042, reported. Effects such as eosinophilia. proteinuria, pru- led by NSAIDs alone.
4. Cohen M. et ol Acute disscmin1ttd cnccphalomyclilis as a com- rirus, and rash arising during gold treatment should be Sodium aurothiomalate therapy should only be under-
plication or lr<atment with sold. BM.I 1985; 290: 11 i9-80.
S. Dubowit.z MN. at al. Gold-induced neurocncephalopathy re.
allowed to resolve before therapy is continued. taken where facilities are available to cany out the tcs!S
S]'IOnding todimctc1prol. l.oncd 1991; J37: 850-1. Licensed product information recommends that annual specified under Precautions, above.
6. Garrido JA. et al. Mloquimias inducid11.s por sales de Of'O. Nt!11r- chest X-rays should be canied out.
ologio 1995: 10: 23S- 7. Sodium aurothiomalate is given by deep intramuscular
Effects on the skin. Chrysiasis is a dislinctive pigmen1a1ion Breast feeding. TI1c American Academy of PediatTics consid· injection; the area should be gently massaged and, due
that develops in ligh1-cxposed skin of patients receiving m that gold compounds are 1.1SUally compatible with breast foed- to the possibility of vasomotor reactions, the patient
~ten.I gold salts. In a $1Udy 1 of 31 patients with chrysiasis in&' . should remain recumbent for I 0 minutes and kept un-
who were receiving intramuscular sodiuin aurothiomalate for Gold has been dotccted in breast milk2 .. and found bound to the der close observation for 30 minutes after each injec-
rheumatoid arthritis, it was noted that visible changes developed red blood cells of breast·fed babies.?.l In a report' ofa breast-fed
above a lhreshold equivalent to 20 mg/kg gold content. l lie se- infant it was calculated that the weight-adjusted dose of gold re- tion. In the UK, I0 mg is given in the first week to test
~rity of the pigmentation depended upon cumulative dose. F<>- ceived by the infant exceeded that recci~d by lhc mother al· the patient's tolerance. If satisfactory, this may be fol-
cal agRg..tes of gold are deposited in the reticular :i.nd papillary though the infant exhibited no 111-clfccts during I00 days of lowed by doses of SO mg at weekly intervals until signs
dcnnis with no obvious increase in mel30in. The pigmentation is breast feeding and de"clopcd nomally thereafter. Nonetheless. of remission occur; the dosage interval is then in-
pcnnanenl but benign, 1llhough the cosmetic effects may cause because oflhe rdativcly high exposure it was recommended that
some patients distress. Prevention of cluysjas;s is difficult but breast-fed infants should be closely monitored
creased to 2 weeks until full remission occurs and then
avoidanoc of expoiswe lo sunlight may be helpful. I. Atnfncan AC2dcmyorPcdiatrics.. Tht 1r-&J\Sfcr of drugs ond olh- increased gradually 10 every 4 to 6 weeks. Treatment
J. Smith RW, ~'of. Chrysiash: rcvi1itcd: 1 cli ni~I and pathological « chemicals into human milk. PeJ1iJf,i<$ 2001; 108: 776-89. may be continued for up to 5 years after remission.
study. BrJ D<rmolol 1995; 133: 67HI. (Retired MQy 2010] Cone<:tion. ibid; 1029. Also available at:
http: //a appo Ji c y.11 ppubl ic at ions .o rat cg i/c nntenllfu I II Improvement may not be seen until a total dose of 300
Hypersensitivity. Many adverse effects associated with gold pcdiarrlcs%lbJOS131776 (•«t5'cd l)/l l/06) to 500 mg has been given. If no major improvement
treatment have an immuoologieal basis. Patients wnh oontael al- 2. Blau SP. Mt&aibofism of gold during ladal,on. Ar1hri1is Rlk:mn
has occurred after a total ofl g has been given (exclud·
lergy to gold may exhibit a flare.up, associated with cytokine re. 1973; " ' 1n-3.
lease, when given sodium auro1hiomalate intramuscularly. 1 l . Nttds CJ, 8t00k1 PM. Antirheumalic: mtditalion during laeta· ing the test dose), therapy should be stopped; alterna-
lion. BrJ Rht!1tmol1J/ 1985; 24: 291-7. tively in the absence of toxicity, I 00 mg may be given
Small amounts of nickel have been detected in sodium aurolhi-
4. Bennett PN, rl ol. Use of .sodivm 1urolhiomal1tc durins lada-
omalate injection1 and in sodium auro1ltiog)ucose injec1ion3 and cioH. 8,. ) Cliff rftortn«o/ 1990; 29: 177-9. weekly for a further 6 weeks; should there be no re-
it has been suggested that gold therapy may also exacerbate or sponse at this dose other fonns of therapy should be
induce hypcmensitivity to nickel.l .. Porphyria. Sodiuon aurothiomalate has been associated with
acute allaeb ofporphyria and is considetcd unsafe in porphyric tried. Jn patients who relapse while receiving mainte-
Anaphylaxis may occur occasionally-' but vasomotor or nitritoid patiatts.
reactions (see Effects on the Oirdiovascular Systtm, above) may
nance therapy, the interval between doses should be re-
produce similar symptoms. Pregnancy. Although healthy neonates have been born after 1,,. duced to one week and should not be increased again
I. MOiier H, ~'of. The Oart-uprcxcao.ns aftCT systtmic pro'·oe.a1ion utero exposure to gold compounds,1·1 011imof studies and a until control has been obtained; however, if no re-
in oon1.ac1 allergy 1n nic.kt-1 and aold. Con1oc1 Dr:nno1i1il 1999; repon 1 ofnialfonnation in a child born to a woman trea1edwith sponse is obtained within 2 months, ahemative treat-
40: 200-4. sodium aurothion1alatc led to a suggestion that gold miglll possi· ment should be used. It is important to avoid complete
2. Choy EHS. er ol. Ntcktl contaminocion of gold pits: hnk with bly have tennogcnic elTects. Licensed product infonnation ad-
g.old·1r1duced skin rash. BrJ Rh~11n1tUoJ 1m: 36: IOS4-I. vises that sodium aur0thiomalate shollld be avoided during preg- relapse since a second course of gold therapy is not
3. Wijnands MJH. et al. Chrysolhttepy pM"VOkin: exacrrba1ion of nancy. usually effective.
con1ac1 hypcrs<nsilivity to niokd. Lone., 1990; 335: 867-8.
4. Fulton RA, ttr al. An0tht'r h.urd of sold therapy? Anu Rlm1111 I. Ro..t rs JG. el nl. Possible- lcntogenic cffccls of gold. All.II Par- For doses in juvenile idiopathic arthrilis, see Adminis-
Dis 1982; 4l: 100-1. d/o/I' J 1980; 16: 19~S.
S. Neustadt OH. Anochcr anaphy1actie reaclion 1t1u gold (aur04hi· 2. Benncn PN. e1 al, U1.t or sodium auroth•omalale durina lac1a· aotion in Children, below.
om.ab.re) injtction. J Rhtumoto/ 1995: 22: J90. 1K>n. Br J OiH Ph<Jrnurct>I 1990: 29: 777-9. NSA!Ds may be continued when sodium aurothioma-
Pancreatitis. ll was suggested that pancrca1i1is reported in a late therapy is begun.
woman receiving gold injections and in a woman on oral gold Interactions
Other gold compounds lhat have been used include au-
therapy may have been due 10 a hypencnsitivity ruction. 1 There is an increased risk of toxicity when gold com·
I. Eistmann AD, ti ol Pancrtatitis and 8C't1d trealrn~nl of rheuma- pounds are given with other nephrotoxic, hcpatotoxic, ranofin (p.26). aurothioglucose (p.27), aurotioprol
toid 1rthri1is. An11 /1Nrrn Mtd 1989; 111 : 860--1. or myelosupprcssive drugs. Use of gold compounds (p.27), gold keratinate (p.65), and sodium aurotiosul-
with penicillamine may increase the risk of haemat<r fatc (p.129).
Treatment of Adverse Effects logic or renal adverse reactions. Administration in child ren. For children with progressiveju-
The treatment of the adverse effects of gold is usually ~ni le idiopathic anhritis, the sug&t$lCd initial weekly dose of
symptomatic and most effects resolve when gold ther- ACE inhibitors. For a possible increased risk of nitritoid reoc· sodium aurotbiomalate is I mglkg by deep intramuscular injec-
lions when gold oompounds are given 10 P"licnts Llking ACE tion loa maximum of50 mg weeldy(one·lenth 10 one-ril\hofthe
apy is stopped. Jn severe cases a chelator such as inhibitO<S. see Effects on the Dirdio\-ascular System. above.
dimercaprol (p. I 584) may be used. calculaled iniliol weekly dose may be given for 2 lo 3 weeks to
Penicillamine. For a discussion on the elTccls of pre,•ious ther- tcst the paticn1's tolerance). Weekly doses should C011linue until
apy with gold salL• a1Tce1ing pcnicillamine 1uxicity, see p.1600. signs of remission occur, at which point the dosage interval m.iy
Precautions be incre:ised to fortnightly. With full remission, the dosage inter-
Gold therapy is contra-indicated in exfoliative denna- Pharmacokinetics Vlll may 3g:iin be increased gradually to C\-ery 4 "'<:<:ks. Ifno im·
tilis, SLE, necrotising cnterocolitis, and pulmonary fi. provcmcnt has occurred after 20 weeks, the dose could be raised
Sodium aurothiomalate is absorbed readily after intra- slightly or 3nother an1irheum:nic dnlg lricd.
brosis. It should be used with caution in die elderly and muscular injection and 85 to 95% becomes bound to
in renal or hepatic impairment; use is contra· indicated In the UK, gold oompounds are no longer used lo lreal juvenile
plasma proteins. With doses of50 mg weekly a stcady- idiofl,'lthic arthritis. see Rheumatic Di»Otdcrs. below.
if renal or hepatic disorders are severe. Patients with a statc serum concentration of gold of about 3 to
history of haematological disorders or who have previ· Asthma.. Fo.r comment on the use of parenteral gold com·
5 micrograms/mL occurs in 5 to 8 weeks. ll is widely pounds in the 1rea1men1 of asthma, sce under Auranofin, p.27.
ously shown toxicity to heavy metals should not be distributed to body tissues and fluids, including syno-
given gold salts, nor should any severely debilitated Pemphigus and pemphlgoid. Coni005tcroids arc the main
vial fluid, and accumulates in the body. tn:atmcnl for blistering in pemphigus and pomphigoid (p.1722).
patient. The scrum half-life of gold is about 5 to 6 days but this lntraniuscular gold therapy has been used conoomitantly lo pc.I·
It is recommended that diabetes mcllitus and heart fail- increases after successive doses and after a course of mil a reduction in corticosteroid dosage al1hooglt f!\·iJence for
ure should be adequately controlled in any patient be- the steroid-sparing effect is lacking; I.:! it has been su&gcstt:d that
1reatment, gold may be found in the urine for up to I gold thcnpy should be reserved for pQlicnts who caMot toleral~
fore gold is given. Patients with a history of urticaria, year or more owing 10 its presence in deep body com- corticosteroids or in whom they arc coolra· indicated. 1
eczema. or colitis should be treated with caution. Pa- partmen!S. Sodium aurothiomalate is mainly excreted I. Oyitryn J·C, Steinman NM. Th: idjuv•nl thtr.1py of pfll'lpht1u$:
tients with a poor sulfoxidation status may be more in the urine, with smallt:r amounts in the faeces. an up<la••· A«h Dft-•f{f(o/ 19%; 132: 203- 12.
susceptible lo adverse effects of sodium aurothioma- Gold has been detected in the fetus when sodium au-
2. Pandya AG Dyke C. Tro11nen1 of pemphiaus witn gold, Al'ch
Dmnarol t99S; t34: 1104-7.
latc. rothiomalate was given to the mother. Gold is distrib- Rheumatic disorders. Gold co01pounds arc among the dis·
Use of gold compounds with other therapy capable of uted into breast milk. ease·modifying ontirheumatic drugs (DMARDs) !Mt m:iy be
inducing blood disorders should be undertaken with used in the l!Clltment ofrllcuma1oid arthritis (J>.12). Ahhough
0 Reviews.
caution, if at all. 1oxiei1y has now reduced its popularity, intramusoobr gold has
I. Block• KC.N. et ol. Clinical pharmacokinC"tics of oral and lflJCCt-
Because of the risk of vasomotor reactions, patients i."lblc gr.Id oompouncfs.. CHn Phormacokllr~ 19S6: JJ: 133-43. long been used for the treatment of rheumatoid arthri1is 1... and
2. TC'tl SE. Clinical phannacokinetic$ uf 1tow·acting anliTheuni:uic was often the stmtdard against which Uie efficacy of lllhcr treat·
should remain recumbent for about JO minutes after drugs. ('/,n Pbarttr(X'okl1't'I 14>93; ~::: 392-401. 1ncnts was measured. Oral 11Pld is less toxic bul is also much less
each injection. effective. It is unclear if there are differences between available
Urine should be tested for albumin before each injec- Uses and Administration intramuscular forms. "'1 • stuJys in 120 patients oon"erted from
tion and a full blood count carried out. Patients rcceiv· aurothioglucose to aurOlhiomalale found that 29 withdrew from
Sodium aurothiomalate and other gold compounds are U1e lanerdnJs wi1hin 12 momhs, mtJ<itly because oflack of cm.
ing gold compounds either orally or parenterally used mainly for their anti-inflammatory effect in active cacy or the dtvelopment of adverse elTects nol seen with the prc-
should be warned to report the appearance of sore progressive rheumatoid arthritis and progressive j uve- •ious drug.
All cross-references refer lo entries in Volume A
 Sodium Aurothiomalate/Sufentanil 129
Gold compounds hn"calsobem used in lhc1reauncn1ofju•~ilc Pharmacopoeias. In Fr. Sodium Thiosalicylate
id;.,p.1hic arthJ'iliS (p. I Ii: llOWC'1tt. lbe BNFC 20iJ9 stales tbal
~old is no lonser used for this indication. (for suggested doses in Profile Toosahciiato s6dico. Sod<fn 2·51.!!fanylbcnzoate.
j11V<!11ilc id1opa1hic arthritis, sec Adminisuation in Children, Sodiwu 111.-nlisule has becll used as an analgesic in the treatment TH<l<ZN<Ul1."'~ HaTP""'
above.) c>f mu:sculooikelc1al and j oint disorders. It is also used a~ a pre- C1Hs01NaS:: 176.].
sen11livc. CAS - ! 34-23-6.
Gold compowuls may also be ofbencfi1 in pseriatic anhritis (see
1111dcr Spondyloanhropathies. p.14 ). UNI/ - C2091TW048.
I. Epstein wv. u; ul. Etr«t or p-=arcntcr.illy ad111iniim:.rcd gold lhcr·
apy on 1he course C'faduh fflc-umatoid ar1'1r11is. Aim lmrm Med
1991; 114: 437-44. Sodium Salicylate
2. Anonynl(M.IJ. Gold llu:rupy in rhnnuat0id an.hrhis.. LtmCtl 1991: Nwi salicylas: Natrio sokiatas; Natriumsalicylat Nalr'Unsalisy-
338: 19-20.
3. Kt;nkhotr AV, Teufel A. How low can )'OU 10? Use or very tow
taaru: Natri..·1H1alic~at Sal~o s6dico: Sa~cytan sodr.y, Sodo...rn
dosaae of sold in patients with 1nucocu1ancous ruc:tions. J sacytate de; Sodu saliC}'lan; Sodyl.m SaSWl Sodium 2-llydroxy-
Rhe1..•otol 199S: 22: 1657-9. benzoa.te
4. Cl11i: P. er al. lnjtdablc a~ld for rheumitoid anhritis. Avail:1.blc
i11 The CNhrnne· DallbaK or Sys.1cma1ic Reviews: ls.sue 4. CailMW<t.aT HiTpwl
Chichcs«r: John \\liley, 1997 (accessed 13111/06).
S. van Roon. EN. ttf ul. Parenteral gold prcpararions: cfric:acy and
C1HsNa03 160.1.=
CAS - 54-21-7. Profile
~rtty of 1hcr3py 111ner swikhing from aurothioaJucose lo :au- Sodium lhiosalicylate is a salicylic acid deriv•live (see Alpirin,
rothionialatc. J RJ.c.,matal200S; Jl: 102~0. ATC - N028A04.
p.21) that has been used pazenterally in !he treatment ormuscu-
ATC Vet - QN028A04. lo.skeletal disorders, oSlcoarthritis, rheumatic fever, and acute
Pr-eparations
UNI/ - WIQ I H8SSYP. gput. •
BP 1010: Sooun AuUt>'ornalate ~
USP 33: Gold Socr.rn Tuom.l.ie ln1<'<lion Pre parations
Proprietary Preparations (dctoils arc given in \l:llume 8) Proprietary Preparations (detail$ are ii""" in Volvtne BJ
Aunrol.: Myocrorc Austria: TN'ldont Canad.: M~. C'!-: USA: Re><olltot.
lU'<clcn: Den m.: M )OOlSWl Rn.:~ Ger.: Tauredorc Gr.: Mocm;
~ Tua-.donf; Hunf" T~: lrl.: M)Qtrisint. Neth.: r ......
don; Norw" Mycy..ns.ot: NZ: M)QcYisr< P""-" Ti1.ttdon; Slngopon:: l"i-
ocm; Spoilt: l'tocr.-< Swed.: M)«risn Switz.: liv'°"1: Thoi: M,o<n.
l•n: UK: Myocnsil>; Ukr.: Taure6on (T•7PeA°"). USA: Aurol.lte:
,.,~
Sufentanil (BAN. rWN) ®
Pharmacopoeias. In £111: (seep.vii), Im.. Jp11. US. and f/ie1. R· 307». Sufentani ~~ Sufentan1lis; Sufentanilo: Sufentanlt.m;
Ph. Eur. 6.8 (SodO.rn SarlC)late). Colourless small crystals or S:nlcntani N-{4-{Methoxymc11iyt)-l-[2-(2-thie'\yf)ethy1}4-pip-
shiny Oakes.or\\hiteoralmos1 white, cryS1allinc powder. freely ericfy!}propionanilide.
Sodium Au rotiosulfate (rNNJ soluble in water; sparingly soluble in alcohol. Sto<e in airtight
Aur01iosUfate de Sodi.JfT( Au-o<IOSA.llfato de s-:>dio: Gold SodOJm containcis. Pr0te<:t from lighl C*HTII"""
~ Natrii Aurot:oslifa~ Natri Aurotiostrlpha$; NatrU- USP 33 (Sodi11'n Sajc)".a<.e). Amorphous or microcrysulline C12H10N202S = 386.6.
ma~faatti: Natri.Jmaurotio•ufot Sodium Aurothiowl- powder or scales. II is colourless or has no! more than a faim pink CAS - 56030-54-7.
pl'late: SodL'fTI Dnlios.Afatoaurat". tinge. h is odourless or has a faint characteristic odour. A freshly .'\TC - NOIAH03.
made 10% solution in water is neutral or acid to litmus. Freely ATC lier - QNOIAH03.
H~T9'-'R AypoTMOCy~T
(and slowly) soluble in wMcr nnd in glycerol; very soluble in
Na 3Au(S,0,),.2H:O = 526.2. UNll - AFE2YWOllZ.
boiling water and in boiling alcohol; slowly soluble in alcohol.
CAS - 10233-88-2 (anhydrous sodium ourouosul(ot•): Protect fiom light.
10210-36·3 (sodium ovrotiosul(ote dihydrote).
ATC - MOICB02. Adverse Effects, Treatment, and Precautions
ATC Vet - QNIOIC802. As for Aspirin. p.21.
UNll - CKSI YQ9Wlj (sodium ovrotiosul{ote dihydro1e); Although sodium salicylale has been used in the 1rea1ment of
6GKU52ZCIO (anhydrous sodium 01Poriosul(ote). meumatic fev<.T, its high sodium content may cause problems in
paticntS with cardiac complication~
The use of aspirio and other acctylaled sa~cylates is generally
not rccomn1ended for children because ofthe risk ofReye's syn·
dromc, unless specifically indicated. Some licel\SCCI product in-
fonnati011 exlc-nds this prccau1ion to sodium ~alicylace.
Effects on tho eyes. Retinal ~emorrha~es were reported in 1
60-ycar-old woman taking oral sodium salicylate 6 g daily for 2
mouths and in a 10-year-<:>ld girl taking oral sodium salicylate4 g Phannacopoeias. In Eur. (see p. vii).
daily for40 days. 1 In bolh cases the ~emonhagcs gradunlly re- Ph. Eur. 6.8 (Svfentotlil). A white or almost white powder. Prac-
Na• Na• sol"ed after lbe trtalmcnt was stopped. tically insoluble in waler; freely soluble in alcohol and in meth)1
I Monee!> A. Al>boud I. Re11n>I hoem0<rhag<:< 1f1<rptolo~ ""' alcohol. Pro1eet 6-om light
Profile uf ••lic-ylatts. Br J Opl111tnhnol l973; 57: 199-200.
Sodiwn aurotiosulfate has a gold content of about 37%. II has
Int eractions
Sufentanil Citrate (8ANM USAN. rlNNM) ®
similar actions and uses to those of $Odium auro1biomal1te 01rato de sufen'..lnilo; R-33800; Sufentani1lis~raattl; SufenWil cit-
For in1er.ic1ioos :issociatcd with salicyla1cs, sec Aspirin, p.24.
(p.1 27). It is given by intr.imuscular onjeclion for ~ie treatment of
rit; Sufentan1!, citrate de: Sufentlnil Sitrat: Sufcntanicitrat s.kn-
rlie11111ato1d arthritis (p.12) in a usual dose of56.I mg every S to Uses and Administration ;atli dtras; Sufcntanilio citraw; Szufentanil-ci1rat. N-(4-(~
7days. Sodium salieylutc is a salicylic acid derivative that ltas analgesic, ~ 1·(2·(2·thienyl)e1hy!j·1-poperidyl)propionanilide cit-
Preparations anti-inflammatory, and antipyre1ic llClions similar to diose of as·
pirin (p.24). Sodium saticylale I g is cquivalenttoaboul I. I g of me.
Proprieury Preparations(clciails arc giwn in Volume 8) Mpirin. It is used in the rn:atment ofpain, fever, and in rlieumatic Cycjte><n><"llil UATPaT
Jlrr.: Cr/lien: Chilo: Cryllon;r. Ital" Fosfoaisolo. disorders such as ostcoartlvitis and rheuniatoid :inhrilis. The c,2H10N202S.CsH007:: 578.7.
usual oral dose of sodium salicylate for pain or fever is 325 to CAS- 60561 -1 7-3.
650 mg every four hours as required. The oral dose for rheumatic ATC - NOIAH03.
Sod ium Gentisate (rfN~O diSCl<'CIM is 3.6 to 5.4 & daily in divided doses. Sodiu1n salicylare ATC Vet - QNO/AH03.
has also be<:i1 used in the S)lllplOOlatic treatment of rheumatic
Gcn\/satc de Sod-un; Gentisato de SO<fio: C...rnisato Sodico; UNJI - S9ZFX8403R
fever bul ii> bil!h sodium content may cause Jlroblcm~ in pr1tients
Natrii Gcnti!.as. Sod'U'Tl lS·dihyO'oxybcnzOil!e <thydnlte with <•rdi111: complications. Pharmacopoeias. In £11r. (s"" p.vii) and US.
Ph. Eur. 6.8 (Sufentan» Citrate). A white or almOSI while pow-
Hnpo·~ reHTM?aT Sodium solicyta1e has also bocn given by inlntvcno\IS infusion der. Soluble in water and in alcohol; freely soluble in methyl al·
C,H\Na0,.2Hi0 = 212.1 and topically.
coltol. Pro!eCI from light .
CAS - 490-79-9 (fMl•<K acid): 4955-90·2 (anhydrous Preparations USP 33 (SUenlri Citrate). A white powder. Soluble in water;
sodium genlisote). <poringly soluble in alcohol, in acetone, and in chlorofonn; ITce-
UNI/ - OX2PU05H81 (onhy<1rous sodiu'll gentisc1e); USP 33; Sodium Sal;cylate T~lllou.
ly soluble in methYI alcOOol. Store a1 a temperatuJC or2s•, excur-
Y75S7S5fl3 (sodium gt1;1iso1e '1ydro1e). Proprietary Preparations (details :ire given in Volume 8) sions p<:rmitted between Is• and 30".
Ccnod" Dodds: s.l·,.a. NZ: fhl-•cience SNmpoot: Tuti<.: Enter·s.t UK: Stability. Sut'cnunil (as the citrate) dil uted to
locl:son"s Poin &i:e-: USA: Avosil.
HO
SO inicrogramslmL with sodium chloride 0.9% remained stable
Multi·ihgredienc Stoz..; A Saude da M~ AbaclttSdt; Filuras De for al least 14 days when stored at room temperature in PVC res·

Q-{ OH
Wtfsf: Conod.: PWc Chile: Euce'ln Sl>ampoo An1iaspat fu:oin si..,,.,.
poo P"• c~ Tr·•tl'T>cnlo do la c.ipa; Fr.: SN'e>e; Hong Konr- Gly Th)mct
O)<.,.;,,. Thymol Co: lrl" Kl': Mon.: Qy<o-Thymolno: S.A(r" C~
jlhtnf; Ooans Sackadle P'"'t: t.Ycot TC?!: UK: Antisep:.C t'~
Oo.tts e.ctc.clle Pll• TCF: USA: C,..wc Scot·Tussin 0r...,.1 S·A<'.icr<
T - Y•n•z.: Boodlint; lnqvl.imt.
ervoirs for portable palicnt-controll~-d systc:ms.1
I. ChapalAin·P•rp~ S, et al. Mictobiolo,ical ;ind physjcocli<m·
ical SUtbilil)' orrcntan)1 •nd surClltanil solutions for patim1~con-­
lfOIJtd dchvcry systems.. J Pa;,, SymplfJ111 Monog« 2006: 31:
90-7.
Homoeop..th;c Ccnod.: Notti. Rash l83t, lkanl>OMt; Fr.: Eu)i><>r·
(gencisic acid)
"""'c~ No sa:
Urvlhone. De pendence and \l)t'ithd rawal
As for Opioid Analge.~ics, p.1 05.
The symbol t denotes a prtparation no longer actively marketed The symbol® denotes a subs1ance whose use may be restricted in certain sports (seep.vii)
130 Analgesics Anti-inflammatory Drugs and Antlpyretics
Adverse Effe cts, Treatment, and Pre cau- tively limited wheocomparedwi1h fcnt.anyl. In practice the phar- of procedure. Doses of up to the equivalent of
tions macokinctics of sufcatanil may vary aocQrding 10 the age and 8 micrograms/kg of sufentanil produce profound analg·
condition of the patient and the procedures undertaken. For ex-
As for Opioid Analgesics in genera~ p. I06 and Fenta- ample, the elimination half-life ofsufentanil has been reponed to
esia. Higher doses produce a deep level of anaesthesia
nyl, p.58. be Ion&!" in patients undergoing cardiac surgery (595 minutes).l but arc associated with prolonged respiratory depres-
Breast feedine. Concentrations of sufen1anil were simila1 in in hyperventilated patients (232 minuteS),' in those undergoing sion and assisted ventilation may be required in the
coloslrum and scrum in 7 women &ivcn sufentanil by continuous abdominal aorticsw-gcry(more than 12 hours),s and in ventilated postoperative period.
epidural infusion di.ring the first po6topcra1ive day after caesar· intensive care patients under sedation (25.S hows).'
I . M onk JP. ~ ol.. Suftnbnil; a review of it~ phumacok>gk:aI prop--
When used as an analgesic adjunct to anaesthesia
ean section. In lhc light of its poor oral availability such an
ainount was not considctcd IO be a hu.Ard to lhc bn:asl-fed infao~ cnieu nd therapeutic U$<. Drug, 1988; 36: 286-) t3. with nitrous oxide and oxygen for surgical procedures
2. Schott J,. "ol. Clinical phamiacokinetics of :alftntAnil, fcntanyl
and a maternal dose or S micrograms/hour c:pidurally was con· and surcn11nil : an update. Cli1t Pharmacokfo,t 1996; 31:
lasting up to 8 hours, the total intr(l\Jenous dosage
sidcred to be safe for such infants.' 27S-92. should not exceed I microgram/kg per hour. It is usual
1. Ausseur A. ei of. Contiriuous epidural infusion of sufcn1.anil aJ\cr l . Howie MB, ft tJI. Sen.im conccnn1ions of sufcntanil and fcnt>- to give about 75% of the dose before intubation fol-
caesarean scccion: concentration in breul milk. Dr J Anae.sth nyl in the post-operative course in eardi3.c surgery patients. lln-
1994; 72 (suppl I}: 106. uthulology 1984; 6t: Alli. lowed as necessary during surgery by additional inj ec-
Effects on t he cardiova<CU!ar syste m. For a n:fercncc to lhe
4. Schwaru AE., ~t al Pharmacokinc1ics or sufcntanil in neurosur.. tions of I 0 to 50 micrograms or by a suitable continu-
1;c:•jr~rns undeq;oina hyperventilation. Br J AntHSlh 1989; ous or intermittent infusion given so that the total
effects of sufentanil on histamine release compared with some
olhcr opioids, sec under Pethidine, p.118. 5. Hudson RJ, er ol. Pharmacokinclje:s of sufcntanil in patients un- hourly dose is not exceeded. Thus, for an operation
de1Join1 abdominal aonic. surgery. A.IH!Stlre-Siology 1989; 70: lasting 1 10 2 hours the total dose would be I to
Effects on the nervous system. Toni<><:lonic movements or 426-) I. .
seizures have been seen in a few patients receiving sufentanil. 1 6. Ethuin F. ti al. Ph1rmacokinctics of long•letm sufentanil infu- 2 micrograms/kg with 0.75 to 1.5 micrograms/kg be·
There was no evidence of corticarseizun: activily in a patient sion for sedation in JCU palicnts. /m~nslv~ Care MN'l003; 29: ing given before inrubation.
whose EEG was recorded,2 suggesting that !he myoclonus was 1916-20.
not a convulsioo or seizure. Administration. References to the pharmacokinerics of sufen-
When used as a primary anaesthetic in major surgery
l . 2.ace:ua ~ct ol. Clinical fta1urcs1 palhogcnesii and manaieme.nt tanil given epidunlly, 1 ~ intralhecally, 1 or tntnSdermally.l incrawnous doses of 8 ro 30 micrograms/kg arc given
ofdrv,.induecd seiZlJres. Drvg Soft/)' 1990: 5: 109-SI. I. Ionescu Tl, tt ol. Ph1rm1ookinetic study of e>tcndur31 and in· with 100% oxygen; doses of25 to 30 micrograms/kg
2. Bowdle TA. Myoclonus followiqa sufcnt:mil withoul EEG sei- tnd.eeaJ surentanil anaulhcsia for major sul'cery. Br J .4nodtlJ
Dlt'C ec:tiviiy. An<"h.,.;o/ogy 1987; 67: S93-S. block sympathetic response including catecholamine
1991; 66: 458-64.
Effects on the respiratory system . Sufen1anil, like Olher 2. Hlllnsdonir V, el ol. The cc4'cbrospinal fluid and plwna phenna.- release and are indicated in procedures such as cardio-
opioid agonistS, causes dose-related respiratory depres.<ion. cokinctics or sufcnLlni1 after thoracic or lumbar cpidunl adf?tin· vascular surgery or neurosurgery. Anaesthesia may be
There have been n:ports ofsigniflC3llt rcspiratory depression as- isirot>on. Anuth A""lg t99S; 80: 724-9.
3. Sebcl PS. fl al. Ttan!derrnal absorption of fenunyl and sufco· maintained by add itional injections of 0.5 to
sociated witb chest wall rigidity in the early postoperative period la.nil in man. £ur JC/in Phormoeol 1981; 32: S29-31 . I 0 micrograms/kg or by a suitable continuous or inter-
after anac~ with intra"enous sufentanil •.> Respiratory de·
prcssion has also been reported after intrathccal sufentanil for Children. Ncooa1es (up to I month old) bad a significantly low- mittent infusion given so that the total dosage for the
J>OSIOpCntive analgesia' and labour pain.' A retrospective chart er plasma cleardllce rate and greater elimination half-life than in- procedure does not exceed 30 micrograms/kg.
review' or a 6-ycar period, during which 4870 patients received fants (I month to 2 years). childrm, and adolescents.' Otbcrs2
have found that infants and small children (J month 10 3 years)
In postoperative pain, sufentanil is given epidurolly in
iniratbecal sufentanil for the management of labour pain, found an initial dose of 30 to 60 micrograms, which should
!bat the case above was the only one of respiratory est
reported with cardiac disease had higher clearance rates and shorter clirn-
inolion hllf-li'l'eS lhan reported for adults. Older children (aged 2 provide analgesia for 4 to 6 hours. Additional boluses
in the group. .
I . Ooldbeig M. a ol. Pouoperativc rigidily follO'lling sufenl:.J.nil to 8 ye.vs) wilh no history of cardiac, rcoal, or hepatic disease of up to 25 micrograms may be given at intervals of not
administ111tion. A'Nllhe.fio/ogy 19SS: 63: 199-201 . hove also been noted to have shorter elimination half-lives and less than I hour if necessary.
2. Chana J. Fish KJ. Acute rcspi111tory ana1 and riiidity after an· higher clear.!Jlce rates than adults.1
nthcsia with sufo111anil: a case report. An•stltuiology J98S; 63: I. Greeley WJ, «t ol. Sufen&anil pharm1cokinctics in pc:diatoc c.r- Sufentanil is also given epidurolly for the relief of pain
710-11.
3. Fournier R, «I ol. Respiratory depression after $ ,,i"mS of in-
diovascular patienu A.ntbArt0/g 1987; 66: 106":-72. during labour and delivery. Recommended doses arc
2. Davis PJ, et al. Photnnxodynaini(S and phannacokinetica of
tnthccal sufcnoanil. A-th Analg 1998; 87: I377-8. hi~ sufmtanil in inCants and children undergoing cardiac
!Oto 15 micrograms given with IOmL ofbupivacaine
4. Fcrou1. F. e1 al. Risk of respiratory arrest aft.er lntrathccal sufen.. aurgcry. Anam Anolg 1987; 66: 203-8. . 0.125% (or its equivalent) with or without adrenaline;
tanil. Ant.1th Alfolg 1991~ 85: 1088-90. 3. Gu.ay J. «I al. Phannaookin~ics of S\lfmtanil in normal childrtn.
ConJAnoesrh 1992;39: 14-20.
the dose may be repeated twice at not less than one-
The elderly. The phaim•coklneticl; of sufcntanil in elderly pa· hour intervals until delivery. The total dose of sufen-
ticnts have been variable in di!fermt Sludics, but a review' con· Hepatic impairme nt. Because of the efficient hepatic cxtrac-
sidercd lhat there had been oo evidence ovt:rall for differences lion and clcar•nce of sufentanil 1 liver dysfunction might be ex· tanil should not exceed 30 micrograms.
between the elderly and YoWJStt adults. Never1hcless, as with pcctcd to affect its pltannacokinetics. However, elimination ki· OReviews.
fentonyl, reduced init.ial doses have been advised in the elderly. nctics and plasma protein binding were found to be similar in I. Monk JP. n ol Sufcn1tnil: 1 revjcw of itS pha.rmacolugical prop·
1. Monk JP, ~r ol. Suftnlanil: 111 reYit:w of its phannacoloz:icaJ prop- cinhotic and non-cirrhotic patients after a singk dose of sufen- mies and 1h<rapw1ic use. D'"t' 1988; 36: 286-313.
cnics and 1hcrlpcv1ic use. Dfllgs 1988; 36' 286-)1). tanil.1 2. Clotz. MA, Naheta MC. CJinical uses of (cntanyl, sufen11nil. and
Handlinc. Avoid contacl wilh skin and the inhalation of parti- I. Schcdewic H. 1 1 ol. Sufen~i1 arid fcnt»nyl hepatic cxtr1e1.on alfentaniJ. Clin Phorm 1991: JO~ 581-93.
cles ofsufcntanil citrate. rate and clcilranu in obc~ paticn1.s undcl'going gastroplas1y. 3. SavoiA<-' rt al. Sufentanil• an overview of its use for acute pain
Clin Phomuxol Th«r 1988; 43: 132. management~ Mme:n"O Anest~riol 200 1; 61 (suppl I ): 206-56.
O besity. The eliminatiot1 half-life and volume of distribution of 2. Chauvin M. e1 al. Surcrunil pharmacokinc•ics in patienas with Administration. Sufcn1anil is usually given inl111vcnously, but
sufenlanil were increased in obese subjects. 1.l Licensed product cirrhosis. Anuth Anali 1919; 68: 1-4.
!he qiidural route is i lso used (sec below). lnlr.lnasol (sec Anaes-
information recommends that for obese patiats more than 20"/o Ren,.J impairment. The pharmacokineties of sufentanil were thesia, Pain, and Sedation, below). intmtltecal (see below), and
obove ideol body-weight \he dosage of sufentanil should be de· reportcd 1 IO be unaffected in patients -.itb chronic rcMI failure, sublingual use (sec Pain, below) ha\..: also been tried.
tcrminccl on the basis of their lean body-weight al~ elevated plasma concenll"ttions of sufenlanil have been
1. Schwartz. AE. ~r al. Ph.ann1eokindic:s of sufentanjJ in the obese. noted2 in one such patient. EP1ouuo.. Jn a laboratory assessment of epidural sufentanil in
h..sthuiology 1986; 65 (suppl JA): A562. 1. Sear JW. Surentanil disposition in p:uicnts undcrgoing R"n::tl healthy subjects, 1 a dose of SO micrograms produco:I anolge-
2. Schwartz. AE-. tJ al, Pharmacokinctics of sufen1anil in obese pa· traniplantotion: inOutncc of choice of kinetic model. Br J sia for 2 to 3 homs; analgesia was intensified and prolonged,
tients. A"Ulh Anvlg 1991; 73: 790-3. 1fnouth 1989; 6J: 60-7. and respi12tory and other adverse cffocls, especially drowsi-
2. Wiagum DC. a al. Postoperative respirauwy depression and c l.. ness, were reduced by the addition of adrenaline. Epiduul
Interactions C.\3tcd sufui&anil levels in a pati-cnt with chronic: renal failure, sufentonil or fentonyl provided effective postoperative analg-
A""tha;.fogy 198S; 63: 701>-IO.
For interactions associated with opioid analgesics, see esia following cncsarean section with comparable adverse
p. 107. effect profiles.1 Sufcntanil doses of 20 aod 30 microg,ams
Uses and Administration showed equivalent efficacy and provided greater analgesia
Benxodiazepines. For the effe<:IS of usin& opioids such !Ill sur- Sufentanil, a phenylpiperidine derivative, is an opioid for a longer duration than a dose of I0 microgr.uns. Addition
entanil with benzodiazcpines, see Analgesics under Interactions nnalgesic (p.108) related to fentanyl (p.60). It is highly ofsufentanil to local ••aesthetics such as bupivacaine during
ofDiazepam, p.1093. labour has considerably reduced the local anaesthetic
lipid-soluble and more potent than fentanyl. Sufentanil requirementsl and improved the quality of epidural analge-
Pharmacokinetics is used as an analgesic adjunct in anaesthesia and as a sia.' Combination ofsufentanil with a local anacsthetic (rop-
After parenteral doses sufentanil citrate has a rapid on- primary anaesthetic in procedures requiring assis1ed ivacainc or bupivacaine) has been used for patient-<:ontrolled
set and shott duration of action. The terminal elimina- ventilation. It has a rapid onset and recovery is consid- epidural analgesia (PCEA),s-9 ollhough an early siudy sug·
ered to be more rapid than with femanyl. lt is also used gested that PCEA with sufentanil alone had little advunlage
tion half-life of sufentaoil is about 2.5 hours. It is exten- over patient-controlled anal gesia with intravenous mor·
sively bound to plasma proteins (about 90%). It is as an analgesic in the management of postoperative phine.10
metabolised in the liver and small intestine by N· pain and labour pain. Elrecti\'e analgesia has been achie-.-ed in children witl1 epidural
dealkylation and O-deme1hylation and the inactive me- Sufentanil is given as the citrate either intravenously by sufcntanil. 11
tabolites are excreted in the urine and faeces. About slow injection or as an infusion, or epidurally. Doses I. Klepper 10,etol. Analgesic and respiratorycffccuof cxtndunl
are ex.pressed as the base; sufentanil citrate sufen1onil in volunteers and the influence or adrcm.linc ~s an
80"A. of a dose is excreted within 24 hours and 2% is adjuvant. Br J AnM$1h 1987; 59: I 147-S6.
I5 micrograms is equivalent to about I 0 micrograms
eliminated as unchanged drug. Sufentanil crosses the
placenta and is distributed into breast milk.
0 Tiie pharmaeokonctics of sufentanil have been revicwed. 1.2
of sufentanil. Lower initial doses are advised in the eld-
erly and debilitated patients. For obese patients more
:m==
2. Grass JA~ tt ol. A r:andorniz.t:d. dout>k·blind, dose-response
:~f!~~~!!:J:~~~,;cm7~~c:'j6t;~.'''csia af-
3. Buyse I. et nl, Effect of s:ufcnlanil on minimum local anolgc.sic
than 20% above ideal body-weight the dosage of suf- concentrations of epidural bupiv.cainc, ropivacaine and lev-
Sufentanil is very lipid-soluble. Like alfentanil it is highly bound obupivacaine in nullipara in early labour. Im J Obstd A.nc11h
to plasma proteins, mainly IO <> 1-acid glycoprotein. The elimina- entani l should be detennined on the basis of their lean 2007; 16: 22-8.
tion half·life lies between that of alfentanil and fentanyl. The body-weight For details of doses in children, see be- 4. Reynolds I'. Exlnd""'I opioids in labour. Br J Anoalh I98Q;
manufacturers or sufentanol have given values for a three-com- low. 63: 2SI-). •
S. Ooprten w. ~t al. A muhicentrc triaJ comparina dirrcrenl con·
partmcnt phannacokinetic model with a distribution half.life of centra11ons o(ropivJcaioe pfu,s sufcn:anil "'ith bupivacainc plui
1.4 minutes, a rcdisuibution half-life of 17.I minutes, and an In all patients supplementary maintenance doses wftnt1n1 I for paticnt-eonll'OJltd epM!:ur..I anJtlgcsia in labour.
elimination half·life of 164 minutes. Ac:cumulation may be rela· should be based on individual response and length £11rJ Annwheslol 2004; lt: 38-4S.
All cross-references refer to entries in Volume A
 SufentaniVSulindac 131
6. Boselli E. " al. Ebr~ground anrusion is n0t bencfici~I cJorins Sedation. Sonw. references'·; lo the use of surcnianol for seda- Effects on the CNS. Acute deteriurotion uf parkinsunism oc-
labor pa1icnt·conlrolltd a~lg_esia with O.J "/" rophac:tint plus tion. See also An•CS1hesia. above. cu1Ted on a patient afier slarting sulindac. 1
O.S micro&lml surcn1anil. A11e.sthniologv2004; 100: 968-72..
j, Bat~i BA.~' elf. A comparison of intr•m1saJ sufcrtland and mida- See also Hypersensitivity, below.
i. Brcmcnctl OH. al 11/. Comp;1ril0ft of conlinuouJ h»ckground in-
fu..,ion plus demand dose Md dcruaf'ICM>nly panuricnt-controlled zolain to in1ramllscular meptridin:. prome1l,azinc. and c:hlorpro· I. S:indyk R. GiUman MA. Acute t,;oc-.:rbt1tu•1n (If P.:a;i;;in$Ol"l 's dis·
epidural MN1li:~$ia (PCEA) usin1 roph'K:tinc combined with matine forcon.sciousstd~tion inchil<trcn...A11n Emerg Med 1994; case wi1h sufoxfac.. Ann N~"'"' 1985; t7: 104-$..
1u(enianil for l3bor and dclho.ery. /nl J ObJt~ .4ne111, 200S; 14: 2'1: 646-St.
114-20. 2. l..cflWlt JY, er al. Sufenumil a.hot' dbe'liort mfusion for postope:r· Effects on the endocrine system . A case of reversible 8)1·
~. Miss:Jnt C. 11 al. Paticnl·cornrollcd cpidu~I ana.lgc:sia following ath-e scd3tion in critic.:>lly ill p;itients. Br J A1we.s1!1 1995; 7-4 naecomastia associalcd with suhndac1herapy has been reported.1
(<uppl I): 114.
i:;'~i~::,:rn;:~~~:~~~:,ni~fu~ii~~~ .~~~7,~;~:~rC!~;
1 There has also been a report? of reversible hypothyroidism in an
j. Kinirons 8P. ~t nJ. Scd31lon Yd'h surco:anil and midazolam de-
crease.$ p1in in patients undergoing upper limb surgery under elderly patient Inking sulindac.
~005 : 33: ~S?~.
multiple ne"-e block. Am:11h Anfllg 2000; 90: I I IS-2t. I. Kapoor A. Reversible gynecomast.ia a$SOC:ioncd with sulind:ic
9. ;~;:n~~!!;l~~::i-,~~/c;!':~~!~~~i:i;f~~~!'°~~~::: Preparatio ns
tl1Cr•PY· JAMA 1983; 250: 2284-S.
trolled in1r3venous analgesia. A11~11h A11olg foo6; 103:
USP 33:Suf<t'<ri ~~.
2. 1)-er RP. Ouckttt GK. R~vcrsibl c ~oncbry hypo,hyroidism in-
duced by 5'11indoc:. BM./ 1985: 290: 1788.
1311-17. . ..
10. Gn11 JA, e1 ol, P.atimt-controllcd 1nala,esia after cesarean <f.e.. Proprietary Prepar.u:ions (deiails arc given in Volume 8) Effects on the gallbladder. A "sludge• composed or crys1al-
liwry: epidural sufen1anil \'C:r.\US inttO\otnou.s morphine.. R~ A11.: S.lent.o: Au1'rio: Sulenta; ScJi.: s.lcntll, Bn>L: Ftstf:n; Solmta: Co- li11c mc1aboli1es of sulindac bas been found in the conunoo bile
A11esth 1994: 19: 90-7. nod.: S...lentilf: Chile: ~ C<.: 5u1en1., O•nm.: SOJret\12: Pm.: So.lent>:
11. Bcnlabcd M. ~'al. AnalgC1i1 and vcncilatory response 'o CO:i Fr.: Su«<>ta: Ger.: Sufento: G r.: Fenwrorl; lndon.: 5'.lfentJ: Ital.:~ duct during surgery for biliary obslruclion in patients who had
foJIO\\-ing tpi<,iur31 sufc:ntOl"lil in childttn. A11es1h~iofogy 1987; fentatitrit Malaysfo: Sufcntot:Neth.: Sulenu; No rw.: Suf"""' Port.: been taking sulindac.1
67: 948-51. s..e.u: SA fr.: SufCJlta: Swed.: Subu; Swlt7.: Sufonla: Tuil<.: Sulema: I. Anonymous. Rart comp11ca1ion with sulindac. FDA Drui Bull
USA: SulerQ. 1989; 19: 4.
INTRATHECAL Sufentanil, alone 0 1 in combination, hu been
given intrathccally for Jabour pain: a combinalion of sufen- Effects on the kidneys. Sulindae-induced renal impairment,
ianil, bupivacainc, and adrenaline given intrathecally provid- in1erslitial ncphnlis, and ncphrotic syndrome have betn report-
ed excellent analgesia during labour and had a more r.ipid on- Su lindac (8AN USAN. rlNN) ed.' It has been suggested lhat sulindac, as a prodrug, may noJ
w. a longeT duration of action. and reduced local &naesthctic inhibil renal p<O$taglandin synlhesis in lhetapeutic doses. How-
requiremenlS compared with epidural adoninistr.ition.1 ln- MK-23 1: Su~ s...daco: Sul.ndacum; Su;.1dok: Srulildak. ever, lhis polcntially importllnl lherapcutic advantage has not
1r.11hecal sufentanil and bupivacainc provided shorter dura- (Z)·(5-Fluoro-2-methyl-1-(4-me'.hytsvlphinylben.tylidenejn:len- been uniformly seen in short-1cnn s1udies in palients with renal
1ion of analgesia when gi\'tn during lhc advanced stages of 3-yl)acetic add. dysfunction.2"'
Jabour compared wi1h early labour. 2 There has been some Cy...........a< 1l1erc have been reports of renal slones consisting of between I0
concern about the effect of introthccal usc on fetal heart rate. C10H11FO,S = 356.'I. and 90"/o of sulindac meiabolites developing in patients given
An early srudyl found no signilicanl difference in lhe heart OS - 38194-50-2. suJindac.s
rate when intrathecal sufcntanil was compared with epidural I. Wheh.on A. tt nl. Sulindac and~• i1npaimlc1ll. JAMA 19&3;
ATC - /AOIA802.
bupivaca ine; however. a more recent studyA reported that 249: 289:!.
high-dose imrathecal sufcnlanil (7.S micrograms) when given ATC Vet - Q,\101A802. 2. Klas.sen OK, c1 ol. S11lindac kinetics and ctrcctJ on renal function
on its own increased the risk of fetal heart ra1e abnonnali1ics UNll - I 84SNS8VUH. and ptoit11llndin excretion in renal iNufr~icncy.J CUn Phar-
ni«ol 19&9; 19: I 037-42. '
when compared with low-dose intrathecal sufcntanil
3. Eriksson L·O. el al. Effcclsof suli.ndac and naproxc-n on prosta.g-
(LS micrograms) given with bupivacainc and adrenaline. landin excrt1ion in p3licnt$ with lmpaittd rcn3l fo nction and
None1heless, there was no evidence of a difference in adverse rheumatoid arthri1is. AIH J Metl l990~ 89: 313-21.
neonatal outcomes between the groups. ""*· Whelton A. a al. Renal efrects of ibuprofen. piroxicarn. anCI
A small study in patienls undetg<Hng hip replacement found tha1 sdind:Jc jn p3ticnlS with asytnptomatic renal failure. Aun lntcm
Med 1990: 112: S68-76
inmuhecal sufe.ttanil 7.~ micrograms produced better and longer S. AnonymOU$. Rare comphca1ion wilh sulind:a<'. FDA ~ 811/I
Ja$1ing analgesia than the same dose g;_, inlnlvenously.' 19S9; 19: 4.
lntrathecal sufcnlllnil has also been lried in the 1rea1mcn1 of Effects on t he live r. Hepatotoxicity reported in palicntsreceiv-
chronic pain.' ing sulinda: includes hepa1ocellular injury and cholescatie jaW>-
I. K~n11w111di SL ~' ol. Spinal an~la:esi3 durin& ltttor wilh low- dicc.1.! Symploms of hypcrsensilivity including rash, fever, or
do:..c bup1,·acaine. sufcntanil, and epinephrine: Ji comparison cosu1ophilia have been reported in 35 lo SS% of patients with
wi1h epidural anals~ia. Rc-z AneJth 1996: lJ: J9J-6.
'!. Viscomi CM. et nl. Oura1ion of inl1'3ihec~ l labor an.:dgesitt: eotly
sulindac-induccd liver dam•ge;2 in these patie111s lhc liver dam-
versus •dvanced labor. A....,111 Annis 1997; 84: 1tOS-12. age occurred usually wilhin 4 lo 8 w.:clcs ofbeginniog sulindac
3. Nielsen PE. ti al. Fet:il heart r.i1c: ch::ingcs oOcr imrathecal ru(cn· therapy. Forrcfcrence to a report citing the strongest evidence for
t.a:n1I or epidural bupivacait)C for bbor analgesia: incidence and an association ofsulindac wi1h liver disease com~ wilh oiher
clin~ I sig11ific-ance. Anu1h •.foo/1 1996; 83: 742-6. Pharmacopoeias. Jn Chiu., Eur. (seep. " ii). and US. NSAIDs. see undcrNSAIDs.p.102.
4. Van de Vtldc M, •fol. JntnuhecaJ 11.1fentanil and fc.11)1 heart role Ph. Eur. 6.8 (Sulindac). A yellow, polymorphic, crys1allinepow- See also Effects on the Skin, below.
abnonn1lities: • doublc-bJin4. double placc~onlro llcd trial
comparina two tOmu, of combined spinll cpidwal analgesi11 with der. Very slighlly soluble in wala and in ether; sp:tri ngly soluble I. Gall&nolll AO. Spykcr DA. Sulindac h~pa lOlOXic:ity: a case re·
tpidura.1 aMilac.sia in labor. Antsth Anolg 2004: 98: I l S3-9. in alcohol; soluhle in dichloromelhanc; dissolves in dilute solu- pon ind review. C/i11TuxH:ol198S: 23: lOS-38.
tions of alkali hydroxides. Pro1ec1 fiom Jighl 2. Tanzi EM. e1 uf. Sulincbc-3.$.SOCiat.cd hq)atic injury: analys.ts of
~. Foun1icr R. ~' ol. lntr::rhcir;al sul'Cnlanil i.s mo« potent than illtta· 91 uses reported 10 the food and Orua, Ad1ni11is.1ration. GuMrv-
venous for poscopcr11jvc. analgesia aRer totol--hip rcpla«men1. USP 33 {Slindac). A yellow, odourless or pr:iclically odourless, ,.,,.,ofogy 1993: 104: S69-74.
R<g A11mh Pol11M<d200S: 30: 249-54. crysialline powda. Prac1ically insoluhle in waler and in hexane:
6. Wur:i·\VOllHt KL a al. A review or intruhccal fenunyl and slighlly soluble in alcohol, in acetone, in chloroform. and in me· Effects on the lungs. For rtfercnce to pneumoni1is assoc1a1cd
sufentl'lnil for the lrcat.mC'nl of c:hronfc pain. Pain Mui 2006, 7:
251-9.
1hyl nlcohol: very slightly soluble in ethyl acelate and in isopro- wi1h sulindac ""'"'PY·sec Jiypersensitivity, below.
pyl alcohol. Effects on the slOn. Toxic cpidennal nccrolysis has oceu1Ted
Administrat ion in children. Although expe1ience orpaediat- in patients laking sulindac.1 ln a patien1 toxic hepaliti$ and the
ric usc is limilcd, sufenlanil ci1n1e is licensed for 1he induction Adverse Effects, Treatment, and P recau- Slevcns-Johnsonfloxie epidermal necrolysis S)1ldrome resulled
and nuintenancc of anaesthesia in children under I 2 years ofage in dcath.2
undcrsoing e:1tdiovascular suigcry. lnlnvcnous doses of 10 10
tions
As for NSAIDs in general, p.100. Urine disooloration An umrsu31 pcmio-like reaction affecling 1hc 1oes, which was
25 microgramsll;g are given with 100'~ oxygen wilh mainte- also confinncd by rechallenge. has been rcponcd.'
nance doses of up IO 25 IO 50 micrograms. ' has occasionally been reported with sulindac.
Sulindac has also been reported 10 c:11u..e photosensiriviiy reac-
Anaesthesia. Sufenianil, like fcncanyl (p.61), appears to pro- Sulindac metabolites have been reported as major or tions...
duce fewer circulatory changes lhan morphine, which may offer minor components in renal stones. It should therefore I. Snul1 RE. G1n1eu WR. Sulindac:-1nduecd tox;c epiderm31
some advantages in cardiovasculnr surgery. be used with caution in patients with a history of renal n<t1'olysis. Clln Phori11 1988; 7: 766-71.
P1·emedico1io11 with sufentanil gh-cn intranasally has been tncd J. Klein SM. Khan MA. Htpauhis, 1oxic: tpidmnal 1\tcrolysis and
stones and such patients should be kept well h~rated p3ncrc:11itis in ossociaiion '"'i1h sulindac therapy. J Rh~1111101ol
in children'·' and in aduhs.'
while receiving sulindac. 1983: 10: Sl2-0.
Sufentanil is one of1hc opioids Iha! h3ve been used wi1h a ncu- 3. Reine"scn Jl.. Unuiuil remio·likc re:;ic1ion '" Sl~l1ndx. Anh1·i1l1
rolcplic to produce 11q11rolep1a11olgnio. UK licensed product infonnation recommends that pa- R/Jcmm 1981 : 14: 121~.
I. Henderson JM.~' al. Pre·inductin:. orsufattl)nil .Aottslh«sicilogy tients with hepatic impairment should not be given 4 Anonymous. Of'Ug.s thit c:i.usc phoU.lscnsith il)'. ~fed Utt Drugs
198S; 68: 671-S. sulindac; in the USA, however, licensed information Thcr 1986: 28: Sl-2.
2. Zcd1c N. ~' ol. Conlp<irisou of intr.10¥.tl micbwbm and sufc:n- States that patients with poor hepatic function may be Hypersensitivity. Hypcrsensi1iviiy reactions 10 sul~ndac in·
11n1I prcn1edie:J1ion in p~di;uric ou1pa1itms. Clin Phormt1<:ol elude pneumonilis, 1.? generalised lym~hadcnopalby,' aseptic
TM/· 1996: S9: 3• 1- 8. given a reduced dose of sulindac with close monitor- meningiti~4 and :maphyfacto;d reacrion.
3. 63yn:k F. er ol A comp1ti.son of ornl midaioh1:m. oral tramadol, ing. The dose of sulindac may also need to be reduced Soc also Effecis on lhe Liver ~nd EffeclS on lhe Skin, above.
and in1~nasa l sufcntanil prc1nedic.ation in pediatric: pa\icnu. J
Opiold Monag 1001. l: 14-1.
in those with renal impairment. Licensed infonnation I. Smith FE. Liodbcr& PJ. Lifc·thrcatcaif'!g hypccscnshivhy to
<C. Helmers JHJH. ct ul Comparison of iinravc:nous and intran.asa.1 recommends that sulindac is not used in patients with sulinda<. JAMA 1980; 244: 269-70.
s.ufcntanil ab>Orptton and K<blion. Con J Annuth 1989; 36: advanced renal disease. but this appears to be based on 2. Fein M. Suhncbe end pneumonitis. Anu """" M*d 1981; 95:
494-7. 24S.
a lack of data in such patients. 3. Sprun, DJ. SulitdK causing a hypc1'$rt1siti\'tl)' reaction ..·ith pe-
Pain. Forthc epidural orinlrathecal use ohufcnla'hil in lhe man- ripheral :md mediastin:il lymphodcnopo1hy. Ann lnttrn Med
agernenl of pain, see above. lntran3$81 sufcntanil has bcC<l tried Effects on the blood. AgJanulocytosis,1 tnrombocytopenia,2 19~2: 97: S64.
for breakthrough cancer pain' and pos!Opcrative analgesia.2 It haemolytic anaemia,l and aplasiie anaemia' have been report.cd .f. Fordham von Reyn C. RCC\lfftnt as.cr1ic mcnin:itis due to s,ulin.
has also been tried ~ublingually in lhe managemen1 or break- on pa11cnis 1akins sulindac. dK. Ami !tuem Med 19Sl~ 99: 34l-t.
1. Romeril KR. <r ol. Sulind1c induced •@nnulocytosis and bMC 5. Hyson CP. KaznkofT MA. A sever.: muhisystctn rcac1iOt1 (0
11\rough cancer pain.' sulind:tc.. "''"'h }Jlftm M«/ 1091: 151: 387-8.
11"1ill'TOWCuhurt. lone<'l 19SI ~ U: Slj.
I. Jackson K. f1 ol. Piloc dose: findi ns Sludy ofin1n.nas3I sufcnt:4nil 2. K1rachali0$ GN. Pariaorakls JO. Thront~ycopcnin and sulin-
ror bfeaklhrctJl.h a.nd incident cancer-H"ocia1cd pain. J Pain Pancreatitis. Repo11s1.. ofpancrttli1isassocia1ed wilh ~t1lindac
d><. Ann /Nnr. Md t9S6; 104: tl8.
S,1'mpt011• l>lonuR• 2002, 23: 450-2. ), fohnson FP~ « ol lm1nune hemolytic anemia associoied wilh therapy.
2. M)lhicu N, el al lnctanlSll ,ourenLanil is cfrcct.ive ror pos10pcnti· $Ulindac. A~lt In/Ctn Med t98S; 1 4 5~ I $1 S-16. I. Gold.stttn J, tt ol. Sulindac associ3led "it.h ~ncrtatitis. An11 J11-
tive analgesia in 1dults.. Con J Ancs1h 2006: 53: 60 6. 4. Andrew' R1 R\.1$$C:ll N. Aplasric 3naemia a.ssocia1ed with a non· rern -'kd 19». 93: ISi:
3. Gardncr·Nix J. Or•I transmucosal fc:n1anyl and sufcntanil for in- s1croidal a.n1i·inRamm.atory dru1: relapse 1ftcr exposure 10 an- 2. Siel'kin AD. Suli~c and p;mcrealitis. Ann'"'"" Med l980; 9.'.\:
cidel\t ~in. J p,.;,, S)'mptom Uanagt lOOI ~ 12: 627-30. oohcr 1uch drug. B~U 1990; 301: 38. 932-3.
The symbol t denotes a preparation no longer actively market•-d
132 Analgesics Anti-inflammatory Drugs and Antipyretics
3. Lilly EL. Pancre:uilis ancr odm inisna1ion or sulindac. JAMA adenonia1ous polyposis. Some'-9 consider that sulindac is unlike· wi1h a compact confonna1ion mainlaincd by about 4 gram-atoms
198 J; 246: l680. ly 10 replace ~wi:cry as primary therapy for familial adcnoma· ofchelated divalenl metal.
4. Mcmon AN. Pancrea1iti1ii iind sulind1c. Ami lm~m Med 1982; 97; IOUS polyposis.
139.
A sulfonc metabolite ofsutindac., exisulind (p.789) has al£o been Pegorgotein (USAN. nNN)
in\"esrigatcd for the treotment offam iliaI adenomatous polyposis. Pegorgoteina; Pegorgot6-i~; Pego•goteini.m: PEG-SOD; Win-
Inte ractions Suli.odac has also been reported lo have produced beneficial er. 2211a
For interactions associated with NSAIDs, sec p.103. feet$ in a patient with duod<nal pol}")lS associaJed with Gardner's.
syn&ome10 but a placebo-controlled srudy bas suggc:s1cd tb3t ii n ...opror......
Dimethyl sulfoxide reduces plasma conccnlilltions of may ROI be effccth-e apinst sporadic type colonic polyps. 11 CAS - 155773-57-l.
the active metabolite of sulindac and use of the two For • discussion of evidence suggesting that regular use of Description. J>cgorgotcin is a supcroxidcdismut.aSeconjugated
drugs together has also resulted in peripheral neuropa- NSAIDs may protect against •arioos rypes of malisnan1 oco- with polyethylene gl)COl lo prolong iis dun11ion of a•tion.
thy. Diflunisal and aspirin are repoJ1ed to reduce the pbsms of the gastroin1es1inal tract, see Malignant Neoplasms in
plasma concentration of the active metabolite of sulin- NSAIDs, p.104. Sudismase (riM'i!
dac. Unlike other NSAIDs, sulindac is reported not to I. Giardidlo FM. er o/. Trcahncnt of colonic and rccul adcnomH
Sud1smasa: Sodismascm.
wi1h 1ulind~c ln familial adenom.atous polyposis. N E"gl J M•d
reduce the antihypertensive effects of drugs such as thi- 1993; 328: J3J3-J6.
CyA-.,JMaJa
azide diuretics, but nevertheless licensed product infor-
mation recommends that blood pressure be closely
2. ~d~b~~~~1~~; ~r:·P~~:~~~,~~/~;;~~;~J~~i.Ps in ramili~J CAS - 110294-55-8.
3. Tonelli F, Val3nzano R. Sulind.c in familial adcnomatoU$pt\I)'·
monitored in patients taking an tihypertensives with posis. Lo11Cot J993: 342: 1120. Description. Sudismase is a human N-acelylsuperoxide dis-
4. Lab~ylc D. (!f al. Sulindac in familial adeoomatous polypo1is. mul8Se produced by recombinant DNA technology and contain-
sulindac. Lo0<et J994; 343: 4 J7- J8. ing a copper and ?.inc prosthetic group.
S. Keller JJ. tt ol Rtc1al epithelial apoptosis in familial adenoma·
tous polyposis paticnu 1rc1tcd wilh sulindsc. GJ11 1999; 45: Adve rse Effects
Pharmacokinetics 822-8. Anapbylaxis and other hypersensi1ivi1y reactions. somc:times fa-
Sulindac is absorbed from the gastrointestinal tract. It 6. Thorson AG- ti ol. R«tal cancer in FAP palicnl after sulindac tal, have beeo reported will> orgotcin. Local reactions and pain
is metabolised by reversible reduction to the sulfide Lottctt 1994. l4l: 180. m1y occur at the si1e of injection of QliOlcin.
7. M11s;uhuhi N. ~I ol. Rcc1al canca after sulindac 1hcr3py a ror
metabolite, which appears to be the active form, and by sporadic adenomaious colonic polyp. A111 J Gm1roen1tt011991; Pharrnacokinetics
irreversible oxidation to the sulfooe metabolite. Peak 93: 2261~
8. CNt~ca M, et ol. Long~tcrm uatmc:nl with sulindac in f> O Refcnnccs.
plasma concentrations of the sulfide metabolite occur mih1l 1dcnomatous polyposis: a prosptt1ive cohon study. Gtn· l. TAO C. 11 al. Pharmacokinetics of rccombtnant hum1n supcro~·
in about 2 hours. The mean elimination half-life of '"""'"°'•t»2002; J22: 64J-S. ide di.smulase in h.eahhy voluntcc:n. Clf,., Pltormoc.ol Th•r 1991 ;
9. Gi1rdidlo FM. •I ol. Primary ch.emoprcvention of ftmilial 1dc·
sulindac is about 7.g hours and of the sulfide metabo- nom1tous po l)'JIOSi~ with sulindac. ;v Engl J Med 2002: 346: 50: 713-20.
lite about 16.4 hours. Sulindac and its metabolites are JOS4-9. 2. Ue:niauu T, e1 al. Phanna.cokinclics and u fcty or in1ravc.nous re-
10. Patkcr AL. '11 ul. Oisappca1ancc of duodenal pofyps in Oard~ combinant human supcroxide dismu1asc (NK34 I) in hcahhy
over 90% bound to plasma proteins. About 50"/o is ex- er'a syndrome with sulindac 1herapy. An1 J Castroc,,terol I993; subjeclS. Im J Clin Ploam1ocol Titer l 'W4: l2: 638-4 I.
creted in the urine mainly as the sulfone metabolite and 88: 93-4. 3. JadOLQ. et al. C linical pharmacokinetic.s and delivery of bovine
11. Ludcnhcim J, ttt of. EfT'tcl or sulindac on $porf(lic colonic. pol· supero:d dc dismu1ase. Cfin Phormncoklnll I 99S; 28: 17-25.
its glucuronide conjugate, wi th smaller amounts of yp$. Gost,,,.n1crolo11J· l99S; JOB: J083-7. 4, Rosenfeld WN, et ol. Safety and pharmacokinc1i<:s of recom·
sulindac and its glucuronide conjugate; about 25% ap- Premature labour. The most common approach 10 poslpon·
binant homan supcroxidc disrnutue tdministcrtd inlra\t)Cat11y
pears in the faeces, primarily as sulfone and sulfide me- neonates with respiratory distreu syndrome. Ptdi·
\O prc.m11ure
ing prcm1ture labour (p.2166) \\ilh drugs 00s historic•lly bwn otl"ics 1996;97: SIJ - 17.
tabolites. Sulindacand its metabolites are also excreted with a selective beia1 agonist. However, as pro.taglandins have a S. o~-.is JM,~' of. Sa(cty and phann1colc.ine11cs of mulliplc doses
in bile and undergo extensive cntcrohepatic circula- role in urerine oon1taction and cer.ical ripening and dilaiation, of rcconibinallt human CuZn supcro,i6e <lismutase adminincrcd
prosbglandin S)'lllhewe inhibitors such as indomeiacin have intrathccaUy to premarurc neonates with rrspitalory Jistrc:ss syn-
tion. drome. P<tlio1r;cs 1997; JOO: 24-30.
also been used. Suhndac has also been tried12 as an alternative 10
0 References. indomciacin u ii appcMS to have tittle pla°'n18l 1r.1nsftr and may 6. Schwedhctm £.'et ol. Clinial pharmacokinetks or on1io.,tcbnts
and their impact on systemic oxida1ivc stress. Cli• PAo,.,,.ocoki-
I. Davies NM, Watson MS. Cl1n1cal phmnxokin.c1ics ofsutindac:; therefore have fewci feW adverse eftCcis. 1 However, the authois ntt 200;;: 42: 4 37-S9.
1 dynamic: old drut. Clin l'hantracokin<1 J997; 32: 437-59. of a subsequent study suggested that sulindac had many of rite
same advel$0 feal eft~IS as indocnctacin and ilS use could only Uses and Administration
be described as invesligationaJ.l A study' using relatively low Supecoxide dismutascs have anli·inflammatory properties. Or-
Uses and Administrat io n doses of sulindac (100 mg twice daily) did nor note any signifi- gotein, a bovine derived supcroxide dismutaSe, has been given
Sulindac is an NSAID (p.103)structurally related to in- cant feiat or maternal odversc effects but also found lhe drug 10 by local injection, into the join\S for degenerativejoint disorders,
dometacin (p.70); its activity appears to be due to its be ineffective in c.'lending gestation or improving ou1come. bu1 hypersensitivity reactions have limited ils use. It bas also
sulfide metabolite. Sulindac is used in musculoskeletal 1. Carfon SJ, 11 ol. R111ndoinizcd coniparalive trial of indomethacin been tried for 1he amelioralion of adverse effects from radiother-
and 1ulind:ac ror the lrtftlmcnt of refracLory prtlem• labor. Ob.fief apy. Fonns of human superoxide di<mu1ase derived by rccom·
and joint disorders such as ankylosing spondylitis, os- Gyn.col 1992; 79: 223-8. binanJ DNA 1cchnology have been developed.
teoat1hritis, and rheumatoid arthritis, and also in the 2. Carlan SJ, ~t al Oo1pa1ienl oral sulindac to pre"cnt rccuncncc or Su peroxide dismutases are also under invcstiga1ion for their fret.~
short-tcnn management of acute gout and peri-articu- pre1em1 labor. Ob.<rul Crnecol 1995; 85: 769- 74.
3. Kramer WO,~' ol. A nmdomitcd double-blind srudy compuina radical scavenging propenies in a varieJy ofconditions.
larconditions such as bursitis and tendinitis. It has also 1he fc1al effects orsulindac to 1erbut.alinc duri:ng lhe mana,gttnenl Bronchopulmonary dysp!asia. Use of sodismase in prcma-
been used to reduce fever. or prelcrm l1bor. Am J Obst<t Gynttol J999; J!O: 396-401. rure infanJs treaJed for respiratory distress syndroine did not pre-
4. HumpNty R~ ft ol. SuliDd.c to prt'VCn1 recu:rrenl prelcnn labor:
A usual initial oral dose ofsulindac is 150 or 200 mg • randomited con110ll<d 1rial. 06sre• GyMcol200J; 98: HS.-62. vent development of bronchopulmonuy dysplasia (p.1638) in
twice daily, reduced according to response; the maxi- the lls$t month.' However, ltealed inllullS su~ucntly showed
Pre parations a lower incidence of severe respin1ory disease and hospitalisa-
mum recommended daily dose is 400 mg. Licensed BP 2010: SUondK Tal*U: tioos in the lirst year, suggesting a reduction in chronic lung in-
product infom1ation recommends that the treatment of USP JJ: SulindK Tablou. jury. The antoxidant was given intratncheally in a dose of
peri-articular disorders should be limited to 7 to 14 Proprleory P reparations (details are si- in ~U1ne B) S mg/kg every 48 hoUJs as long as inrubation and ventilation
days; for acute gout, 7 days of therapy is usually ade- Au..,.oL: A<*'< Cf.ncrit. Austrlo: Oir.onlj; S.lg.: Onot~ Conod.: Apo- were n~ry. A systematic reviewl was unable to reach a furn
s..lii: ~~ Cz.: Onorilt; Oenm.: QinQrif: Fr.: Anlirocino: Gr" conclusion about the efficacy of supcroxidc dismutases in pre·
quate. N~fin: SvJ... Uc!oloc; 2'rof*"' H ong Kong: Aclirc Oo-oorilt: lrl.: 0"'°"
venting chroruc lung disease.
Sulindac sodium has been given by rectal suppository. ~t:'~~~~ M: ~~~·~~1~:,~~:~~'iJ:. I. Ou,·is JM, ~' ol. Pulmooory outcome 1( 1 yc~r cotrcctcd age in
Norw.: Oincn1t; NZ: ~ii: D•clin: Port.: Artribiclf; Singapore: Af» premature infan1s treated at binh wilh ttcombin~nt human Cu7..n
Administration in hepatic or renal impairment. The dose ~J.fA~~t~;;;._~d~;,;r.1: Thai.: cer.lid.x: Clnoril: ut<: CJino. supero."l:idc di$mutast. Pediu1rfcJ 2003: 111 : 469-76.
of sulindac may need IO be rc:due<.-d in pa1ients wilh hepatic or 2. Surcsh GK. e1 al. Supcro.xjde dismu1asc for preventing chronic
renal impairment but sec Adverse Effects and PrecauJions. Jung disea~ in mech::.nk.ally vcntit11cd prctcnn iorants. Avail:>.·
above. ble in The Cochrane O::.tab:lsc of Systcmalic Reviews~ Issue I.
Chich..ter: John Wiley: 2001 (accest<d 09105JOS).
Gastrointestinal disorders. In plaocbo-controlled studies 1•1 Supe roxide Dismutase Head injury. Pegorgotein was found' to be liJtle more elTectivc
sulindac ISO Jo 200 mg twice daily ror 610 9 months has reduced SOD; Super6xico disrMasa. than placebo in improving neurological outcome or redUcing
the number and siu of polyps in paticnis "•ith ramilia.I adcnom-
atous polyposis but the elfcct may be incomplete and in a study2
Cynepoo<e-Myt"a» monaliJy in patien\S with SC\1're head injwy.
ooly polyps less th3n 2 rrun in size~ In addition, the size Oe$cription. Supcroxidc dismutase rcpresenlS a group of wa- I. Yo-ung 8. el ol. Effects o(pc-gorgo1etn on ncurolo;,JC oulcome. or
patients with ~ttt bead inju.ry: a multtcmcer. randon1iud con-
and number of polyps have been repo<ted 1 to incrnsc on stop- ter-soluble proccin congeners ""idcly distn"buted in nature wbich uolled !rial. JAMA 1996; 276: ~:;8-4J.
ping treannent. The benefit of long-tcnn thc~fY has therefore caJalysc the conversion of superoxidc radicals to peroxide. $e\-
been studied. Reduced efticaey has been seen with long-term cnl different forms t.•iSt, which vary in their metal content; Motor neurone diseas<?. A small pcrccnla&c ofpatienls with
or
use but others• havc rq>ortcd management recurrences by ad- fo""• containing copper or copper and zinc are common. familial amyOlrOphic lateral sclerosis (see Mo1or Neurone Dis-
jusbnenl of maintenance dosaic; there seemed to be individual ease, p.2614) ha'-e been shown 10 have a muiation in the gene
variations in sensi1ivi1y to sulindac wirh rtSpect to prevention of Orgot eiri (SAN, USAN. rlNN) encoding for the enzyme copper-zinc wpcroxide dismulase but
polyp recurrence al1hough an average main1enance dose of there has been no consensus as to whe1hc:r palil!nlS with this mu-
Bonne Supe<"C»Ode 01Smutase; O<gotciin'. Orgotelna: Orgot- talioo should be given superoxide dismuiasc supplemenJs. 1
200 mg daily appcattd to be needed.' eine: Orgoteinvm: Ormetein.
TI1ere is evidence' 1hal sulindac allcrs the ratio of apoJl(osis of I. Onell RW, dcSelleroch• JS. Supcroxide dismullS< •nd ALS.
Opr0Te>1>< lo.,cet l'W4; 344: 1651-2.
swface cells relative 10 lhosc lying deeper in the crypt of rcclal
mucosa, thus allering epiJhelial homoeos1asis. Whellttt sulindac CAS - 9016-01-7. Radiotherapy. Although some studies1l indic:."ltc that oigotcin
prevents malignant dcgeneraJion is unknown bul there have been ATC- MOIAX/4. can ameliorate the adverse effects of radiotherapy for bladder ru-
rcports6-8 ofpatienJs who developed rectal cancer during 0< after ATC Vet - QMOIAXJ4. mours, another study3 was 1ennina1cd prematurely because of
long-term therapy for adcnom31ous polyposis. A more recen~ UN/I - PKE82W49VJ . unacceptable hypersensitivi1y rcadions and apparent ioelTicacy.
placebo-<:Onrrolled study' has •ISO reponcd tha1sulindac did not Description. Orgotein is a supcroxide dismutase produced I. Sandlii. F. e.t of. Pm.rentionofmdioindu«d cys1itis byorg<Mein:
reduce the developmenl of 3denomas in palicnlS with familial 1iom beef Ii vet as Cu-Zn mixed chelate. ~ol. wt about 33 000 1 randomized $lUdy. Anticonc<r Rtt 1996; J6: 202S-S.

All cross-references refer to entries in Volume A

 Superoxide Dismutaseffenoxicam i 33
2. V:i.lencia J, 4!' ul. The efficacy nf orgott in i 11 the lre<llment <lf Tapentadol (IJ.S.4r~. ,rr•1Nj Tenoxic:am {EA:<. 'f>Al'J. rlNNJ
acute' ~~ic ity due to radio1hen1p)' on head and r.l!Ck tumors. Ti1-
mo1'i 20()2; 88: 38S-9. BN-200: CG-5503: T<pentadofJm. 3·[(1R.2R)-3-(0imeth)'iami· Ro-1 2-0068: f\o.12.Q06SIOOO: Tenol-.sil<aami: Tenol:sikam: Ten-
3. Nielsen OS. et a/. Orgotcin in rndi:nion lrcttlment of bladder c:in- no)· I -ethyl· 2-met hylpropyljphenoi c!<Sikamas; ·rencxica,.on: Teno;.c::amum: Tenoxkarrt Tenoxik2m.. 4-
c.tr: 3 l"C(>Ort oo 11llcrg_ic rcac1ions and lack ofradioprot«tive ~r­ TarreHTaA.OA Hydroxy-2-metll)l-N-(2-py1id',ll}-2H-thieno{2.3-e ][I .2)thiozine-
fcct. Aou 01t~ol t987: 26: I01-4.
Preparations
C,.Hi;NO 221 .3. = 3·carboxamide 1.1-dioxid~.
CAS - 1755 91-23·8. Te11cKc1-11<aM
Proprietary Preparations (derails are gi"en in Volume B) ATC - N0 2AX06. C 13H 11 1\1 30,S1 = 337.1.
Spain: On:oseint. ATC Ver - QN02/1X06. CAS - 59804-37-4.
Multi-Ingredient: Arg.: Vttix lndon.: G!isodin: nutli".fision: Ital.: Le-
u.-.,11 - H8A007M585. /ITC - MO IAC02.
galor1Pl1:s./v1ex.: Aviti!: Sodimel ATC Vet - QMOIAC02.
UNll - Z i R9NO/'. J9 9.
H3C,N,...CH3
Suprofen (BAN. U5J',"l.11NNJ
. 0 0
R-25061 : Suprofeeni. Svp<ofene: Suprofeno: Suprofenum: Suto-
c ~//
profen. 2-[4·(2· Thenoyl)phenyf)propionic acid.
Cynpo¢eH .
(r'S,~/ H~
c,,H,,o,s = :260.3. CH3
CAS - 408 28-46-4. 's~N~
ATC - "'10 1AE07.
ATC Vet - QMOtA£07. OH 0 N~
OH
UNll - 988GUZF9PE.
Pharmacopoeias. In Eui: (sec p. vii).
Tapentadol Hydrochloride (rlNNM; Ph. Eur. 6.8 (TC>JOxicarn). A yelfow, polymorphic, crystalline
powder. Practically insoluble in water; very slightly soluble in
Hidroclo.-uro de tapentacot Tapentadol. Chiomydrate de: Tap- dehydrated alcohol; sparingly soluble in dichloromethane; it dis·
entadoli Hydrochloridum. solves in solutiollS of acids and alkalis. Protect from light
Tar.eHTaAOl\a r"IAPQx/\OP»A
Stabiiity. An admixture of tcnoxicam 0.02% and ceftazidime
C t<Hn NO,HCI 25 7.8. = 0.5% (as the sodium salt) in glucose injection 5% appeared stable
CAS - 17559 1-09-0.
when stored for cp to 120 hours at 25° in glass bottles;' when
ATC - NOZAX06.
ATC Yee - QN02AX06. stored in PVC ba~. the admixture was stable for up to 72 hours
UNll - 71 204Kll53. at 25° and for up to 144 hours al 4°.
1. Wang D-P. et nl. <:omp:nibility ancl ~tah i l ily of ct flai idimi: sod t-
Pharmacopoeias. ln US. Dependence and Withdrawal um and lcnoxicam in S% dc~'(trose injc~t ion. Am J Heallh-S,is1
USP 33 (Suprofen). A white lo off-white powder, odourless or As for Opioid Analgesics in general. p. I05. Phann 2004; 61 : t924- 7.
having a slight'odour. Sparingly soluble in water. Adverse Effects, Treatment, and Precautions Adverse Effects, Treatment, and Precautions
Profile As for Opioid Analgesics in general. p. l06. As for NSAJDs in general, p. I00.
Suprofen is an NSAJD (p.100). Suprofen has been used as 1% Interactions Incidence ofadverse effects. Adverseeffects associated with
eye drops to inhibit the miosis that may oe<:ur during ocular sur- For ioteractions associated with opioid analgesics, see p.l 07. <cnoxicam have been revicwcd. 1The majority ofadverse effects
gery. relate to the g:.strointestinol tract (1 l.4%). nervous system
Pha~macokinetics
It was foru1crly given orally in mild to moderate pain and in os- Tapentadol is •ubjoct to extensive first-pass metllbolism with a (2.8%), or skin (25%).
teoanhriti> and rheumatoid anhritis bur, after repons of adverse mean absolute bioavailability of about 32%. lt is widely distrib- Gastrointeslinal disturbances including nausea and vomHing
renal reactions. marketing of the oral dose fonn was suspended uted throughout the body and plasma protein binding is about (14.7%) and dyspepsia (2.3%), surgical site bleeding (4.3%),
worldwide. 20%. Tapcntadol is cxtcm,ivcly metabolised, mainly by glucuro- wound infection (2.7%). dizziness (5.7%), and headache
Preparations nidation. It is also metabolised, to a lesser extent, via the cyto· ( l 0.7%) were U1e n1ost common adverse effectsreponed in a pla-
chrome P450 isoenzymcs CYP2C."9, CYP2Cl9, and CYP2D6, cebo-controlled study involving I001 patient< after the perioper·
USP 33: 5'4>'0fen O phthall1K SolutlOI\ ative use oforal and intravenous tenoxicam.' It was noted, how-
before fuithel' conjugation. None of the metabolites have analgc·
Propriettry Preparations (det~ils are given in Volume B) sic ac1ivity. After oral dosing, about 70% of the dose is excreted ever, that 1he incijence of dizziness. nausea and vomiting, and
0

USA: Profen>lt . in the urine in lhe co1tjugated fonn and 3% as unch3ngcd dmg. headache was greater in the placebo group and U1at the difference
The terminal half·life is abou! 4 hours after oral dosing. in the incidence of dyspepsi• between the 2 groups was not sig-
nificmt.
Uses and Administration 1. Todd PA, Clis$01d SP. Tenoxicam: an upda1c of i!s pharmacology
Suxibuzone (MN. tfNN) Tapenrodol is an opioid analgesic (p. l OS) that is primarily a µ- and therapeutic cffic3ey in rheumatic disea!:eS. Dmgs 1991~ 41:
Sui<sibutscni: S.uksibuzonas: Suxibuzon; Suxhizona: Suxibuzon- opioid agonist .lnd also a noradrenaline reuptake inhibitor. Jt is 625-46.
uni: Szuxibuzon. 4-BvtylA-hydroX'ymethyl- 1.2-dipheny'.pyi·azolid· used in the lteatment of 111odcrale to severe acute pain and is giv· 2. Merry AF, et al. Clinical tol~rabi li ly of 1terioperalivc lt11oxicoiin
en orally as the hydrochloride but doses are eApressed in terms al i1\ l 00 1 pati-c01s - o pro~pec1 i v~. con1rolled, double-blind. m\llti-
ine-3.S·dione hydrogen <ucdnate (est.er). ccntrc study. Pain 2004: 111 : 313-22.
the base; 58.2 mg of tapentadol hydrochlo1idc is equivalent to
Cyxc"6)'30H nbout 50 mg oflapenladol. Dosesof50, 75, or 100 mg are given Effects on the kidneys. A review' oftheeifects oftenoxicam
C1,H l 6N 10, = 438.5. every 4 to 6 hours depending on the intensity ofpah1. On the first on renal function concluded that tenoxicam could be gi"en at
CAS - 27470-5 1-5. day, a second dose may be given l hour after the ini1ial dose if nonnal recomme.1ded doses to elderly patients or those with
ATC - fA02AA2Z. pain relief is inadequate; subsequent doses should be given every mild to rnoderate renal impainnenl who were 11ot at high risk of
ATC Vet - QMO! AA90; QM02AA22. 4 to 6 hours, adjusted according to response, to a maximum total renal failure or receiving potentially nephro1oxic therapy. Data
UN/I - 86TDZ:5WP2B. dose of700 mg on the first day and of 600 mg daily on suhse- from lhe manufacturer's database' on 67 063 patients, including
quent day;;, 17 005 over 65 years of age. who had received tenoxicam indi-
For doses in pa1ients with hepatic impalnnent, see below. cate!d that there had been 45 adverse events relating to urinary
system function, described as severe in 7. ·nie prevalence of ad-
0 References.
verse events was similar in elderly and non-elderly patients, the
I. Hale M. Cl al. Tokr;)bili1y of 1api:nlado1 immediate release in
palients with lo\-.t r back pain or osteo3rthr i ti~ of the hip or knee
most common eftects being dysuria and renal pain.
over 90 days: B rnndomized. double-blind study. Curr Med Res 1. Hti1uz RCA. Teaoxic:im and renal funclion. Drug Sn/ctJ• 199$;
Opin 2009: 25: 1095-1104. 12: tt0-t9.
2. Hanrick C. ~1 nl. Etlicocy and tolerability o(tapentadol immedi- Effects on the liveY. A report' of acute hepatitis associated with
ate release an<I oxyeodone HCI immediate fcleai::c in palients
3wai1i1tg primary joint replacement surscry for end-stage joint the use of lenoxicam.
disease: a I O-d<1y. phase Ill. randomized. doublc·blind, acti\'C• 1. Sungur C, ~I al. Acute hc:p:ni1is caused by le:no.'tic:un. Ann Phtu-•
aod placcbo·c<lntrolled ~tudy. Cli11 Tht!r 2009: 31: 260-71. moeclhttr 19Q4; 28: 1309.
3. L>anicls S, ,,, of. A rnndomi7,ed, douhlc-blind. pl3eeh(l.COntrollcd
phase 3 study of the rel~1 ive e fficacy and tolernbiliry uf tapc:nt.a- Effects on th<! skin. A repo11 of 3 cases of toxic epidennal
dol IR and ox:ycodcine IR for acute poin. Curr Med Res Opiu necrolysis (Lyelrs syndrom•) associated with tenoxicam.'
Pharmacopoei~. !11£w: (seep.vii). 2009: 2S: 155t -<S I. For the g~neral incidence of dennatological effects see above.
Ph. Eur. 6.8 (Suxhtzone). A white or almost white, c.rysralline 4 . Wade WE. Spruill WJ. Tapen1adol hydrochloride: a c-cntrally. I. Chosidow 0 , ('I of. Tuxidcrrnits sCvCrcs au 16noxicam (Til-
11c.:1ing oral analgesic. Clin Tlte1· 2009; 31: 28~ 18. cotil$).Ann Dtrmotol Vcne1~/ 199 1; I IS: 903 ·4.
powder. Practically insoluble in water; soluble in alcohol; freely
soluble in acetone; practically insoluble in cyclohexane. Administration in hepatic impairment. Tapentadol hydro·
Interactions
chloride should be given with caurion to patients with moderate For interactions associated with NSAlDs, see p.1 03.
Profile hepatic impaimient; treatment should be started with oral doses
Suxibuzone, a derivative of phenylbutazone ( p. 12 1), is an equivalent to 50 mg of tapentadol given at intervnls of no less Pharmacokinetics
NSAJD (p.100) U1at has been applied topically at a conccnlrnfion than every 8 hours (maximum of3 doses in 24 hours). Thcrcaf· Tcnoxicam is well absorbed after oral doses; peak plasma con·
of about 7% in musculoskeletal and joint disorders. Concern ter, maintenance of analgesia may be achieved by adjusting the oentrations occur within about 2 hours in fasting subjects; this
over safety and toxicity after oral use has led to its withdrawal dosing inter\'31 according to tolerability. may be delayed ro about 6 hours when tenoxicam is given with
from the marke1 in mariy countries. Use in patients with severe i111painnent has not been studied. food but the exter.t of absorption is unaft'octcd. It is also rapidly
Preparations absorbed after intramuscular inj(.'Clion. Tt:noxicam is about 99%
Preparations protein bound andpenetrntes synovial Ouid. The plasm• elimino-
Proprietary Preparations (de1ails arc given in Volume B) Proprtetary Preparations (details arc given in Volume B) tion half-lite ranges from 42 to 81 hours; with daily dosage,
Spai": Oantcn USA: NuC)'l\1<! steady-stale concentrations occur within 10 to 15 d~ys. Tenoxi·
cam is completely metabolised co inactive mclabolites: which are
The symbol t denotes a preparation no longer actively marketed
134 Analgesics Anti-inflammatory Drugs and Antipyretics
excreted mainly in the urine: there is some biliary excretion of Profile WHO' confmncd that cystitis was more commonly associa1ed
glucuronidc conjugates of the metabolites. Tctridaminc is an NSAID (p.1OOJ that has been used as the with liaprofenic acid than with other NSAIDs. The Australian
0 References. malcatc as a douche in the ireatmcnt of vaginilis. Adverse Drug Reactions Advisory Committee had received sim-
I. NilJiCn OG Clinical phanna~kinctics or tcnoxic:am. Cli,, Phar- 0 Between January I 99 I and December 2003 the Spanish Poison ilar repor1s.l Since the 1994 warning, 1hc CSM 8 had received rc-
111ocokl11111994; 16: 1µ3. Control Center hod received 77 rcporu where vaginal prepara· poru ofa further 74 eases ofcystitis, but the majoril)' ofthese had
2. Guenterl 1'W, et ol. Relative bioavailabilil)' o( oral dosage forms tions containing tetridaminc had been ingested olone, mainly due occurred before the waming was issued. The duration of lrtal·
of 1cno,;ieam. Ar:1teln1!11t/for11·chunf. 1994: 44: 1051-4.
to erroneous miSUSC. I Qf these, 60 patients WtlC asymptomatic me11t in patients affected had varied considerably. Mosl patients
3. Nilsc.n O(l ct ol. Single. ond multiple-dose pharmacokinctics., recovered when tiaproftnic acid was wilhtlr-d\\'Tl.
kidney tolcmbilily end pliu1nft protein binding or lenoxicam in and in the remainder the mos1 frequent symptoms were vomiting
ren1lly Impaired p:uicnl! and healthy volunteers. Phormoc.o/ (SJ, cpigastric pain (4), hear1bum or oesophageal irritation (4), llic CSM recommended thal tiaprofcnic acid should not be giv-
Toxicol 2001; 89: 265-72. dizziness (4), and nausea (3J. The clinical severity was mainly en to pa1icnls wi1h urinary·tract disorders and that it should be
Uses and Administration benign but 1 patient became comatose after ID.king 4 gin a sui- stopped in palicnts who develop urinary-Imel symptoms. Pa-
Tenoxieam, a piroxieam (p.122) analogue, is an NSAID (p.103J. cide a1tcmp1. No deaths occwred. tient~ should be advised that iflhey develop syn1p1oms such as
h is used in the symptomatic management of musculoskeletal I. Baltcs;cros S, ~' ol. Oral tctridaminc exposures. Clh1 Toxl~ol urinary frequency. nocturia, urgency, or pain on urination, or
2009: 47: 15()-2. have blood in their urine they should stop taking liaprofenie acid
and jointdisordtrS such as osteoarthritis and rheumatoid arthritis,
and also in the short-term management ofsofl-tissue injury. Ten- Preparations and consult their doctor. Older patients may be at increased risl<.9
oxieam is given as a single oral daily dose usually of 20 mg. In Proprietary Preparations (dcuoils an: 11iven in Volume BJ l. Ahmed M. Davi.50n OW. ScHrc cystirii :is,;ocia1cd wilh 1iaprO-
acute musculoskeletal disorders ll'Utmcnl for up to 7 days is usu- ltol: Dea Spoln: Fomcne. fenic acMI. BM/ 1991: JOJ: 1376.
ally suffieicntbut in SCVttCC3SeS it may be given for up to a max- 2. O'Keilt GFA. Tiap<nfenic acid 2s a caust af Nln-hxtcrl:al cy~li·
imum of I 4 cloys. Doses similor 10 those gh'en orally ha"e been 1is.MedJAus11994; 160: 123-S.
given by intnmuseular or intnvenous injection for initial ueat- 3. Auscralian Advcr.5C Dru& RcactlM.$ Ad"isory Com1nin~
Thurfyl Salicylate (AORAC). Update on tilprofcnic acid ind urinory sympl0m$.
ment for I or 2 days. Tcnoxicain has also been gi''Cn by roc1al Aidt Ath<ru Dn<g R">et Bu/11994: IJ: 6.
suppositoiy. Saldato de n.rilo. Tetrahydrofurflryt sa!icylate.
ORcfercnces.
C, 2H 140 4 =222.2.
CAS - 2217·35·8.
'4. CSMJMCA. St\'CR cysiitis wi(h Liaprofenic add (Surprn). c,,,...
n1r1 Probl#tm 1994; 10: 11.
I. Todd PA, Clissold SP. Tcnoxicam: an upd1t< of ill ph:annacolOl)I S. Hamson WJ. a ol AdvC:rK rtae:tions 10 tiaprofn.it xid mim·
and therapeutiC' ctTecacy ;n rhe.umioc disease.a. Drtt's 1991; 41: ockong ontmtitiot cySlltis. BM.I 1994: 309: 57~.
62S-46. 6. Mayall f'<l « ol. Cystitis and ur~ttic obslmction in pa11er11s •~le·
Preparations
SP 2010: Tena.iam lr\«'""1: T.......wn r.btets.
Proprietary Preparations (dctails are aiven in \~lume BJ
A_ustria: Ticodt: S•li.: TilcClllt Broz.; lnftaeet A'OdO ic•~ T~ Teno-
QyoJ) 1ng tiaprofe:nic acid. BMJ 1994: 309: S99.
7. The AOR Signals Analysis Project (ASAP) Team. H°"' don
cyJtitis affect a eompara1ivc: tisk profile of tiaprofcnic acid wi1h
other non-steroidal an.~inflammatory drugs? An inrem•1Kmal
study boscd on sponlanecus rtpOR• and drug wage do1J. P,.,,,._
biof; TMOCM'nt, Tet>0te<; T"'°"""1: n.ttI - . Ti!O>Ount. 1 ~t. OH 0 mot:O/ To>lco/ 1997; 80: 211-17.
Chilo: Biolloro; M.'troU: R«.lltx Tolc04J. Oonm.: ~ F1n" Tltotit, fr" 8. Cnwford MLA. ~'al. Severe cystitis associated '4-ith ti3profenit
Ticott Gr.: l\Onirat Aljl>-Vetc AmcNlot ~ l\nfe><Gltr< ~&in; acid. Br J Urol t 997: 79: 578-8~.
Biodf\lfr. Doclicomc Or>nat ~tic:.otr< Jndo.1-.;: ls1otosat Uad<ryt Neo- Profile
aclibamf'c Neo..r>tipersum: Neo-e""'- OCl>vtnrc 0)()'l•t Pailenmc Thwfyl salicylatc is a salicylic acid derivative that has been used 9. Buchbinder R, ~' al. ClinieaJ fature5 of tiipro(cnic l'CiJ (sur·
fllnsclit: Fl:irtonil· ~c Sotv. Tone»< T...ifP"nit rliatirc TOSCOQm v.i,,. g:im) usoc1otcd cystitis and a. study or risk (actors for its dcvel-
similarly to methyl salicylate{p.89) in topical rubefacient prepa- OfJ<YICfll. J Clin Epid•miol 2000: S3 : I 013-19.
r«: VoW: Zibel.>nt: Honr Kon1: Seftjf: TenO>C Tilcc:tilj: Hunc.: Tolcotil:
India: Tol>ttil: lndon" Ntticom: Medi1>1t: NotrillS. 0"3il>m; Nopil: Then•: rations at concentrations of up to 14% for musculoskclelal,joint,
liarc0< Tilcotil: Tilnam: Xolilo<l: lrl.: Mobilexf: Ital.: Bart Dolmen; Rex.a~ pcri·articular, and soft.tissue disordtrS. Interactions
g"' Tilcotil; Jpn: To/coli: M olayslo: Nadomcnt. SIM Sonoratt: TilcOOI: For interactions associated with NSA!Ds, sec p.103.
Mex.: Tikotilf: Neth.: TicoUI·~ NZ: Tolco-J: ~l>Jllpp.:, Rheullex; Tolc~til:
Preparations
Port: Sioraicamt. Colt>talt: OOX>Gln: Tenolg"': Tllcotol; S.A(r" Til:otolt: Proprietary Preparations (details are given in Volume 0) Pharmacokinetics .
Tol>ilit. Slngopore: N•domerc Spain: Artril.rict. Reutenoo:: Sw•d.: ,AJ. Multl-lngredlent: AustNI.: B:osal An:hriti$f; Sele.: Tr~nt1ane: lrl.: Tiaprofcnie acid is absorbed from the gastrointestinal tract and
g'1>!>: Swiu.: Tolcotil; Tho I.: 11emzotlt Sel\il: Si'oorol: Toca""' Tcnax: Tcn- Transvastt UK: Transvasin Heat Rub. peak pl11sma concentrntions occur within about 1.5 hours aflcr
=:~~~~~;~lilf:!:t.~~mt~~..~~ oral dose.~. It has a short elimination balf-Jife ofaboot 2 hours and
Zi!<,rat UK: Mob~e.>c: Vonez.: llodix: Tcamt: Tenoxirc TllCotlt. is highly bound to plasma proteins (about 98"/o}. Excretion oftia-
Tiaprofenic Acid (MN. rlNN) profenic acid and ilS metabolites is niainly in the urine in the fonn
of acyl glucuronides; some is excreted in the bile. Toaprofenie
Acide liaprofenique; Acido tiaprofenico: Acidum tiapro(er.cum: acid crosses the placenta and is distribuled inlo breast milk.
Tepoxalin (USAN. rlNN) FC-3001: Kyselina tiaprofef'>C:M; RU. 15060; Tiaprofeenihappo:
ORF·20485: RVV)-20485: Tepo1<$aroini: Tepo>Qlina; Tepoxalin~ Tiaprofenik Asit; Tiaprofeno rug<tis; Tiaprofensyr<1. HS·Bcn· OReferences.
Tepoxalinum. S·(p·O.lorophenyl)-l ·(p·meli>c»<y~l)-N­ zoyl-2-tt'Oenyl)propionic acid. 1. Oev1cs NM. Clinic1Iphannacokincticsoftiaprofcoic acid and i1s
methylpyruoie-3·propionohydroxamic acid. cnantiomcrs. Clin Phorn'IQ~inet l996; Jl~ 331~1.
TH•npo<j>e••C>ll<!" KHU.OTa
Tenoi<CiW<H =
C,.H,201S 260.3. Uses a nd Administration
C2oH~CIN10J
CAS - 103475-41 -8.
=385.8. CAS - 33005-95-7
ATC - MOIA.Ell.
Tiaprofenic acid, a propionic acid derivative, is an NSA IO
(p.103). ll is used for die relicfofpoin and inOammation in mus-
ATC Vet - QMOIAE92. ATC Vet - QMOIAEI I. culoskeletal and joint disorders such as anlcylosil\g spondylitis,
UN/I - TZ40X61974. UNlo - llS IT6R34C. osteoarthritis, and rheumatoid anhritis. in peri-articular disorders
such as fibtositis and capsulilis.. and in soft.tissue disordas such
as sprains and Sll'lins. The usual oral dose is 600 mg daily gi~cn
in 2 or l divided doses; in poticnts with cardiac, hepatic, or renal
impoirrnent, licensed produc:t infonnarion suggCS1s that the dose
is reduced lo 200 mg twice daily. A modified-release preparation
may be available for once-daily use. liaprofcnic acid has also
been £ivcn rectally. It has been given intramuscularly as the
tromctamol salt in acute conditions.
Pharmacopoeias. In Eur. (seep.vii). 0 References.
Ph. Eur. 6.8 (Tiaprofenic: J>.:id). A white or almost white, CIY$-
talline powder. Practically insoluble in water; fncly soluble in al- I. Plosker GL. Wa;st.a<T AJ. Tiaprofcoic .icid: a re.a.pprai:S3l of iu
pharmacnloa.1cal properties and u.q- in lhc m.anagemcnE of ~u-
cohol, in ace1ooe, and in dichloromethane. Protect from light. l99l; SO: 1050-75.
1n 11ic discucs. Dr11fs
Adverse Effects, Treatment, and Precautions Administration in hepatic or renal impairment. liapro-
A$ for NSAIDs in general, p. 100. fenie acid is contra-indicated in paticnlS with sevue hepatic or
Tiaprofenic acid may cause cystilis, bladdu irritation, 3nd other renal impainnent; for dosage details in those with moremodera1c
Profile urinary-ltact symptoms (sec below). II should not be given to JXI·
Tepoxalin, a propionic ocid derivative, is an NSAIO (p. JOO) used impainnent, sec Uses and Administration, above.
tients wilh active urinary-tract disorders or proslatic disease or a
in veterinaiy medicine for the treatment of inna1nmation and Preparations
histoiy of recwrcnt urinary·tract disorders. It should be stopped
pa in in dogs.
inimcdiately if urinary-Imel symptoms cx:cur and urinalysis and Proprietary Preparations (details arc given in Volume B)
urine culture performed. .Aunrol: SurgaO"C Co nod.: 5'#'2.vnt. Cz.: Su<iam: Thialgn Oenm" Sucga·
'Jiaprofcnicacid is contra· indicated in patients with SC\'crc hepat- mif; Fin.: Surgamyt Fr.: fl>ni:l, S°l.flt•m: Gor.: S.,rgam; Gr.: ' ' "lian< Hung.:
Tetridamine (rlNN) ic or renal impainnent. S"'l>'"' lrl.: ~lll'llt. Ital.: S....giltl'!Yt T;apror..,t: Mex.: Suri:•m: Neth.:
S.Jivm: N Z, 5.Jr~>m: Pol.: Stq<rn Pott.: S<J<ta.T< S.Afr.: Sur,r.mt: That:
POU-67; Tellidamina; Tctridamine: Tetridamiium: Tetrydami"le Breast feeding. AJU1ough tiaprofcnic acid is distributed into Feogamf: Turlc.: :i<i<g•tr< UK: Surgarn: Venn.: Tocpa>.
(l/SAN). 4.S.6.7·Tetrahydro-2-methyl-3-(methylarnno)-2H-inda- brcnst milk, the amount is considucd by die BNF 59 to be too
zole. small to be harmful to a breas1-fed infant Licensed product in-
TeTP"'A>l....., formation also stales that c:xpOswi: to tiaprofcnic acid via breast
Tiaramide Hydrochloride (BANM. t.ISAN, rlNNM)
c,H ,sN1 = I 65.2. milk is unlikely lo be ofpbannacologieal siguificancc; however,
it is recommended th•l ei1hcr lrealmcnl or breast feeding is Hidrocloovo de toaramida: NTA- I94: Tiaperamide Hydrodfo-
CAS - 17289· 49·5.
UNI/ - NQ7W01PF6S. stopped as neceSS81)'. ride: 1iaramidc:. Chloitl)'Clrate de; Tial'3midi Hydrochioridum. S-
Effects on the urinary t ract. Cystitis and bladder irritation 0.Joro-3-(2-[4-(2-hydroxyethyf)piperazil'>- 1·yf}2-oxoethyl)ben-
have been associaled with the use of tiaprofcnic aeid. 1" In Au- zothiazofin-2-one h)odrochloride.
gust 1994 the UK CSM stated' tha1 since the introduction oftia-
proftnic acid in the UK in 1982 lhey had received 69 rcportS of r ""l>i"'>W rl'IAPO"''olMA
cyslilis aod 32 Olherreports ofurinary-tract symptoms associated C 1sH,,CINi01S.HCI 392.3. =
with tiaprofenic acid including frequency. c!ysuria, and haematu- CAS - 32517·55·2 (tioromide): 35941-71-0 (tioromide
ria whereas only Scasesofcystitishad been reported for all O(hcr hydrochloride). ·
NSAIDscombincd. Analysis ofspontaneousrepomrccei"ed by UNll- ITY1616X9T
All cross-references refer to entries in Volume A
 T epoxalinfTolmetin Sodium l 3S
3. Hnjda JP. "' al ScqucntiaJ fir~L·pas~ meuiMl iun ornon1hd1ne: Tolmetin Sodium (BAN•!< U.IAN, tfNNIA)
Lhc :ictive me11bolit.c of the synthclic opioid drus Lilidine. JC/in
Plmrmttcol 2002i 4?: 1257-61. McN-2559·2 1-98; McN-2559 (tolmelln); Navi Tolmetinum:
Cl 4. Brennschcidl U. et,..,/. Phann.acoki.ntticJ ortllidinc and na1oxonc- Tolmctina sOo'ica; Tcl.-netine Sodiquc. Sodium (l-melhyt-5-p-

¢ S
h
N\
'(0 0rN\__/N~"--OH
/\
•n paaicm.s wi1h severe hrpatic impairment. Ar=ut!imitt~l/MSC'­
h11•>s 2001; 57: 106-11.
Uses and Administration
Tilidine h}'tlrochloride is nn opioid analgesie (p.108). 11 is used in
the conlIOI of moderate to severe pain.
Tilidine hydrochloride may be given in IJSU3I oral doses of up 10
50 mg rour times daily. II has been given as a supposilOry, or hy
toluoylpyrrol· 2-yt)acetate <ihydrate.
Hup..i< TOilbMen•M
c sH,.NNa03.2H,o :: 315.3.
CAS - 26171-23-3 (tolmtlin}; 35711-34·3 (anhydrous
tolmetin sodium); 64490·9].] (iolmetin sodium dihy·
<Irate).
...re - MO IA803; fl102M2 r.
in1mvenous. intntmuscular, or subcutaneous injection. Tilidine .A.TC Vet - QMOIAB03: QM02AA2 1.
has also been giYCn as the phosphate in modified release tablets. UNtl - 02NITZF99F.
(tioromlde} AS a de1emn1 10 abuse combined oral preparations oftilidine hy-
drochloride with naloxone hydrochloride are available in some
countries.
Phannacopoeia.s. In Jw1.
Prepar ations
Profile Propriecary Prepa,.ations (details are: gi~·en jn Volume B)
Tiaramidc hydrochloride is on NSAID{p.100) thaiis given oral· 8•1f.: Tnolco<; V.~.ran: Cz.: Valoront. Gor.: Andolor; Cell<101or: f'ondol '."t-
ly for lhe relief of pain and inOanunation. A dose equivalent to Nalii:tn: Ti <:on-µ Ti!l..P\Jre.-. Tolft: Tllicorrcx actabt: ~ c"""" lilidin
100 mgoflhe base may~given th= limes daily. N: Tiidio !*IS Tidon-...,.: liliduraj: Tolimet'cl<j; ~ Valoron N: S.Afr.:
V.tloron: Switz.: Y.llc>'on.
Preparations
(tolmecin}
Proprietary Preparations (dcuiils arc given in Volume Bl
Jpn:Sollt>1.il Tolfenamic Acid (!Im rlNN)
Pharmacopoeias. In US.
Acide Tolrc!namiqo.ie: Addo tolfenmco: Acidum tol'.enamicum: USP 33 (Tolrnetii ~).A lig)ll yellow to light or.inge crys-
K~ tolfenamov~; Tolfenaamihappo; Tolfenaminsav. TolieN· talline powder. Freely soluble in waler and in methyl alcohol;
Tilidine Hydrochloride (UWt plNNM) mo rug;ti5: TolfenamS)n N·(3-Chloro-o-tolyl)anthranJoc a6d. sligJttly soluble in aleohol; very slightly soluble in chlorofo1111.
T()Hj>et<aMoeai< K«CAOTa Adverse effects, Treatment. and Precautions
GO 1261-C; HicYodorvro de t11id"1N; Tldate Hydrochloride
(8AN!~): To>diinih)'dr'okloridiherrihydraatti: Tiidine. Ollomydrate C,,Hi;CIN01 = 26 1.7. As for NSA!Ds in general, p. 100.
CAS - 13710-19-5.
de; Hidine (~e de) hemihydratC: Tilidon-hydrochlorid Breast feeding. No advc:rsc effects have been seen in breast-
ATC - MO IAGOZ.
heniihydrat: T1ld~ henV"lydrat; Tjidn Hydrochlon- ATC Vet - QMOIAG02. fed infonts whose motbers were given 1olmc:tin, and the Ameri-
dum: rilid1ni hydrocNonct.J.-n hemihyd1icum: Tilidino hldrochlori- UNIT- 3G943Ul8KM. can Academy of Pediatrics con$idcrs1 !hat it is lherefore usually
dis herrihidratas; W-5759A (±)-Ethyl !Jl10s'·2-dim~I· compatoble with breast feeding. Howcvet, licensed product in·
~cyclohex-3-ene-I ~ hydrod1loride he~ fonnation rcconunends Uia11olinetin should be avoided in nurs·
ing mothers.

x:~~CI
drate.
I. American Academy of Pcdiaatics. The transfer of dru&J and oth·
T ""'W'Ha rHAPOXllOfl1'1A er chcmie1ls ~n&o human milk. Ptdiutrics 2001: toa: 776-89.
C11HnNO,.HC!.'l;H10 318.8. = (Retired May 2010) Conoaion. ibid.; 1029. Also •••ibble al:
CAS - 20380-58-9 (tilidine}: 27107-79-5 (anhydrous Ii·
lidine hydrochtcride}: 14357-97-9 (onhydtous +-t:ons-tili-
dine hydrochlorid•}.
ATC - NOZAXO I.
vU
Pharmacopoeias. In £ui: (see p. vii).
h 11p: I Ina ppol 1C)'. u ppubl ic ac i ons.or&/t 8 i /c on1en1/fu 11/
pedia1rics%3b I08/3n76 C•=ed 08111 /07)
Effects on the blood. Case repons of agi'Snulocytosis1 and
dU"Ombocylopcnia' associated wiU1 tolmetin.
Ph. Eur. 6.8 (Tol~mic kid). A white or sliglltly yellow crys· I. Slkli J. Jwq>h MW. Tolmt1i11 and apanuk>cyto.J:is. N Engl J
Al( Vet - QNO:ZAXOI. Med 1978; 29lk 1203.
1olline powder. Practically insoluble in water; sparingly soluble
2. Lockhart JM. Tolmetin-induecd 11'\romboeylOpCl'lia. Arthri1h;
in dehydrated alcohol and in dichlorometbanc; soluble in /ll1<11m 1932; 15: 11~4-5.
di1ncU1ylfonnamide. It dissolves in dilute solutions of alkali by·
droxides. Protect from light. Effects on the CNS. S« Hypersensitivity, below.
Adverse Effects, Treatment, and Precautions Effects on the gastrointestinal tract. Eroshe ocsopbagi1is
As for NSA!Ds in general, p.100. has been repotted 1 in an 11-year-old child ofter ingestion of a
dose of 1ohnelin while lying down and witliout drinking any wa-
Dysuria, mo.st co11101011ly in moles and probably due to local ir·
ler.
ritalion orlhc urethra by a metabolite, h•s been reported. Tremor,
I. Pak>p V, 11 al. Tolmetin-induocd Cl(lphaae:il ulcer3lion. Nm
euphona, and fatigue have also occum:d. l'olfcnamic acid is con· Pt>ar.oocorhor 1997; 31: 929.
lra·indicated in patients with signifoc..111 hepalie or renal impair-
mcnl.. Effects on the kidneys. JnlctSl.ili•l nephritis' and ncphro;ic
(ul1dine} syndrome23 have been reported in patients si'"" lolnielin.
arcast feeding. Although tolfcnamic acid is distributed into 1. Kal.z SM, er 411. Tolmctin: association with revet$iblc renal (nil·
breast milk, lhe amount is considered bv the BNF J9 and Ii· t•rc ;1nd acute Milcrsciti1I ncphri1is. JAA!A J911; 246; 2-43-S.
Pharmacopoeias. In Eur. (sec p.vii). censed product infunnalion IO be too small to be hannful to a 2. Chatterjee GP. Nephrocie Jyndromc induced by 1otmectn JAMA
Ph. Eur. 6.8 (Til6:ie H)'Qochlonde Herrihydrate). A while or bn:asl-fcd infant. 19SI; 246: 1589.
almost while, crys1alli11e powder. A suia.ablc amoxidanl may be 3. Tu:tjcn OP. Rtc\lrten« and 5pccHJcity of nephrolic syndrome
added. freely soluble in waler and in ak:obol; very soluble in Effects on the lungs. Pulmonary inliltru1ion has been associat· due to tohnctio, Am J ~ 1989: 87: 354-5.
dichloromcchane. Pr0tec1 from lighL ed with 1olfena1nic acid 1rea1mcn1in6pal~nts. 1
Hype rsensitivity. Anaphylactic shoek,1 urticaria and an·
I. Su·omb<ra C. rt 1Jf. Pulmon3r)' infihrattons induced by tolfonam-
Dependence and Withdrawal ic 1cid. Lll1K't:1 1987; ii: 6S!-. gioeclema,l and aseptic meningitis' are aonong the hyperscnsitiv·
As for Opioid Analgesics in general, p.105. cty reactions reported in patic111s laking tolmetin.
Interactions I. Rossi AC, Knapp OE. Tolm(;lin·induced anaphylac1oid rue·
Adverse Effects, Treatment, and Precautions For interactions associated with NSAIDs, see pJOJ. tions. N Engl J Med 1982; 307: 499-SOO.
As for Opioid Anolgcsics in general, J'I · I06. Pharmacokinetics 1. Pc.nte CO. Wisman R. ·rolmC1in.induccd lOrtic.:irialangiocdC'rM.
Dmg /nr<ll Clin Pharni 1985; 19: 479-SO.
Overdosage. Cyanosis, ,...piralory depression, and seizure$ Tolfenamic acid is readily absorbed from lhe gastroinlescinal 3. Ruppert GB, Banh WF. Tolmctin·induccd ascplK: m~nin1i1i s.
developed in o W-yc~r-old worron ofter an overdose ofa combi- trnet and peak plasma concentrations occur about 60 to 90 min- JAM.4 1981; 245: 67-$.
nation preparation of 1ilidine and 03loxonc. 1 The authors com- utes after an 01111 dose. Tolfenamic acid is about 99% bound to
plasma proteins. The plasma half-life is about 2 hours. Tolfcnam- Interactions
me111ed th~t lhc amount of naloxonc included in the prcpamtion, For interactions associated wilh NSAIDs. ~e p. I03.
in order 10 prevent abuse, was insuffocie11110 prevt:nt respiratory ic acid is metabolised in !he ln-.:r; lhc metabolites and unclum!!Cd
depression aller severe overdose. drvg arc conjugolcd with gluc\ronic acid. Aboul 90% of an-in- Pharrnacokinetics
gested dose is excreted in lhc wfoe and Ute remainder in the fae. Tolmetin is almost completely absorbed from lhe gastrointestinal
I. Reacn11lal R.. a al. Poisoning with lilidine and n:1Joxonc: toxi· ces. Totrrnamic acid is distributed into breast milk. tnc1 and peak plasnia conccntr.1tions occur about 30 10 60 min·
cokinc1ic and clinial obse1va1ions. /h1•,, E.f.p To.ri<:ul 1998~ 17:
59l-7. Uses and Administration ures after ingestion. It is extensively bound 10 plasma proteins
Tolfcnamic acid, an anthranilic acid derivative related 10 (OYet 99%) and has a biphasic plasma half-life of a~ul I 10 2
Porphy,ia. Tilidine lw been associolcd wilh a<:Ule all•eks of hours and 5 hc:ows, respec1ivtly. Tolmctin penetrates synoviol Ou·
porphyrio and i$ considered unsafe in porphyric patients. meferu1mic acid (p.84). is an NSAJD {p.103). In lhe 1rea1mc111or
acute ottacks of migraine tolfenamic acid is give11 in a usual oral id and very small an10u1t1s arc distributed inlo breast milk. II is
dose of200 mg when lhc firsl symptoms •l>J>CLr; ifa satisfactory c•crc1ed in lhe <Sine as an iJ1ac1ivc d~rt>oxylic aeid mc1aboli1e
Interactions
response is nol obtained Ibis dose may be repeated once alter I and its glucuronidc and as tolonc1in glucuronidc with sm311
For interactions aMocialed with opioid ana lgcsics, see p. 107.
to 2 hours. Tolfenamic acid has also been given for 1hc relief of amount~ of unchanged dnig.
Pharrnacoklnetics mild 10 modol'•tc pain in disorders such as dysmenorrhoea, tf1eu. Uses and Administration
Tilidine is ob$orbcd from the gas1roon1ts1inol trac1. It is mea.abo- matoid arthricis, or os1coarthri1is in closes of I00 to 200 mg three Tohnc1in sodium is an NSAID (p. 103). It is used in musculoslct l·
lised and C}.CZ1:1ed in lhe urine mainly as metabolites nortilidine tnnesdaily. ctal and joint disordctS such as osteoanhritis and rheumatoid at·
(nortilidate) and bisnortilidine (bisnortilidate). Nortilidine is re· lhritos, includingjuvenile idiopathic arthritis. fl is given onlly os
sponsible for the analgesic activity oftilidinc. Preparations
tbesodium sah al~1ough doses arc expressed in tenns ofthe blse;
Proprietary Prepo.ratlons (douils arc Si"en in Volume 8) tolmetin sodium dihydrate 122.5 mg is equivalent 10 about
0 References. f:
Arg.: Floc"': Auwio: M'2C>t. Cz.: M:g.. Oenm.: Clota!!'t; Migeo: Fin.:
100 mgoftolmctin.
I. Vollmer K·O, ttol Phcrmxoldn.e1ics nf1ilidine and Mc1aboli1es Clotamt: Migt•t. Gr.: C'lotirn: Gaot~: M~ ~ A'mactaln: Pu~
in man. Ar11Ntlmt11tlft>r&ckffl'R 1989; 39: 12SJ-8. falo><: Tol!amoc; ,.~ N•"'·' Ooumt: Roc<i,nt: N_ , Miga Pot.: For the !raiment of rheumatoid aotluitis and ostcoenhritis, die
Migea: UK: Clown: Von•z.: Oo;.mt. usual initial oral dose is lhe equivalent of 400 ms of 1olmctin
2. Seiler K· U, at til. Pharmxokinerics oflilidinc in terminal renal
f1ilu~. JC/lll P/wn,,oeo/2001; .. I: 79-.S'4. three times daily. Doses should be adj~ aller I to 2 weeks
The symbol t denotes a preparation no longer actively niarketed
 136 Analgesics Anti-inflammatory Drugs and Antipyretics
according to ""J'O'ISC; maonwiancc doses of 600 mg io a maxi· despite an inacase in ils use, tramadol continued to show a low 5. Laba1e A. ,., al. Tram1dC1I and ncw--oesc:t seizures. Med J Aust
mum of 1800 mg daily on divided doses have been used. level of abuse and concluded lhat there was not sufficient evi· 2005; t Sl: 42-3.
dence to justify a futther re\oiew. 6. Boyd IW. Tromodol and sciZ'1rc.. l.kJJJlust ZOOS; t82: S9S- 6.
For dol'age de1ails in childmi. sec below. 7. Gleason PP. ct ol. Oebilit1lin1 ttaction following the initial d~
Tolmotin as the free acid bas been applied IS a topical gel. Nevertheless. there have been repons»S of dependence and of tramodol. 11110 Phormocothtr 1997; 31: 11*-2.
abuse. particularly in opioi<klependcn1 persons, and of wilh-
Administration in children. For the lreatmenl ofjuvenile drawal symptoms. Jn Oclobcr 1996, the UK CSM9 commented Effects on die respiratory system. RespiratDr) dcp<cssion
idiopathic arthritis in children aged 2 years and over, 1olmetin thal since June 1994 they had received repons of drug depend- has been repo<1Cd afu:r uan1adol infusion anaesthesia, 1 allhough
sodium is given in initial oral doses equivalent IO 20 mg/leg of ence in 5 patients and wilhdrawol symptoms associated with ll'a· in a pustopcntive study2 trarnadol had no significant respiratory
1olme1in daily in tine or four divided doses; maintenance doses depressant effect when equianalgcsic doses of morphine, penta·
madol in 28 patients, which corresponded to a reporting ra1e of
of 15 mg/kg to a maximum of30 mg/kg daily have been used. about I in 6000. Doses in excess ofthe recommended maximlllD -me. pethidine, piritramidc, and tramadol were compared.
Preparations of400 mg daily had been taken by 5 ofthe patienls. The duralion 1. Parav,e:ini D, et ol. Tramadol·infusionsanac11hcsic mil Substitu.
tion von EnOuran und difrcrcnten Uchgaskon2cnlt'ttioncn. ;1,,_
USP)): Tolmet;n Sodu~ ~ T - Soo..m Tabl<U. of treatment before onset of these ell'ccts ranged from l Oto 409 ""1hnl11 I 9SS; 34: 2()-7.
Proprietary Preparations (details arc given in Volume B) days (average 3 mnnths). Withdrawal symptoms reporled were 2. Fechner R. tH al. Cllnic:al invcstiiaLiOtlS on •he cffetl of mor-...
Austria: 10lo<1"t: Gr.: Tclccbn. Mu.: Tolee1i" S.Afr.: Tolecor¢ Spain: typically lhosc of opioid withdrawal in ~cneral. A more recent phine. pcntazocine. pethidine, phi1nmMSe and tramadol on rcitpi·
Artrcc>ptin; Turi<.: Tolecli-< USA: Tolecfo report from the Swedish Medical Products Agency10 Slllled that ration. Anosth J,,t~nsivmed 198S: 26: 126-32.
between 1996 to 2005 they had received 71 repon.~ of withdraw- Overdosage. In a mulricentre case series, 1 126 cases oftrama-
al symptoms associated wi1h tramadol; trca1menl duration dol loxicity were repoJ1ed between October l 995 and AuguSI
ranged from I week 10 over 3 yean al daily dose.• of bctwe~ 1996; of these, 87 invoh'Cd exposure 10 tramadol al-. Com-
Tramadol Hydrochloride somg to 2a. mon symptoms included lethargy, nausea, tachycardia, and agi-
(BANM USAl\l rlNNM) I.~!!,~i.~~~Jxf:'bC:;'~~e: ;j 1~~83~~f:~~~i!h:: talion; scirures were also no1ed. Respiratofy depression was seen
in only 2 patients. The inhibitory effects of tramadol on
CG-315: CG-315E: H'.rodol\lro de tramadot TratNdol. chlo- hnp:lllibdoc. who.intltrs/WHO_ TRS_91 S.pdf (accc.ucd
26!06/08) monoamine rcuplake, rather than its opioid effects, was consid-
rhy~lrdte de: Tramadol H~rolcJO<U"; Tramadol~rid: Tra- 2. WHO. WHO cxpen comminee on ctrus dependence: thlny· ered to resull in much of its toxicity. A similar paltem of toxicity
madol-hydrocNorid: Tramadolhydroldond: Trzrnadolo hyciro- founh r<pon. WHO T<eh Rep Ser 9411006. Also available at: has also been seen in a mon: recent report.2 ln 190 ttamodol-only
chloric1.om Tramadolihydrokloridt TramadorK> 1-idrodl!oridas: U· h11p:Jtlibdoc.v.:ho.in\/1rsl\VHO_TRS_942_en&.pdf (access;cd exposures rcpottt:d between January 1999 and July 2001, the
2M>6l08)
2622.SA. (±)·V()(ls-2-Dimeth)Qmin0tnelhyl- I-(3-me1Jla><)'phe- 3. Rodrigllct Vi11amalian JC. rt ol. Withdrawol ayndrome afttt main symptoms of ovcrdosage Wl:rc CNS depression, nausea
~;exanol hydrochloride. lona-term treatment wi1h cramadol. Br J Gen Prncr 2000; so·; and vomiting. lachycardia, and seizures. Again, the incidence of
r paMa,o.oAa rHAPOXAOpM.f. 406. rcspiratO<)' depression was rare, with only I ease reported.
4. Yates WR. e.t al. Tra.madol dependence with no history orsub-
Cl6HzsN02.HCI 299.8. = 5-t.3ncc 1buu Am J h_vchiof'f')• 200J; 158: 964.
S. Brinker A. 11 ol. Abuse, dependence, or wilhdrawal asSO(i11ed
1. Spdlcr HA. a ol. Prospective mul1icenter cv11uation ofln1madol
cxpolAlrc. J Tozico/ Clio Ttnicol 1991; JS: 361-4.
CAS - 17203-91·5 (cromodol); 222CU-88-2 (cramodol
h)•drochloride); 36282-4 7-0 (1tamado/ hydrochloride).
,.;th tnmadol. Jfm J PJ)'Chiotry2001; 159: 881.
6. Sk. ~per GE. et al. Tnmadol abuse and dtptndcncc among phy.
2. ~~:~a~~~~;~~~:;,,~'t:!=~~~~~~:~~~~e
ATC - N02AX02. 1i<1ans. JllMll 2004; 191: lllS.-19.

;,
ATC Vet - QN02AX02. 7. Soyka M, et '11. Tremadol use and dtptndence in chronic non-. Precautions
c1nctr pain p;i1ic:n1s.. Phannncoptye.hiotry 2004; J7: 191-2.
UN/I - 9N7fl.477WCK. As for Opioid Analgesics in general, p. l 07.
8. ~\1=~ ~ ~;,:~;;):;i"~~:r;'t;~~;l~. ddayed u~ma-
9. CSMIMCA. Tramadol-(1'ydol, Tramakc and Z•madol). Cur-
Tramadol should not be given to patients who arc sui-
TVll Probltms 1996; 22: 11. cidal or prone to addiction. It should be used with cau-
10. U k•mtdtlsver1m (Medical Producls Ag<1lcy-Swcd<n). U1- tion in those who usc alcohol in excess, or suffer from
s3nnincs~.ak1ioncr av tramado)-..c:n stOOc problem In fbnln·
tat? (issued 14th No'll'cmbcr. 2006). Available: at: http:// emotional disrurbance or depression. Tramadol shou Id
u~~~~~~~~;~~k~i;!:~~t~~~:'~'a'd~l~:.·t~~~r~c~~!:~!~f be used with care in patients with a history of epilepsy
orvaniat.J (accmcd 02/08110) or those susceptible to seizures. See also Effects on the
CNS under Adverse Effects, above.
Adverse Effects and Treatment Tramadol should also be used with caution in patients
As for Opioid Analgesics in general, p. l 06. with renal or hepatic impainncnt and should be avoid-
Tramadol may produce fewer typical opioid adverse ed ifrenal impainnenl is severe. Removal by haemod i-
(uo:nodol) effects such as respiratory depression and constipation. alysis is reponed to be min imal at 7%.
In addition 10 hypotension, hypertension has occasion- Abuse. Sec under Dependence and Withdrawal, above.
Pharmacopoeias. In Chin., Eur. (seep.vii), and US. al Iy occurred.
Ph. Eur. 6.8 (Tramadol Hydrochloride). A white or almost Anaesthesia. Liccn~ product infonnation warns agilinsl us-
while, crysialline powder. Freely soluble in water and in methyl
Deaths associated with tramadol use have been report- ing tramadol dwing very light planes of gcnerdl anacs1hcsia be-
alcohol; very sli&hlly soluble in acetone. Protect from light. ed in patients with a history of emotional disturbances, cause of possible intra-operative awareness, although ii may be
USP 33 (Tramadol Hydrodlloride). A while, crystalline powder. suicidal ideation or attempted suicide, or misuse of used intra-opcra1ively provided anaesthesia is maintained with a
Freely soluble in wa1er and methyl •lcuhol; very sligb1ly soluble CNS depressants such as alcohol and anxiolytics. potent volatile or intnvenous anacslhetic. (ntra-opc:rati\'e aware·
in a«.1one. Store in ainiiflt coniaincrs at a temperature of 2S 0 , ncss was reported in 65% ufa group of20 patienis when used 10
excumons permitted between I5° and 30". Effects on die CNS. The UK CSM' commented in February provide aua!gcsio durin1' lig)JLgcnaal onaesthcsia with niaous
I99S that since June 1994 Ihey had received reports of IS pa- oxide :ind in1cnni11ent cnOurane. 1How"""'• in a studyl of51 pa-
lnc;ompatibility. Some manufacturers state chat irarnadol hy- tients who had had co11/usion and/or hullucina1io1is while laking tients &iven 1ramadol during slablc lighl conlinuous isotluranc-
drochloride injection SO mafmL is incornpao'ble with injections tramadol. The majority of the n:actiuns developed I to 7 days ni1rous oxide anaesthesia there was no clinic•lly sign iii cant
of diazq>am, diclofenae sodium, flunilra2Cpam, glyeeryl trini- after staning uca1mcn1 and in most palicnts resoll'cd rapidly on lighlening ofanaesthesia and others have comnientcd that during
tra1e, indomciacin, midawlam, piroxicam. and phenylbutazone if withdrawal. It WIS no~ lllal psychi•tric reaclions C<1mprised extensive u.1e of 11amadol intra-operalivcly over several years,
mt'&! in lbe same syringe. A 51Udy 1 also found ltllmldOI hydro- abou1 I0% of all reaclions repot1ed wilh tramadol 1here had not bun any incidence of recall in any palicnl 1rca1ed
chloride injCl::tion (diluted IO 400 microgram.Vml) to be incom- In a later commen11 in October t996, the CSM noted thol 27 at their clinic.J
patible wilh iteiclovir aod clindamyein when mixed iosether. rcpo11S of canwlsions and one of worsening epi lepsy had been I. Lehmann KA, 11 al. Zur Sedetl.tuna von Trnm::idol als inttaopc.r·
l . Abanmy NO. 1.1 al. Compatibility of1nmadol hydrochlOtklc in~ received, which corresponded to a reporting rale of about I in auvcm Anal,ctikun': eine randomisicnc OoppclblindStudie i1n
jccdon with r.ele((Cd druas and solutions.""' J Heolth·Syst 7000. Of lhe S palicnls receiving intravenous tramado~ 2 had Vcrg~ich zu Plocebo. Der Jlnomlttti>I 19SS; 34: 1l-t9.
Phor"' 2005; 6?: 1299->302. been given doses equivalerit to 1.45 and 4 s d•ily, well in excess 2. Coctxeo JF, Cl ol. EIT<ct ofiramadol on dcr1h of anaesthesia. Br
J .4"'1u1h 1996; 76: 4)5-IS.
Stability. Oral suspensions of iramadol hydrochloride ofUlOSC recommended (see also Overdosagc, below). Ofthe pa- 3. Budd K. Tra,...dol. Br J lln<1esth t99S; 75: SOO.
S mglmL, prepared by mixing crushed 1ablcts willl a strawbeny tients receiving oral 1t11madol, lhe majority were taking other
syrup and Oro-Pl11S(l:I) or wilh Ora-Sll'eetand Oro-P/14(1 :!) drugs known to cause convulsions, including tricyclic antide·
were found to be siablc for al least 90 da(5 when Slored either in prcssants and SSRls. A similor JXlllCm has been reported in the
Interactions
the refrigeralor or al room tempcrorure. Oral suspensions con- USAl and Australia.•~ For interactions associa1ed with opioid analgesics, see
taining tra1nadol hydrochloride 7.S mgfmL and paracclamol A debilitaling CNS·mediatcd reaction to an initial dose of ltllnu- p.107.
65 m~1L, prcpored by mixing 1hc aushcd 1ablcts ofa combina- <k>I bas been described in a patient' Symptoms. which lasted Carbamazepine is rep0ned to diminish the analgesic
tion preparation with the above vehicles, were also found to be about 4 hours, included alllXia, dilatation ofthe pupils, numbness
slable for at lcas1 90 days when slorcd under similar conditions.2 in a II limbs, IJcmulousncss, and dysphoria. Althoup the cxacl
activity oftramadol by reducing scrum concen!J'ations.
I. W11~cr os. e1 DI. Stabilil)' of oral liquid prcpara1;ons of tran11· mechanism of the reaction was unkno"'n, it was suggested that The risk of seizures is increased if tramadol is used
dol in Slf'aWbcrry syrup and a sugar-free vchictc. Am J Htoltlt· since the patienl was an ex1ensivc mctabolisc:r with very high ac- with other drugs that have tl1e potential to lowerthe sei-
Sytt P/ronn 2003; 60: 1268-70.
2. Johnson CE.. o al. Stability of 1r1mldoJ hydrochloride-acetami· 1ivity of the cyrocbtome P450 isocnzyme CYP206, high con- zure threshold. See also Effects on the CNS, above.
nO(Jhen (Uhracet) in Slnlwbtfl")' syrup and ih a sucar-rree vchi- centrations ofthe acti\'C 0-desmethyl mclabolite were the cause.
clc. JfmJ Hwlth-Syst Phorm 2004; 61: 54-7. The paticn1 recovered \\ith no sequelae. JI is possible Iha! lllis Tramadol inhibits rcuptake of noradrenaline and serot-
represents a case of the .<ertJIOnin synd1-ome, since tramadol is onin and enhances serotonin release and there is the
Dependence and Withdrawal kflown 10 he associated with this condi1ion, pa11icularly at high possibility 1hat it may interact with other drugs that en-
doses or when given wi1h oiher drugs 1ha1 rai~ serotonin con· hance monoaminergic neurotransmission including
As for Opioid Analgesics, p. I05. centrations.•
Tramadol may have lower potential for producing de- I. C:SMIMCA. Tt.llmadol (Zydol)-psyc.hiatric reactions. C11rt'tnt
lithium, tricyclic antidepressants, triptans, and SSRJs,
pendence than morphine. Probltms 199S: 21: 2. thereby increasing the risk of serotonin syndrome; it
2. CSMJMCA. Tram.dol-{Zydof, Trtmake ond Z•madol). c,,.. shou ld not be given to patients receiving MAOls or
0 A WHO CJ< pen committee' considered in 2003 that !he availa- rrmJ P<0bltms 1996; 22: 11.
ble infonnation on tramodol was not sufficicnl 10 warrant inter· ). Kahn LH, •I ol. S.izu«s r<part•d with tmnadol. JJl.IU 1997; within 14 days of their discontinuation.
national control. Studies in animals indicated thal tramadol pro- 278: 1661.
0 Me<abohsm of tramadol is mediated by the cytochrome P4SO
duced little toleranoe, bad mild wilhdrawal symptoms, and a 4. AdverSt: Drug Reactions Ad"·isory Commutcc (AORAC). Trt·
rnadol-four yc.:irs ~ptric nce. Allll AJ.~1 Drirg React Bull isoenzymes CYP206 and CYP3A4. Use willl specilic inhibitors
lower abuse polcntial than codeine and pentazocine. Subse- 2003: 21: 1-2. Also •vailohlc at: hnp://wwwta• health.gov.au/ of these enzymes may incre:isc conccnlr:llions of traonadol and
quently, when rcviewca in 2006, the commirtee2 considered lhat. odrlladrbl..dr0302.pdf (accessed 2M>6/08) Iowa conccntmlims of its active me~boli lc. The clinieal coose-
All cross-references refer lo entries in Volume A
 T ramadol l-lydrochloride!Trolami'."le. Salicylate i 37
quc11ces of this effect ore mclear although the rislc ofscilllftS or (Uftram. PriCara) recommends a maximum dost of o-Jg•n: Trod:>: Trvnot Hons Kong: Aculf'icf: t'o>b<ont. Sefm.>i:
serotonin syndrome may be increased. Tr....t Tromot: Hun1.: ~""" Con!r>m2; fl4erc Tr.tmadolor. TrarnaJ.
300 mg daily in such patienlS while an increase in the g;c; India: Cotllr""'t Tramacipr Trom.uc: TRO.C,,,,1.11: Urg....oot lndon.:
Anticoagulants. For repons of the cffec1 of tramadol on oral dosage interval is often suggested in UK product infor- And.Ji>hat; &illlfllmj: C.m;iool< Catllt3';c; Conv-.m: Corsadot Oolana;
an1ico.1g11lan1s. sec AnalgcsiC$ under Interactions of Warfarin. Doig.W.: Oolcu1< Oolsic: Forge>ic: K.lma<lot !Ytr~~: Nooalgesl Nuf'!><>
mation. Preparations containing tramadol hydrochlo- inm: Orasic: ?riore<: !\idol: Scm;noc. s;matral Tlusic: Trldosik T~
p.1565. T,..g<sik: Tramal Tmilc: Traumalicf: Tr""11: Tug.,.1: Zeplianal: Z'"'1atr.om:
ride with other analgesics such as paracetamol arc also
Antidepressanu. For reference 10 pO!'Sible cases of •erotonin lrl.: Biodot ll'!-M•dot Tradot Trom•ke: Tramapine: Tramexj: Trox<loi:
used. X,met Zamadot Zydot l1roel: Trobor: Tramadoic Tramal; Ital.: Adamon:
syndrome associated with use of tramadol and SSRJs. see Opioid Contnm•I: fcnr.dol: Fnxidolt: Pront•'fi':
Tradonal; Tranasl\; T...iodie:
Analge.<ics under lnteracti0tts orFluoxetine. p.42&. When used paren/erafly, a dose of 50 to I 00 mg may Tramolin; Unitr.ma: Mo/oyilo: A<uteioc: Anolab: Oomadot Mabron:
S-HT1-receptor antagonists. 1l1e pre-operative use of,,,,_ be given every 4 to 6 hours by intramuscular or intra- f'l!rq,""'c: Sdmat Tr>cKlot To..,.,do:
Tromalt. T~ Tramundn: Mex.:
venous injection over 2 to 3 minutes, or by intravenous 0.,odor, Nobbgan: l't'Ontolot1: Trado1: Tralrc: Tramed: T~ '/eldro<
donsetrot• has been noted to reduce the postoperati\'C analgesic Neth..: Do~ard: Theridot Tridor.al; Tram•&elit: Tramat Trame~
elfacy of11amadol. I.! In one study, 1 the cumulative dose of ira- infusion. For the treatment of postoperative pain, the Norw.: NobliJaan: Trado'.anj: T~ NZ: °'""'1-.m: Tramot Traln!do;
nudol was up to 35% greater in those patients who also received Zynmt: PloiTipp~ AtNryt Oomadot Dolmat Oobnt Oc>paz Dom·
initial dose is I 00 mg followed by 50 mg every JO to '>ee Gesidot Marclot Miaodot l"i.odar. Mos<!>ln: ~ l'l!plt><t A.-
oodanserron compared wtth those""'° received 11Q;1Dticmctic. ln 20 minutes if necessary to a total maximum (including z.adot ~TOI: Totnlt. Traaine: Tr>donal T - Tromal: T~
addition there was no difference i11 the incidence ofpostoperative T.-: Tnrron6n:U>tnl. ,..,1.: ~ -U.XOnlffn:R>ltr-.m:
nausea and YOmitins between 1hc rwo groups. the initial dose) of250 mg in the first hour. Thereafter, T~ Tt3mat Tr>mcoctf: Tr"""""'1: T......aat Port.: Oolprt.Gc:lc-
I. De Witte JL, ~' ol. The 1nilscsic (ffiQC.y ofLran-iaOol is impaired doses arc 50 to 100 mg every 4 to 6 hours up to a total tnlb; ~ P.>xWar: Tnmot T""'Yf: T,._ T~ Zydot 2;<rvrc
by conc.urrcnt 1dministn11ion of onda111etton. AMslh Anolt daily dose of 600 mg. Rus.: Mb<>n (Miliiloo<t, l'laz:adol (~~ Sontradon (~)t
2001:92: 1Jt9-21. Tmlol (T~OA): Tramaldosidol (T~... .....,.,.._): Tram.I (Tpi,..,.):
Usu aI rectal doses by suppository arc I00 mg up to 4 Tr.vnoin (Tpa....,,....): s.A(,, Oolo"""1: Oomado\ Noblig"': T~
., Arcioni R. ~t ol. Ond~nselton inhibits the ~nalgcSic. effects of
Tnimal: Tramasiierc Tnll\'\alX Tnrmsese Sln1oporc: Mboo: Pe~csic:
U'31Tt3dol: a pouiblc S·HT1 spinal receptor involvcm~.nt in acute limes daily. Selmat T.-adot Trimal: Tramium: Spain: Adolonla: Cepilidirc Oolodot
pain in humans. An1111h Am1lg 2002; 94: 1$53-7. Dolpir; Gelotradot NOOCigon: So<rodolf: Tt0ner: TnodONt Trawolt. Zy-
For deiails of doses in children and in patients with he- lr>m: Swed.: NOlllig•n: T""°" Tradolan: Z•madol: Swlu..: Oolo""'*>o::
Pharmacokinetics patic or renal impainncnt, sec below. EcOdolor: Tradonal: Tramat Tnrm\Mdn: Thol.: Amanda; /lmmitroirc At»·
doc Analabc M•bront: M.ldot MadolK Matradot Milidot Mod""'11: P:.cma-
Tramadol is readily absorbed after oral doses but is <> Refcrettces. dolc Pair.dot l'tlarinodol: Rorradot Rol'y: Sclmot Tamot.11: Tra<:ino; Tr.idolge-
subject to some first-pass metabolism. Mean absolute I. Scon LJ. Perry CM. Tramodol: ;i rt\'icw of ilJ USf in ptriC'pcm- sic: Tradonalt. Tramada: Tramadit Tnrmadorc To·Mlit ·rramvned( Tramax
ti\'e poin. D,.ut;• 2000; 60: 139-76. T.,.,,...c: T....-rood>; Trasic: Tr>umtd: Tro1oc; VolCidot Turk.: Contramcl:
bioavailability is about 70 to 75% after oral use and 2. McClcllon K. Scott W. TramadoVponocctamol. Dmgs 2003: 63: Tnm>clola: Utramex; Ui<; Oromado!j. L.Jr.,,.m: Mabt<tn: Maxitram;
I 00% after intramuscular injection. Plasma protein 1079-86. Co1-r<ction. ibid.: 1636. NoClf'S""! Oldoram: Tradoroc Tramolce. Tramqvot Tramuficf: ZUNdol:
3. Grond S. S.blOIZki A. Clinical pharmacology o(tnmadol. Cl/11 Zeridime: Zydol: Ukr.: T""""&" (1 po.....,,..)1: USA: Rybbc P:yrolt: 1-'-
binding is about 20%. Tramadol is metabolised by N- Plron•ocoltinct 2004: 4.J: 879-923. tram: Ytnu.: Tromlll
and 0-demethylation via the cytocltr0me P450 isoen- 4, l.eppett W, Luczak J. The role of ltamadol in ca.nccr pain tttll· MutO<;ngredient: Ar~ C.m.dor Plui: Tromo.Qooodol PU: T...-nocel:
zymes CYP3A4 and CYP206 and glucuronidation or nicn•-a re\ sew. S11ppon COtV" COM.:rr 2005; 13: S-17. A....- :z.ldir. 8etc-: Zo!ISr. llnlz.: \.lltxct Conod.: Tr""""°" Chile:
J. CIOJe BR. Tram1dol: does it have a role: in cmersency rncd1· ,,....... S>p; Crotv.: Oclot..-c r-WOdol """' - PU; Pnmot hlin;
sulfation in the liver. The metabolite 0-desmethyltra- cine! EIMrg Mttl A1ntralas 2005: 17: 73~3. bldoar. Zolodor.f': Cz.: Oot-eto. ~: fr.: blpwrc Zalciu: Gu.: 2¥<1¥:
madol is phannacologically active. Tramadol is exact- 6. C<ptdl MS. <I ol. Tra,,,,.dol for osicoartlvilis. A'idlable in The Honi Kong: Ultr.rn: HunF Zll6«: Indio: Tolydot Tr>rN<ip PM; 1-'-
Cochnnt Dar:i.bueofSystc"maric Reviews; Issue:. 3. Chidlfl\t:t: trazac: lndon.: Un<et ZU!r. lrl.: ~ 1.,,..1: ~; Maloyslo: l-'-
ed mainly in the urine as metabolites. Tramadol is John Wiley: 2006 (occc=d 26"06/08). tr3Cet: Mex.: Ganwnaool: Siner(i>< Tromocet Tremoptr( Z-: Noth.:
7. Outhn1ke: RJi.1, "' ol. Tnmadol ror ncuropathic pmin. Available ~ Z.l<B: P/ollipp.: Cetodot Cc!ra: Ooicot Pol.: Z.klar: Pore T.ta-
widely distributed, crosses the placenta, and appe.ars in lgirc Z.ldi•r: Rus.: For$0dol (<Do;><OA.OA}: Z•ld...- \ 3 - ) : S.Afr.:
in The Cochrane Dai.abase of System:atic Reviews; fssut 3.
small amounts in breast milk. The elimination half-life Chiche""' John Wiley; 2006 (ace<sscd 26/06.l'.IS). Tramacet Singaf><>re: l.lt'actt Spoln: Pal!IJI. fbn..i.;c; :Z.id.¥: Switz.:
is about 6 hours. 8. ~G~~~f-~~ · Tromadol su.iain«l-rclC2s• capsules. Dr1111 ~006; Z•'dar: Thai.: Uotra<el; UI<; Tn1macet: Ul<r.: Zlldlar (3M<.i>p)t: USA: Ul-
1t1~ct: Venez..: Utracct Zald1;iir.
<>References. 9. ~1:i'i~~?~:z;~· T1'ain:tdol cxtc:ndcd·releast tablel$. Drug,, 2006;
I.cnc-e
~!~d~.e~~:~d~~~f:=i~bfc~:~~~ t~!r:!i~~~~!1::::~!~
0

produtl folio\\ ing sin.ale:·do.se and muhiplc-dosc admini!>·

I 0. Freeman H. ef ul. Randomiud study of 1r.amadoll•celami-
nophcn vmus placebo in painful diabetic peripheral ncurol""'I· Trimeperidine Hydrochloride (IV.NM. t!NNM)
tta1ion. J Clin Phormncol ~010: SO: S,.4-Sl. thy. C1wr M•d R., Opln 2007; 23: 147~1. Hidrodoniro de trimeperidir.a; Promedol (trimeperidine):
Children. References. Administration in ch~dren. ln the UK, uam•dol hydrochlo- Promedolum (trimep~): Trim~eridne, Chlortlydrate de:
I. Murthy BVS. et a'. Phannte0kinctics of tramadol in children !lr· riclc is licensed for the management of moderate 10severe pain in T~ H)drochloridum 1.2.5-Trimtthyl-~-pheoyl-4-pip­
1ec i.v. or caudal epidural administracton. Br J .•1tMJth 2000: 84: children 12 years ohge and older; usual oduh doses may be giv- .,~ propio:>ate h)drochlonde.
346-9. en (see above). However, in some 01her European counlries ii is
2 . Payne KA. rt al. ~rmilcokinaics of o~I tr.tmadol drops for licensed in )'Ounger children allhoun.,h lhe age range permitted TJ>H"--pt<.Ql<!Q rl<APOXM>Jl"IA
postOjOCnti»c pain reli<r in cloildrtn aged 4 to 7 yea..s-a pilot can vary: for eumple. in Fro11U, a~usual dose in those aged 3 C17HisNOi.HCI 311.8. =
••udy..41...s1hP~200J;49: 109-ll. ~and O\'Or is I to 2 mg/leg onlly, which may be reP""ted 3 or CAS - 64-39·1 (trimependine): 125-80 4 (urmoperidine
3. Zwa~lin~ J, n 11/. PhamlACX>kinetks of rcca.:tl ttamadol in post· 4 timc$daily, whereas in Gvnrony,similardoscs :uepcrmilted tn hydrochiorid~).
o~rarh·c pxdiatric p31icncs.. Br J Anoc11h 2004; 93: 224-7.
4. G~cridoQ MJ, ~'al. Popula1ian ph1rmacokinctic!pharm1codyn;;m-
children as young as l year old. Tramadol has also been given
ic m('l(felting of the nn;lgcsic efrecu O( lr.imadol ln p<'dia1tiC$. paren1etally to children in doses similar 10 those used orally.
Phann Ra 2006; 23: 2014-23. Some referc11ces1.. on the useoftramadol in children.
S. Saudan S, Mabrc W. Pt11ticulorit~s phnrm:icologiquc$ du 1ram:1- I. Fink( IJC. ct al, ·"" cvalu.:uion of the efficacy and 1olcn:1bilily or
dol chcz l'cnfant. Amr Fr A11e11h Rttmim 2007; 26: S60-;. out 1r~1nt1dol hr.drochloridc l~blets for the uea1men1 o( pos1sur·
The elderly. Pharmocoki11e1ic parnnietcrs in elderly patients gical JM1in in children. A11eMh Anolg 2002; 94: 1469-13.
''-ere found to be similar 10 those in younger patienlt;. 1 2. Dcminm1n Y, *' t1I. A '-'<>mparison of the postoptr:uive anatge.ie.ic
tfficAc)• or single-dose epiduu11 1ramadoJ versus morphine in
I. Likar R. tf c1/ Phannacokinettc ond pharm:»cod)1lamic pr0pet- child.-co. 0f'J Att<ttslh 2005~ 95: SI0-13.
1ics nflramadol IR and SR in elderly patiena: :ii prospective. ag~ J,, Botkurl P. Use of tra1Mdol in child1'Cn. Po(•dibtr Ano,Jth 200S:
grourr-controlled $1udy. C/i11 Tlr<r 2006: 28: 2022-39. IS: 1041-7.
Metabolism. Production of the aotive met•oolite 0-<lcsnlClhyl- 4. Chu Y..C. rt ol lnuaopenti\'e ad1ni1listruion of U2tnadol for
lramadol is dependent on the cytochrome P450 isoenzymc po)topcra11vc: nurK-conLrollcd analgesia resulted in earlier
:.wakeninJ and less scdalion than morphine: in childreq :after c:ar·
CYP206. wllich shows genetic pol)lnorphism.':2 For a refer- d••c su11:rry. A11wb Anol1 2006: l 01: 1668-73. {trimoperidir.e)
ence to a debilitating CNS-mediated rcoc1ion in a patient \\flo
was an extensive mell!boliser with high CYl'206 aetivi1y, see Ef- Administration In h"patic or renal impairment. A dos-
fCCIS on the CNS, above. age interval of l 2 hours is recommended for lmll3dol usage in Profile
I. Poulsc:n L. t!I ol. The hypoalcuic: d(ea o( lram.adol in rclatioo ~ere hepatic impairment; US licensed product information Trimcpcridioe hydrochloride is an opioid onali:esic (p. lOS) with
to CYP206. Cli11 l'ha1·•>0<t>I Th<r 1996; 60: 636-44. suggests that Jl(ll1cnts wtth cirrhosis should be given oral doses of actions and uses similar 10 those of pethidine (p.118).
l. re<krscn RS,~' ,J. Enantioselecci,·e rhann:icoki11CliC$or1rama- 50 mg every 12 hours. 111• dosage i111crval should also be in-
dol in CVP206 extensive and poor nictabolizc1rs. £,,r J Clin
Plwrumcol 2006; 6?: Sll-21.
creased lo 12 hoors in patients "''h a creatinine cle<1rancc (CC)
uflcss th.'n 30 mUminute; in the USA licensed product informa-
lion suggeslS that lhc maximum oral dose should not exceed Trolamine Salicyla.tefpJNNM)
Uses and Administration 200 mg daily in these p:nicnts. Tramadol should not he given 10 Salicilato de trietanolarnir>a; Salocilato de trolarnna; Trieth-
· Tramadol hyd rochloride is an opioid analgcsic(p. l 08). pnticn1s with more severe ren11l impainnen1 (CC less than i1110lamine Salicyfate: T'Olamine. Saticylate de: Trolamini Salic~as.
lt also has noradrenergic and serotonergic properties 10 mlJminutc). Tp<m!M~H· Ca'"'"""'T
that may contribute to its analgesic activity. Tramadol Preparations C13H11NO, = 287.3.
is used for moderate to severe pain. BP 2010: r,..,.,,adol ~ CAS - 217./·16-5
UNI/ - H804040BHD.
Tramadol hydrochloride is given orally, intravenously, ~:;~~and Tn1madol Hyd.-ochlocid< Tab~u: Tr.,_.dol
or rectally as a suppository. The intramuscular route Proprietary Preparations (d<tails .,. given in \.bfume B)
has also been used. It may also be given by infusion or Arr~ C - . ~ ~ Tram.t Tmmanovai: Aurtrc>/" 0
as part of a patient-contr01led analgesia system.
Usual oral doses are 50 to I 00 mg every 4 to 6 hours.
Olrotnrrc Tr....._.., Trrwt Trwnodo: Z)'dot Austria: Adotnor< eon.
~ CrotN10dot Oo1c1t: t...~t: Noa>< UlCX Nycodolj: T . . -
Tr...-: T~-: TAtNt Tr~ T~ T,.,.,....w; Tro·
('oH ~OH
~OH
~ Sele.: Contromot Ooctnm>do; Dclzam T~t T...........
Tramadol hydrochloride may also be given orally as a &=: ~ e>ortou: Scnovam:Syt.dar: Toma!<:nt: T...i.r. Tl1/1\ldc:ft HO~N-...._/'..OH
modified-release preparation once or twice daily. The ~~~.,,;J'=~<=.;'~t ~T~t1f:::_
total oral daily dosage should not exceed 400 mg. Usu- broro Noax uno. Protradon. Trab>rf: Tradet Tr><lon•lf: Tnlf.it T"'"'t>ene
al doses may be used in elderly patients although in Tr>mag<t: T...,11>1: Tram.in6'c Oonm.: Oolol: Mandolgin: NCJttsat< T•dot Pharmacopoeias. Jn US.
T'.idolal\ Fin.: Tradol•n. T,....,adr( TrafnaiCtic: Tramat TratrOc>; T~ USP 33 (Tro12mine Sakylate). A compounded mi~turc of
those aged over 75 years the elimination half-life is in- Z..-nadolt: Fr.: Biod•I;,: Con1rarnat Monoatgic: Monocrixo: Monolramat irolamine and salicylic acid in propylene glycol. pH of a 5% so-
creased and a reduced dose may be required; the Ii- Oro<amJdol: Takadol: TOj)Olgic: To~o1: Zarrudol: Zuma1g<: Ger.: Amil· lution in water is between 6.5 and 7 .5. Store in aiiiighl con1oincrs
• dot. Oofevar: Juudo1: T-1~ na1t; Tradolt; Trama: T""riabt-U: Tranwdoc:
censed product mfonnation for one US preparation T.-.m•dolor: t11m16.lraf: TrlfMl'I: T.-.m•I: Tnr.-r.J<'drc TrOY<x o.e: Gr.: in u cool place.
The symbol i denotes a preparation no longer actively marketed
 138 Analgesics Anti-inflammatory Drugs and Antipyretics
Profile
Trolamine salicylate is a salicylic acid derivative used similarly
(a prodrog of valdccoxib,
serious skin reactions.
=
p.116) had been associated with Zalt opro fen (rlNN)
to methyl salicylatc (p.89) in topical rubefacicnt prcpanttions in CN-100; Za~.oprotene; Zaltoprofeno; Zalop:o~nulT'~ ZC-1 Cll.
The incteascd risk of serious skin reactions with valdecoxtb (±)-10,l l ·Di~-mc\hyt-IO-oxodbe.-ao[b./Jthiepin-2-acetic
a concentration of 10 10 20% forthc relief of muscular and rheu- treatment was ooe of the =sons the drug was generally with-
matic pain. h has also been used as a sunscn:cn. acid.
drawn in April 2005.
Percutaneous absorption. In eontnst to methyl salicylate, I. Gia~ DI., Burroughs SH. Vatduo.•ib-induccd todc cpidennal
3aN.Ton;><>4oett
which undergoes constdcrablc absOtption and produces higll 2m1b~l~.~rtient allergic IO sutf1 dr\lgs. P/tor1"«01Mr'OfN C11H .03S 298.4.=
subcutaneous and dermal conoc:ntntions of salicvlic acid after CAS - 89~82-Ci0-8.
application 10 intact skin, conccnrations of salicylic acid after 2. Health Ca~il. Valdttcu:ib (Bel.ira:tl): severe cuc:.MOUS ruc- UNll - H8635NGJPY.
tions. OmAtlwruRt«tloew.2()1)1,; 14(1): 1-2. Also1v1ilablc
topical application of trolaminc sahcylatc were substantially 11: hnp:l"'~"w.hwe.ic.ca/dhp-mpshlt_fonn•ts'11pfl>.dgpsalpdf/
lower in tissue 1 and undetectable in serum. 2 medcfll'cam-tia:1_vt4nl-g.pdf(11CCC!$<d 29/08/08)
I. Cross S~ e1 ol. ls there tissue pcnctradon aftt:r application of 3. EMCA. EM~ public ttlllcmcnl on V>ldecoxib (B<xtra/Valdyn)
ropical salicyl.alt formulation~ Unc~t 1997; 350: 636. and parttox1b sodium {Dyna.s11t/R1ymn): card10\-asculir risks
2. Morra P. ~' "'· Scrum concentr11ions of ulicylic acid rono..ing in coronuy ortcry byp.,s gall (CABG) surgery and scrio"' ad·
ropically applied salitylatc dcrivanvu. Ann Pho,moco1h~r verse skin reactions (issued 15th December, 2004) Availab1t It:
1996; 30: 93s-40. hn p: f/w ww. em ta. euro pa. e u/pd f s/h um an / pr c:sslpu s/ OH
20480204cn.pdf (accessed 29/0Ml8)
Pre par at ions
Preparations
Proprietary Preparation• (dctoil.< arc given in Volume B)
Aurtrol.: Doncorub Pr.M\:s: Goanna ArtMlls Cro;im: MeUal AR Analee- Proprietary Preparations (details are given in Volume B)
sic: Conod..: Ai:t111e>c: Anllpl11ogirtitit R.b A-535 No Odovr. Aspet'Cf'eme: Broz.: Bextrat: Indio: 9'oval: Valdrl'f. Vald00<: V•ldone Valu~ Vor'\hf:
B<ngay l"Mclc Pa;n No Odoi: Creme ~e ~ Mex.: My- N orw-.: Bexlr.!t. Switz.: Bextraf: Thoi.: Be"1111t. Vonor.: Be><1111t. NOTE. n.. nrunes Borbit, Pclcton, Peon, Salafapinon, Soleng,
orlex: Sinfopo,.: Mc\sal AA AN.!&eMc: Spain: 8eMido-mil: USA: Analg~sia Soluirubin, and Zatfcron have been used ~s trade marks for zal-
Creme: Ana1gesic Creme: Aspercrtme: Coppenone Tan M>gn.1...-; Fl"'- Multi-ingredient lnclio; Valus lnstat Valls·XTt. Vectr,..P: VOnh lnstat:
Pow.:r f'trtorman:e Spoi·u: Mobisyt M)'illlc>; Sponxremc: Tropial B:end ""'1J>.XTt. toprofen.
Tan MagM'ier. Pharm acopoeias. Jn Jpn.
r.r,tit'.~~~;·z:~~'f.:' Duo Minoxit Conod.: M)<>flC?>< Extra Strenzth Profile
Vedaprofen (8AN. USAN. 11NN) Zalloprofen is an NSAID (p. I00) 1hat has been given in an oral
CERM-10202; PM-I SO. Vedaprofeenr. Vedaprof~ne: Vedapro- dose of80 mg three rimes daily for pain and mu.<euloskeletal and
feno; Vedaprofenum. (±)·4·Cyclohexyl-a-methyl: 1-naphlhatene· joinl disorders.
Valdecoxib (8AN. USAN. 11NN) acctic acid 0 References.
SC-65872; Valdt!cOXJ'b: Valdecoxitlum: Valdekoksib. p-(S·Methy~ ~npo<j>eH 1. lshiuki T, ti of. Phannacokinetic profile of a new nonstcroidal
3-phenyl-4-isoxazo'>'l)beroeMSUl~riamode. :inti-inflammatory agent~ CN-100, in huma.is. Drug lll\'est I 991;
6aN>ACKOKCH6
=
C,9H2202 282.4. 3: 1-7.
CAS - 71109-09-6. 2. Hatori M, Kokubun S. The long-term cflictcy and tolerability of
Cl6H,.N,o,s = 3 14.4. ATC Vet - Qlv101AE90. the new an1i-inflarnmalocy ag.e:nt zaJcoprofen in rheumatoid ar-
CAS - 181695- 72-7 UNll - OKXB8E0701. thritis. Curr M<d R.s Opin 1998; 14: 71)-87.
ATC - MOIAHOJ. 3. Hase K~ et al. The dfcct ofultoprofen on physM>thc:rapy for lim-
ited shoulder movement in breast cancer ~ients: a single-blind-
ATC Vet - QMOIAH03. ed bcfo-ftcr ll'i•I. Ar<h Ph.•~ M•tl Rehol.:12006; 87: 1618-22.
UNI/ - 2919179Q3W.
Preparations
- OHO\_ Proprietary Preparations (clc!•ils arc gh'CJJ in Volume D)

0-0--Co Mex.:Sc>lcton

N
-- 1f'
- . CH3

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

Ziconotide (llS.w 6'INJ
0· 1009: ,..C,onoto.... M VllA; SNX-111; Zicoootida; Ziconoti-
I S- NH2 Ph. Eur. 6.8 (Vedaprofen for Veterinary Use: Vcdaprokn dun. L·Cystenyl-t.·l)'S)o1glycy.-t-lysyil)d-Hlanyf·t ·lysyk-cyst0-
0 \\ 0)il-L-seryi-:.-arginyt·L·lcuC)i-L-methionyk-1)-rosyl-L·a·aspartyi-L-
0 BP(Vct) 2010). A white or almost white powder. Practically
insoluble in w:iter; soluble in methyl aloobol; freely soluble in cysteinyk-cysteinyk-ttreonyiglycyl-1.-seryk·cysteinyf·t:arginyt.1-
CH3 acetone; it dissoh·~ in dilute solutions of alkali hydroxides. serytglycyl-1.·lysy!-1.-cysteinamide cy-
clic( I-+ 16),(8-+20),( IS-+25}tris(di!Ul6de).
Profile
Profile \k!daprofen, a propionic acid derivative, is an NSAIO (p. 100) 3'.KOHOT"A
Valdecoxib is an NSAIO (p.100) reported to be a selective inl1ib- used in veterinary medicine for the trcauncnt of inflammation C,o1HmN 100nS 1 2639.1. =
itor of cyclo·oxygenasc-2 (COX-2). It was given orally in the and pain. CAS - 107452-89· I.
treatment of osteoarthritis and rheumatoid ar1hritis, and for the
pain of dys111cno11hoca. lne ri.:;k of serious skin reactions with ATC - N02BG08.
valdecoxib, in addition to its cardiovascular adverse effects ~<ec ATC Vet - QN02BG08.
below), prompted its general withdrawal worldwide in April UNll - 7164C51016.
Viminol Hydroxybenzoa te (rlNNM)
2005.
Oiviminol Hydrox)'benzoatc: Hidroxibenzooto de viminol: Vimi-
Effects on the cardiovaseular system. TI1e shor1-tcnn use nol. Hy&oxybenzoate de~ Vminoli Hydrox)'benzoas; Z-424 H-C~1y-Lys-G!y-Ala-Ly;:,.:r-se-r-~- Leu-Mel-Tyf­
of pruccoxib •nd valdccoxib afler coronary ar1e.ry bypass graft
surgery has been associated with•• increased risk of adverse ef- {viminol). I·[ 1-(2·Ch'orobenzyt)pyrro!·2·ylJ-2-(df-sec-butyf)ami· AJ.p-Cys-C,S-Thr-G:Y-Ser... Cys-Arg- Scr-Gty-Lys-Cy$-NH1
fects such as myocardial infarction, deep-vein thrombosis, pul· noethanol 4-hydro><ybenzoaie.
monary embolism, and stroke. 1 Wben compared with patients in 8 V.MMHOlla rio1APOKCM6eK30i1
the placebo group, the risk of such effects was almost 4 times C11H;1CINlO.C,H,03 =SOI.I. Zico notide Acetat e (tlNNM)
greater in those who had received intravenous parecoxib for 3 CAS - 21163-18·8 (viminol); 21466-60-~ (viminol hy-
days followed by oral valdecoxib lOr the next 7 days. Those pa· droxybenzoore); 23784-10-J (wminol hydro>ybenzoote). Ace'.ato de ziconotida: :Z.ConoL:&!, P.a!tate de: Ziconotidi Ar.e·
ticnts who received oral valdccoxib only for 7 days postopera- ATC - N02BG05.
las.
tively had a non-significant increase in risk for adverse catdio- )..KOHOTIWI AueHT
vascular efti:cts. ATC Vet - QN02BG05.
CmHmN 1,0nS1• C;H,0 2 = 2699.2.
The adverse cardiovascular etfecu associated with valdeeoxib ATC -
treatment '"""° one of 1he reaoons Uic drug was generally with-
N026G08.
ATC Vet - QN02BG08.
dnl'"" in April 2005. UNI/ - T21226K69M.
1. Nussmeicr NA, 11 nl Complica11ons or \he COX·l inhibiton
p>f«O\ib and valdcwxlb ancr c•d»e wrgcry. }I £nil J Mn/ Adverse Effects a nd P recautions
200S; JS2: IOSl-9t . The mOSI common advcise effects reported with zioonotide have
Efl'e<ts on the skin. Toxic cpitlcnnul nccrolysis dc,'CloPro in a included diuincss, nausea and vomiting, nyst3gmus, abnormal
paticnl who took valdcco~ib for 8 days, despite stopping!he drug gait, blurred vision, bc:>dac:hc, ele\'ated creatine kinase levels,
~t the first signs of a rash and statli11g treatment with oral prcd- and aslhenia. ~itiYC impairment, particularly confusion and
oisolone;1 the patient had• history of hypersensitivity to sulfon- unpo.ircd memory, is also very common, and typicolly develops
amides. Health Canada' n0ted in Janua.ry 2004 thal it had re- after several weeksofttealmenL SevezeC\!S symptoms such as
(vi'11inol) hallucinations, paranoid J'Cactions, speech disorders, aphasia,
ceived 5 reports of serious cucaneous adverse reactions
associated with valcle<ioxib over IC$S than I year from marketing and decreased alertness may occur but con·rulsions, stroke, delir-
oftbe drug in Dce<:mbcr 2002. HO\.'Cver, J'IOOC ofthe.«e were cry- Profile ium, encepb;ilopathy, and coma have been reported less com-
thema multifonnc, S!evcns-John.<on syndmme, or toxic epider- Viminol bydroxybenzoate has analgesic and untipyrctic proper· monly. Creatinc kinase may be elevated, ond monitoring of
mal nccrolysis although such reactions had been reported to Olh- ties. TI1e equivalent of 400 mg dllily of viminol bas been gi,-cn blood concentrations is recommended, but clinic<l.I myopelby or
cr regulatory uuthoritie.<. In December 2004, the EMEA3 slllted orally in divided doses. rhabdomyolysis is uncommon. Ziconotide may cause or exacer-
that it had received repons of ftll 3 r.:actions, as well as exfolia- bate depression. Patients with a histcxy of psychosis should not
Preparation_s be treoted with 1..iconotidc.
ti\'e dennatitis; most of rhcn' hMI 0«urred within the first 2
weeks of starting 1reatment and the incidence rate appeared Proprietary Preparations (dc11ils oro given in Volu1n<l B)
Braz.: DMdol: Ital.: OMdol.
0 References.
greater for valdccoxib than other selective cyclo-oxyge11ase-2 I. Penn RD. Paicc JA. Adverse effects associ31Cd wi1h the inlmlh-
(COX-2) inhibirnrs. The EMEA also noted 1hat use ofparccoxib cul administrc1ion oftico1\0l.ide. Pain 20CO; 85: 291~ .
All cross-re ferences refc1· to cntri~s in Volume A
 Valdecoxib/Ziconotide 139
Uses and Administtation permitted, O\'U a period of at lcaSI 3 "eds. up IO a muimmn i. Wall..IJIJ JA. ~.I
Ziconotidc: 1n •pdei.e and ~ic- C:rpert
Lconolidc is o syn1heuc: form ofa pqxidc dc:r1~d from '"" - daily dose of 19 2 mitr'Opf!IS. o,,•• p....,_..,,.,.,
200&; 9: tS7S-8.1. • •
om of\lle cone shell C"'7'JS mag11s (a sea snail). h 1i n:poncd IO Z-icalOlid< h~ b<cn tried in Olhcr cond1t1ons 5UCh as head trau- $ Vn•I• V "tll ln<nlhccal lh<npy with -id<· cl•ucol n·
ma. pencn« tM CCMUtdnauonJ ('lft ils UK /tllfJf"nO AM,IUfOI
be a neurone-specific calcium.channel blocker. l1cono1Jde is 2003; 7•: 717 .;3
i"""' as a continuous intrathc<:al inf11Ston m the marugcmcnt Of 0 Refcrcnces.
~:~":~n~r:'m~ ~~~ ~:C,~~~l!fnc~~%c~2~~:
9
sci ere dlronic pain in patients who art 1moleran1 ofor refractory I. Wcnneling D. ct nl. Phann1C:oL1Mtl(t and phamlacodynamics
296-303.
to more CM\'entionol treatmcnts (sec Choiot ofA11algcsic, p.2). ot anlnthccal zk:ono1idc in chronic: pun patlc'nts. J CJ;,, Plwr·
""1Col 2003; 43: 624-36. 10. Rauck R.L. t:t nl. Jnutthteal ~1cnnn1idc for ncurC"11>11h1c J\l•ri· a
Ziconotidc is gj~en intra1hec1lly as 1hc ace12te: doses rmy be ex- 2. St•~ts PS. a al. 1ntro1hect1tlconotid:1n lhc tttat.n~nt of rcfrac· rcvic-.. Pof,, r,.oct 2009: 9: 327-37.
lOf)' pain in pa.huts w1lh e1nccr or AIDS: 1 randomized control·
pressed in terms of the base or the acctnle. In 1hc EU. the initial led 1rial.J..IAIA 2004; 291: 63-70. 11. ~=~' ~'/,!~~~!~id:.1~~:~~~ ~t;a n1~:,:vhh ti~ 9 3
dose (expressed in tennsofthc base) is2.4 mieroat1m>da1ly ad-
~·~d~~rr.:'.~;~.::.'l"~~~d~fnb~~~~~ :"~e~:~
3 1 12. Schmi<tllto A." al Ziconolidc for ucat.mcm o( uvett' chronic
justed according to response, in increments of up to · poin U.-12010;375: IS69-77.
2.4 micr08l'lmS. to a maximum daily dole of21.6 microai-s.
s,...,.,_
Jllin.•I Pol• Utt•lfP 2000: 31: 393-406.
4. Lyn.:h SS. " of. ln1r1th:cal z1conoiidc for rcfroaory dlrooic: Preparations
Liccnled product information recommends thai the intorval bc- poin. Am• Phor-J,,., 2006; 40: 129)-1 )00
n."CCn dMe ina= is at ICHI 2 da)'S. In the USA. the initial }. L)'t<•t·W•lhamsna KA. hnyC. Z>conohdc CNSDntg.2006;
2CI: 331-8.
f"roprlatary ,.rtparations (c!Nils arc '"'ell
in ~ume B)
Aull/lo: f'nM: Ci: fl'al. 0......., - . Fo: Pr.z!:: w,,., ,,,.. c;,, ........
<kw (c.\prascd in terms of the ..:eta:e) lbould be no mote than 6. Wallace MS. <to/ Ziccftol• fl.OU Slody Croup. 11'11J111hccal lrl.: PnaA. hoL: ....... Heth.: PN1t. H_, Pr'*: Pon.: P1...t: 5j101n: fn.
2 4 micropams daily, adjldlcd occotdittg IO rapomc. Dose in- iicMol.idc far~vCT"Cdnoetept\ft u.fctybd 1o&uabiluyra.hs alt Switt.: PNlt. UK: ...... USA: ........
or., opcn-bbcl. lona·ccnn en.I ,..,..,, Anals 200&: 1K :
c r - of up 10 2 4 miaogr.ims 1wo or lhree times a week an: 62'-H.

l'hc symbol t dcno1es a prepar1tion no longer actil'cly marl<eled

Anthelmintics
Antytostorriasis, p. MO made at appropriate times, usually to coincide with the • cchinocoocosis
~sis.p.140
Asariasis. p.140 infective stage ofthe cycle, and for the choice ofappro- • hymenolcpiasis
up;ilariasis, p. I 1 I priate control measures. • taeniasis.
Oonorchiasis. p.111 The nematode infections can be divided into filarial in- Trematod e (or fluke) infecrioos are caused by parasit-
Cutaneous larva migr.ru. p. I4 I
Cy<!icerc<><is. p.111 fections, intestinal infections, and tissue infections. ic worms of the class Trematoda. There are 4 catego-
Diph~s. p.112 Filoriol nematodes are endemic in large areas of the ries of fluke which are pathogenic in man; the blood
D~p.112 flukes Schislosoma i;pp., the intestinal flukes Fasciol-
EdW>ococcosis. p.112
tropics and produce considerable morbidity. The adult
Enterobiasis. p. I~2 worms may live for several years, releasing large num- opsis, Helerophyes, Metagonimus, and Nonophyetus
Fo.ciobsis. p.142 bers ofmotile embryos known as microfilariae into the spp., the liver flukes Clonorchis, Fasciolo, ond
Fu:iolopsiasis. p.112 blood or skin, depending on the species. Transmission Opisthorchis spp., and the lung flukes Porogonimus
Gnathostomias;s, p.142
Heterophyiasis. p.142 is usually by biting·insects, which form the intermedi· spp. Symptoms are usually only seen in heavy infec-
H<>OloNorm iNeclians. p.142 ate host. In some endemic areas multiple infections tions and commonly include fever, pain, and eosi-
H)menolepiasls. p.14 3 with filarial nematodes are common. nophilia.
lntesti\al lloA<e infecbons. p.14 3
lNer ~ riections. p.143 Filarial nematode infections include: Trematode infections include:
Loiasis. p.113 • loiasis • intestinal fluke infections
L'"'6 lh..olce irlections. p.143
lymphatic filariasis. p.143 • lymphatic filariasis • liver Oukc infections
Mmsonella infection5, p.144 • m1111sonclla infections • lung fluke infections
Metagonimiasis. p.1 +4 • onchoccrciasis. • schiRosomiasis.
Nano~p. 144
Necatoriasis. p.111 Jntestinol nematode infections (roundworms) are very
O~p.M4 common especially in developing countries in the Ancylostomiasls
O~p. 114 tropics and subtropics. Children are particularly at risk
Paragorirnias4. p.144 See under Hookworm Infections, below. Larvae of Ancy-
Sctistosomia.sis. p.144 and these infections contribute to morbidity througll lostoma spp. are also a cause of cutaneous larva migrans
S~loidiasis. p.115 malnutrition, vitamin deficiencies, diarrhoea, anaemia, (sec below).
$',<lg;vnosis. p.145 and pneumonia. Poor sanitation and sewage disposal
iaeiiiasis.p. 145
Toxocariasis. p. I i5 perpetuate infections with soil-borne nematodes. Often Angiostrongyliasis
Trichinosis. p.115 several different worm infections are endemic in the Angiostrongyliasis is due to ac:cidenial infection with spe-
T~p.115 same region, resulting in mixed infections. When this cies of the animal nema!ode Angiostrongvlus.
Tricl-..riasis.p.116
occurs, broad-spectrum anthelmintics may be used to Infection wi1h the larvae of the rat lungworm A. cantonen·
reduce the overall infection burden in the population sis causes an eosinophilic meningoenccphalitis. Transmis-
This chapter describes the important hehninth or worm (see under Ascariasis, below). sion follows ingestion of raw or undercooked snails or
infections that occur in ma11 (sec Table I, p.141) and lnlestinal nematode infections include: crustaceans, or ofcontaminated vegetables. The disease is
the anthelmintics used to treat them. generally self-limiting but a minority of patients may de-
• angiostrongyliasis velop severe encephalitis, coma, and death.
• ascaria5is Intestinal infeclion with A. costoricensis can cause cosi-
Choice of Anthelmintic • capillariasis nophilic gastro-entcritis. It most commonly occurs in chil-
Helminth infections are among die most common in- • enterobiasis dren after ingestion of vegetables contaminated by infeel·
fections in man, affecting a large proportion of the • hookworm infections cd slugs. Surgical resection of the affcCled bov.'CI may be
world's population, mainly in tropical regions. In de- • strongyloidiasis necessary.
veloping countries they pose a large threat 10 public • trichostrongyliasis Mebendaiole and, panicularly, albendazole have been
health, and contribute lo the prevalence of malnutri- • trichuriasis. tried in the management of both these infections, alone or
tion, anaemia, eosinophilia, and pneumonia. Helminth The tissue nematodes represent a miscellaneous group with a corticosteroid, and may reduce the duration of head-
infec.tions causing severe morbidily include lymphatic causing a variety of pathological conditions in man. In ache in patients with meningitis. However, in A. ca11tone1>-
sis infection, severe host reaction to the dying larvae may
filariasis (a cause ofelephantiasis). onchocerciasis (riv- cutaneous larva migrans and toxocariasis, the nema- result Symplomatic treatment wilh analgesics, conicos-
er blindness), and schistosomiasis (bilhar7.iasis). These todes have a primary animal host and the human dis- teroids, and removal of CSF may relieve presswc in A.
infections can affect 1he majority ofpopula1ions in en- ease is caused by infection with infective larvae which can/onensis meningitis. 14
demic areas with major economic and social conse- do nol subsequenlly matl.lre in man. Trichinosis and ) . Abtamowicz M. ed. Drugs for pnro.,ilic l1t/«Jltm.1. 2nd ed. New
quences. WHO is making strenuous efforts to control a gnathostomiasis affect some carnivorous animals and Rochelle NY: The Medical Lener. 20t0.
2. Sawanya~isuth K. Sawanyawi.suth K. Treatment orangiostrong.-
number of these infections in endemic areas. Control man is an incidental host. Syngamosis is mainly an in- ytiuis. TrnnsRSoc Trop1'1'4Hn;'l00$; 102: 990-6.
of these infections in botl1 i11dividuals and populaiions fection ofdomeslic fowl and wild birds although infec- 3. Wang QP, tt ol. Homan ana1ostrongyliai;;l.1t. 1.anctt ll!fec'I Dis
2008; 8: 621- 30.
depends not only on the use of chemotherapeu1ic tion in man has been reported rarely. In dracunculiasis, 4. Ramirc:l.•Avila L.. ti of. .Eoiinophilit meningitis due to An1ios-
agents but also on preventing transmission by advice man is the primary (definitive) host. Althougll lhcse 1rong)'lus and Gnathostom:. species. Clin Jnf~et Dis 2009; J8:
on food preparation and hygiene, lhc provision of ade- diseases are not generally fatal they cause a considera- 322-7.
quate sanitation and sewage treatment (especially ble degree of morbidity and treatment is complicated
where sewage is used as fertiliser), the provision of by the lack of effective, non-toxic systemic an- Ascariasis
safe potable water supplies, and effective vector con- thelmintics. Ascariasis is an infeclion caused by Ascaris lumbricoidcs,
trol. Tissue nematode infections include: the common or giant roundwomt. 1lic term roundwonn is
also applied to nematodes in general. II is usually an infec-
• angiostron&yliasis tion of the small intestine but on r.ire occasions there may
'The worms that cause infection in man generally fall • cutaneous larva migrans
either into the phylum Nematoda, which includes the be severe ectopic infec1ions. It is commonly found in the
• Jtacunculiasis tropics and especially in rural areas. Eggs are excreted in
nematodes or roundworms, or into the phyltun Platy- • gna!hostomiasis the faeces and can remain viable in moist soil for sweral
helminthe.<>, which includes the ceslodes or tapcwonns • syna;imosis years. On mgestion of mature cw the larvae hatch and
and the trematodes or flukes. penetrate the intestinal wall. They migrate in the blood-
• ioxocariasis
• trichinosis. stream via the liver to the lungs where !hey cnler the alve-
The nematodes (or roundwom1s) are a large group of oli. The larvae then move up the bronchial tsce and are
wonns, some of which are capable of producing infec- The cestodcs (flatworms, segmented worms, or tape- swallowed. The malure adult develops in the intestines,
tions in man. In many cases man is the primary (defin- worms) cause infection in man in most pans of lhe o.nd it has been estimated that a gravid female is produced
itive) host but human infections caused by parasites for world. Man may be lhe primary host, harbouring the aboul 2 months after infection. The life span of the adull
which animals arc the primary hosts also occur. Nem- adult wom1 in the intestine, or an intermediate host car- worm is I to 2 years. Ascariasis may be asymptomatic.
atodes do not generally multiply in man; strongyloidia- rying the larval form. With the except.ion of Hyme- When symptoms of intes1inal infection do occur they in-
sis is an exception as re-in fection can OCCID' without en- nolepis 11ano the adult wom1s do not usually multiply clude anorexia, abdominal pain, and diarrhoea; nutritional
vironmental re-exposure. Nematode infections are within the same host. However, larval forms may be deficiency may result The puhnooory stage may c.:iuse
most common in warm, moist climates, but some spe- produced and, as with infection or ingestion of these pneumonitis and bronchospasm often accompanied by
forms, systemic infection may develop. cosinophilia. Heavy infections can cause intestinal or bil-
cies of nematode can tolerale cool or arid conditions iary obstruction. Migr.uion of the worm from the small in-
and infective fonns can persist in the environment for Ces1ode infections include: testine can produce ectopic infection of the genito-urinary
long periods. An understanding of the life cycle of the • cysticercosis tract, lwigs, liver, or heart. Such infections are rare bul se-
infective species is necessary for diagnostic tests to be • diphyllobothriasis rious.
All cross-references rercr to entries in Volume A 140
 Anthelmintics 141

Table 1. Helminths: classification and diseases. C utaneous larva m igi-ans

Cutaneous larva migraos (creeping eruption) occurs when
Group Helminth Cornn1on l\arnc Clinical infection man becomes infected with the larvae of animal llook-
wonns, usually AncylosJoma bl'(lzi/iense or A. co11i1111m,
hookwonns of cats and dogs. "Other hookwonns may also
Ncm1todcs Brugia molt~~,i lymphatic filanaslS (Malayan, bn1gian) be involved or may cause otbcrinfeciions (see Hookwonn
(filoriall Brugla tfmorl lymphatic filariasis (Timorian, brugian) Infections, below). The larvae penetrate the ski'n and lhcn
loo/1'1<1 eye-wonn loiasis migrate causing characteristic trails in the skin. TI1is mi-
Monso11ello spp. Mansonella infections gration can persist for several months and wrn be a source
Onchocerca volvztlus onchoccrciasis (river blindnoss) of intense pruritus. Occasionally larvae migrate to ihe
W11chen:rio boncrofti lymphatic filariasis (bancroftian) lungs causing cosinophilia and pulmonary symptoms. Al-
bendazole or ivermectin may be given orally and niay be
Ncmacodet Ancylosfomo duodenale Old World hookworm ancylostomiasis better tolcraled than oral tiabe11d37..0Je; albcodazole or tia-
(intestinal) A11gios1ro11gylus cos1orlcensis angiostrooayhasis bendazole can also be applied topically bul may be oflim-
A:rcari.f lumbncnidts• common round\1.orm, ascariasis
itcd value for multiple lesions.
@.)3nl roundworm Infection with G11othos11Jma spinigenim or Stro11gyloldes
stercorolis can also cause cutaneous Jarva migrans (see
Copillol'/O philippinensis capi llariasis
Gnathoslomiasis wid Strongyloidiasis, below). ~ular and
Elfteroblus ~1ermimlai'i.s* thrcadwonn, pinw<>nn cnterobiasis visceral larva migra11s are features of toxocariasis (see be-
Hecotor america1tus New World hookworm necatoriasis low).
Slrongyloides stercoralis sometimes called stroni:yloidiasis References.
threadworm in USA I. Caumcs E. Trc3tmenl of cutaneous lar,·a m1anns. Clln Infect Dis
Trichos1ro11w/11.J spp. triclloSlrongyliosis 2000; 30: 811-14.
Tl·ichud~ tricluura • wbipwonn trichuiiasis 2. Abr:unowicz M, ed. Drugs.for JXWOsilic i11/eclions. 2nd ed. New
R0<:hclle NY: The Medical L<11cr. 20 10.
3. Hochcd~z P. Caumes E. Hookworm-related cu1anCOU$ bJVa mt.
Ncm~todes Ancylostomo spp. dog/cat hookworm cut3neous larva migrans (creeping eruption) !flM.J Trav<I M<d2001; 14: 321)-33.
(tissue) Anglostrongy/111 camonensis angiostrongyliasis 4. 8owm3n OD, er ol. Hookwonns or dog.s and cau u ucnts of
c:ut:rncou.~ larva migran.s. Tl-ends Porosilo/20 10; 26: 161-7.
D1·oetmci1/us medinansis guinea-worm dracunculiasis (dracontiasis)
Gnotl1'Jstoma spinigerum &Jl&lhostoiniasis
Syngomus spp. gapewonn syng;imosis Cysticercosls
Infection wilh the pork lapewonu, Toenlo solium may re-
To>.ocara spp. • toxocariasis (visceral larva migrans, ocular sult in t11eniasis (intest inal infection wilh adult 1apc-
larva 1nig.rans) wom1s--soe below) or cyslicercosis (lissue infection wilh
TrichiM/lo spirofis• trichinosis (lrichinellosis) larval forms). Cysticcrcosis may develop after ingestion of
T. solium eggs in food or wfttcr contaminated with infected
Cestodes Diph)'llobothrillm /arum broad fish tapewonn diphyllobothriasis human faecal malerial, or as a result of auto-infection in
(tapeworms) Echinococcus spp. echinococcosis (hydatid disease) inteslinal carriers of adult tapewonns. Jnges1ed cw re-
Hymtmolcpis 110110 dwarf lapcwonn hymcnolcpiasis lease larvae that may penetrate lhe intestinal wall to be car-
Tnem·a suginata• beef tapeworm tacniasis ried via the bloodstream to skeletal muscles, heart, eyes,
Taenia solium* pork tapeworm cysticercosis (larval form). 12oniasis (adul t brain, and spinal cord where they fonn encapsulated cyst~
worm) (cysticerci). Hwnan cysticercosis is associated with pover-
ty and endemic in areas whel'e hygiene is poor and sanita-
1hmotodes C/0110rrhis sinensis Chinese liver fluke clonorchiasis tion inadequate.
cnukcs) Ft»ciolo hq>atica liver nuke fasciohasis Infection is typically subclinical, but symptoms may de-
velop when the encysted larvae die and elicit an inflamma-
Fasciolopsis bwki in1es1in•I nuke fasciolopsiasis
tory reaction. Clinical fealUres depend on the number, size,
H•terophyes he1erophyt1s intestinal nuke hcteropbyiasis location, and ~tage of developmenl of the cysticerci, as
Afc1agonimus yokogowi intcslinaJ fluke mctagonimizsis weU as on 1he host's immune response. CystS in the CN_S
Nanophyefus salminC'Ola intestinal nuke Mnophyctiasis (neurocysticercosis) may result in seizures and head-
Opi11harchis spp. liver nuke opisthorchiasis aches, and are a com mon cause of epilepsy in endemic at-
Paragonlmus spp. oriental lung fiuk• paragonimiasis <:as. Oth.:r symptoms include confusion, attention deficit,
Schmosomo spp. blood nuke scbistoso1niasis (bilharziasis) and ala.~ia. Hydrocephalus and intracranial hypertension
may result from obstruction of CSF Clow. Cysts in ihe spi-
NOTE: Infeetions due to worms morked with an asterisk may occur in tempeute climates. Infections due to other worms ore nal cord, eyes, or heart may also cause serious morbidity.
generally limited 10 tropical or locali«d areas. but may occur in traveller.; who ha•e visircd those areas. Treatmen t of neurocysticercosis consists of managing
seizures with antiepileptics. Antiepileptics can usually be
stopped if patient$ have been seizure-fr~-c for more lhan 2
Treatmenl is with a benzimidazole carlxlmate derivative 3. Keiser J. Ul"Zingcr J. Efficacy or CVm:tlt drugs 1g2inst soil-tra.l\S- years.I
such as oltitndazole or mebendazole1" with both drugs be- mincd he:lminth inrcc1ions: syStcmauc rc\l'icw and 1ne1a-analysis.
JAAIA 2008; 299: 1937-48.
The use of anlhelmintics in the treatmenl of neurocysticer-
ing equally highly effective. Pyrantel embonate3 and le- cosis remains controversial.1"; Live cysticerci usually do
4. WHO. Prrrrnril-'C cht.m1>1f1erapy lu h'mttm bdminthi4lis: coordi..
vamisole arc allernatives, while lhe po1ential of nitazoxa- 1wtttlu1c ofOR1iM.lmin1hic drt1gs (11 <'t>lllloli,,Un?ntions: o mamlCll not provoke seizures whereas dead or dying parasites can
nide for the treatment of ascariasis is being investigaled. 1 /01· healthpro',asi<Nds "'"'programme IPtmiogns. Gnicva: WHO. elicit an inflamma1ory response, seizur-...s, and transient
lvenncclin has also been used. 2 Such brood-spednlm ther- 2006. Also :ivail~i~ ac: hu~//whqlitxSoc.who.inlfpublica1i<1n51 neurological effects, hence lrealmenl does not necessarily
2006/92A1541103_cnc.pcJr(oc«.sed l7/08109)
apy can be useful if the patienl is suffering from a mixed reduce seizure frequency. Patients with viable or degener-
intestinal nematode infection. Drugs such as liabendazole ating parenchymal cysL~ and those wilh ex~parenchymal
with little or no oclivity against Asc:oris should be avoided C apillariasis cysts (such as subaracbnoid cysts, including giant cysts
for the initial treatmen I ofmixed infections since they m3y Capillariasis is caused by infection will1 Copi/lario philip- and racemose forms) may benefit from an~ielmintics. 1 J.•
stimulate lhe wonn to migrate to a different body site. pinen$iS. a nematode endemic in the Phil ippines and Anlhchnintics are ofliale or no benefit in patients with in-
southc:m Thailand. Infection in man is through eating raw uc1ivc. culcified lesions, and are contra-indicated in pa-
Moss treaunenl programmes may be necessary in endemic tients wi1h cysticercolic enccphali1is as ll1ey may c.~acer­
areas 10 reduce the overall burden of disease. 1 WHO or undercooked lieshwater fish containing infective lar-
vae. The l11rvae mature in the intestines and the aduhs pl'O- bate intracrauial hypertension. 1•1 A double-blind, pl~ccbo­
recommends' the use of albcndaz.olc or mebendazole or conlrolled study in poticnts with seizures due to viable pa-
duce both eggs and infective larvae so that auto-infection
altema1ively levamisole or pyrantel 1arge1ed at preschool rcnchymal cysts confirmed lhal albc:ndazolc therapy (with
occurs and heavy infections can result Symptoms are
and school-age children, women of child-bearing age (in- de:xamethasonc)was safe and decreased the burden ofpar-
mostly gastrointestinal, with abdominal pain, vomiting,
cluding pregnant women in !he second and third trimesters asites and the number of generalised seizures.' Albenda-
and severe prolonged diarrhoea leading to cachCl<ia and
and lactating women). and adults engaged in high-risk oc- zole is now considered lo be the drug of choice,~.7 bul
muscle wasting. Tiie infection has a mortaliry rate of be-
cupationi'for soil-transmitted helminthiasis, such as tea- praziquantcl may also be used.1.4 •7
tween 20 and 30% if untreated. Prolonged treatmenl with
pickers and miners. Children less than I year of age and
mebendazole for 20 days1 for new cases and 30 days for Adjunctive corticosteroids are recommended for paten-
women in 1he first trimester of pregnancy are excluded
relapsed cases or, altemalively, albendazole for I 0 days,1 chymal infections if !here ar.: many cysls, or if neurologi-
from such mass treatment programmes. The frequency of cal symploms or intracranial hypertension dc:velop after
is necessary.
intervention should be detennined by the prevalence and starting treaunenl. Patients wilh subaracbnoid cy~1iccrco­
intensiry of infection among school-age children. I. Abnmowic:z M, ed. DrirgJ for po101Hk i11fectitJr..s. 2nd ~d . New
Rochelle NY: The Medico I L<Ucr. 2010. sis should also be given adjunctive corticosteroids. How-
I. Bethony J. et al. So.Ht1t1s1niued hefminth infttlions; ~riuis., ever, use ofcorticosteroids with praziquantcl may be com-
irichuriasis, 11ld hool<-m. Lance/ 2006; 367: l~l-32 plicated by a pharmacokinetic inleraction- see
2. Abramowicz M. td. °"!:'for pomsitk il~(tclicms. 2nd ed. t\ew
Clonorchiasis Corticosteroids, under Interactions of Praziquantel p.162
Rochelle NY: The Me~heal l~ttcr, 2010. Sec under Liver Fluke Infections, below. for further details. If hydrocephalus is present, surgical re-
 142 Anthelm1nt1cs
moval of cysts or vcn1ncular shunting may be indicated.'
Detailed consensus gu1dehncs for the lreatmcnt of ncuro-
2. ¥~~~';';~ .~;-~"°'""'" <••'•'" Womt dn..-) CIM.f appendicitis or salpinauis may occur. Tiic adult wonn has
) , WHO. Dracu:ncul1asit er11dicaticm-;Jobal surveillance summ1. a life span of about 6 weeks and, ifre-infec1ion cam be pre-
cysticercosis have be.en dcvcloped.2 1y, 2009. WAI)• Epldrm /111< 2010; 85: 166-i6. ~tcd, the infection is self-hmiting. While addirional hy-
Prevention of infection with T. solium is possible by giene measures can prevent ro-infection, treatment of the
avoiding ingestion of uoderoookcd pork and food nnd wa- whole family with an anthelminticshould remain the main
ler contllllinated with human l9cccs. Ideally, prevention
Echinococcosis
&:hinococcosis, or h)dat1d disease, in man is infccoon therapeutic response; more than one course may be re-
measures should include adequate sanitation, sewa&e quired.
trcatment, and abeaoir inspection. Those already inf«1cd with the larval stage of the a:stodc Echinococcus ironulo-
sus or E. mulriloc11fans. These two species cause distinct Treatment is with a benzimidazole caibunate dcnvahve,
with T..solium and their close contacts should be !Teated such 1s albendazole or mebcnda2Dle, or v.ith pyrantel em-
with anthelmintic$ in order to interrupt or reduce the cycle fonns of Che disease known IS cystic echinococcosis and
alveolar echinococcosis rcspectJVely. Various animals are bonate.1 Such broad-speclNm therapy can be useful if the
of direct person-to-person llansmission. Universal or se- patient is suffering from a mixed intestinal nematode in-
lected treatment of human taenL3sis with pmziqunntel has !nvolved in the tra~smiss!oo ofthe disease, man becoming
infected through mgC$tton of CJ!iS from contaminaicd fection. Other anthelmint1cs used in entcrob1asis include
significantly reduced the prevalence in areas where T. so- pipcrazine or pyrvinium cmbonale.
faeces. The eggs hatch in the intestine and the embryos

=
li11m infection is endemic.''
I. Takay1nagui OM Thaapy for neurocystica-cosis. &pn, ~~v pene~te the intestinal wall and invade body organs, usual- 1. Abr.i.mowic:l M, ed. Dn1gs/w· purositK' infectiolf.I. 2nd ed. New
Rod>ell< NY: The Mcdicol i..aer. 20 IO.
Ncv"1iher 2004; •: 129-39. ly the h~ ~e embryo dcvcl~ into a cyst which slowly
2 Gattlo HH. d "' Clin<n1 consa""" p11cltl0..S for 1re>1m<n1 of macases m size and may remain iniact for many years.
llC'WOC)"Sticer<osJS Clm Mkrol>iol JI.. 2002; IS: 747-56. Al>O Symptomatic infection usuaUy only occurs when the cyst Fascioliasis
ot: hllp:Hc!"r _...,...'rqriolll S1417•7.pd( c....- is large enough to CIU5C obslruct100 or to oomprns ad.J&- Sec under Liver Fluke Infections, below.
3. ~~ Hl1,e1o/. Taou•IOl-<ystt«r<..t$. '-«2003;3'1: cent struetun:s. or if rupt:ulCOCQll'S. Where JlOSSlble. surgi-
6 cal removal of the intact cyst is the first line oftn:atment.
• . O<I Bnmo OH. n ol Mcu-a11alyt••· cy>1icidal dnip for ......,. Fasdolopsiasis
cysticercos..- 1fbenda20lc and prtt.iquamC'L Am• J,.,o,. Mtd In cysf!c echinococcosis, drugs may be given locally or Sec under Intestinal Fluke Infections, below.
2006; 145: •J-51. sysicmically before surgery to kill infccrivc larvae within
S. Garcia HH. f1 al. A 1riil of 1ntip.ru11ic trea1men1 ro ttduc:c the the cyst and reduce the risk of funher infection. TI1cy arc
~;;,of.:;~z;r•due locercbnl cysilcm:o1tJ. N Eng/J Mtd2004; also given postoperatively if a cyst ruptures duri ng sur- Gnathostom lasis
6 Abba X. et ol. An1hctmintics forpeoplt with nc.uro cysli«ttOSd. gery. Local injection of a laivicidal agent such as alcohol Gnathostomiasis is an infection with, in most cases, rhe
Ava1t1ble in The Codwartc O.tabue ofSy&1cmaric Reviews: ls. cctrimidc, ot bypcrtonic saline has been used. Chemother~ larval fom1 of!he nematode Gnathostoma spiniget-um, ul-
'"" J. Chichester. John W~<y. 2010 (accused 22/0mo~
7 Ab<1n>0"><ZM.«LL>nrs1forpwtnukmf<e1-. 211dcd. ~
apy is also used as an adjunct or when surgery is no1 pos- though other Gnotlwsroma spp. ha\e been iden1ificd. a
Ro<l..llc NY: The Mcdt<al 1Al1tt, 2010 Stble. The prefemd drug for associated systemic treatment .sp<mgennn inhabits the stomach of caIS and dogs. Eus
&. WHO. c.,,,,.,,i qfarwoeysr~.,., Ca><>oo WllO, 200J Also is albendarole. Mebenclazole may be used, although some shed m their faeces are 1ni¢St.ed by freshwater crustaceans
available at. lll1p://1pps who tw,bl>rduwlpdr filnlWHAW hove suggested it is not IS elfecth-e as albendazole. f'r121- and hatch into larvae which arc ingested by fish or other
caS610pd((oc:cess<d 29.07110) -
quant~I has ~so been reported to be effective, and may be animals; man acquires the infection by consu1npbon of the
combmed with albendazole. Albendawle may be a suita- '.8w or undercooked flesh of these secondary hosu Once
Dlphyllobothriasis ble alternative to surgery as initial treatment in uncompu- mgested the larva penetrates the ~ut wall and migrates via
Oiphyllobothriasis is an intestinal infection with the fish cated cases; use "ilb cimctidine (to inhibit irs metabolism) the liver to other tissues including skin, eyes, and CNS.
tapewonn Diphyllobo1'1ri11m /arum and other Dipltyllo- may increase its efficacy. Rarely, dermal infil Jration may result in cutaneous larva
bo1llrlum spp. and is acquired in man through ingestion of A further option when surgery is not possible is the PAI R migrans (above).
raw, infected, freshwater ftSh. The infection is rarely (puncturelaspirationlinject1on/re-nspiration) procedure The preferred treatment of gnathostomiasis is surgical re-
symptomatic. HOWC\'CT, beause the adull wonn oompc:leS which consists of ultrasound-guided cyst puncture fol- moval of the goathosto1nc but this is 11Tely possible. Al-
for viWT!in B 1l> so111e pahenlS may develop megaioblastic lowed by aspiration of the cyst lluid, local injection of al- bend_azole ot, 1ltemathcly, ivcnneain, may be used; 1.1
anaemia with its associated neurological sympcoms. Con- cohol or bypc:nonic saline into the cyst, and re-aspiration multiple eoorses may be needed for some pa1ients.'
ocntratioos of oilier vitamins may 1lso be reduced. Treat· of the cyst contents. Concomi ta!ll chemotherapy is recom- I A~ic:M.cd.D<t~p-l/k,,Ytt1io•1. 2ndcd N..,
ment is with a single dose of praziquan1el; niclosamkle is mended. Rodlell< NY: The Mcd1cal l.<lo<r. 2010.
an allemative. 1 Vitamin supplements should also be given 2. Ramin z·Avila L. ti M EM.inoph1hc mtning1t1s due ao AllC~
E. multilocularis infection (•h•eolar echlnococcosis) i.s ~;~r.us and GnaihGOloma >p<cics. C//n /nfttr Dis loot. 41:
to COITCCI any deficiencies. more invasive and is chanictcrised by a tumour-like infi l-
I. Abnmowicz M. ed. Drt'f'far porOl//IC /nfecllont. 2nd ed. he" trative growth; it usually requires both surgery and long-
Ro.hello NY: The Med1<1I Lcucr, 2010.
1e1m treatment with a bcnzimidazole, such as albenda.iole, H eterophyiasls
althougll some lesions arc inoperable when dia~ed and Sec under Intestinal Fluke Infections, below.
Dracunculiasis patients have improved on albcndazole alone. Prolo~ged
Drac:uncuhasis (dracontiasis, gu1nea-wonn infection)1·1 is treatment has proved larvicldal in some patients.
caused bY infection with the nematode Dracunculus ~ References. Hookworm infections
mmsis. It has been endemic m pans of Aliica and Asia, I. Komar A. Qmopo6ya7 TK MaNgcmcnl or •)dolitl diJHM Infections with the hoolcwonns Ancylostoma dwxk11ale
but attempts are being made to mdica1e it and in 2009 or1hc h'<f'r. l'onvodM#d./ 1992, 61: 15~ (ancylostomias1s) and Nccator amuioanus (necatoriasis)
· Jc7i~~r:;J;,•;t, 1;~o';~"'or...._hyd••tdo•il a,
on ly 3190 cases were reported, tlie majoriry from the Su- 2 are a major cause of iron-deficiency anaemia in large areas
dan and the remainder from Ethiopia, Ghana, Mali, and 3. WHO Jnrormal Working Graup on Ed>U>O<OC<osis. Ouldellnu of the tropics and sub-11op1cs, especially in rural corrunu-
Niger: "!11e disease is tronsmitted through drinking water ::,;r;;]ic,e~~8~;'/:ii~3•1~2h'.ri!',~~l~bico:~osis in humans. nities. Eggs deposi1ed in wann moist soil hatch into larv~e
conuumng water fleas (Cyclops ~cies) that have ingested which develop further inro lhc infective form. Infection is
h11r:l/whqlibdoc v.ho int/bullc1in/1996/Vo174-No3/bullc11n
Drocunculus larvae. 11lc larvae penetrate the intestinal 1996_74(3)_231·20.pdf(ac<CJS<d 27/08/09) normally by penetration through the skin although it may
mucosa and develop into adult worms in connec1ivetissue. 4, Reutc.r S, n al. Btn11"'ida20Jcs in 1tx treatmc:nt or ah·colat be by ingestion. The larvae migrate to the lungs and arc
«.h1.nococcosH:· I COfftpi,..llVf Sh~dy and l"t\-'iew or the hlt:rl• subsequently swallowed and mature to the adult form in
The adult female slowly migrates to the subcutaneous tis- tin ../ Ami•i<rf>I> (M,.orhe• 2000; 46: 4S 1-6
SUC$ causing intense pain, sometimes with nonspecific 5 ~~DP. <t al l:eh•OO<O«Gsis. L1mttt 200}; 362: the smaU intestine. Eggs appear in the faeces about 6 to 8
sympcoms such as fever and rd!, and about 10 to 14 wedt.s after infection and the adult \YOrm may li\'c for sev-
months later emerges through the sltin, usually at the feet, 6. ~RA.~tal Pe~11tpntioo-injcc:1ion.tta.1r;suQhOD eral years. A. du«knale l11tVae are capable of remainina
tln=g< plus •1-.0lc .. -ndatolc r.,. hcpott< <)'SlJC
producing oedema. a blist.cr and eventually an ulcer, sec- ~~l~cos111: • -ta""tO&IJStt C//n /nfu1 Di1 2003. J7:
dormant in the tissues, only maturing to the adult -.·hen cli-
ondary infection is a common complication. Pain and matic conditions are favourable. Symptoms COITCSJIOnd to
symptoms decrease once the blister has ruptured. When 7. Smego RA~ Seblnqo P. Tre:11ment opoons for hcpatte cystic 1hc stage of infection. Visitors to endtmic areas may devel-
echinococcon1. /n1 J l•f«I l)i1 2005; t: 69-76.
the affected body part comes into contact with water the 8. Abr1mowitt M, ed. Drugi/or parasIlk lnftt1/011s. 2nd <d. Nuw op intense pruritus, erythcma, nnd papu lovesicular erup-
female worms release their larvae and set in motion a new Rochelle NY: The Medinf Lener. 20t0. tion at the site of infection, known as ground itch. Migra-
life cycle. 9. Jutt&}lanu T. ~' aJ. Clinic11 m.anaacmem or c-ysaic echinooocco- tion through the lungs during the first infection may cause
The most effective method ofcontrolling clracunculiasis is ~;~•1:::r7~ :o"i~len11. ancJ J><r>P<<•i•u. AmJ TNPMtJ pneumonitis and bronchospasm with accompanying eosi·
by provision of safe dnnlons water. The WHO eradicatJOn I0. Moro P, Schantz P\4. Eeh11'10C'Otter1i1: a revttw. /n1 J /ilf«I Du
2009, 13: 12.S-H.
nophilia. The main symptoms of intestinal infectJOn arc
campaign is based on health education, and the provision iron-deficiency anaemia and severe hypoalbuminaemia.
of safe water by Pleasures including water treatment with In addition, abdominal pi1in, dianhoea, aod "eight lcxs
pesticides such as tcmefos and encouraging the use of do- Enterobiasis Dl')'OCCUt.
mestic filcen. Enterobiasis is an infection with Ente1-obius venmculoris Tiuunent is usually with a beni.imidazole carbamale de-
There is no effective dirCCl dnJa therapy against any stage (pinworm, thrcadworm). It is one of the few intestirnil rivat.ive such as mcbcnclaz(llc or albendazolc,.., and such
in man. The tradilional trcaunent is removal of the adult nematodes which is common in temperate climates and is broad-spec1rum therapy can also be useful if tile patient
wonn by gentle traelion sometimes over several weeks. panlcularly common in young children. Like triclnniasis it has a mixed intestinal nematode infection. Albenda.7.olc
Mctronidazole or tiabendazolc may provide sympJOmatic is an infection of the Jarioc intestine and tnnsmission fol- may be more effective than mcbendazole.• Other an-
benefit in the management ofdracunculiasis although they lows iligcstion or inhalation of mature eggs. TI1e larvae thelmintics used in hookwcrm infections include levami·
have no direct anthelmintic effect. 11\ey are thought to 1c1 mallR. in the gut in about 2 months. TIIC eggs are not re- sole or pyrantcl embona1e,l-4 but these may be less etrec.
b)•wukcoing the anchorage of the worms within the sub- leased mto the gut contcmS but !he mature female migraJes tivc 1gainst N. americonus than agaiost A. duodenale.
cuwicous tissues, thus allowing !hem to be remo'ul more to the anus at night and lays irs eggs on the pcrianaJ and lmn-dcficiency anaemia caused bY hookwonn infections
quickly. penncal skin. The eggs become infective within 6 bow'$. responds rapidly to oral iron therapy; folic acid supple-
I WHO. Eradicaw>g p jnea·-.n d11tuc. A.....ilabl< a1 l!ltp:// Diaanosis is based on detecting eggs around the anus. The ments may be necessary in some patienis.
whqlibdoc.who.101111"'200&/WllO llTM NTD PCT ?008 I m~ common symp10m is perianal itching but many i11- Mass trea1ment programmes may 6c necessary in endemic
ens pd((act<IMd 16/07/09) - - - · - fCCl10ns arc asymptomatic. Rarely ectopic disease such as areas lo reduce the overall burden of infeclion.2J WHO
AII cross-references refer 10 emnes in Volume A
 Anthelmintics 143
recommends6 the use of albctidazolc or mebcndazole or Fascioliasis in the acute phase is usually charae1erised by 1
Treatment is with praziquantel or bithionol. Triclabcnda-
altemativcly lcvamisole or pyrantel targeted at preschool fever. gastrointestinal symptoms, pain due to liver enlarge- zole is considered elfective and wcll iolerated. 1 ·~
and school-age children. women of child-bearing age (in- ment, and m2Iked eosinophilia, but these symptoms de- I. Ab"mowicz. M. ed. Dnrssfor parosili(" infttli('n$. 2nd ('(t. New
cluding pregnant women in the second and third trimesters cline as the worms enter their final habitat in the bile ducts. Rochellt NY: The Medical Lener. :?.010.
and lactating women), and adults engaged in high-risk oc- Acute symptoms occur rarely with clonorchiasis and 2. WHO. WHO utxkl fammlary. °''"'"" WHO, 2008. Also
~v1ilablc at: h11p://\\.'Ww."·ho.int/sclcction_mcdicinr-sllis\/
cupation; for soil-transmitted helminthiasis, such as tea- opisthoo:hiasis and infections tend to be asymptomatic for WMl"..oo& pdr(•CUSS<d 21Al&/09)
pickers uid miners. Childn:n less than I year of age and many years. AdQll flukes live in !he bile duclS and symp-
women m the first trimester of pregnancy are excluded toms of biliary-tract obsauction appear afieT repeated or
from such mass treatment programmes. The frequency of heavy infections with liver flukes. Cholangjocarcinoma lymphatic filariasis
intervention should be dctennined by the prevalence and (bile-duet cancer) is now generally accepted to be associ- Lymphatic filariasis is a parasitic disease caused by filarial
intensity of infection among school-age children. ated with liver nuke infection although its exact pathogen- nematodes. The three species of filariae th.at cause lym-
I. Hocez FJ. tt ol Hool:worm infcetion. N En:IJ Med 2004: 351: esis is unclear. phatic filariasis are Wuchereria bancrofti (bancroftian
7W.-807. • Praziquantel is used for the treatment of most liver fluke filariasis), /Jrugia 1110/ayi, and B. rimori (brugian filariasis.
2. Bcthony J. ~' ol. So11·ttansmittcd hcJmuMh infttciont: 1sc1ri3Sis,
infections,1.l but rriclabendazole is considered the treat- also known as Malayan and Tunoriao filariasis respective-
crichurfasis. and hookworm. IA-I 2006. 367: I$21-32. ly). Adult worms produce larvae (microfilariae) which en-
3. Abramowicz M, ed. DNlfsfor porosll1e hl/tttlo1u. 2nd ed.., New ment of choice for liver fluke infections caused by Fosci-
Rochell< NV: The Medical ~cncr. 2010. · olo. Bithionol is more effective than praziquantcl in fasci- ter the peripheral bloodstream and through mosquito vec.
4. Keiser J. Utzinger J. Efficacy o( cumnt dtup against soil·ttan5- ol iasis and is an alternative to triclabcndazole· tors infective lzrvae may be transmitted from person 10
mincd helminth in(tclions: systematic rtvicw and mc,a..analy-
sis. JAMA 2008; l??: 1937_.&. dehydrocmetine has also been used, and nitazoxanide~ person. 1l1c larvae l)ligrate from the skin to the lymphatic
may be effective. system where they marure intO adult worms that may Jive
S. Idris MA. tf al. EITcc:tivc. control of hookworm infection in for several years. Development of lymphatic filariasis re-
school children from Oho far. Suhinate of Omen: a four-year cx- Praziquantel remains the treatment of choice for clonorch-
pcricnc~ wich a1bencbiole mus chemotherapy. Acta Trop 2001: quires multiple bites from infected mosquitoes over a pro-
80: 1311-43. iasis and opisthorchiasis.1.l Albcndazole is a suggested al- longed period of time (months to years); consequently,
6. WH·O. P°rf1'C'JJ1i1'C chemo1lternpy In 11111,,1111 ht:lmi111Mo1l.r: roordi- ternative for clonorchiasis.l ·
people living in endemic areas are at greatest risk of devel-
norttd "''' qfomll1tlmin1hlc drugs In t'on1rol lmcr"'1.n1/ons: a man11- I. WHO. Control or foodbomc 1remotode inrcctions. HIHO n-ch
ol for liealth pr'O/culo1tnls 011d pro1,tamme manQRus. Geneva: Rep Ser 849 1995 . Available :n: http:/mbdoc.who.intltn/ oping the diswe.
WHO, 2006. Also avoiloble •I: hllp:l/whqlibdoc.who.inlf WH0_ TRS_849_Cparl I ).pdf and hllp:lllibdoc.who.ln1/1r$/ Filarial infection is usually contracted in childhood and
publicacionsf.!00619241~47 1 Ol_•na.pdf (a«essed 27/08/09) Wli0_ TRS_849_(pon2).pdf (oCCt$>Cd 16107/06) most infections are initially asymptomatic, although near-
2. Abramowitz M, ed. Drtr,'!,J fol' pora!.ili<: 111/ection.f, 2nd ed. New
Rochelle NY: Th~ Medical L.cucr, 2010. ly all those infected will have some degree of subclinical
Hymenolepiasis lymphatic and kidney damage. Iilfeetion may remain oc-
Hymcnolcpiasis is an infection of!l1e intestine withliyme- cult or species- and body-site--Oependeot symptoms may
Loiasis follow.
110/epls nano, or dwarf tapcwomi. Infection is acquired
Loiasis is an infection with the filarial nematode loo loo
through ingestion ofeggs in contaminated food or water or • Acute inflammatory reactions to immature and dead or
which occurs in areas of Central and West Africa. U is
on hands and can be passed directly from person to person. dying adult wonns in the lymphatic system arc referred
transmitted by tbc biting tabanid fly Ch1ysops. The infec-
It is more common in children. Clinical symptoms occur to as ade110~1mpha11gi1is, and are characterised by epi-
tive larvae marurc to adult wonns which migrate through
in heavy infections and include diarrhoea and abdominal sodic attacks of fever, malaise, and inflammation of the
subcutaneous tissues and occasionally the subconjunctiva.
pain. Treatment is with a single dose of praziquantcl. •.l inguinal lymph nodes, testis, and spennatic oord, and fo-
Symptoms include prurirus, swelling, and pain, with occa-
Nitazox<nidc1 and niclosamide1.l may be used as alterna- cal lymphocdema. These acute episodes usually resolve
sional subcutaneous swellings. often on the arms or legs.
tives. spontaneously after about a week. but can recur several
that arc characteristic of the disease. Passage of a wom1
1. Al>nmev.bM, td. Drt¢1forportn11lclt(tt.lio111. 2nd ed. Nrw times a year.
Rochelle NV: The M«fteal L<n<r. 2010. throu~ the subconjunctiva produces intense corliwictivi-
tis. Eosinophilia may be se"crc, especially in visitors from • Chronlcfilm1asis may develop JO to 15 years after ini-
2. WHO. W/10 ••~ fommlor.. Ccncva; WHO. 2008. Also
aullatlc at: http:Jtw,..."'.who.iHt/sctc:c1ion medicines/list/ non-endemic areas. Other complications include renal dis- tial symptotns and results from recunent inflammation
WMF1C08.pdf(--.l l1/0SI09) - ease, endomyocardial fibrosis, encephalopathy, and pe- with subsequent damage to the lymphatic system, lead-
ripheral neuropad1y. ing to impaired lymph drainage and lymphoedema.
Manifestations include mild lo massive enlaigcmcnt of
Intestinal fluke infections Dielhylcarbamazinc is used for treabncnt; 1.l it is effective
the legs, arms, breasts, or genitals (testicular hydroccle
The intestinal nuke infections fasciolopsiasis, betero- against the microfilariae, latVal forms, and a proportion of
or swelling of the vulva), chyluria, and elephantiasis
phyiasb, metagonimiasis, and nanophyetiasis arc adult worms. In some cases, treatment has been associated
(grossly swollen limbs with thickened, hard, rough, and
caused by Fasciolopsis buski, He1erophyes heteropl\ve.s with acute encephalitis, particularly in patients with heavy
fissured skin). Lymphangitis may result from secondary
and some other Helcropliyes spp., Metagonimus yokoga- microfilaraemia. It has been assumed that this is related to
blockage of capillaries in the brain and meninges and for bacterial infections.
wai, andNanoph;ietus .rolmincola respectively. Fasciolop-
siasis, hctcrophyiasis, and mctagonimiasis arc endemic in this reason small doses of dielbylcarbamazine aie given in- • Occult filariosis refers to filarial infection in which mi-
the Far East and Southeast Asia, and hetcrophyiasis is also itially, with a corticnsteroid and Antihistamine, gradually crolilariae are nol detected in the peripheral blood but
common in the Middle East. Nanophyetiasis has occurred increasing to full therapeutic doses over several days. may be found in other body nuids and tissues. It is mre
increasingly in the Pacific Northwest of the USA. Fasciol- However this does not eliminate the risk of encephalitis and is thought to result from a hypersensitivity reaction
opsiasis is cAused by the inges.tion of infected aquatic entirely and the role of the microfilariac in this syndrome to filarial antigens. Clinical manifestations include trOp·
plants, while undercooked or raw infected fish arc the has been questioned. Albendazole may be useful where ical pulmonary eosinoph ilia, glomerulopathies, en-
sour-ces of H lu:leropliyes, M yokogawai, and N. salmin- diethylcarbamazine cannot be used, but repeated courses domyocardial fibrosis, filorial arthritis, and filarial gran-
cola infections. may be needed. 1 Some consider that ivermectin could be ulomas in tl1c breast.
Fasciolopsiasis is usually asymptomatic, but heavy infoc- used 1 ·~ but, as with diethylcarbamazine, there is concern There is no entirely satisfactory treatment for individuals
tions can cause diarrhoea, abdominal pain, and, rarely, in- over its potential neurotoxic effects in patients wid1 heavy with lymphatic filariasis. Current treatments are effective
testinal obstruction and an allergic oedematous reaction. microfilaraemia; this is also a potential problem where against microfilariae, and thus prevent disease transmis-
Mctagonimiasis is also generally asymptomatic but may ivermectin is distributed for mass treatment of onchoccr- sion, but have little or no effect on the adult worms and do
cause mild diarrhocn, while pain and mucous diarrhoea arc ciasis (p.144) in areas co-endemic for both diseases. not halt tl1e progression of symptoms once the disease has
common in heterophyiasis. Similar gastrointestinal symp- Diethylcarbamazine is also used for prophylaxis1 but it has developed. Diethylcarbamazine removes circulating mi-
toms plus eosinophilia occur in nanophyetiasis. Eggs of M been suggested that it should be reserved for subjects at crofilarioc and is partially effcclivc against the adult wonn
yokag(11rai and H. he11!1-0pl~ves may rarely pertetrate the high risk of exposure. Vector control is regarded as and is considered the treatment of choice.1 Treaonent may
bowel v.all and enter the bloodstream to be deposited in impractical and methods aimed at reducing contact wilh trigser"acutc lymphangitis, and diethylcarbamazine should
various organs, leading to serious complications such as the vector such as window screens and protective clothing not be given during an acute episode as it may cause fur-
heart fai:lm: or fatal embolism in the heart or brain. are recommended. ther wonn death and thus exacerbate !lie inflammatory re-
I. Abr.unowiC".t M. ed. f>rttgsf<>t' µt11asitk inftt·fion~ . 2nd ed. New sponse. lvcrmectin is only active against microfilariae and
Tn:atmc:lt of intestinal fluke infections is with praziquan- Rochelle NV: The Medico! Lener. 2010. is mainly used in areas also endemic for onc)jocerciasis or
tcl.12 2. Padgeu JJ. Jacobsm KH. Loiasis: African eye worm. Trttnt R loiasis. Albcndawle plus either of these two drugs is con-
I. WHQ_Control of food'bome 1riemalock infec1ions. WHO T«b Soc Tmp Akd Hyg 200$; 101: 983-9.
sidered to incmise their efficacy and such combinations
11.'p 5,,. ''9 199S. A~:ultblc aa: h11p:lnibdoc.who.m1l1rsJ
WHO TRS_149 _(panl ).pd( and hup:Jltibdoc.who.inlicrs/ arc recommend.!d for in= ~nnent programmcs.2 How-
WHO)'RS_S-49_(plrll). pcl((aettS$«! 16!071'08) Lung fluke infections ever, systematic rc\iews of randomised srudiesl-• found
2. Abn1m&\l.icz M. t.d. Dmpfor poros11" t1t/ttrlo111. 2nd ed.. New The lung Ouke infection paragonimiasis is caused by insufficient evidence to either confirm or reject the obser-
Rochel• NY· The Medical Len<r. 20 10. Paragoninrus spp., commonly P. weslermani, and occurs vation thal albendazole with dielhylcarbamazinc or iver-
in Asia, Africa, and Central or South America. The disease mectin is more effective than either drug given alone. Sec-
Liver fl~ke infections is transmitted by the ingestion of raw infected freshwater ondary infcctio:is with bacteria and fungi occur in poorly
FO$ciolc hcpa1ica, F. gtgamlco, Opislho~hi.r vivetTini, O. aabs or crayfish, or from drinking infected water. vascularised tissues and therefore rigorous hygiene, skin
feli11e11s, and C/oll()rchis si11e11sis arc liver flukes transmit- The flukes mature in the lungs where they cause local care, physiothetapy, and other measures 10 promote lymph
ted by the ingestion of infected aquatic plants, grasses or necrosis, haemorrhage, inflammation, and fibrosis. Symp- now in the affected areas are recommended; in some cases
water (F. hepo1ica and F. gigantica), or raw or under- toms of paragonimiasis include fever, pain, and chest com- antimicrobials arc needed. Large hydroceles and scrotal el-
cooked fish (Opisrhorchis spp., C. sinensis). Fascioliasis plaints, but mo~l ligbt to moderate infections are asympto- ephantiasis are generally not reversible with drug therapy
is mainly a disease of sheep and Cottle and human infec- matic. The worms may also develop at other sites, and usually require surgical intervention after a treatment
tions may occur wherever these animals arc raised, where- particularly the brain where they CJl.n cause epilepsy, course with diethylcarbamazine.
as clonorchiasis and opisthorchiasis are seen mainly in symptoms of cerebra l tumours, or cerebral embolism, Fi laria have been shown to contain Wolbochio endobacte·
Southeast Asia and eastern Europe. which may be fatal. ria which are essential for larval development and adult
144 Anthelmintics
wonn fertility and viabi lity. This symbiotic dependency M ozzardi infections1 and may be the drug of choice for Committee10 have implemented recommendations for
has provided a new approach in the creatment of filariasis. M streptocerca. ivennectin mass treatment programmes of onchocerciasis
In patients infected with Ii'. bancrofii oral doxyc)'cline for Filaria have been shown to contain Wolbachia endobacte- in areas co-endemic for loiasis.
8 weeks has resulted in a reduction in adult wonns and ria, which are essential for larval development and adult Before the introduction of ivem1ectin in I 988, diethylcar-
prolonged reduction in microfilaraemia,5 while a 3-week worm fertility and viability. This symbiotic dependency bamazine was the usual treatment for onchocerciasis, but
course of oral doxycycline followed by a single dose of has provided a new approach in the treatment of filariasis. it is no longer recommended by WH0.4 The major limita-
ivennectin plus albendazole 4 months after the start of In patients infected with M perstans, daily oral doxycy- tions to its use are the severe allergic reaction (the Mazzoni
treatment, was found to be more effective in inducing cline for 6 weeks resulted in significant reductions in mi- reaction) issociated witl1 its microfilaricidal action, aggra-
long-tcnn cleardllce of microfilariae than standard treat- crofilaraemia at J 2 months and continued suppression 36 vation of existing ocular lesions or precipitation of new
ment with iverrnectin plus albendazole, but was insuffi- months after treatment. 3 ones, and the need to give repeated courses of treatment for
cient to kill adult wonns.6 ln patients infected with B. ma- l. Abramowicz M, ed. DMlgl for porosUic ;nfectkms. 2nd ed. New continued suppression of the disease.' Suramin has also
layi a 6-week course of oral doxycycline, either alone or Rochelle NY: 11>e Medioal Lener, 2010. been used in the treatment of onchocerciasis and is effec-
2. Brc~ni E-R, ti ol. Comparison of different ;mthelmintic drug
followed by a single dose of diethylcarbamazine plus al- regimens against Man.sone11a pen1ans filariasis. Trm1s R So~ tive against adult worms.4 However, iL~ use is restricted be-
bendazole 4 months later, significantly reduced Wolbachia Trop Med Hl'g 2006; 100: 458-63. cause of its toxicity. Moxidectin is an anthelmintic used in
levels and led to a decrease in microfilaraemia that was 3. Coulibaly YI, e t al. A randomiud trial of doxycyclinc for J.{an- veterinary medicine and is currently being evaluated for
sustained for al least l year after treatment. 7 Doxycycline sonello perstons infection. N Engl J Med2009: 36J: f 44~58. human use. 11 Amocarzine has also been evaluated in on-
may also prevent or ameliorate serious adverse effects to choce.rciasis.4
standard antifilarial treatment.6•7 Metagonimiasis Recently it has been shown that adult wonns contain Wol-
Tropical pulmonary eosinophilia responds to a 3-week See under Intestinal Fluke Infections, above. bachia endobacteria, which are essential for adult wonn
course of diethylcarbamazine but patients may relapse and fertility and viability. 1bis symbiotic dependency oo Wol-
require re-treatment. Filarial ar1ltritis responds rapidly to bachia has provided a new approach in the treatment of
Nanophyetiasls
treatment with dielhylcarbamazine. onchocerciasis. Treaimcnt with oral doxycycline daily for
See under Intestinal Fluke Infections, above.
In comlJJunities where lymphatic filariasis is endemic 6 weeks has been shown to sterilise adult worms for the 4-
mass treatment of the entire community is the basis of the month stud)' pcriod. 12 When given with a single dose of
Global Programme to Eliminate Lymphatic Filariasis.2 N ecatoriasis ivenncctin, embryogenesis is interrupted for at least 18
The ·primary goal is to eliminate microlilariae from the See under Hookworm Infections, above. months.13 The long dox.Ycycline treatment regifnen.is not
blood of infected individuals thereby interrupting trans- suitable for mass treatment programmes, but it may be
mission: The programme recorr.mends a single dose of 2 used with ivennectin for treatment of patients who perma-
Onchocerciasis
drugs (albendazole plus either diethylcarbamazine or iver- nently leave an endemic area.
Onchocerciasis (river blindness) is a parasitic disease
mectin) given once-yearly for 4 to 6 years.2.3 Albendazole caused by infection with the filarial nematode Onchocerca In non-endemic areas ivermectin may be given every 3 to
plus ivcrmectin is used in a.reas where onchocerciasis or
loiasis are also endemic. Pregnant woinen, lactating wom-
volvulus. It is endemic in large areas
of West and Central 6 months depending on the recurrence of symptoms or
presence of microtilariae.
Africa, areas of Latin America, and Yemen. It is particular-
en in the first week after birth, children under 90 cm in ly prevalent near fast flowing rivers, the breeding ground Vector control with larvieides, continued for the life span
height (or weighing less than about 15 kg), and the severe- of the blacldly which is the vector of the parasite. After of an adult worm, is used to interrupt the transmission of
ly ill are excluded from mass treatment programmes in ar- infection, the larvae mature into adult worms in fibrous infection and was the main strategy for onchocerciasis
eas where iveimectin and alber.da.zole are used. In areas nodules, usually in the subcutaneous tissue. The adult fe- control before the introduction of ivennectin. However,
where diethylcarbamazine and albendazole are used, preg- male worms release large numbers of microfilariae which despite initial success fly re-invasion became a problem,
nant women, children under 2 years of age, and the severe- migrate from the nodules into other tissues, most notably as the flight range of the vector was longer than expcct-
ly ill are excluded. s An alternative approach is the use of the skin and the eyes. Death of microfilariae in the eyes ec1. ••
diethylcarbamazine-medicated salt for 6 to 12 months causes severe inflammation and scarring that may lead to I. Saint Andr~ A, et ol. The role of cndosymb101ic Wo1bachia bac-
throughout the community at risk. teria in the pathogenesis of river blindness Science 2002; 295:
lesions in the eyes and inipaired vision. There is some ev- 1892-S.
Ongoing vector control should be carried out before or idence that antigens released from symbiotic Wolbachia 2 . Hoerauf A.et al. Onchocerciasis. BMJ 2000; 326: 207-10.
during peak transmission season, in order to consolidate bacteria within the microtilariae also play a role.•-> Re- 3. Udall ON. Recent updates on onc:hoccrcia~is: diagnosis and
trcatmon~ Clin Infect Dis 2001; 44: 53~0.
tl1e effects of mass chemotherapy. People living in or vis- peated infection over several years may result in irreversi- 4. WHO. Onc·hocercias;s and its control: report of a Wt~O ex.pen
iting endemic areas are advised to sleep under a mosquito ble blindness. In the skin the dying microfilariae trigger a committee on onchoccrciasis control. WHO Tech Rep Ser 852
net and use mosquito repellent on exposed skin between 19 95 . Also available ac: htlp:f/libdoc.who.int/trs/
subcutaneous inflammatory response that causes intense WHO TRS' 852.pdf (accessed 03!t OIU7)
dusk and dawn. itching. Over time the skin becomes swollen and thick- S. WHO:- Onchocerciasis (river blindness). A\"ailablc at: http:/!
I. Cox FE~ el nl. (tds). Topltyond J-f.'ilson i microbiologJ-' and mi- ened (lizard skin) and may lose some of its elasticity and www.who.int/blind·ncssfpartnenhips/onc.hoccrciasis_home/en/
crobial infections: porasi1ology. ){ith ed. London: Hodder Ar- index.him! (oe<cssc<l I 5/06/06)
pigment (leopard skin). 6. Pond B. Distribution of ivermcctin by he~llh workers. lon<:CI
nold, 2005.
Onchocerciasis is controlled either by treating the infected 1990; ~35: 1539.
2. WJiO. Eliminme filor;n~is: uffack pcw:rrr- o g1U-11 light fitJm tire 7. WHO. Pnvt!uti'*·e chemotherapy;,, humo'n f.tlmint/JioJis: COQ1-di-
Global AIJ;tmce, Gencxa: WHO. 2000. Abo available al.: http:// patient, thereby reducing the transmission of the infection na1cd r1sc ofmulhclminthk dnrgs in conrrol inten-entions: o man-
whqlibdo< .who.inVhq/2000/W HO_CDS_CPE_CEE_2000.5.pd f from the human host to the vector. or by interrupting the ual for heo/1/1 professionaltt 01td progrommt managers. Geneva:
<•=d 03/08/07)
transmission from vector to human. The drug ofchoice for WHO, 2006. Also available at: hllp://whqlibdoe.who.int/
l . Tisch DJ, e1 nl. Mass ehcmotherap)' options to control lymphetic publications/2006.'924 l S47103 eng,pdf (a«:"5Sc:d 09.'09"'9)
filariasis: a sys1e1nitic review. l<inc.:t Infect Dis 200S; 5: the treatment of onchocerciasis is ivem1ectin.2-s A single 8. Gardon J, et of. EffeelS of standard and hig)" doses of ivennectin
514-23. oral dose of ivermectin rapidly eliminates microfilariae on adult wonns ofOnchocerca. voJvuius: a randomised control·
4. Addis$ 0 , c1 al. huernational Filciri~is Review Group. Albcnda· from the skin and more gradually eliminates them from the led trial . Lonce1 2002; 360: 203-10.
zolc for lymphalic tilariasis. Available in The Cochnme Data• 9. Osci·Atwcncboana MY. et al. Prevalence and intens.ity ofOn-
baseor System3tic Rc\"iews~ Issue 4. Chichcslcr: John Wiley; cornea and anterior chamber oftbe eye.4 It has little effect choeerca volvulus infection and cfficacv of ivcrmcctin in en-
2005 (•<~.Std 02110/06). on the adult worms altboug)l it suppresses release of mi- demic communi1ies in Ghana: a 1wo·Ph~se epidemiological
S. Taylor MJ. et ol. Macrofilaricidal activity afler doxycycline crofilariae for several cycles. lvermectin therefore only srudy. Lo,,ce12007;369: 202t-9.
treatment of Wuchel'cria b~ncrofli~ a duuble-blind, randomised 10. The Mcctizanf> Expert Committee and Tcchni~l Cons.ultativc
placcbo-c:onirolled triul. Lancei 2005: 36S: 2116-21.
controls the disease; it does not cure or eradicate it. Control Comminec. Rcwmmenda1ions for the treotmem of onchocCrciasjs
6. Turner JO, etol. A ~ ndomized.double-b lind c:lintcal trial ofa 3- of the disease in endemic areas relies upon the use of iver- with Mectizanei in areas co-enc.Jemie foronchoccrciasis and loiasis.
wcck cour~c of doxycyc:line plus albendazole and ivermeclin for mectin every 12 months in Africa (and every 6 months in 2004. Available at: hllp:/fwww.mectium.org.isitcs/defaullJfiles/
En&lishMECTCCLoaRecs·Junt04_1 .pclf(aa:essed 29/U7/IO)
!he uuunent of Wuchcrcria bancrofti infection. Clin 111/ecr Dil Central and South America) and this may be combined 11. Cotreau MM. tfl al. The anti~rasilic moxidectill: SCtfely, 1ole:ra...
2006; 42: 1081 -9. bility, and phann3cokine1ics in hum3ns. J Clin Phurmocol
7. Sup::ili T, cl al. Ooxycyclinc ltcn1ment of Brugi;;i m:.iloyi-infec1ed
with vector control (see below). Because the adult wonns
2003; 43: tlOS-15.
pcr~ons reduces micmfilAremia :md adverse r1:actions after di· live for about 15 years, treatment will need to be continued 12. Hoerauf A, et al. Endos_ymbiotic blJctcria inwonns as forgets for
cthykarbamaiine 3nd albendazofe 1rcattncnt. Clin lnfttt Dis for many years. !vermcctin is donated by Merck through a novel chemotherapy Ill filariasis. lonce1 2000; 3SS: 1242-3.
2008; 46: J385-93. the Mectizan Expert Committee (MEC) for human use in 13. Hoerauf A, et al. Deplelion of wolbachia endobacleria in On-
8. WHO. Prewmtfre chemotlre;·opy in bumon helmi111hiosk· <VJor.Ji- chocerca vofvuJus by doxycyc.::linc and microfilaridcnnia after
noted use vfontih~lmimhic drug$ in co11h--ol ;n1erwntiou: o mamt-
community-wide mass treatment programmes in all coun- ivermc:e1in treatment. Lancet 2001; 351: It J5-6.
ol for heo"h pmfessionofs ond programme managers. Geneva: tries in which onchoccrciasis is endemic, where it is given 14. Thylerors. B. Alleman M. Towards the elimination of onchoe<:r~
WHO. 2006. Also :ivailable ;ii: h11p:flwhqlibdoc.who.in1/ to all but pregnant women, breast-feeding mothers of re- ciasis. Am1 Tl'Op Med Pora.filol 2006; t 00: 733-46.
jl4Jblic.alioos/2006/9241547103_rng.pdf (acc<>scd I t/09/09) cently bom babies, children weighing less than 15 kg
(equivalent to about 90 cm in hei~t);and those unable to Opisthorchiasis ·
Mansonella infections walk or otherwise seriously ill.6 • For further details, see See under Liver Fluke Infections, above.
lnfectio11s with the filarial nematodes Mansonella per- under Jvennectin. p.154. Increasing the frequency of the
stans. ,I!, ozzardi, and M. streptocerca are generally standard doses of ivermectin to every 3 months appears to
increase efficacy compared with annual treatments.8 Evi- Paragonimiasis
asymptomatic but symptoms including malaise, fever,
dence from Ghana suggests that ivenncctin-resistant poJ>- See under Lung Fluke Infections, above.
joint pain, and meningeal symptoms have been described.
Infection is transmitted by biting midges and flies. Treat- ulations of parasites arc emerging and that its ability to
ment with diethylcarbamazine may be effective depending suppress skin microfilariae repopulation is reduced over Schistosomiasis
on the infecting species (although it has no eftect in M oz- time in somecommunities.9 Schistosomiasis (bilharziasis) is a parasitic infection
wrdi infections 1). Although M perstans infection is gen- In areas where onchocerciasis and Joiasis are co-endemic, caused by Schistosoma spp., largely S. mansoni, S. japon-
erally considered to be relatively re!i-dctory to treatment care should be taken because ivem1ectin may cause seri- icum, and S. haematabium, and to a lesser extent S. i11ter-
with conventional antitilarial drugs, mebendawle may be ous adverse effects, including encephalopathy, in some pa- calatum and S. mekongi. The disease is seen mainly in Af-
effective alone' or witl1 Ievamisole or diethylcarbamazinc2 tients with high Loa loo microfilaraemias (see Incidence of rica, Asia, South America, and the Caribbean, where it is a
in lvf. perstons; albendazole is considered the drug of Adverse Effects, under lverrnectin, p.153). TI1e Mectizan hazard to individuals exposed to fresh water containing the
choice in this infection.1lvermectin has been suggested for Expert Committee and the Technical Consultative intcrmi.xliate host, infected freshwater snails.
All cross-references refer 10 entries i11 Volume A
 Anthelmintics 145
Free-swimming cercariac arc released from the snail and I:.as1 Europe, Japnn, and the USA. In contrast with other eggs may be excreted in the faeces so maintaining the cy-
penetrate human skin causing a prurilic papular rnsh in intestinal nematode~. •he eggs of S. s1ercaralis hatch be- cle of reproduction. Treatment is with a single dose of
sensitised individuals (swimmer's itch). Parasites mature fore leaving ~1e gasu-ointcstinal tract, and can cause au- pmziquamel, 1 which has the advantage of also being ac-
in the lungs and liver within about 6 weeks, then migrntc toinfoction, particularly in im1nunocompromised patients. tive, in higher doses, against the larval fonri of T. solium.
to the blood vessels, the bladder, or intestines. Mature Larvae reaching the soil can either mature into free.living Niclosamide is also effective' but is only active against
female wonns produce eggs which arc excreted in urine or adults ur remain in an infcct.ive larval stage. Infective lar- adult worms.
Slools, or become lodged in tissues, and immunological re- vae cause infection by penetrating 1he skin. The larvae mi- I. Abr11nowit:z. M. ed. Drugs/"' J'tUnui1k i1{t4'1iol11. 2nd ed. Nt:w
action to these eggs results in disca.sc. The acute reaction grate to the lungs, mo,·e up the bronchial tree to be swal- Rocbc:lle NY: Tht Medial L<««. 2010.
1o egg deposition has ~n tcnned Katayama fever, a sclf- lowed, and finally penetrate the mucosa of the small
limiting but sometimes fatal illnc.ss resembling scrum intestine where d1cy mature. Eggs are deposited about 28
Toxocariasis
sickness and roost frequently seen in S. joponicum infec- days after initial infec1ion.
Toxocariasis1is infection with the larval fonn ofToxocara
tion. The chronic phase of infection is often as),nptomatic Infection may be asymptomatic, but commonly patients co11is or, less conunonly, T. coti. The adult worms live in
fur many years, but usually results in granuloma fonnal;on have symp1oms relating to the stages of infection. Penetra- die intestines of dogs and cats respectively, and man be-
and fibrosis in tissues where eggs are deposited, such as tion of larvae through the skin causes intense pruritus and comes infected when eggs excreted in animal faeces are
the liver, lungs, intestines, or urinary tract, the site depend- an crythematous rash. The rash may follow the course of ingested. Once ingested the eggs batch and the larvae mi-
ing on the infecting species. · migration and is one of the causes of cutaneous larva mi- grate from the intestine to other organs, most commonly
Praziquan tel is used for the treatment of chronic grans (above). An inflammatory response to migration the liver, lung, and eye. Most infections are asymptomatic
schistosomiasis 0·S and is effective against all species of through tl1c lungs may be seen and may include pncumo- but two clinical syndro!"cs, ocular larva migrans and vis-
schistosomes. Metrifonatc and oxamniquine have been nitis and bronchospasm. In heavy infections, which a.re ceral larva migrans, can occur, usually in children.
used as alternatives against S. loaematobium'~ and S. most common in immunocompromised patients as a result
mansoniu.• respectively. The anemisinins have been of autoinfection, massive pulmonary inv11sion can oocur Ocular larva migrans occurs when larvae invade d1e eye
fotmd to be effective against immarure scbistosomcs in resulting in fatal alveolar haemorrhage. Abdominal symi>- causing a granuloma which may impair vision and can
laboratory studies2 and ancmisinin derivatives used alone toms include colicky pain, diarrhoea, and vomiting, lead- cause blindness. There is no specific trcat!1JCnt.~ An-
or with pra.ziquantcl arc under invesrigation for S. manso- ing to nutritional deficiencies and weight loss. Eosi- thclmintics such as albendazolc or tiabcndazole, conicos-
ni,6.1 S. loaemalobium,8 and S.joponid infections. How- nophilia may also be present Disseminated disease may tcroids, ocular surgery, and laser photocoagula1ion have
ever, results from these studies arc variable and a system- occur in immunocompromised patients (including trans- been used but assessment of tbctr efficacy is difficult be-
atic revicw2 on the use of drugs to treat S. looema1obium plant paticnts2) and produce severe pulmonary and ab- cause of the variable natural course ofthe disease.
found that evidence of benefit with anemisinins was dominal symp1oms, shock. encephalopathy, meningitis, The clinical symptoms of visceral Jarva migrans depend
inconclusive. McOoquine plus anesunate, given orally and Gram-negative septicaemia. Since strongyloidiasis is upon the organs involved but commonly include cough,
once daily for 3 days, w~s found to be effective against commonly fatal in these patients, "lllncrablc patients from wheezing. fever, and hepatomcgdly. Encephalitis and sei-
S. haema1abi11111 infection in children; high cure rates and endemic areas should be screened regularly and treated zures may occur and there is usually cosinophilia. Acute
egg reduction rates were also seen in those coinfected with promptly at 1he first sign of infection. infection nonnally resolves without treauncnt.3 However,
S. mansoni. 10 Jvcnncctin is considered to be the treatment of choice.1·3 severe or prolonged infections may be treated wid1 alben-
Mass rreaunenl programmes may he necessary in endemic Tiabcndazolc was widelv used, and sti ll is in some coun- dazole;4 diethylcarbamazine, 5 mebcndazole, or tiabenda-
areas to reduce the overall burden of disease. WHO tries, but albcndazolc is 1oorc effective and better tolerated. zole have also been used.1·•
recommends" tbe use of praziquantcl targeted at school- Mcbendazole has also been suggested but it must be given I. Despom1nitt D. Tu.'.\uc11riui»: clinical 111spccls. cpidt:miology,
age children, adults considered to be at risk (including for longer periods than albendazole since it has only a lim- medical ecology, and molecul:ar Hpccls. Clin Microln'o/ R~v
2003: 16: 26S-72.
pregnant and lactating women or those engaged in high- ited effect on migrating larvae. A combination ofivcrmec- :!. Shields JA. Oc\llat lO~oari:asis: a ~view. s,,n· Oph1halmol
risk occupations involving contact with infested water), tin and albendazole has been suggested in disseminated 1984: 2S: 361-81.
and entire communities living in endemic areas. Children disease.; These broad-spectrum anthclmintics (except ; . Gillespie SH. Honun toxocoriasis. Co.uwn Dis R~p 1993; 3:
less than 4 years of age or 94 cm in height arc excluded tiabcndazole) are also useful if the patient is suffering from Rl40-Rt43.
from such mass trcaunent programmes. The fi'equency of a mixed intestinal nematode infection. 4. Abramo\\ic:z M. ed OntJlfol'portr!oltk mfections. 2nd ed. New
intervention should be dctennined by the prevalence ofin- Rochelle NY: The Medic.I Letter, 2010.
I. Scpn-•Ncwnharn M. Manifestations.. diagnosis. ind untmcol
S. WHO. lf'HO ..-lfoHl1•lhl'1- GenC\'O: WHO, 2008. Available >t:
fection or ofvisible hacmatuna (for S. haemalobium only) of Stronsyloides sttte0r:Hs infe<:tion. Amt Plwrm«OJlutr 2007:
hnp://www.who.int/sc:lcction_mcdicincsllist/WMl'2008.pdf (ac-
among school-age children. 41: 1992-2001.
oesscd 19111/09)
l. Roxby AC. ti al. S1ron11yk>idiasis in 1r1nsplan1 peticnb. Clm /,,.
Niclosamide is used as a molluscicide for the treatment of f«I Di.• 2009. 49: 1411- 23.
water in schistosomiasis control programmes. Copper sul- 3. Abramo·wicz. M, ed. Dn!gs for porwMc infrttlan1. 2nd ed. New
fate or sodium pcntachlorophcnare have also been used but Rochell< NY: The Medico! Lener. 2010. Trichinosis
to a lesser extent. Trichinosis' (u·ichinellosis or trichiniasis) is an infection
caused by nematodes of the genus Trichinella, most com-
Schistosomiasis vaccines are in development. Synpmosis monly Trid1i11ella spimlis. Man becomes infected through
L WHO The con11·ot of schi1tosomiasis: second repotl o( the Syngamosis, or g;ipewonn infection, is caused by Sy11ga- ingestion of raw or undercooked meat.. usually poric, con-
WHO <'J"'rl commi11<c. H!HO Tech Rep Ser 8JO 1993. m11s and /t{ammomo11oga111us spp. and is mainly an infcc-
Available 11: h11p;//Jil>doc.who.in1hrslW HO_Tl!S_~ 30,['dl (•<· taining infective larvae. TI1c larvae mature into adult
«SJ<d IMl7.'081 1ioo of domestic fowl and wild birds and m~nun~ls, al- worms in the small intcSline and the mature females de-
though infection in man has been rcpo1ted very rarcly. 1 ~
2. ~~1~~f:~~ ~· ~:· ~~:,: 'Oa~~~~ri:~r~·Y~~::,~~~:: Man may become infected by eating foods contaminated
posit larvae which migrate in the blood to skeletal muscle
and sometimes to the mync:ardium. Syrnp1oms usually oc-
''icws, luuc ) . Chichester: John Wiley; 2008 (11ccr::.isc.d
09/09/09~ "'ith infective larvae which penetrate the intestinal wall cur only in heavy infections. Invasion of the intestines by
3. Sacmale\ H. Au.Uah A. lnt'1'"en1ions for tttlrling sc:hisloSOn\ia· and migrate to the lungs, where they mature into adult the maturing adult wonns can cause diarrhoea, abdominal
$i5 mansom. Available in The Cochrane O.mbascofS~tc:mat1c wonns. The major S)mjl(om is cough, due lo irritation of
R•• i<ws: 1.... 3. Chichester: John Wil<y; 1999 (•ccu"d pain, and vomiting followed about a v.-eek later by hyper-
16/0S/OS). the bronchi and increased mucus production. The infection sensitivity reactions 10 dle migrating larvae. 111ese may in-
~. Ro.. AGP, <t al S<hi>1osonuasis. N El1~1 J Mttl 2002; 346: may be confitSed wilh asthma. Tiabendazolc and meben- clude eosinophilia, fever, muscle pain, periorbital oedema
1212- 10. dazole have been used successfully to treat the infection in
:.. Gr)'sccls li. N nl Hutnan ichi:nosornio.sis. La11e~t 2006; 368: and, more rarely, encephalitis, myocarditis, or pneumonia
JI06-18. man. which may be fatal.
6. Oc Clercq D. cl nl. 6fficacy ~f artcsunatc agaiMI Schisto.soma I . Timmons RF, et ol. lnfcdion of1hc rcspinil01)' tuct wilh Mum--
mRnsonl infections in Richard Toll, Sene~I. Trn11s R Soc Trop momanos,3mus (Syog.amus) laryngeus: a nc:w cue in Largo. All patients with conlim1ed or suspected infection should
Me</ H.•'8 2000: 9~ : 90·1. . Florid~. and a summ3ry of prcvi<.'Utly rc.-partcd cas~s. Am R~•· be treated to prevent the continued production of larvae.
7. Uttin;er J. N " '· 0 1·al oncmcthcr for prevention ofSchiStOAoma Resp;,. Dis I Y~3: 1211: 566-9.
m:m~ni infeclion: randomised controlled 1ri~.I. lancet 2000~ Albendazule or mebendazolc are considered to l>c the an-
2. Gardiner CH, Sc.Mn~ PM. Mam1no1ncmnaa1nus infection in a
355: 1320- S. hum;m: rcporl ofa cn.~c. Am J Trop Med Hyg 1983; J2: 995-1. lhel mintics ofchoicc:21iabcndazole has a!so l>een uscd.3 A
3. Borrm:urn S. "' at. Ar1c.stma1c and pruiquan1cl for the 1rca1mc:nl corticosteroid should be given for severe hypersensitivity
of Schistosoin:a hatmalobium infection.<-: a double-blind, rand· ). L~crs \VO. t'I al. Syngam~is, an unusu:il C'IUSC of Ulhma· •lie:
om11..cd. ptoc:cbo--controllcd study. J /llf~c1 Dit 2001: 184: first reported case in Canad:a. Ca1t M~d A11oc J 198S; 132: rcactions.2.4
1363- 6. 269-70.
4, Nosanchul; JS. r1ol Cascrcporl o(anddescrtption of par.Hile in i. Gousicin li. ~' "'· Epide1nioln~. di~sis. CrclttrMnl, and con·
9 Hou XY• ., al. A nn<lomiud. double-blind, placd>o-controll<d trol oftrichintllosis. Clin M1tmbfol Re'' 200C); 2'2: 127-tS.
uiitl of safety and cffic:ac:y of combined pruiqu~icl and ant· MammonlOaogamus laryngcus (bum:tn synpn1o•is) infcctiori. J
mtthet 1re~1mcn1 for acute schiJ10$0tl"lilsi$ j1ponie1 in China. Cl/., MicrolHol 1995: 33: 991-1000. 2. Abrnmo";ci. M, ed. o,.,,., /OI' p.ww;1k inff'Clionl. 2nd ed. New
HNI/ WHO 1~; 86: 1SS-9S. S. Turncr P. ''"'· A osc or human synaa.mos.s Trgw/ M~d lufttt Rochelle NY: The Medico! L<ll<r. 2010.
10 Kei.Stt J. rf tll. Emcacy and safct) of mdloqu1nc. anuunatC'. DiJ 2003: I: 231- 3. 3. W:ict G. et of Bhndcd. pl~bo·contR>lltd trial of :mlipuasitic
1ncOoquinc·1U(s.unat('. ind praziquor.rucl apirut Schl.uosomo 6. C>SlailO JC• ., al. Reponc dtl pri....-cuo humono de infccci6n dnlgs ro. lrichinos1> m)ositis.J 1"/«1 Dir :!000; 182: 371-l.
hMmo1obf1u•: random1U'd. cs:plor:ilory open-label lri11. C/fn pirisi11ria por M~momooogamus laryngcus en Colombia. Bi+ 4. Shimoni Z.. ~I al. The: USC o( predniso!)C in the lrC31Jntm o(
lnf'i!N Dis 2010: 50: t20S-13. OIMtf'ICa 1006~ 16: ;;J-41. 1richirK"Uos.ls. /sr MN AJJ« J 2001; 9: 537-9.
11. WHO. Pi'tt*Cilfl\~ C'h~mot~1trp)' in lurma.,, f,~/1nittthlos.l1: t:OOl"-
df,,ottd ;111 of ont;htlminlhir drugs in <'1)11h'()/ ;,,ltTW1'lio11s: a
nwmiol{QI' l~crllh /)l'O.(cnio"als and programme monogcrrs. Cit"-
11 e v :i: W~IO~ 2006. Also ovailablc: 111: h11p :I/
Taeniasis Trichortrongyliasis
whqlihdoc. " 'ho.1nllpublicotions/1006/9241547 I03 _cn9. pdr Taeniasis is an infection of !he intcsti11e with heef tape- Trichostrongyliasis is an infection of the small intestine
(•cccmJ 09109109) wonn, Taenia saginata, or pork tapewonn, T. solium, ac- caused by Tl·ic!tostmngylus spp. incl uding T. colubri-
quired tlU'ough ingestion of cont:uninated raw or under- fonnis. 1l·iclto~·11-011gy/11s spp. are nonnally para~itcs of
Strongyloldiasis cooked meat. TI1e larval fonn of T. soli11m can cause t!Je herbivores, but infections in man have been found. They
Strongyloidiasis1 is an infection of the small intestine systemic inft:etion cysticercosis (see above). have a similar life cycle to Ancylosloma duodenale (sec
caused by S1rongvloides stercaralis, known as thrcad- Infection with the adult wom1 usually produces symptoms H9(lkwonn Infections, above). P¥f3ntel embonate, albcn·
wo011 in the USA. It generally occurs in the tropics and only when the wonn reaches a size that can cause obsttucr dazole. or nM:bendarole arc recommended for tl1~ treal·
subtropics and can also occur in some areas of South and tion or related problems. Segments oft he wonn containing ment of trichostrongyliasis.1 Successful treatment with
146 Anthelmintics
iveanectin has occurred in areas where widespread use of Albendazole (BAN. USAN. rlNNJ associated with impaired growth in those with low levels of in-
benzimidaz.ole carbamate derivatives in grazing animals fection.' However it was considered that !his $hOuld nol prevent
has led to resistance to these drugs.2 AlbendJtsoli; Albendazot AlbenduoW: Atlendalolum( SKF- the use ofsingle doses in mass ll'Catment programmes.:
I. Abramowicz M. ed. Dntgs .for para.sine ;njec1ions. 2nd ed. New 62979. Methyl S-propytthio-1H·benzimidazol·2-ytcarbamate. I. Forrester JE, et ol. Rondomised uill of albcndawle and pyran\d
Rochelle NY: The Medical l.erter. 2010. in symptomles.s triehuriH is in ch;ldren. Lonee/ J998; JS? :
AN.6e>w.30A 1103-8.
2. Ralph A, a ul. Abdominet pain and eosinophilia in suburb1n
p l keepers. M.U J Aust 2006; 184: 467-9. Co,rection. ibid.: c,,H ,sN302S = 265.3. 2. Winnanley P. AJbc.ncbzole for mus ltealmcnt of asymptom;i1ic
185: 4 9. (1i1le] 1richuris infci:.tions. l.oll('c/ 1998: J52: IOSO 1.
CA S - 51965-21 -8.
ATC - P02CA03. Effects on the liver. Jn a series of 40 patien1s given albcnda-
ATC Vet - QP5 2ACI I.
zole for echioococcosis, 7 developed abnormalities in liver func-
Tr ichuriasis lion testS dwing thcr1lpy. 1 Six had a hepntoccllul:lr type of abnor-
Trichuriasis is an infection of Ille large intestine with Tri- UNI/ - F42 1601 9LN. malily a1tn'butablc to albendaz.olc; the seventh had cholestalic
c/111ris h'ichiura, sometimes known as whipwonn. Distri- jaimdice which was probably not due 10 albencfo20le. Sec also
bution is worldwide, but most infections occur in the trop- Incidence ofAdverse Effects, aboYc for reports of r•ised serum·
ics arid subtropics. Eggs arc excreted in the faeces and can transaminase levels.
remain viable in the soil for extended periods. Under opti- Albcndazole should only be used in the treatmenl of ecbinococ-
mum conditions the eggs become infective in about 2 to 4 oosis if there is constant medical supervisioo with regular moni-
weeks. After ingestion, larvae are released from the eggs toring of serum-transaminase concenu·a1ions and of Jeucocyte
and develop within the wall ofthe small intestine for about and platelet counts. Patients wilh liver damage should bc treated
3 to I0 days, before migrating to the lumen of the large with reduced doses ofbcnzimidazole carbamates., ifat all'
intestine where they remain attached to the mucosal lining. I. Morris Of.., Smith PG. Albendazole in hy.lolld d11...,~<polo·
Eggs are detectable in the faeces about I to 3 mooths after Pharmaeopoeias. In Chin.• Eur. (seep.vii), /nt.. US. and Viel. cellular roxicity. 71'ons R Soc Trop M<dHYJ 1987: 81: JH-4.
Ph. Eur. 6.8 (Albendude). A white to faintly yellowish pow- 2. Davit A. rl ol. Multicentrc clinical trials ofbcniimidu.olccar~
infection. Trichuriasis is often asymptomatic, but heavy bamatcs in huinan cystic cchinoeoccom: (pbase 2). Btdl WHO
der. Practically insoluble in waler and in alcohol; very slightly
infection can result in anaemia, dianl1oea, and rectal pro- soluble in dichloromethane; freely soluble in anhydrous formic 1989; 67: 503- S.
lapse. acid. Protect from lighL Pregnancy. Albcndazole is lcralogaiic in some animals end
Treatment is with a benzimidawle caibamatc derivative USP ll {Albendaiole). A while to f1inlly yellowish powder. there arc no adequate and well controlled studies in human preg-
such as albcndawle or mebendaz.ole 1·1 and such broad- PraClically insoluble in water and in alcohol; very slightly solu- nancy. Albendazolc is therefore usually contra·indiealcd during
spectrum therapy can be useful if the patient is sufferini; ble an ether and in dichloromethane; freely soluble in anhydrous ptqnnncy and US licensed produel infonnation cautions against
from a mixed intestinal nematode infection. lvcrmectin' formic acid. S1orc in airtight containers. becoming pregnant while taking olbcndazole or within one
and nitaz0xanidc4 arc alternatives. However, a systematic month of completing trealment.
review3 considered the treatment of 1richuriasis to be Adverse Effects and Precautions
unsatisfactory with current drugs. As for Mebendawle, p.156. Interactions
Mass treatment programmes may he necessary in endemic Adverse effects are usually mild and resolve without Anthelmintics. 11ie plasma conccnlration of alhendazolc sul-
areas to reduce the overall burden of disease. WHO treatment. However, in patients being treated for echi- foxide bas been increased by proziquant-1, 1 although lhc practi-
reco1111nendss the use of albcndaz.ole or mebendazole or cal consequences of Ibis wue eonsida'ed uncertain. ·
nococcosis (hydatid disease), albeodazole has caused I. Homeida M, e1 al. Phumecoktnet1c m1craction between rn.tiqu~
allcmativcly levamisole or pyrruitel targeted at preschool
mild to moderate increases of liver enzyme values in antel a.net albendazolc in Sudan«e men. A,,n rrop Med Parmi1ol
and school-age children, women of child-bearing age (in· 1994; 88: 551-9.
eluding pregnant women in the second and third trimesters about 16% of patients; hepatitis and acute liver railure
and laClating women), and adults engaged in high·risk oc- have also been reported. Leucopenia has occurred in Antiepileptics. Phenytoin, wrbomozepf110, and pheuoborbital
cupations for soil-transmitted helm_inthiasis, such as tca- less than I% of patients; while agranulocytosis, aplas- appear to induce the oxidative melabolism of albend=lc via the
tic anaemia, neutropenia, or thrombocytopcnia are cytochrome P450 isoemymc CYP3A by roughly the same ex-
pickers and miners. Children less than I year of age and tent, resulting in sianiricanlly reduced conocnlJ'lrionsofalbenda-
women in the first trimester of pregnancy are excluded rare, deaths due to ganulocytopenia and pancytopenia zole sulfoxidc. lbis intcrac1ion'is likely to be clinically signifi-
from such mass treatment programmes. The frequency of have been reported. Patients with liver disease, includ- cant when albcndazolc is used to treat systemic worm infections,
intervention should be dctcnnincd by the prevalence and ing hepatic echinococcosis, appear to be at increased and increased doses of albendazole would be nceded.1The inter-
intensity of infection among school-age children. risk of bone marrow suppression and in these patients action is probably not clinically sianiftcant when albendazolc is
I. Bcthony J, 11 al. Soil-t~nsmilled hclminth infections: 1~.ariasis. used for inlcstinal worm infections.
Lrichuriasis. and hookworm. lam:et 2006: 367: l.S21-32. blood cell counts and liver function should be closely
I. Lanchotc VL. e/ al. Ph1nn.c:oltine1ic 1n1erac1ion bclwctn albcn-
2 . Abramowicz M. ed. Drugs/or parasilic inf«JtOAI. 2nd ed. New monitored. dazole sulfoxidc tmnttomers and anlicpilcptic drugs in patimu
Rochelle NY: The Medic:>l l.eucr, 2010. with ncurocys1iee.rcosis.. 1'ber Drug Monlt 2002: 24: 338-45.
3. Keiser J, Utzinger J. Efficacy of currcn& ctrugs 1g1in1t i1oil uan1..
0
Patients being treated for neurocysticercosis should be
mined helminlh inrcctions: l)'Sltmatic revlew and mc1111-analy- given corticosteroids to prevent cerebral hypertensive Corticosteroids. Plasma concentralions of the active mctabo-
sis. J.4l•Lf 2008: 299: 1937-'18. e pisodes during the first week of therapy. Anticonvul- li1e of atbend:i.zole {albcndazole sulfoxide) were rcponed to be
4. Juan JO, et al. Companuive clin.cal Sl.udi~ ofnilaMxanide, 11- raised by about 50'.4 in a study in 8 patients rcecivingtlct\'ameth-
bcnduolc »nd prariquantd in the. uc.a1meu1of as.c11riasis, trkhu- sant therapy also may be necessary. Albendazole may oso11e.1 ..
riasis ond hyineno1epinis in children from lleru. TNJnt R Soc cause irreparable damage when used to treat ocu lar or I. Juna H. ~,al. [)e:xamethasonc lncrc.&Sd plasma levels of iilb.:11 ~
Trop M•d Hyg 2002: 96: 193~. duole. JN..,rt>l 1990: lJ7: 279- 80.
spinal cysts, even when corticosteroids are given, and
S. WHO. PrcwnthVJ cM.mctMmpy In lt11m011 htlm1"tlsiosi.s: coor•
dtn011d u:e of0111iMbni1J1h/c dri,gs In «Jmrol lntUMmlions: a an ophthalmic examination should be perfonned be- Gulr'OintestinaJ drugs. Concentr0tions of albcndazole sul-
manual/or n.otllt professionals 011dprogromm~ 111onoger1. Ge · fore treatment to exclude intra-ocular cysts. foxidc have been found to ·be raised in bile and hydatid cyst fluid
ncva: WHO. 2006. Also :.vailable &1: http://whqlibdoc;:.who.inV when a lbcndazo1e was given with clmctuli11e, which 1nay
publications/2006/924 Il47 I03_eng..pdf (accessed 09/09/09) tnddence of adverse effects. Ahhough_gencrally well-toler- increase efficacy in the trcalmenl of echinococcosis.'
ated, the following adverse rea<'ioos were reported in the first I. Wen H, ~' ol. lnlliat obSCl"\'ation on albendatotc in combin.atiOfl
phase ofW}JO~oordinated studies' involving 30 palicnts given with cimclidinc for the llUtmcnl of human cystic t~iMCocco­
higJ>.dose thcrnpy wi1b albenduok for the treatment of c:ys1ic sis. 11,,n Trop /tl~d Porml1ol 1994i 88: 49-52.
Abamectin (lJSAN. <INN) echinococcosis (hydalid disease): raised serum-transaminase
Abamec:1ina; Abamectine: ~ MK-0936. A mixnJre levels (2 patients), reduced leucoeyte counts (I), gastrointestinal Pharmacokine tics
o( abamectin component B1• and abarr«tin component B1e. syi11p1oms (I), alletgiccondi1ions (I), and loss of hair (I). Tu:a1-
men1 was stopped in a funher paric11t with alveolarcchinococco- Absorptioo of albendazole from the gastrointestinal
A6aMet<TW< tract is poor but may be enhanced by a fatty meal.
si~ because or depressed bone•marrow a<'ivity. In the second
CAS - 65195.55. 3 (componeM B,.J; 65195-56- 4 (com· phase of1hesc studics,1 of 109 pa1icnts given albendazolc for Albendazole rapid ly undergoes extensive first-pass
ponent 6 1.,). cySlic cchinococcosis, 20 had advenc effects; similar findings
ATC Vet - QPS•AA0 2.
metabolism. Its principal metabolite albcndazole sul-
were reported wi1h mcbendazole. The range of efl'eclS with foxide has anthelmintie activity and a plasma half-life
UNI/ - 5U8924TI IH albcodazolc was: elevation oftransamin=s (5 paticnlS), nbdom-
inal pain and other gu1rointcs1inal symptOmS (7), severe head- of about 8.5 hours. Albcndazole sulfoxide is widely
ache (4), Joss of hair (2), lcucopcnia (2). fever and fatigue (I). distribu ted 1hroughout the body including into the bile
""'· 14,C, thromboC)1opcnia (l),and utticaria and ilching (I). Albenduole and the CSF. It is about 70% bound to plasma protein.
.o-{)-o-{)-o .~ had 10 be wilhdrav.n in 5 patients bc:cousc of adverse effects, al-
though in 3 tl1e wilhdrawal was only temporary.
Albendazolesulfoxide is elimina~ed in the bile; only a
·~ed· ..p;'
small amount appears to be excreted in the urine.
I. Davis A, r 1 al. Mulli<:tntTe clinical trials C'fhC':nzimidawltt:ar·
bamatcs in human cdlinococeosis. Bull WHO 1986. 64: 383-S. 0 Refereoo:s.
2. Oavi1 .~. t1 ol Mulliccntre clinical trials or be:ntimidazolecar- I. M1niner SE, 11 of. Pharm3rokinctics oh lben<l1zole in m:>n. £11r
bamatu in human eystic echinoc.occosis (phase 2). Bull WHO J ClinPham1ocu/ 1986: 30: 70~.
1989; "'so~ . 2. Monis DI.., ti al. Pcnemujon or albcodu:oae sulpho>:idt. inti) hy·
Breast feeding. Tiie results of a study' in 33 women given a datid cysts. Gut 1987; 28: 75-80.
3. Steiger U, et al. Albcnduok tteatmcn• of cchinoeoc.cosis in hu·
"" single oral 400-mg dose of albcndazole suggested 1ba1 albcnda-
'tOle and i1s aclive mctabolilc attained low concentrations m
mans: effcclS on microcomal metabolism and dru1 lolmnc:e.
Clin Pharmacol ~r 1990. 47: 347-53.
breast milk. The authors considered Iha! albendazolc was unlike- '4. Juna H. e1 of. Clinical pharmac:okinctics of albcndatolc in pt·
ly to be hannful lo brC3.Sl·fed infants. ticms with brain cyJ.ticercosis. J Clin Phormacol 1992 ; 32:
Profile I. Ahdtl·1nwab AM, es oL Albcnduole and i1s meiaboJitcs in 1he 28-31.
Abamec1in is an avermeclio an1helmi1ltic used in veterinary S. Juns H, "ol. Oinical phllnl"acokinctk:s o f 1lbend.tt0le in chi I·
medicine for nemalocle infections. It is also used as a systemic !r:~~~~ o~~cic:~:'P:O~cc!}>~gQ~~fs~ ;~1~2~n1 dose or drcn with nc:urocysticercosis. Am J Tl~ 1991; 4: 23-6.
veti;rinary ectoparasiticidc. 6. Dayan AD. Albcndazole. mebcndu.o1c a.nd prniquan1cl : re\•iew
Effects on growth. A mulliple-doseregimen ofalbenduole in of notK:linkal toxici1y and pharmacokiMt1cs. •4c--tn Trop 1003;
children ,.;a, asymptonia1ic ttichuriasis has been reported 10 be U: 141-59.
All cross-reference~ refer to entries in Volume A
 Abamectin/Albendazole 147
Uses and Administration For ccs1ode infections the following doses arc rcco1111ncn<lcd: 6. Ki.'Shmiri M, et ul. Albtndnuh: \•t:r~ui. ph1.<:cho in 1rc:a1mc111of
cc:hi11ocC1Ccosis. Trcms RS« Trop Med Hyg 2001: 95: 190-4.
Albendazole is a benzimidazole carbamate an- • for eel\inococeosls children from 2 years of age may be given
7. fa~gas ME, Bliziotis IA. Albcnduolc for the ll'Cfltmcnl of hu-
thelmintic Sllucturally related to mcbendazole (p.156) a dose of7.S mg/k& !\vice daily (to a maximum daily dose of man echinoeoccosi.s: a rrv1c:v. o( contp:ir.itivc clinical lrials. ,.fm
800 mg) for 28 days; the 2lk!ay course is repeated after 14 J Med Sci2001: 334: lil-9.
and with similar aclivity. It is used in relatively high days without 1rea1mcn1 lo a total of2 to 3 treatment cycles
doses in the treatment of the cestodc infections cyst- • for neurocyst!cercosis children may be given a docse of
Giardia!is. Albendoi2ole has been tried in the treatment of giar-
icercosis and echinococcosis (hydatid disease). In diasis (p.9-08) with •-ariable results; however, a mcta-analysi.s 1 of
15 mglkg daily in 2 divided d<l5CS (to a maximum daily clo.\c
some countries albcndazolc is used in the treattnent of of 800 mg) for 8 10 30 days
8 ~ies suggested that an oral dose of 400 mg once daily for S
days was as effective as; and better tolcralcd than, standard treat·
single and mixed intestinal nematode infections in- Asatia.sis. ;\lbendazole is used as an alternative to mebenda- mcnt with IOCIJ'Onidttolc.
cluding ascariasis, enterobiasis, hool..-wonn, strongy- wle in the m:auncnt ofasc:ariasis(p.140). Both dtu&sareequally I. Solayrnani-Mohammadi S. •t al A mt1:.-onal.)"51s of the effec--
loidiasis, and tricburiasis. It may also be used in the highly effective ,.;th a cure rate greater than 98'.4 rcponed for liva'CSS of aJbcl'k:bmle compared w11h 1nt1ronid1zo1e as uu.1-
albendazole in one midy. 1 ments fM infections with G;o,t:/Jo d11~1tnlls. PLoS N~ Trop.
treatment of angiostrongyliasis, capillariasis, gnathos- o;, 2010; 4: "682.
lomiasis, and trichostrongyliasis. Albendazole may be I. Albonic:o M. et al. A ..-ndomizcd controlled trill comp:arina me·
bcndatolc ind albcnduolc againtt Ascaris., Trichutd and hook· Gnathostomiasis. Albendazolc has been reported 10 bcclfcc-
effective in the treatme111 of the tissue nematode infec- worm inrccli<lns. 7l·n.s R Soc Trop Med H)'g 1994: 88: SSS-9 tivc in the treatment of gnathostomiasis (p.142). Oral doses of
tions cutaneous larva misrans, toxocariasis, and trichi- Caplllariasls. Albendazole in an oral dose of 400 mg daily for 400 mg once or rwicc daily have been given for 2 or 3 weeks.I-'
nosis and has been tried in loiasis, and, with other an- I0 days has been suggesled' as an alternative to mebcndazotc for I. KraivicJ1inn P. et a l. Albcndaz.olc for ihc 1rcatmtn1 or human gna-
lhehnintics, in mass h'eallnent programmes in areas the 11'C1111ncn1 of capillariasis (p.141). 1hos1omia$is. Trall.f R S<>e Trop Med !~111. 1992; 86: 418-21.·
I. Ab111tnowicz M. ed. Drugs/or parasitic inf«tior.s. 2nd ed. New 2. Sunlharasamai P, ti al. Albend11zole 31imulatcs oulward migni-
where lymphatic filariasis is endemic. For discussions Rochelle NY: The Medical l<:Ucr, 2010. tion orGnathosloma spinigcrum lo the dennis in man. Somltea11
of these infections and their treatment, see under A.•101> .I Trop Med Public H1t1/t/1 1992: 13: 71~22.
Q1oie<: of Anthelmimic (p.140), and under the individ- Cutaneous larva migrans. Albendazole has bt:cn rcponcd 1" 3. Nontasut P, ''al. Compari~n or ivenncctin and albc:ndaiole
10 be ccrec1ive in the lrealmenl of cutaneous larva rnig1ans lKiltmcnt ror lilalhottomlasis. SomltlOJI Atfo,, J Trop Mtd Pr1b-
ual headings below. (p. t41) and is an allema1ivc to 1iabcndawle or ivcnnec1in. lk Heol1h 2000: 31: 374-7.
ln the treatment of echinococcosis, albendazole is giv- Albcndaicle. gcncr.illy in an oral clo.\cof 400 mg daily for thrce 1 4. Abramowicz M, ed. Dr~z•fw pot'OJitk l •/«ri<>M. 2nd ed. New
or fiw:l days. has alleviated the discomfort of culaneous larva RO<Mlle NV: The Medical L<11er, 2010
en orally with meals ma dose of400 mg twice daily for migrans; tn:atmcnt for seven days may be more clfccth'C and has H ookworm infections. Hook"''Oml infections (p.142) are
28 days for patienlS weighing over 60 kg. A dose of no1 been associ3ted with an inacascd incidence of adverse ef- commonly treated with benzimidazole carbamates such as
15 mg/kg daily in two divided doses (to a maximum fecis.• A single dose of400 mg has also been effective.1 An oint- albendazole. In 77 patients with light necatoriasis (NetXJtor
total daily dose of800 mg) is used for patients weigh- ment oon~ining albenda20le 10%, applied 3 times daily for 10 americorrus infection) a lbcndazolc, in a single 40<l-:mg ~pro­
ing less than 60 kg. For cystic echinococcosis, the 28- days, was reported to be effective in treating cut&nCOUs larva mi· duced an 84% cure rate and an 82% reduction in egg count in
srans in 2 young children.s those patients no! cured.1 In another study,' although the cure rate
day course is repeated after 14 da}'S ·without treatment I . Jones SI<, ~t al. 01'11 ~1btndatolt for the 1tc:11mcnt of cutaneous was only 56.8"/o after a sinS)c 400-ing dose of albendaiole this
to a total of3 trealtnent cycles. For alveolar echinoc~ . l•iva rnignons. Br J DmnatQ/ 1990; Ill: 99-101. was S\lperior lo treatment with mebendazole -.11ich bad a cure
cosis, cycles of 28 days of treatment followed by 14 2. Sangui&ni s. t!I al. Albcridazole ill the lhcrapy or 1.:ul:uu.:ous larva r.ilc of 22 .4%. A further Sl\ldyl con1paring albendazole with
mianms. Trtms R Soc Trop Med Hyg 1990; 84: 831.
days without treatment may need to contin ue for l. Orihcu l ~ AR, Torres JR. Single dose or albc:ndn.ole io 1hc 1rc:n·
mebendazole and pyrantcl in the treatment of nccotoriasiS also
months or years. incnt of cu1anc0t1$ larva· migr.an.-.. All'b Dcrmn1ol 1990; 126: fowld albendazole to be the most effective.
39&-9. Albendazole is given in mass trcanncnt programmes lo reduce
In the treatment of ncurocysticercMis, US licensed 4. Vcnldi S, Rizzilelli G Effei:tivencss or a new therapeutic rcai· the overall burden of infection.'·'
product information recommends doses of albendazole 1nen with albcnduote in. cu:ta.neous larva mi.vans. Eur J !Nrm"-
I. Nahmias J. et al. Ev:duauon or 1lbcndacle. pyrantcl, bcphc-
tnl 1999: 9: 3S2-l.
forparenchymal cysts simi lar to the doses used in echi- 5. Caumes E. EIT.c:acy or albe.ndazolc ointment on anant'OUS larva
nium.. pyranlcl-p-1iiquanttl end pyrantel-bephtnium foT single-.
nococcosis (see above); the recommended duration of dos.: 1nas.s lle3tment or neanoriasis.. Amt Trop Med Portni1ol
mi11ans in 2 young children. Clin/ef;.-a D<S 2004, 38: 1647-8. 1989; 83: 625-9.
treatment is 8 to 30 days. Expert opinion also favours Cystieercosis. 1bc use of amhelmintics in the trealment ofncu· 2. Albonico M. et ol. A randomitcd controlkd u-'81 com~mc·
similar doses of J5 mg/kg daily but \1-ith a duration of rocysticercosis (sec C)'Sliceroosis, p.141) rcrna.ins con1r0vcnial, btt.dazok: and albcndaiolt a.pins1 AICaris.. Thchuris and hook-
worm infce<ions. Trot11 fl Soc T"'p Ut:d HJ'!l 1994; 88: ~S>-9.
tttatmcnt of only 8 days for parenchymal disease and but if indicated oral albendazole is considctcd lO be the drug of
3. Sad<.o M. tt of. Comporison of tht ttliucy of mcbcnda>.olt. al·
about I month for extraparenchymal disease, such as choicc.1·l The dasc of albendarole originally uU:d was the same ba\da20lc and pynntcl '" 1rca11ntnt or hu:man hookworm infec-
as that used in echinococrosis, typically about 15 msfkg daily tjons ;n lhc southern region of Mali, West Aft-tc:.. Trans R Soc:
subarachnoid, ventricular, and spinal cord cysticerco- orally for I monlh. There is now some eviclence tl1a1 sh0t1er Trop Med Hn t 999; 93: IYS- 203.
sis. For further information on dosage regimens, sec courses of1rca11nent may be appropriate in some fonns ofneuro· .t. Idris MA. ~' al, EtlCclive con1rol cf hook:woml jnfe<tion in
Cysticercosis, below. cys1icorcosis. A srudy' confirmed that a IQ.day course of alben- school children from Dhoflr, Suhanate of Oman: a four-year cx-
daicle 400 mg twice daily, with dexamelhasonc, was safe and pc-ricncc with albcndu.olc mus.~ chc:mothcr.:ipy. Acta Trap 2001;
Albenda1..0le is given orally, usually as a single dose, in decreased the burden of para,ile;; and the number of generalised 80: 139-43. .
the treatment of single or mixed intestinal nematode seizures in patienls with viable parenchymal cysts. Albendazole Loi::.sis. Albendazole has been invcstigatt-d 1 ~ 10 reduce micro-
infections. The usual dose for those with ascariasis, en- hllS ulso been reported 10 be elfee1ive for cxtraparenchymal in· fiwiasis in palicnts inf~tcd with loo Joo (see Loiasis, p.143)
fc~tion. such as subaracbnoid, veutricular,l.SA and spinal cord ,yjth modest success.
terobiasis, hookworm infections, or trichuriasis is
cystictrcosis,1 but the longer treatment period of l month with a 1. Kl ion AO. fl ol. Albcndazolt- in hu1n:1.11 lcHasis: r~lts of a Juu·
400 mg as a single dose; a 3-day course of treatment is dose of 15 1ng,'kg daily is usually used. Alternatively, a higher bl.,.blind. pl•ctbo..:ontrotlcd lri•I. J hif"t Dis 1993: 16S:
needed for heavier infections with trichuriasis. In cn- dose of albcnda20tc for a shoner time may be considcn:d. A 202-6.
terobiasis, the dose may be repeated in 2 to 4 weeks. In study' of36 patienL< with subarad1noid and intTavcnlricular eyst- 2. Tabi Tf... ~ nl. Human k>iasfS in a Cameroonian village: a dou·
strongyloidiasis, 400 mg is given ooce Of twice daily iccn:osis found that 30 mg/kg daily for 8 days was safe and more ble·blind. pl1c.cbo-conuolled.. cros.sover clinial viii or a thrtt·
effective than 15 mg/kg daily for 8 days, boCh regimens being dayalbcnduolc «&i•ncn.A.. J Trap Med H)lg 2004; 7J: 21 t-15.
for 3 consecutive days; this may be repeated after 3 given with cOtticosteroids. Lymphatic lilariasis. Although the cvideooe for such use is rel·
weeks if necessary. t. Sotelo J. Juns H. Phinnacokineiic opt1n1tG11on of lhe 1re1tmcnt ativcly wcak, 1 albcndazole is used in the management of lym-
Albendnzole has also been used to treat giardiasis or neurocys:tieercosjs. Clin Phonn«Oltmttt t993; ll: so;- 1S. phatic fil8riasis (p.143). In cndcinic areas mass tn:almcnt of the
2. Taklyanagui OM. Therapy for neurOC)'S11ccrcosis. £¥~,., Rn1 entire population (excluding ncona1es, pregnant women, and de·
(p.908); suggested oral doses are 400 mg daily for 5 Ne11rother 2004; 4: 129-39. bilitate;l individuals) with appropriate drugs can reduce the in·
days. ) . Del l)ruuo 011, d al. Mcca-an11Jysis: cy11icid11 dn1as for nturo-
tensity of transmission and the incidence of disease. The Global
cy11icercnsii: ::ilbend.-zole ;:ind pr:n:iqu1n1el.A1m lnlCl'lf Med
For details of doses in children, see below. 2006: 145: 43-51. Programme to eliminate Lymphatic Filariasis launched by
4. Garcia uti. et al, A trial of an1iparasilic irealnlcnl to reduce the WHO, with other international agencies, advocates a single oral
Adm inistration In children. Albendazole may be given oral· rate of seizures due to ccrebrnl C)'Sticetcosis. N £,,~/ J M~t/2004; dose of albendazolc400 ms wi1h either a single oral dose ofivcr·
ly to children for the 1rc.1menl of singte or mixed in1es1inal 11cm· 350: 249-58. mectin 150 10 200 micro~ramslki& (if there is co-endemic loiasis
olode infection.' and for ccMode infections such as ncuroeysticcr- S. Oongoro-Rivcr• F. e1al. Albonduolc trial a\ IS or 30 msJ!lglday or onchocerciasis) or with a single oral dose of dicthylC11r-
cosis ond echinocoecosis. ror,subarachnoid and i:llta\"tnu-icular C)'S\iccrcmii. Nt!uralogy bamazinc 6 mg/kg (if th.re isnocCH:ndemic loiasisoroncboc•r-
2006; 66: 436-.'l.
For nemulode infections the following doses 3rC recommended: ciasis): 1hese dosc:s arc aivcn once each year for at least 5 ye:irs.
6. Proa1'o JV, e1 ol. Medical treatment for neuroc)'s:ticcrco$iS char-
acterittld by giant subaradinoid cys1s. N £11gl J Mtt/2001; 345: I. Addiss 0. ~' ol. International Fllaria.sis Revlew Gro1.1p. AJbend:a·
• for .ascariasis, enterobi1lSis, bookworm infections, and tri- $79-M. zQlc for lympNiuc fitarusi:s Anilablt in The Cochrane Data-
chosrrongyliosls children from 12 months to 2 ycaB of age base of Systcmanc ltcvf<.,•. Issue 4. Chic'1cslcr. John Wiley;
may be aiven 200 mg as a single dose and those mo~ than 2 Echinococcosis. Albcndazole is used in the 1reatmCl'll of cch.i- 200S (occused 16110/09)
years of age may be given .WO mg as a single dose. For enter· nococeosis (p.142) as an adjune1 to, or instead of; surgtt)•. II is
generally preferred to mebendazolc. Microsporid'iosls. Albcndazole has bttn tried'"' in ~treat·
obiaslS infcc1tons the dose should be rcpeal<d after 14 to 2S ment of the protozoa! infeelion microsporidiosis (p.911) in po-
days ReferCt\CCS. tients with AlDS. Albenduote has also been used empirically in
• for capillariaslt children from 2 years of age may be given a I . Tcgsi A.nu/. Thcrapyofhum3nhydatid Jiuue withmcbcnda- the \TCatmcnt of HIV-associated infections and complications
7.ole •nd ol~nd:tzolc, Antimkrol> Agtms C/tcmotl1cr 1993; 37:
doseof400 mg daily for tO days 1679-84. (p.946).
• for srrongyloldlasls children from 2 years of age may be aiv- 2. Gil-Grande LI\. et al. Randomis'd controlled trial or efficacy of I. Blan5h.ard C. tf of. Trc:umcnl of intC$1inal micfO!iporidiosis with
en a dose of 400 mg onoe or twice daily for 3 doys; the dose albtnd.:itol~ in intra-abc.lomirn1I hythilid disease. Lllnce1 1993; olb<nd•1.0le in po1icn11 wilh /\IDS. AIDS 1992; 6: 311-13.
may be 1~pc:11 ed after 3 weeks if necessary 3~2: 1269-72. :!. Dieterich OT. tt al. Tre1umcnt with albeOO:n:olc: for intntinal
3. Wen H, n al. lni1ial observa1ion on 1lbcndu.olc in combination disrasc due 10 E111crocytoioon ~i<: n c:usi in patients with AlDS.J
• for trlchurlasis children from 12 months to 2 years of age with c:imctidine for th' treatment of human cy,.tic echinococco- lnfw Dis 1994: 169: 178-82.
may be gi,·cn 200 mg ilS a single dose for moderale illfcctions; sis. Ann Tmp Med P11ros1tol 1994; 88: 49- 52. 3. F.=anun C,et al. lnh:s.tinal micrusporidiosis with Seprata intcsti-
for more severe infections an initial dose of 200 mg is given 4. Wen H. et al. Albcndazolt chcmothc:npy for human cystic a.nd nalis in a patlent with AIDS-response 10 albendazolt. J hf/«1
alveolar echinococcosis in nonh•WC:!tcrn Chin3. Tnm.s R Soc 199S;JI: 237- 9.
followed by I00 mg twice daily for 3 days. Those mo<e than Trop Med H;vg 1994;88: 340-l. 41. OoteGJ. 11 ol. Disscmi1\3tCd micro:.-poridiosis due to Sepc:ita in-
2 years of age may be given 400 mg as a single dose for mod· S. Liu Y. ti ol. Conlinoous lonf•krm •1"ndnolc therapy in in- 1estin111i.\ tn nine paticnls infected with lht human immunodtfi ..
crate infections; for mo~ se...e.c infections the usual dose is tra.abdominal cyslic cchinococcosis. Cltin Mtd J (Engl) 2000~ cie~y virus: rtspomc 10 therapy "'ilh albcndazole. Clin ln/ttt
400 mg daily for 3 days 113: 827-32. o;, 199S; lt: 7o-6.
 148 Anthelmintics
S. Molina J-M-. ~' al. Albcnda.tole for U'Cllmea1 and prophylaxis of Zettet Cz.: antelt: Fr.: Eslwole: ~ Gv.: Ell<>.tole: Gr.: Ell<azo:e: Antimo ny Sodium Tartrate
microsporidiosis due Ene-epha1iluz.oon intcsuna1is in pa!iC11l$ Untd: India: Alberole. Bcncltl( ~A; Emantllalt, Ncrnmo:c:
"ilh AIDS: a nndomizcd double-blind conttolltd trial. J In/eel o-m Zentel: /srae~ Esbzolt: ltol.: Zemel: Moloy1/o: Abondo't: Antim. Sod Tart.; Antirncnco scSchco. tart.rato: Sodi.m Anti'no-
Dis 1993: J77: 1373-7. Ahle><: Champ> 0.Vo.btms: ~n<: Thelb¥< Vemiwl: Zetllet Zoben: nyftartnte: Slib-..,, Nari.Im Tartaricum. Disodium bi;{l'"f2,3-d-
M t•.: Albcmilt; Atdom'n:Alrazot~&adelmiri; o.zoc.n.~

-en:
6. Trcm(lulet AH, et nl. Albt.nduolc ther•J)Y for Microsporidium hydroxybuw>cdioato{"l·)-01,01:0l.O'J}diantmonate(2·): Oiso-
diarrhea m immunoeompc1cn1 C-o5l• Rican ch ildr~n. PdioJr /n- ~ubilc o'i"UnOt ~ E11<Wc £...->11ien: flztezolt. Helm· c..cco:
fttt Di1J2004: 23: 915-18. i<Ons1: llodt>; KolO>W< i.o-.< Ll.fnbrilar: Lurde>< Olbencfalj: RNm>t Ser· dium bis{.,-(L-(+)-tartrato(4-)J)d1an1Jmono1C(2·~
bendazot: S)'l'1>ll)'n: Teribe>C: Ve<an>ol: Vermin Plus: Zelfon:
Strongyloidiasis. Albcndaz.ole is generally preferred 10 1iabcn- ze.,axin: Zent« Neth.: Es<azote< Phlllpp.: - 8eruct Zen'.el: Pol.: AMTID...OK1t'\-'T~PTP3T HaTp•itR
da.zole or mebcnda1..0le in the treaunent of strongyloidiasis Z"'11et Port.: Zen<et Ru..: Nemozolt (HeMo>c>.). $.Afr.: Bendox Wo<' C 1H,Na2012Sb2 = 581.6.
ma.dolt! Zentcl: Slneopore: Alz:em.at 2emet Spoi": Eska:zole: Switz.:
(p.145) 1lthoush h-.:rmcetin is now gcnenlly considered to be ZMl<t Thal.: Abcntcl: Albatet Al>en: M>er>Hara Al>cnda: Al>enz: Aft>. CAS - 34511 -09-0.
the drug of choice. Both drugs h•ve been used together in dis- aol; "lck: Aldazo'<: Alfuca; Alzol: An:llOdo: Anthetf: S.")'id: foben< fztet P hannacopoeias. Jn Int. {as C,H4 Na0,Sb ~ 308.8) at>d US.
seminated disease. Gelldazet Llbenda: Leo-'IO:>; Manazide: ~ My<otclt. Prodazolr. ~ USP 33 (Antimorl)' Sodium Tartratej. Odourless. colourless,
Salt Verrnixide: Vetobtn; Zol:te:t Zeta: amel; Zenzeri: Turi<.: Anda2<>l
Ref~ UAE: Abenda: Ul<r.: ~ (Bop.,""): USA: A1bcnu: Vtt>Ut Al>ezot ttansporent crystals or white powder. The ayslals dllor~ on
I Rossignol JF, Maisonneuvt H. Albmduole: ph1«bo--controllc:d Abicar: a..Mdazot Held;~ tarorc Vendazot Zcnl<l exposure to air. Fn:ely soluble in water; insoluble in alcohol.
study in &70 .patients w•lh intestmal helminthiasis. Ttons It Soc Hu1ti·ln&redient: Mex: C Cobrsul: fomvver: ())Qt Thol.: Alblmcd.
Trop MOii Hyg 19SJ; n: 707-11.
2. Ch11uh1\'antd' P. et ol. Repeated doses of albendatok a"°insl Sodium Stibocaptate (BAN.llNN)
strongyloidiuis in Thii children. Sou1heas1 Atioo J Trop Med Antimony Sodium Oimercaptosucooate: Estiboc.aptato de sodc,
Pub/I< H<nlth 1989; 20: 221-6.
3. Mojon M. N.etsen PB. TTeatmcnt of Stror\iYloides sccrcoralls Amocanine (tlNN) Natrii Stiboc,apw: Ro-'4· 1544/6; Sb-58: Stibocaptate; Stlboc,ap-
with albendnolc: a cure ral.C of86 ptr CCl\l. Zvrrralbl Btlkt~rlol Arnocarzna: Amocarzinum: CGP-61"1(); Phenthi~; S. me de Sodium: TWSbl6. M.:roony sodium meso-2.3-dinerGaJ>
MibobKJI Hyf (A} 1987; 263: 619,-24. f()OJ 6. q.Methyl-4'-(p-ri".manilno)thio- I·piperazinecasboJCalli- tosuccinate.
4. Archibald LK. et o(. AJbendazok is cO'cctivc lrCatmen1 (Of
clironiC$1rongyloidiasis. QJ Mn/ 1993; 86: 191 -S. lide. The formula varies Crom C 12H1 Na0 12SoSt>, 906.1 to =
Pom$Uriyasak P. el o/. Disseminated srrongyloidiuis succ:cssful· c.,H6Na1.01~Sbi =9 I6.0.
AMoi<ap:lMH
1y trc11cd with extended duration ivcrmcc1in combined with aJ.. HaTJ>l'A Cn.6oi<=
bcndar.oJc: :a cue rcpon or intractable strongyloidiasis. South· c,,H21N)02S = 311.s.
#OJI Asinn J Trop /.Wd 1'11bllc ffMltlr 2004; 35: Sl I~. CAS - 36590.19-9. CAS - 306.f·6 l-7 (C 11 H6 No6 0 1,S;$b;).
6. Singthong S. et al. Random lied compantivc uial of IWO hi~· UNll - 99807U4 I ZY.
dose 1lbtnduolc regimens for uncomplicated human stron1>1loi· Stibophe n
diosis S<H.1•01m Asio11 J Ttop Med Publk: Health 2006; 37 (sup-
pl 3): )2~. Estibofeno; Fouadin; S~m. Bis['4.5-dth)odroxybenzene-
Toxocariasls. Albcndazole is one or the drugs that might be
l .3·disulphonato(4-)-0'.CP)antimonatc(S-) pentasodrum hep·
tahydrate.
used for1he trea1mcnt ofloxocariasis (p.145) hut published con-
trolled studies are mostly Jaclcing. ln a small srudy 1 it produced CTH6o+ett
improvement similar 10 that achieved with li•bendlzole bul with c,,H,Na~Ol6S,Sb.7H20 = 895.2.
fewer problems. CAS - 15489-16-4 (stibophen hep1ohydrate).
I. S1Urchlcr D, t.t ol. lliiabend:iwle vs albmdazoSc in 1rc1tme1n of ATC - P02BX03.
1oxoc,1ri:uis: a clinical 1ria1. Ann Trop MM Parosirol 1989: 83:
47)-8.
Trichinosis. Albendazole may be effective io the trcalment of NOTE. Amocarzinc hos sometimes been referred to as thiocar·
trichinosis (p. 145). A re1rospcc1ive srudy in 44 paticnis wi1h bamazinc. Na•
lrichinosis comparing albenda1..0le treatmeni with tiabcndazole Profile
found 1hat, while thc 1wo drugs were of oomparablc efficacy, al- Amocanine is an antifilariaJ anlhelmintie !hat is a<:tivc against
bendazole was the helter tolerated. 1 Albcndazolc has been used the adult WOm>S or Oncltocarca vofl'MIUS. II has been studied for
to trca1 a patien1 infected wi1h Trichine/la pseudaspiralis, l!J1 or- the or.ii treatment of onchocerciasis (p.144).
ganism related to T. spiralls, tl1e usual cause ofoiehinosis.1
I. CabiC A.~' cl. Albenda20lc versus lhi'J'bcndu.ok: H 1her.ip)' for OReferences.
1rich1oosis: a retrospective study. Cun Jnftct Dis 1996; 22: I. Pollefl AA, <I of, Onchoc<fncidll cfTecls of am0«1rz.ine (CGP
1033-S. 6140) io Ltlio America.Lone« 1991; 337: 583-4.
2. AndrC'WS JRH, ct al. Trichincll1 pscudospitalis in human&: de· 2. Coo~r rJ. Cl ol. Onchoccrci:asis in EcuBdor: C\'OhJLio.n of chori· Adverse Effects and Treatment
scription of a ea.$e and its lreatmenL TratU R Sue Trop /tkd Hyg orecinopalhy after amocaninc treatment. Br J Oph1hal11tol 1996; Trivalent antimony compounds are mere 1oxic than pentavaJenl
1994; 88: 200-3. 80: 337-42. antimonials such as sodium slibogluconate, possibly because
Trichostroncyliasls. Albendazole in a single or•I dose of 3. Awadz.i K~ ~I of. The safety and efficacy of amoeanfoc in A fri· they arc excreted much more·slowly. The most serious adverse
can onc:hortrcia.sis 1nd the influence of iYemt«hn on the d in..
400 mg has been suagcsted1 as an altemali\'c to J»tarllel em- cal and pata$llologieal response 10 ll'Utma'M. A1t11 Trop Me.d Par-
effects are on the hean and liver. There are invariably ECG
bonatc or mcbendozole in lhe treatmcnl of lrichostrongyliasis tlJrtol 1997: 91; 281-116, changes during trealJ'TICnt, hul h~ension, brndycarclia, and car-
(J>.145). diac arrhythmias are more serious. Sudden death or carcliova.'ICU-
t Abramowicz M. ed. Dr11g1for porositk inf«.1/ons. 2nd ed. Ne~: lar collapse may occur al any 1ime. Elcva1ed liver enzyme values
Rochelle NY: The Med1c1I Leiter. 2010. are common; li\'Crdamage with hepatic failure 3nd dcolh is more
Trivalent Antimony Compounds likely in pa1icnts wilh pre-existing hepalic disease.
Trichurlasis. Oral albenda1.0le is used in lhe trealment ortrichu·
riasis (p.146). h is nonmlly given in a single dose and is often Compucstos de antrnor.io trivzlente. Adverse clTCCIS immediately after inlr.l\"tnOUS use of trivalent
used in mixed intestinal nematode infections.' However, it has antimonials, in panicular the ta11rales, have included coughing,
Tpex~ C~HeH'1ll Cyp,,...,.
been rcportcd 1'J that in children wilh mixed inlcstinal worm in· cliesl pain, pain in lht anns, \'Omiting. abdominal pain, fainting.
feet ions single doses of albendaw le are ineffective in eliminal· and collapse, especially aC\cr rapid injection. Ex1ravasa1ion dur-
ing Triclruris lrlclliura and multiple doses 11e required 10 pro- Antimony Potassium Tartrate ing injedion is extremely painful because ofussue damage. An
<Nce worthwhile reductions in egg produclinn. Treatmenl for 3 Anllm. Pot Tart: An~mdnico poWico. W1rato: Antymonu anaphylactoid reaction characterised by an urticaria! r.ASh, hll$l-y
days has been used for bcaviu infections• (but for a suggestion potasu winian; Brediwensten: Karn Stib)'fi Tanta$: Potassium voice, and collapse has been reponed after the sixlh or seventh
lha1 StJch regimens may be associated with impaired growth in intravenous injection of a course of trcatmcnL
Antirnonyltartrate; Stibi et Kal11 Taro-as: Tartar EmetJC Tartarv>
leu heavily infected children, see Effects on Growth under Ad- Stibi3tus. Oipotassium b s{µ{2.3·d 1nydr(l)C)'bvtane""-to(4·)· Many Jess immediate odversc clTeclS have occurred including
verse Ef!'eclS, above). Combined use of albcnda1..0le wilh iver- o•.o1:0'.0'))-0ontimonate(2·) trihydrate: Oipotas.sium bis(p· gastroin1cstin1J disturbances, muscul3r ond joint pains, 3nhri1is,
mcclio may prove =ful.5 A sys1cma1ic review' howcvet con- tartrato(~·)]chnii:nonate(2·) trih)odnte.
pneumonia, dyspnoea, headache, diuillC$$, weakness, prurirus,
sidered that 111 CWTCDt reginicns for the trcattneol oflrichurfasis skin rashes. facial oedema, fcva, haemolytic anaemia, and kid-
were uns•tisfaOIOf)'. At<n<MOM<I\·np-rpaT l<atl'1R ney damage.
I. Hall A, AnM.r KS. Albcnd.nole and lnfcctions with Trichuris C1H.Kp ,iSb;,.3H20 ::: 667.9. Large oral doses of 3ntimony coonpowids have an emetie action.
lridi.iut3 and Oiardio intcs-tinaliJ. So11'h~m' Asian J Trop Med CAS - I I 071-1 5-1 (anhydrous antimony potossium tot· Conlinuous 1tealmcnt with small doses of :1111hnony may give
Public ff•alth 1991; 21: 84-7. 1101e): 28300-74-5 (antimony potassium toruo1e lflhy- rise 10 >ymplomsofsubacule poisoning similar IO those of chron·
2. Hall A. Nahar Q. Albend:u.ole 1nd infections wilh Ascaris tum· droie). ic arscnical poisoning.
bricoidcs and Trichurit trichiun in children in Bangladesh. UNll - DL60Z476V3
T'anz R Soc Tt"OpJl•d lln 1994; 88: 110-12. Trealmcnt ofsc'"'"' poisoning "'ith anlimony compounds is sim-
). Albonico M, er al A randomiz:tJ controlled trial compuing me· ilar to that for orscnic poisoning (p.2473); dimcrcaprol may be or
bcnduolc and albendazolc :a11ins1 Ascaris. Trid1uri1 ind hook· benefit.
worm infections. T'ans R Soc '/'t'op Mw ll)'g 1994; 88: l85-9.
4. Abra?n0'4itt M. ed. Drogsfor porOJitic in/«tio11s. 2'nd ed. New
Rochelle NY· The Medico! Letter. 1010.
.S. Ismail MM, Jay•kody RL. Efficacy of albc-nduole and its com·
bill3tion.s \titilh ivcnneccin or dicthylcarbamn.inc (DEC) in the
K'
0)
\ I
o, ,0 o, ,0
Sb" Sb"
t K'
0 References.
1. Slemmer KL Ph5rm1cok>gy ond toxicology of hClll\. y meals: :iin·
litnony. Phtmnncol TJ,u 1976; I: 1~7-6-0.

Precautions
uea1ment orTrichuris 1ridtiura infec1ions lri Sri Lanka. Ann Trop
Med Parosltol 1999; 93: SOI~. o" ·o o" ·o Tri\Oalcnl antimony therapy has generally been StJperseded by

~0
6. Kcisc.T J, Utzinger J. Efrteacy of c:urrc:nl dNiJ 1pins1 .IOil·trzns· I \ Jess 1oxic ircabnenL It iscontn1-indicattd in the presence oflung.
milted helmin1h inf~ioN: sys.tcmatic rc\•iew and md.a...analy·
Sts. JAMA 2008; 299: 1937-48.
o) l>ean, li•cr. or kidney disease. lntra"ci10us injections should be
given very slowly and stopped if coughing, vomiting, or subs1er-
Pre parations nal pain oe<:urs; extravasation should be ""oidcd.
Phannacopoeias. Jn US.
USPJJ:~Talllets. Soine anlimony compounds >'UCh as lhc tmtratcs cause severe
USP 33 (Antimony Pota.ssUn Tartrate). Odourless. colourless..
Proprietary Preparations (detail• are a•v"!' in Volume B) pain and tissue necrosis and should no1 be aiven by intramuscu-
1r.1nsporen1 crys1als or white powder. The crystals effiorcsc:e on
Atr.: V.sM: llermizole: Aurttol.: E$bzcle: Zentet Aurt<ia.: ESl<ozolc lar or subcu1a11cous injection.
c.'posure to ~ir and do no1 n:adily rehydrnlc C\Ocn on exposure 10
, &vz.: Aba·3. Albel: Al>ent, Abenct'co<f; Albendy, .Albcniq: Al!l<ttet Alo high humidity. Soluble J m 12 of waler, J in 3 of boiling waler, Breast feed"mg. The American Academy of Pediatrics' sta1es
~ Albezint. Albf; Nn Alzc:t>ent. 8ent..,.,.>t: Bentct -
Meter<>< Mooozot Neo 8et""2ot P..-.sn: Paruolt. fct~ Verdizolt. and J in I5 ofglycerol; insoluble in alcohol.IIS solutions are acid 1ha11here have been no n:ports of any clinical effec1on1hc infant
\le"tricla••:: VOll"Rilat Zenlel Zclt>en: Zold°'t; Chile< Cepr.zol; lletTnc*. to litmus. 8SSC'Ciated with the use of aniimony by bttast-fccding mothers,
All cross-references refer 10 entries in Volume A
 Amocarzine/Clorsulon 149
and that therefore it ma) ht considered to be usuolly conipoublc Betanophthol has a po1en1 parasicicidal effect and has been used C:ambenduole (81\N, USJ.N. •INN)
with breast feeding. topically in the trcaonent of SC'lbies, ringworm, and other skin
t. American Acodenly C)fPcdiatrics. The transfer M dn•af.; :lnd 01~ diseases. Cambcndazol ymbeodazo!um: MK-905. lsopropyl 2-(thiazol-4-
er chcm1al~ inlo human milk. Pedi01rk~ 2001~ 108: 776-&'9.
Betanophthyl bcnzootc has been used in prcparalions for the yl)· I H-benzimiduol-5-)karbamate.
(Reti~ M•y 2010) CorTettion. ibid.: 1029. Also nvailoble ot:
h11 r:lluppo Ii c y. 1 appnbli cat ions .ors/cgi /coneent/ fo 111 treatment of gastrointesti031 disord=. l<aM6e>Wl!OJ\
pcd1atncs%3b10&/3i776 (accus-d 02l06/04) Preparations C,.H,,N,015 = 302 4.
Glucose-6-phosphate dehydrogenase deficiency. ln the Proprietary Preparations (derails are tPYCn in Volume B)
event of111'-alcn1 antimony compounds being used. patients witl1
CAS - 26097-80-J.
G6PD deficiency should be excluded. WHO lists stibophen 1 Multi-ingredient: Ari.: t·!Mbetol; Austria:~. ATC Vee - QP52AC08.
among lhc an1helmin11cs to be a,-oided in patients \\oith this defi. UNli - 079X63S3DU.
ciency.
I. WHO. Oluco.c·6-phospha1c d<hydro~tn»c dcr.cicnc:y. B•ll
WHO l~~?i 67: 601-11.
Bithionol t'Bo'N IHI)
Pharmacokinetics B:tllionololvm: Bith:onolum: 8-tionol; Bitionolol: Bitionoloi. 21'·
Antimony compounds are poorly absorbed fron1 thc gas1rointes. 1hobis(4.6-dichlorophenol).
tinal tracL They arc slowly cKcretcd, mainly in the urine, after 6KTl<OMOJ\
parenteral doses. Antimony accumulates in the body during
trca1n1cn1 and persists for several months aftenvards. Trivalent
=
C 12 H,et,o,s 356.1.
antimony has a greater affinity for cell proteins than fot plasm• o.s - 97-18-7.
proteins. ATC - DIOABOI. P028XOI.
P rofile
U ses and Administration ATC Vet - QDIOA801: QP5 2AGOi
Cambenda2ole is a btnzimidazole earbama1e anthclmintic struc-
Trivalent ancimony compounds were used in the trealment of the UNll - AMT77LS620. tur:illy related to 1iabend:izole (p.164). It is used in 1he treatment
protozoa I infeccion leishmaniasis until the ad\'ent orthe less to>.-ic ofstrongyloidiasis.
pentt\'alcnt compounds. They continued to be used in the treat·
ment of schistosomiasis, but ha\'C now been superseded by less P reparations
toxic and moce easily given drugs such as praziquantel.
Cl OH*CI Proprietary Preparations (details are siven in Volume D)
Antimony sodium tartnlte was fonnerly ~ as an emetic. The
sodium tartrate and pota.ISiuin 1artr11te ha\"Calso been used as ex- I~ &o>.: c.mo.mt.
pectorants. · Muld-in&...,dient: Bro..: Eidmint.
Cl S h Cl
Preparations
Propri.,tary Preparatio.,s (ddails are given in Volume B) OH
Multi-inaredie nc: Port.: Sto&t Thai.: 2rcM'l MC<lure Chenopodium O il
Pharmacopoeias. Fr. includes bithionol o.~ide for ""tcrinary
Homooop•thic: Austral: Alorgy 116<~ Cold & Flu l1cspa1ona ~ use.
-rt: 01..-rtioea Relief Tablotst; N.lu<•a flektft: flesp>tona Che<ly Aceite de querioposio; Aethcrolcvm Chenopodii: &enc~ de
Coui1> & No..r Congestion: Stodllj: Ain<rfo: Atmat: 8ronchaJis.Httt Ad verse Effects Q.Jenopodio VenM.Jga: m of Americ;n Wormsttd; W\.nnsa-
~ Nr 2; Tartej)l>cacd: lOnson clwQnis..-h: Broa:.: Tnlcolf: menol '
CA110<1~ Acttj; Bmc.o.;n; llmrl<tot Catnor: Cou C~ C.Oug'1 S)'l\4) Advctse effeccs in patients taking oral bithionol include anorc(ia,
with Honey. H)lands C0<>21"c Hyllnds Fotmull CSt Stoda'. Cz.: BrOncMJis· ~ vomiting, abdominal discomfort. dionhoea. salivation,
Hee~ Fr~~ No T2: Cctraria ~No 6t: Homooecnc Ii: AM&,>v.... eeoe Mac'IO; Mape!!Oe Mac""
dizziness, headache. and skin rashes.
Homec&'W« tpou Compose: P.JmG-Dranol: SIOdot G•'-: A,gMslnt: CAS - 8006-99-3.
BomortM>s~~ ~Ccich<ymc~t. Pho1oscnsitivity «:actions have occurred in persons using soap
fa.opatorium N ~ Ml<oncl>an Ct;~ 2: Rc.piro~j·: containing bithionol. Cross-sensitisation with ~r halogenated UNI/ - 3009681 U6R.
Rhe<ma·HCVC!'t ~·s luCT Tropfent: Rif.ebr.n btor>cho; Vomistop: disinfectants has also occuned.
N eth.: Stoel.II: Rui.: A11no (AT>·~~ Stodal (Cto..,..). S.A(r~ l'narnod:ir· Profile
on 2t, Swlra:.: Stod<l. Uses and Administration Chenopodium oil is distilled wilh steam fiom the fresh flowc1ing
Bithionol is a chlorinated bis-phenol v.ith bacccricidal and an- and fruiting plants, excluding TOOis, of Chtnopodium ambrosio·
chelm intic properties. It is active against most trematodes ides var. anthelminti<:1un. 11 conu.ins ascaridole (p.149) and was
(flukes). Bithionol is used m preference to praziquantcl in fasci- forme rly used as an anlhelmintic for the expulsion of rounll·
Ascaridole oliasis as an altcrna1ivc to trielabcndazok (see Liver Fluke Infec- wonns (Ascaris) and hoo~rms. It is toxic and has caused
Ascaridol. 1-lsopropyl·4·methyl-2.3-diol<llbicyclo[2.2.2]oet· tions. p.143). It is also used in pa111gonimiasis (see Lung Fluke many fatalities.
5-ene. Infections, p.143) as an alternative to pnziquantel. It may be giv-
en in an on! dose (If 30 to 50 mg/kg on alternate days for 10 to Handling. Chenopodiu1n oil inay e.plocle when heated.
Ac..p~Oll 15 doses. Shorter regimens h3\·c been used.
C10H ,,01 = 168.2. Preparations
Bilbionol wu formerly used copieally as a bllc:rcrieide but lhis
CAS - 512-85-6. use has declined because of photoscnsitivity reactions. Proprietary Preparations (dc1.,1s are &imi in Volume l.ll
Prepara t ions Homoeopathic Fr.: Cin• C""'fllcwe No~~
Proprienry Preparations (tkcails arc given in Volume 0)
Multi~ingredi e.nt: Arg.: Fonetp.

Clorsulon (8AN. USAI'{ IN'IJ

Clonul6n: Clorsulonc: Clorsulonum: MK-40I. 1·.Amnc>6-
Bromofenofos ('fNNJ
(trichlorovinyl)ben,ene· 1.3-disulphonatnide.
P rofile 8romlcnoros; 8romofenofos; 8romofenof6s: Bromofenofosum:
Ascaridole is che active principle of chenopodium oil (p.149) and KM>pcyl\OH
has the same actions. B1'00'lerphenophos; Broinphenphos. 3.3'5,S'•Tetrabromo· 2.2' •
biphenyidiolmono(dil)'droaen phosphate). C,H,C13NJO,S1 = 380.7.
Handling. Ascaridole i$ •n un:;table liquid chat is li>blc to ex-
6pOM~Ho4>0< <.AS - 60200-06-8
plode when heated or when trc:u.:d with organic acids.
C12H1Br,OsP =5818. UNll - EG I ZD06LRD.
CAS - 21466-07-9.
ATC Vet - QPS2A802.
Betanap hthot UNll - XTH86 I Q3CR.
fl-Naltot 2-Naftot Naph1hol. Naphth-2-ol
6eTa·M~T~
C,oH 80 = 1~4.2. Br
CAS - 135- f 9-J.
UNll - P2Z7 ICIKSH
Br

~OH Pharmacopoeias. lo US for veccrinary u.•e cmly.

USP 33 (Clorsuon). A whice to off-white powder. Slighlly sol-
~ uble in wacer; IToely soluble in acctonitrile and in methyl alcohol;
very slighcly soluble in dichloromcthane.
Pharmaeopoeias. In Pol. 3nd Swiss.
Profile Profile
Profile Broinofenofos is a bisphcnol derivati»c used as an :uithelmin1ic Clorsulon is a sulfonamide on1hdmin1ie t-' in veterinary med-
Bctanaphchol was fonnctly used as an anlhchnintie in hook- in \'eterinary medicine for the crcalmcnl of fluke infections. icine for the !Raiment oflivcr nuke infoeiions.
wonn and tapewonn infcctions. but it has been •upo:fS<ded by
less toxic and morectricient drugs.
lbe $)1llbol t denotes a preparation no longer actively marketed
150 Anthelmintics
C losantel (11AN. USAN. rl'IN) Profile cease spootaneou.•ly and interruption of treatment is rarely
Oichlorophcn is an amhclmintic that was used in Ilic \leahncnt of ncces."'1)'; symptomatic treatment with antipyretics or analge-
Closantelum: R-3 1520. 5'-Chloro·1' -(1·chloro·«·cyanobenzyl)·
infection by tapeworms but has been superseded by praziqusnlel sics may be helpful.
3.5-di-iodosalig.1-o-toluidide. or niclosamide. lAcal 1-eoctions tend 10 occur later in the coutsc of\leatmcnt
Kl\03aH1e" Dichloropl1cn also has antifungal and antibacterial act.ivity and and last longer; they also disappear sponuneously and inter·
CnH;,Cl2l2N202 = 663.1 has been used topically in die trcanncnl of fungal infecHons and ruption of \leatmcnt is not necessary. Local reactions include
CAS - 57808-65-8 as a gennicide in soaps and cosmetics. lymphadenitis, abscess. ulcc111ion, and uansienl lymphoede-
ATC Vet - QP52AG09. Hyperse n$itivity. Oichlorophen is used r~ its antibacterfal and ma; fimiculitis and epididymitis may also OCCtlt in bancroftian
UNI/ - EUL532EIH anlifunpl~ies in various manufactured products and thele filariasis.
is a report of a patient whose ecut1l3 of 1he lunds and face and It has been suggested that !he n:lcase or interleultiH may be im-
vesi<:ular-bullous lesions or the feet ~ associated with 1he plicated ill dielhylcubomazine's adverse effects in patients ,.,;th
Cl presence or dtchlorophen in 1he leather ofber shoes. h was of l)mphalic lilariasis.2
I note that 1he appearance of the reaction 10 dichlorcphen in palch In mOSt patienl• with onehocerciasls.1he microlilaricidal activi-
1esring was delayed for 10 days. ty or diethylcarbamarine leads 10 a series orevenis with dermal,

~:
1. Barbuzu 0, ct al. l_.1tc patch test reaction to dichl0tophenc. J ocular. and systemic components, known as the Mazzo/ti rea<:-
ltnwtlg All•rgol CHtt /mmunol 2008~ 18: 317-S. tion, wjthio minutes to hours after i1s use.3
Preparations • Clinical manifestations can be severe, dangerous, and debili-
BP 2010: OtcnlorOfllv>n T•blet.<. tating. Systemic reactions include increased itching, rash,
I OH hc.'ldachc, aching musclcs,joint poin, painful swolleo and ten-
Proprietary Preparations (details are giV<n in Volume 8)
der lymph nodes, fever, tachycardia and hypolension, and ver-
Molti-ln&redient: S. Afr" Myt<?tat: UK: Micotl. tigo. Most patients have eye disto1nfort in the ftISt few hours
after diethylcaJbamazinc 11ca1J11CnL Punctate kcraritis can de-
Closantel Sodium (8MW. rlNNM) velop as can optic neuritis and visual field loss.
Diethykarbamazine Citrate WHO no lor1gu recommends lhe use of dic1hylcarbamazine in
Oasantel s6dico: Closantcl sodlque; Closanteiu'n natricum; oncllocen:iasis :is safer alternatives ex isl
!Oosantednattium: Klosantel SO<W s.:A; Klosantelnalrium: Nari (llMMtfNNM) L WHO. Lymphatic filariasis: the disease ind it.t conu-ol: fifth re·
OosanteUn: R-3182a pott or the WHO cxpettcommilltt on fllariasos. H'HO TtchRcp
O:tato de ~ Diethykarbarn. Cit: ~­ Str 821 1992. Also avaibble 11: hllp.l/libdoc.who.int/trs/
Ha-rp•u< l<M>JilKTeA bamazine Acid Citn1C Oiethytcatbamaline. citr.ne de: O.C'th)-1· WHO_TRS_82Lpdf(•C«SS<d 19/11/09)
C22H,.C12l2N202Na = 686.1. oitbamazini crtras; Dieth)otka:bamazifl.cilr.it; Dielil<atbamlzin- l. Yazdanbalcbsh M, ., al. Scum inl«l<llkin-6 lc\cls and •d•ttS<
Pharmacopoe ias. In Eur. (sec p.vii) as 1hc dihydratc for \'etef· citm: Oietill<Mt>amazino c~ratas: Diet)fkatbamo2incitnt; Oietyy- reaC1ion.s to diethylca~muine in •ympha1ic. filariasis,, J lttfec1
inary use. Dis 1992; JU: 453-4.
~karbamruinsitraatti: Oittazini Gtrls; RP-3799. NN·Oiethyt-1· J. WHO. WHO expe11 committee on onchoccrciasis: lhird repon.
Ph. Eur. 6.8 (Closantcl Sodium Oihydratc for Vete<ina<y Use: met~ipe<aline· I·caibo.an-ide dihydrogen otrate WHO Tuh Rep s., 751 1987. A l10 A\'Oolable al: hllp://
Oosantel Sodil.rn Oihydrate BP(Vet) 2010). A yellow, slii;btly AH)T>1111<l1¢aMa)HK<I U.•npa~ Iibdoc.who.intfrrsfWH O_TRS_ 7$2_(pan I).pd r (accessed
hygroscopic, powder. ll exhibiis polymorphism. Very slightly
soluble in W-dter: freely soluble in alcohol; soluble in methyl al- CtoH, ,N,o.c.H,01 391.1. = 19/11/09)

cohol. Store in airtight containers. Protect from ligJ11. CAS - 90-89- I (diethylcorbomozine); 1612-54 -2 (di· Precautions
ethylcorbomozine citrate).
Profile Treatment with diethylcarbamazine should be closely
Closantel is an anthelmintic used in \'Ctcrinary medicine for 1he ATC - P02C802.
UNI/ - OS IZ 389K8S.
supervised since hypersensilivity reaclions are com-
treatment of Oulcc and nematode infccrions. mon and may be severe, especially in palients with oo-
Effects on the eyes. ~ofeyesigl11 was reported in l I wom- chocerciasis or Joiasis. Patients with onchoccrciasis
en who recei•'Cd closantel (Flukiver) in miSlake for a gynaeco- should be monitored for eye changes. (The use of di-
logical producl. 1 Sight was restored after clMantel was stopped e1hylcarbamazine to treat onchocerciasis is no longer
but incapacitating eye pain re.mined.
I. 'Hoen E. ~' ol Harmful hum:.n UK of 6onated ve-tc:ri»ry drug,
recommended.) In patients with heavy Loo loo infec-
IAn«t 1993; 342: lOl-9 tion there is a small risk of encephalopathy and diethyl-
carbamazine should be stopped at the first sign of cer-
ebral involvement.
Diamfenetide (Mii( tfNN) Infants, pregnant women, the elderly, and the debilitat-
Diamferetida: Ooamf!t\etide; Otamfenetidum; Oramphenet.'iide. ed, especially those with cardiac or renal disease, are
~.P'-OxyM(aceto-p-pltenet>dide). Pharmacopoeias. In Chin.. Eur. (seep.vii), /nl.. Jp11, and US. normally excluded when diethylcarbamazine is used in
Ph. Eur. 6.8 (Oieth)'tcarbamazine Citrate). A white or ~lmosl mass treatment schedules.
A!Aa"'¢eHeTHA while, crystalline, slightly hygroscopic powder. ~ry soluhle in
C20H14N20s 372.4. = water; soluble in alcohol; P"'c1ically insotuble in acetone. Store Pregnancy. Pregnant women are normally excluded when di-
C..<\S - 36141 -82·9. in airtighl containtTS. ethylcarbamazine is used in m•ss trca1n1ent schedules.
UNI/ - U4TF)7G86T. USP ll (O.ethylcarbamazine Citrate). A white, crystalline, Animal studies' suggest that the uterine hypermo1ili1y induced by
slightly hygroscopic powdtt, odourless or has a slight odour. diclhylcarbama?.ine is mcdialcd via prostaglandin synthesis; Ibis
\by soluble in water; sparingly soluble in alcohol; practically might explain the mechanism of the abortifacic:n1 action previ-
insoluble in ace1onc, in chloroform, and in ether. Store in airtighl ously rcponcd.2
containers.. I. Joscpll CA. Dixon PAF. Possible prOS1•Jland1n·mediatcd cO"c<:t
of diethykarbamaiinc on nl merinc contl'8c11lily.J Phora• Phor-
Adverse Effects moco/ 1934; J6: 281-2-
2. Subbu VSV, Biswas AR. Ecbolic effect of d>tthyl atbomazmc.
Profile Adverse effects directly attribuLable to diethylcar- lndiunJ Med Rn 1971; 59: 646-1.
Diamfenetide is an aalhchnintic 1hal has been used in veterinary bamazinc include nausea and vomiting. Headache, diz- Re nal impairment. For a study on lhe ellects or n:l13l impair-
medicine for the control or rasc.:ioliasis in sheep. ziness, and drowsiness may occur. ment on the phannacokinctics of diethylc:irb.lnl4Zinc, sec under
Hypersensitivity reactions arise from the death of the l'harmacokinctics, below.
microfilariac. These can be serious, especially in on-
Dichlorophen (6All(11NN) chocerciasis where there may also be sight-threatening Pharmacokinetics
OichlomphCne; Oichlorophel'<Jm; Oidorofeno; Qi.phenth..-.e- ocular loxicity; fatalities have been reported. Encepha- Diethylca.rbamazine is readily absorbed from the gas-
70; G-4. 2.2'-Methyler.ebis(1 ·chlorophcnol). li1is may be exacerbated in patienL~ with loiasis and fa- trointestinal tract and also through the skin and con-
A,>w.Qpo$e>< Lalities have occurred. junctiva. Jt is widelydislributed in tissues and is mainly
=
C 111l ,0Cl 20 1 269.1.
0 Reactions occurring during dicthylcarbamazine 11catmen1 of
excreted in the urine unchanged and as the N-oxide
CAS - 97-23-1. lymphatic lilarlasls an: basically of 2 t)'JlCS: phannacological
melabolite. Urinary excretion and hence plasma half-
ATC - P02DX02. dose-<lepcndenl responses and a n:sponsc of the infected hosl 10 life is dependent on urinary pH. About 5% of a dose is
ATC Vet - QP52AGOI. die deslniclion and death of pan.si!c$.' eliminated in the faeces.
UNll - TIJOJOU640
• Reac1ions orlhe firSI type include weakness, dil7jness, lelhar· Disposition . A phannacokinctic study in 6 paticntS with
gy, anorexi1, and nausea. They begin within I to 2 hotn or oochoccrciasist indicated that die1hylcarl>Qm12ine is absorbed
laking diethylcarb:unaz.ine. and persist f~ a few hours. quickly and almost completely from the 8"Slf0intestino.t tr.ICI,

~
• Reactions or the second type are less likely to occur and an: and is eliminated largely as unchon&ed drug in urine, wilh n:la"
less severe in b:lncroftian titan in brugian lilariasis. They may tively small amounts being excreted os the N-oxide metabolite.
be systemic or local, both with or without fever. After a single rad ioactively labelled oral dose of dictbylcar-

yy Cl Cl
Systemic re.oc1io11s may occur a few hour.; afler the first oral
dose ofdicthylcarbamazinc and generally do not last for more
d1an 3 days. They include headache, aches in other parts of the
body, joint pain, dizziness, anorexia, malaise. transient hnc-
bamazine citrate 500 micrograms/kg given as an aqueous solu-
tion, peak plasma concentrations of I00 10 150 nanogramslmL
were achieved in I to 2 hours, followed by a sharp decline, then
o marked secondary rise 3 to 6 hours ofter dosing, followed by a
manoria, allergic reactions. vomiting. and sometimes auacks steady decline. The half-lifo rangtd rrom 9 10 13 hours. Urinary
Pharmacopoeias. In Bi: and Fl'. of bronchial asthma in astlunatic patienls. Fever and sys1emic cxcn:tion of diethylcarbamazinc 3nd diethylcarbamazine M>xide
BP 2010 ([);:hlorophe'>). A while~ slightly ~am-coloured reactions are positively associated willi microfolaraemia. Sys- was tomplcle within 96 hours; between 4 aod 5% of the dose
powder with a no1 mon: lhM sligh1ly phenolic odour. Practically temic l'C3CHons are n:duced ifdiethylcarbamazine is given in WllS recovered in the faecc:;. Disposition was sinlilor in S healthy
insoluble in water; freely soluble in 1 leohol; ~soluble in ether. spaced doses or in repealed small de<es. They cvenl\lally subjects gi\'en a single 50-mg tablet of dicthylcarbamazine
All cross-references refer ro nmies in Volume A
 ClosanteVEprinomectin 15 l
cilratc. Peak plasma concentrolions were initi3lly 80 10 reactions WHO suggests sta1ting treatment at a dose of Doramectin cw:.
USAN. rlNNJ
200 nonogrnn1slmL, \\·ilh •secondary rise 3 to 9 hours after dos- J mg/kg twice daily and increas ing gradually lo Doram«tina: Doramectine: Doramectinum; Ooramektini; CX,.
ing. 1hc 1cnninal half-life ranged from 5 to 13 how-s. and urinary
3 mg/kg twice daily. ramek~n: UK-<>7991.
exa<ti011 ofunchongcd died1ylcorliama%ine and~·• N-<>"idc was
AOP•'<CKT~H
complelc within 4& hours. For details of doses in children, s.:t: below.
When an alkaline urinary pH was main~• ined, the eliniinalion CAS- 117704-25-3.
Administration. Dic1hylcart>on11zinc was first used as the ATC V.i - Q1'54AA03.
half-life of diethylcarbamvjne and lhe area under U1c plasma
concemration versus time curve were significantly increased chlondc, bl~ was subsequen1ly produced as the dihydrogcn ci1· UNI/ - KGD7A54HSP
compared with when an acidic urinary pH was maiolaincd. l rule which contains only hnlf its weight as base. In reporting dos·
I. Ecfw;irds G. ct ol. Oicthyfearbamuine disposittoo iQ pa1ienu
e.. it was therefore imponant IO indica1e whether they refcncd to
with onchocerciasis.. Clln Plun•mocol TJie,• 1981; lO: SSl-'7. a specific sah or to the base; unless otherwise slated, it could gen-
~. Edwards G. ~'al The efTec1 of variations in urinary pH on the erally be assumed that 1hc dose referred to thecitraie. 1
pitamuu:okinclicl or dtclhyk~m.tti ne. Br J CH11 P"'1nw:Jcol I. WflO. Lymphlltic lilan.,0.: founh report of d,. WHO C><JW1
19SI: 11: 807-1~. commincc on Cil1riaus.. WHO Tech Rt!pStr 702 1984. Awila~c
at: hnp ://llbdoc.who.intftrs/WHO_TRS_702.pdf (ac<:<S$cd
Renal impairment. Results in patients wilh chronic renal im- 16/07108)
peinnent and in healthy subjects, given a single 50-mg oral dose
of dielhytcarbamazinc ciiratc, ind1Cetcd that lhc plasma half-life Administration in child,...n. Oielhylcarbamazine citrate may
e>f dielhytcarbom:izine is prolonged and its 24-hour urinary CX· be given orally to children for 1hc lrcotment of lymphatic 6Jaria-
cr¢lion considerably reduced in those with moderate and severe sis, loiasis and toxocari•sis (visceral laM1 migrans).
degrees of "'131 impaim1en1. 1 Mean plasma half-lives in 7 pa· For the treatment of lym phatic filariasis US el(Jl"rts 1 consider
ticnts with se'""ere renaJ impai1mcnt (creatinine clearance less 1ha1 children inay be given the same dose as for adults (see
1ban 25 mUminute). in S patients with moderate renal impair- above), while WHO recommends that children Llldcr !Oyearsof
ment (creatininc clearance between 25 and 60 mUminu1e), and age be given half the usual adult dose.'
in 4 beahhy subjects. were IS.I, 7.7. and 2.7 hours.. rcspecti\'ely.
For th• t"'1111m:nt of loiasis US experts consider thar children
Th• patient wi1h the longest plasma half-life of 32 houl'S did not
have the pooresl renal function, but it ~s considered likely lhot
may be Kh•en a dose of9 mg/kg daily in 3 divided doses for 12 Profile
days; trea1ment should Siar! with very small doses, increasing Dorameclin is an avermcctin •11thcln1intic used in veterinary
the abnonnally slow elimination of d1clhylc:arlr•mazinc was due gradually over 3 days.' No dose recommendation is given by medicine for nematode infections. 1t is also used as a S)"lcmic
to the high urin.,ry pH (7) rcsuhin& frum sodium bicarbonate WllO.l veterinary ectoparasiticide.
lhcntpy. A funlltt patient wilh a half-life longer than expected
also had a less acidic: uri11e. For the lrcalmcnt of toxucarlasls WllO coosidcr.; that children
I. Adjepon·:V:i:no~h KK, 11 lil. The effccc of renal disease 0 1\ the may be given the samo dose a~ for adullS (sec abovc).1
pharmacokiMtics of d1ethykarbama:tine in man.Br J Clh1 Pltnr- I. Abram°"ic-z. M, ed, Dmgs/or po.rosilic i11/tt1iom. 2nd ed. New Embelia
mocol 1982: 13: '29-34. Rochelle HY: Th< Medical Lener. 2010.
2. WHO. WHOllltXkl/ommlor:i·. Gt1ll!\'3: WHO. 2008. Available 3l: Vidan&
Uses and Administration hupJ/wv.w.who i1tt.fsclcction_mcdicim:sfliWWMFlOOS.pdf {ac:· BHA2Hr3
ccsscd 1911 ll09J CAS - 550-2~-3 (embelir. OCld).
Die1hylcarbamaiine is an anthelmintic used in the
trcalmcnt of lymphatic filarias is due 10 Wuchereria Loiasis. Diethylcarbaimz.inc is Ilic mni11 drug used in lhc rnan-
ba11crojli (bancroftian filario.sis), Brugia malayi, or B. 1geincnt ofloiasis (p. 143~
timori (bOlh known as brugian filariasis and as Malay- Refcrcnc<!S.
Nucn1an TB. f!f Cl/. Lua tua in(tclk>n in lempor.1.l'y l'c~•dcnt1 or
an and limorian filariasis respectively). lt is also used I t'.ndc1uic rcglons: reco.nhion of a byPCrrtspon$ivt 'yndrome
in tile treatment ofloiasis due to Loa loo and toxocaria- wi1h charocccr1~1 ic cl hue al m;inifesouions. J hr{PCt Dis I986:
sis (visceral larva migrans). Diethylcarbamazine is ac- 154: 10-IS.
Nuunan TB. tt ol. Oie 1 h ylca~1nN.inc prophylaxis (OI' human HO
tive against both the microfilariae and adult wom1s of 2. loiuis. 1<"1l1J of a double-blind $1Udy. N ~I J J.l<d 1988; J 19:
J·V. bancrojli, B. malayi, and Loa loo, but only ag;ainst 752-6.
the microfilariae of Ochocerca volvulus. It was used in 3. Nuln\an TB. O:tcscn EA. Oiclhylcubom"iinc and human loii·
onchocerciasis due lo 0. volvulus before ivermectin 4, sis. N E1'BI J MM 1989; 320: 320.
Klion AO.~' ol. fffecci"'e:nns of dicthyJcof'Nmazine in uuliua (embelic acid)
became available. It has been tried in Mansonella in- loiuis :icquircd by cxpa1r.a1c vi~har:\ lo endemic reg,tOIU: &on1·
fections and may be most effective against /11. s~p­ h:m1 follow· up. J /nfectDll I~; 169: 604-10.
Profile
tocerca. For discussions of rhesc infections and their Lympha tic filarlasis. Dieihyk:atbamazine is used in the men· F.mbelia consists oflhe dried Ciuits of t:m/x>lia rib& and£. ffJ·
treatment, see under Choice of Anthe Im in tic, p.140, agcmcnt of lymphalic filariasis (p.143). In endemic areas mass b11s10 ( = E. IJjrJ•inmcollnm) (Myrsinoceae), containing about
and under the individual headings below. trcatmcot of the cn1ire populaiion (excluding neona1es. pregnant 2.5% of cmbelic: acid (cmbdin). It has been used in India and
wCll11e1\, and debilitated indh'iduals) can reduce 1he intensify of Olhcr Asian countrits for lhe expulsion ofi.pcwonns.
Diethylcarbamazine is usually given orally as the cit- transmission and the incidence of disease. In coun1rics where Preparations
rate. there is no co-endemic: loiasis OI' onchoccrciasis, the Global Pro-
gramme 10 Elimina1e Lymphntic Filariasis launched by WHO Proprietary Preparat ions (details att given in Volume 8 )
In the treatment of lymphatic filaii11sis caused by W. wilh 01her international agencies, advoca1cs a single oral cl= of Multi-ingredient: Huni.: I l.,"1od.ct: Indio: H.lw>''""rt·
ba11cr(!fli a total cumulative dose of72 mg/kg is usual- dierhylcarbamazinc citrate 6 mg/kg wi1h a single oral dose of
ly recommended; half this dose is usually effective in albend•zole 400 mg, given on~ each year for al least 5 yars. If
B. mala1•i and B. rimori infections. To reduce the inci- dielhylc:arb3m11tinc-medic:11cd s•h is 10 be employed !hen intake Eprinomectin (V~. llN'I}
dence ru1d severity of hypersensitivity reactions due to of salt needs to be on a daily bclsis for 6 to 12 months. Eprinomcc:tina: ~p~: Eprinomec.,inum; fpnnomekt>nr.
the destruction of 1nicrofilariac an initial dose of Pre parations Epmomcktin: MK-397. A~ of ep<>nomcctin ~-
I mg/kg is given and !hen gradually increased over 2 to BP 2010: ~orbam!.bnc Tablas: 81, and eprinomecti11 '~' s,•.
3 days to 6 mg.'kg daily for 12 days. However, adverse USP ll: ~rbima:i;ine Citri.te TibOIU. 3npMHOMeKT&.4H

effects of diethylcarbamazine may be reduced, without Proprietary Preparations (dc1ails Arc a1vcn 1n Volume B) CAS - 159618-36-1 (epnnomewn); I 13997-26-1 (epn·
nomectin): 133305-88- r (component 8 1.J: 133305.89-2
loss of efficacy, by giving a single dose of 6 mg/kg at Fr.: Note>ine: Gr" H&wnt: Note!ine: lod'.o: Ban:x« Hetraun: T hal.: (component 8 1.J.
weekly or monthly intervals. In areas where lymphatic Di~hizint. ATC Vet - QP54AA04.
filariasis is endemic, mass treatment campaigns can re- Multl·itl.gredient: Indio: Hdmuarrt: Uncart>;u....,_ UNli - 75K?30FD80 (eprinomect>f'}. OOOYS4D31C
duce the intensity oftransmission and incidence of dis- (epr:ncmewn component B,,J. 3 J0Ml2QZOQ (epn-
nomecrin component 6 1.J.
ease. Dicthylcarbamazine may also be used in the fom1
of medicated sail lo control lymphatic lilariasis. For Disophenol
further details, see below. Diso<enot. 2.6·0i'odo-4-n~
Jn the treaunenl of loiasis dielhylcarbamazine citrate 6 C 6HiiiNOl 390.9. =
10 9 mg/kg daily in 3 divided doses for 12 to 21 days CAS - 305-85 -1.
has been given. In heavy infeel ions rapid lcilling of mi- l..JN// - 39S5ZJ6SYN.
crofilariae can cause severe adverse effects including
encephalitis and treatment should start with very small
doses, increasing gradually over 3 days. A conieoster-
oid has bc:cn given concurrently. In the prophylaxis of
loiasis, a dose of 300 mg weekly is recommended by
·o
'w f ~ OH
11
-Q-1
WHO. 0 -
OH
Jn the treatment oftoxocariasis dicdiylcarbamazineci- I
trale 6 mg/kg daily in 2 divided doses for 21 days may Phannacopoeias. lo US.
USP 33 (Eprino.-riectin). Eprinnmcctin is a mix1ure of
be given. Diethylcarbamazine is considered by some to Profile componc111 B,. (C"11l uNO., ~ 914.1) and compo11cn1 B,~
be the treatment of choice while others do not recom- Disophcnol is an anlhelmin1ic used in veterinary medicine for 1hc (C~finN014 •900. I). II comains not less than 90% of compo-
mend its use due to high rates of allergic reactions in- trcalment ofl100J<,\.orm and ga~wonn inftclions. nent B,. and not less than 95% ofconiponenlS B1, and B, .. cal-
duced by dying larvae. To reduce the intensity of these culated on the anhydrous, solvent-flee, and 1ntoxidant-fTte basis.
TI1c symbol t denotes a preparation no lonscr acti\'cly marketed
152 Anthelmintics
AntoxidanlS may be added. A white to off-white powder. Insol- Phannaoopoeias. In Eur. (seep.vii) and US for veterinary use Hyg,.omycin 8
uble in cold water. Slore in ainight conraincrs at 2° to 8". only. Higromior>a B. 0·6-Amif'lo.~-t.-gl)cero-0-galacto.hepto­
Ph. Eur. 6.8 (fenbendazole for Veterinary Use: Fenbendazole
Profile pyranosytidco.e-( I ~ 2-3)-0-jH>-talopyranosyt·( I ~ 5)·2-deoxy-
Eprinomcclin is an avermectin anthelminlic used in veterinary BP(Vet) 2010). A while or almost white powder. Practically
Nl-methyl-O·s"<teptamine.
medicine for nematode infections. It is abo used as a systemic insoluble in water; sparingly 10luble in dimetbylforrnamide;
very slightly soluble in methyl alcohol. Protect from light. f >1<poMV1Ul<H 6
veterinary ectoparasiticide.
USP 33 {Fenbenda2ole). A white toofl'-whitc powder. Practical- C20H3, N30 13 = 527.5.
ly insoluble in water; sparingly soluble in dimethylformamide;
very slightly soluble in mdhyl alcohol. Store at a temperature of
Epsiprantel (MN. 'INN) 25•, excursions permitted between I5° and 300. Prolcct from
BRl.-38705; Epsipranleefi: E¢pr.lntel.im. 2-Cyclone")lcirbonyt- light.
l,2.3.4.6,7,8, 12b~ l -c][2)>enzazepn·4·one. Profile
3ncVlnpa><TeA Fcnbcndazole is a bcnzimidaiole carbamate anthelmintic StrllC·
C10H2,N202 = 326.4. rurally related to mcbcndazole (p.156). It is used in vcrerinary
CAS - 98123-83-1. medicine for the treatment of nematode infections of the gas-
ATC Vet - Qf5ZAA04. troinle$1mal tract and lungs and in tapewonn infections.
UN/I - OCISPQOFSR.

Flube ndazole (&IJ'l.USAN. tHI)

Flubendatsoli: A\benda2d: flubendazolas; Aubendazol\rn; Fluor-
omebenda2ole: R-17889. Methyl 5·(4-fh.Jorobenzoyt)-l H-bem-
amidazol-2-ylcarbamate. Profile
<DAy6e~ Hygromycin B is used as a feed additive in veterinary practice;
use over several weeks is modcratcJyeffcctive in controlling gas-
C,.HnFN,01 = 313.3. tJoinlestinal roundworms io pip and poultry.
CAS - 31430-15-6.
ATC - P02CA05.
ATC Yet - QP52ACI 2.
UN/I - R8M4691 ILR. lvermectin (SAN. USAN. rlNN)
Profile
Epsiprantel is an anthclmintic closely related to praiiquantel. It lvermectina; l.ennectJne: lvermectinl.m: lvennckl•nc l'lcrmektin:
is used in veterinary medicine. lvermektinas.
VIB<Pt..e•mu<
CAS - 70288-86-7 (ivermecrin): 70161-11-1 (compo-
Febantel (Ml'{ U5M( rlNN) nent 8 1.); 70209-81-3 (componenr 8 1J.
Bay.h-5757: Bay-\lh.5757; Febanteelt Ftbantet. Febantelurn 2"- ATC - P<!2CFOI.
[2.3-Bis(mMoxycarbonyl)gv-anidino]-5'-phen)Moo-2-methoxy· ATC Vet - QP5~AAO I: QS02QA03.
acetriidc; Dimethyl {2·[2·(2·mcthoxya;etam•do) 4 (phenylth- UNll - 8883YP2R6D (ivermectin): 91Y21020UW (ivcr·
io)~imidocarbony1}dicartwr41e. mectin componen< H 18 1.): OW28CYl3TU (ivermcctin com-
<De6ameA ponent H iB 1.J.
Pharmacopoeias. Jn Eur. (seep.vii).
ClolinN,06S :: 446.S. Ph. Eur. 6.8 (Flu~ole). A while or almost white powdtt. I!
CAS - 58306-30-1. exhibilS polymorphi5m. Prac1ically insoluble in water, in alco-
ATC Vet - QP51AC05. hol, ua\d in dichlororncthone. Protect &om light
UN/I - S75C4010SI .
Profile
Flubcndazole. a benzimida20lc catbamate anthelminti<:, is •n 80-
alogue ormebcnda.zole (p.I 56) and has similar actions and uses.
For lhc trc:almcnt of enterobiasis in adullS and children, flubcn-
dazole 100 mg is given as a single oral dose, repeated aftcr2 to 3
weeks. For ascariasis. hookworm infections, and trichwiasis
100 mg is given rwicedaily for 3 days. For discussions ofdacsc
inti:ctions and their trcatmenl, sec under Choice ofAnthcl0>inlic,
p.140.
1t is olso used in veterinary medicine for the treatment of nema-
tode and tapeworm infections.
Preparations
Pharma~opoeias. In Eur. (seep.vii) and US.
Proprietary Preparations (deiailsare given in ~lume B) Ph. Eur. 6.8 (l..:rmectin). A mix1urc of ivcrmcclin comp-
~"~Fr.:~Port.:fi.....m.t,~Spoio:~l""'1: onent H2B 1, (5-0-demcthyl- 22,23-dihydroav~rmcctio A 1,;
Vtnu: FkM!rrno>< C,gH,.0 14 •875.I) and ivermcctin componcnl H2 e,. (5-0-
Pharmacopoeias. Jn E11r. (sec p.vii) forveierinary use only. dcmcthyl-25-dc(l · mcthytpropyl) ·25-{ 1-mcthylcth)'l)-22,23-di-
Ph. Eur. 6.8 (Febantel for Vetennary Use; Febcntel SP(Vet) hydroavermoctin A 1,.; C,,H710 14 - 861.1 ).
2010). A white or almost "11ite.. crystalline powder. It cxhibilS A white or ycllowi$h-whitc, slighlly hygroscopic, crystaJlinc
polymorphism. Practically insoluble in water; slightly soluble in Haloxon (llAN. """' powder. Praeliailly insoluble in water; soluble in alcohol; freely
dehydrated aloobol; soluble in acclonc. Halox6n; Kaloxone; Haloxon..rn. Bis(2·c~ 3-chloro-'I· solubk: in dichloromethanc. Store in airtigl11 containers. •
meth'ylcoumarin-7-yf phosphate. USP 33 (lllennectin). A mixture or component H1B 1, (5·0·
Profile
Fcbaotcl is a prodNg that is convened to fcnbcndazole (sec be· demethyl-22.23-dihydro-avcrmectin A 1,: C0 H;40,. = 875.1)
low). II is an anthclmintic used in veterinary n>edkinc for tlic
fa/\Ol<Ce>t< aod component H2 13,. (5·0·dcmcthyl-25·dc:{l·mcthyl-
treatment ofnematode infectious of!he gastrointeslillal 1ract and C,.H,.Cl104 P = 4 15.6. propyl)-22,23·dihydro-25·(1-methylethyl)·avcnncc1in A,.;
lungs and in tapeworm infections. - CAS - 321-55-1 . C.-;HnO,.e861.1). lt may contain small anlOUlllS of suitable
ATC {et - QP52A604. aotoxidant and chelating agent•.
A white 10 yellowish-white, slightly l1ygroscopic, aysallinc
UNll - TBKXA37068.
powder. Practically insoluble in water and in petroleum spirit;
Fenbendazole (BAN. L'SAN. llNN) soluble in acetone and in acctonitrile; freely soluble in dichlo-
~auoli: fenbendazol: ~ndalOlum; Hoe-881 V. Methyl romcthane and in methyl alcohol. Slorc in airtight ccnttincrs ot o
5-phenylthio-1H-benzimiducl.2"}icarb1tm•te.
<DeH6e><Aa30/I
C,sH11N102S = 299.3.
CAS - 43110-67-9.
ATC - ?OZCA06.
Cl ~O
a/'-../ o\,. .-owo
._P
II
,...
::::,... I o
0
icmpcnlw'e of2° to&•. Where the use of an antoxidanl is al·
lowed, store at 25°, excursions permined bctw~en 15° and 30".

Adverse Effects and Precautions

The adverse effects reported with ivermectin in pa-
ATC Vee - QP51AC 13. 0 Cl tients with fi lariasis are generally consistent with a
UNI/ - 6218VT9M36. mild Mazz.o!ti reaction arising from its effect on micro-
CH3
filariae. They include fever, pruritus. skin rashes, ar-
Profile thra lgia, myalgia, asthcnia, orthostatic hypotension,
Haloxo11 is an org;mophosphorus compound (see Organophos· iachycardia, oedema, lymphadenopathy, gastrointesti-
phon<s Insecticides, p.2195) used as an w11heln1intic io veteri- nal symptoms, sore d1roal, cough, and headache. The
nary medicine.
effects tend to be transient and-if trcalmcnt is required
they respond to analgesics and antihistamines.
All cro~-references refer 10 entries in Volume A
 Epsiprantel/lvermectin 153
Jvem1ecti11 may cause mild ocular irritation. Somno· 12. Hunu::ida MMA, el ol. Prolong:!tion <J(prothr<.'linbin timr;: with In the treatment of onchocerciasis, a single oral dose
i\•crntcctin. L1mcc1 1988: i: 1346-7.
lence. transient eosinophilia, and raised liver enzyme 13. Rich:trds FO, cl (1/. lvcrmectin and pr0thrombin lime. Ltm:ct of ive1mectin, based roughly on J50 micrograms/kg
vai11es have also been reported. 19S9; i: 1139-40. may be given to patients weighing more than· J5 kg; re·
1.; . P:tcquc· MC. et nl. lvcmlcctin :md prothtoinbin time. luucct
Jvennectin is not recommended during pregnancy. 1989~ i: 1140.
treatment is usually required, and is given after an in -
Mass treatment is generally withheld from pregnant 15. Barkwtll R, Shie~ds S. Deaths associated w11h ivcnncc1in lre.,1· terval of at least 3 months. For mass treatment in infect-
mcnt of' scabies. lo11c1:1 1997; 349: I I44-5.
women (see Pregnancy, below), children under 15 kg, I6. Diaz_gratuu.los JA, Costa JL. Deaths after iven11cc1in treatment.
ed areas (see below) the dose is given annually or every
and the seriously ill. lunw )997: 349: 1698. 6 months. No :ood should be taken for 2 hours before
17. Rcintjcs R, Hock C. l)calhs associ:Jtcd with ivcrmcctin (or sca- or after the dose. Similar or slightly higher doses, ·plus
Incidence of adverse effects. Some studies have shown quite bies. Laue~/ 1997; 3SO: 2 JS. ·
a high iucidence of adverse effects with ivermectin and have as· IS.Coyne PE, Addiss OG Deaths <:1ssocioted with ivcrmec.tin for a dose of albendazole, are advocated by WHO in the
sociated the effects with the severity of infection. •·; However, in scabies. Umbtt 1997; 350: 215-16. · mass treatment of lymphatic filariasis (see bejow for
19. Alcx.andet NOE. tt (JI. Absence of ivennec:tin.asso<:iated exc~ss
none of these studies were the reactions considered to be Jife- deaths. 1l·ons R Soc Trap Med H.•-g t998; 92: 342. details). ·
tbrealening and only
symptomatic treatment was required. 111e
For the treatment of strongyloidiasis, ivennectin
sevcrily, incidence, and duration of advcrsc·reactions was report- Br-east feeding. Mean ivennectin concentrdtions in the breast
ed to be reduced after repeated annual doses.• When larger milk of4 healthy women who had been given a standard dose of 200 micrograms/kg as a single oral·dose, or daily on
groups ofpaticntS were considered in the Onchocerciasis Control iveimectin were 14.13 nanogr-.ims/mL. 1 lt was considered that in two consecutive days, is given to patiei1ts weighing
Programme (OCP) in West Africa, a much lower incidence of view of this low concenlration the precau1ion of excluding more than 15 kg.
adverse reactions was seen in patients given ivcnnectin for the breast-feeding mothers from ivermectio mass treatment pro-
firs! time' and when treatment was repeated a year later tllat in· grammes should be reconsidered. Some authorities have recom· ORcviews.
cidence was reduced e\'en further. The results from several stud· mended !!lat ivcrmectin should nol be given to mothers who are I. Onesen EA, Campbell WC. Jvcrmcctin in human medicine. J
ies in this prograrnme6 showed 93 severe reactions in 50 929 pa· breast feeding until the infant is at least one week old. The Amer· Antimicrob Chemother 1994: 34: l95-203. .
ican Academy of Pediatrics states Iha~ since no adverse effects 2. 6mura S. lvcrm:ctin: 25 years and S(ill going s-croog. Tm J Anli-
tients (J.83%), most of the reactions being orthostatic micrQb Agents 1008; 31: 91-8.
hypotensi·)n or dizziness (53). ln a 3-year randomised, doublc- have bcel1 seen in breast-fed infants whose mothers were receiv-
blind. controlled study of ivcrmectin for onchocerciasis control ing ivcnnectin, it may be considered to be usually compatible Administration in children. lvcrmcctin may be given oraBy
in 572 pa1ien1s.' 3-monthly treatmenl wi1h the standard dose of with breast fccding.2 to children wcigh'ng more than 15 kg and over 5 years ofage, for
150 micrograrns/kg was associated with a reduced tisk of ad- I. Ogbuokiri JE., {''al. lvcnnC(;tin levels in human b~cast milk. Eur the management of onchocerclasis and lymphatic filari~s~s and
verse reactions, especially oedema, pruritus, and back pain, J Clitt Phnrmocol 1994; 46: 89-90. also for the 1rea11ne11t of strongyloidiasis. Doses used arc the
when colt pared with lhesame dose given annually. Higher doses 2. Amt-rican Academy of Pediatrics. The transfer ofdrug.s and olh- same by weight as tl1ose used for adults (see above).
f'r chemica1.s into human milk. Ptdiowics 2001; 108: 776-89.
of400 then 800 micrograms/kg, given either 3-monthly or annu- [Rc1ircd May 20101 Corrctlion. ibid.; 1029. Also available at; Cutaneous lar va m igrans. There arc some reports1·5 ofiver-
ally. were assoeialed with subjective ocular problems. Another http ://a a ppo Iicy. a appubl icat ions.or g/c g i /c ontent/fu 11/ mecrin being effective in tl1e treannent of cutaneous lar\'a. mi·
study8 found 22 severe reactions in 17 877 patients treated for pediatrics%Jb 108131776 (accessed 02/06/04) grans (p.141). An oral dose of200 micrograms/kg daily for I lO
onchoccrciasis iri an area also endemic for Loa Joa infection, and 2 days has been recommended.6 . .
Encephalopathy. For infonnation on encephalopathy after
demonstrated a relationship to heavy L. Joa microfilaraemia. 1be I. Caumes £.et al. Effic:'lcy of ivenncctin in the therapy or cutane-
Mectizan0 -Expert Committee and the Technical Consultative ivermectln lreatrncnt ofonchoccrciasis in Loo Joo endemic ~reas,
see lncide11ce ofAd"erse Effects, above. ous larva mig1a1s.An:.hDt'rmotol 1992; 128: 994- S.
Conunittee have reported the incidence of encephalopathy after 2. C:iumcs £,et ul. A randomized tr'ia1 of ivcrmcccin \'CrSUS albcn-
ivennectin treatment of onchoccrciasis iii Loo loo endemic areas Pregnancy. l vcrmcclin is teratogenic io animals and there are dazole for the uea1men1 of cuianeous lan«'l migrnns. Am J Trop
to be less tl1an I case in I0 000 trea1men1s9 and have implement· no adequate and well controlled studies in human pregnancy. ModH.vg 1993:49: 641-4,
ed recommendations for ivennectin m:iss treatment programmes lvcnnectin treatment is therefore usually contra-indicated during 3. Bouchaud O. et al. Cu1ancous larva migrans in travelers: :i pro..
spcc1ive study, ,·1ith asscssmcr.t of therapy with ivennecti1l. Clin
of onchocereiasis in areas co-endemic for loiasis 10 reduce the pregnancy and pregnant women should be excluded from mass
lnfecr Dis 200(};31: 493-8. Correc1ion. ibi'd. 2001; 3~ : 523.
risk of serious adverse events. especially in areas where the pop- treatment schedules with i\'ermccrin. However, women not yet 4. del Mar S~ez-De..Ocar it. M, el cl. Tre:itment of IS children wilh
ulation is ivennectin naive. diagnosed os pregnant or unwilling to admit 1heir pregnancy .scabies or culaneous larva mignms using ivenncclin. Clin Mp
Some ~u rcrvision is considered necessary after doses of iver- have been treated. An assessment' of203 pregnancy outcomes Dem•orol 2002:27: 26~-7.
mectin;?.<i the OCP reeoinmendation6 is for resident nurses to in women who had taken ivennectin during pregnancy, moslly S. Senha Y, ~10/. Cas.e of creeping disease treF.ted with ivuin~ctin.
during !he first 12 weeks, found that the rates of major congenital .I Dttrmatt>I 2009: 36: 86-9.
monitor pltiCnlS for a period of3611ours aftertrcannent, whatev-
malfonnatio11, miscarriage, and still-birth associated with ivcr· 6. Abramov.·iC7. M, ~. Dmgsfor paro:silic i11/~aio11s. 2nd td. New
er the level of endemicity. However, the incidence of adverse re-- Rochelle NV: The Medical Letter, 2010.
actions reported after repeated doses al'P"ars to be lower than mcctin were similar to those in untreated mothers. In another
after the first dose and the need for supervision ou re-treatment st\ldy, 110 women also inadvertently given ivcrmeclin during Intestinal nem2tode infections. Iveimectin activity has
has be.co questioned.to pregnaocy had a similar Jack ofadverse effect on pregnancy out- been seen in man against Ascarls /umbrlcoides, Slrongyloides
Neurotoxicity seen in some breeds ofdogs has not been seen in come;~ it was considered that avoiding the use of ivennectin in s1ercoralis, and Trichuris 1richi11ro; 1 although some have failed
women once lhey were known to be pcegi>ant should be adequate to detect activity tgainst Trichur;s,2 ivcnneclin given witb albcn·
carrle or hor$es 11 and nor was ii reported in man in the above precaution. dazole in doses similar to those recommended for mass treaunent
studies. Another potential concern was the prolongalion of pro·
I. Pacque M, et nl. Ptcgn3ney oulcomc sflcr inadvertent ivcrmectin in the management of lymphatic filariasis (see i>clo.w), has been
thrombin times seen in 28 patients given ivem1ectin, 1 ~ but others
treatment <.l uring com munity · b:tsc~ distribution. lam:ct 1990~ studied for 01c trcahncnt ofo·ichuriasis (p.146) and may prove
have nol am finned thiseffet.t1 ~ or seen any bleeding disordcrs. 1:1 336: 1486-9. u.scfill jn areas where soiI-transmitted worm infections and lym·
There has been some concern over t11e use of ivem1ectin to treal 2. Chippaux J-P, et ol. Absence ofan)' adverse effect of inadvcrtcnl phalic lilariasis are public health problcms.1 Roundwonn cxpul·
scabies in elderly patients af\cr a report suggesting a possible link i\'crmcclin lrt!almcnt during prc:;gnancy. 'frons R Soc 1i·t>p Med sion has also been reported as a 'side-effect' ofivcnncclin when
to 011 increased incidence of death among a cohort of 47 pa- Hyg 1993; 87: 3 l S.
used in communily-based treatment of onehocerciasis.4 ln a con·
tients. 15 )(has. however, been argued that no such association has trolled sludy, 5 single ora l doses of ivcrmectin 150 or
bee11 seen in other populations of elderly patients and lhal the Pharmacokinetics 200 microgramsr\gproduced cure rates of94% in strongyloidia·
statistical methods used by the original authors were defi- Ivennectin is absorbed after oral doses and peak plas- sis (see below) and above 67% in ascariasis, trichuriasis, at>d en·
cient. '"''8There was no evidence of an increase in deatl1 rate as-
socialcd with ivenncctin in a oommunity~based study in Papua
ma concentrations occur after about 4 hours. Jvennec· tcrobiasis.. Although so1nc activity has been seen against Nccaior
tin is reported to be about 93% bound to pl'!Sma pro- americ:unus, 1 ewe rates for hool"\vonn were considered w1satis·
New Gui11ca of diethylcarbamazine with or wi1hout ivermectin faclory.s
for lymphatic filariasis. 19 teins and has a plasma elimination half-life of about 12 I. Freedm:in 00, tt ol. The efficacy or ivenn<ctin in the chcmo,
I. Kumarlswami V. ttr al. lvcrmectin for the trcinmcnt or hours. !t undergoes metabolism in the liver, mainly via lherapy of g.astroinlcstinal hehninthi~sis in huu1a1~s. J Infect Dis
Wuchereria b:'lncrofci fil:iri:=si': effic3cy f.lnd ad\'ersc reactions. the cytochrome P450 isoenzyme CYP3A4. Jt is excret- 1989: 159: llSl-3.
JAMA t988: 2S9: 3150-3. 2. Whitwor1h JAGt:r al. A ftcld study of l h~ effect of ivermectin on
2. Rolhova A. e1 al. Side·efrects of ivcnnectin in treatmem of on- ed largely as metabolites over a period of about 2 inttstinal hehninths. in m:i:n. Trons R Snc Trop Med Jl.vg 199 C~
choccrci::isis.. Lonut 1989; i: J439-JJ. weeks, chiefly in the faeces, with less than I% appear· 85: 232-4.
3. Zea-Flores R. er nl, Adverse rcac:lions after community treot· 3. Oclizario VY, era/. A comp.Jrison of the efficacy of s ingle dosei;
men< of onchocerci:1s;s. wi1h ivennec:1in in Gualcmahl. 7i·an..ff R ing in the urine and less than 2% in breast milk (see or :llbendawlc. ivcrmectin, ~nd die1hvkarba1n:izine alone or in
Soc T1<p Med N)'g 1992; 86: 663· 6. also Breast Feeding. above). combin<nions againsl Asc41ris and i richuris spp. Bull WHP
4. Oumham GM. Ad\•erse re-ae1ions 10 ivennedin lre111menl for 2003; 81: 35-42.
onchoo:rciasis: results of a placebo-controlled. double-blind tri· 0 References. 4. Whitworlh JAG. d al. Community•bascd trealmcnt with ivcr-
:i.I in f\.tal"wi. Trtms }( Soc Trop Mfd Hyg 1993; 87: 31 3- 17.
I. Gonz31e.i Canga A. ct al. The phaonacokinetics and intcr:tciions mectin. L<mcer 1988; ii: 97-S.
5. Oe Sol! G, ,., ¢/. L:ick of adverse reactions in ivermcetin ue-ot· of ivern1ectin in hum;ms-3 mini-review, AAPS J 2008; 10: S. N3quir<1 C. et fll. h'ermcc1in f(lr hutmm SlrOllgyloidiasis and 01h-
men1 oron<:hocerci::isis. WrK'tt 1990; 335: 1 1~7 .
42-6. t r.irnes1i1ul hehnin1hs. Am J 7i'ap Med H)i" 1989; 40: 304-9.
6. De Sole G. et ol. Ad\·crsc reactions ancr l:ugc·snle trc:ume.nt of
0T1chocercinsis with i\'crmcdin: coml>incd results from eight Loia.sis. lbcre is evidence ofreduced microfilaraernia after ivcr-
comnu.nity lri3IS.. Bull Wl/O 1989; 67: 707-19. Uses and Administration mectin treatment •.s in patients with loiasis (p.143), but concern
7. Kaiugno J,e1 al. Adverse sys1emic 1eactions to treatm~nt of on·
chocertiasis wid1 ivetmcc1i11 :i.t n<>1·m3Jand t1igh doses given nn· lvennectin is a semisynthetic derivative of one of the exists over its pok:ntial for nelll'otoxicily in pa1ients with a high
~96~~(~ three·m<>nthly. 7i-u1!' H. S(JC Trop Mt<I Hyg 2004~ 98: avennectins, a group ofmacrocyclic lactones produced microfilarial burden. 6 •7 Low-dose regimens (about
by Streptomyces avermitilis. 25 microgi-arns/kg) bave been investiga1ed5 but d id not seem to
s. Gtcrdon J. l!I <ti. Scriuus rc<\\:tions at\1.:r m~ss lrc:umcnl or t)I\· offer much advantage in reduc.ing neuro<oxicity.
thoecr<iasi.s wi1h ivenncctin in 3n are:t endemic for Loa loa in·
fection. lanu1 1997: JSO: 18-.22.
II has a microfilaricidal action in onchocerciasis and re- I. Martin·Pre\'el Y. t!I al. Rcduclion of microfilaraemia with single
duces the microfi larial load without the toxicity seen high·dosc: ofivamectin in loiasjs, Luncc11993; 342: 442.
9. The Mec1fzan\!· Expen Conuniuee: and The Technical Consuhative
2. Ranquc S, e1 nl. Occn:-a&ed prevalence 3nd intensity of Loa loa
CommillC'C. Rec<>mmcnd:uions (or lhe lre..'\lment oronchocertia.sis with diethylcarbarnazine. lvennectin also has a micro- lnfecti()n in :i community trea(td wi1h ivcrmcctin every three
i•h M:ctiz.1nl) in arcasco•t:ndcmic for onchocerciasisand loiasi.s.
\ '-.1
hup:/IW\'ltw. mccti~n.org/si 1esfdcf."'ul(lfih:sf
2004. A\•ailabte <:11: tilaricidal action in lymphatic filariasis and is llsed in months for 1wo years. Tums R Soc Trop Med Hyg 1996; 90:
EnglistMECTCCLoaRecs-June04_1.pdf(o~ed 29/07110) endemic areas as part of a mass treatment regimen. 4•9-30.
10. Whitwonh JAG, e1 of. A ~ommunitv trial ofivermectin for on· ), Ouong TH, et ;,/, Reduced Loa loa microfih.,in count ten to
chooerciasis in Sierra Lcont: adve(sc reactions after the first Ivennectin is active in some other worm infections. It twelve rnon1hs antr a single dose of i\'trmectin. Trans R Scc
~Of-S~a1mcn1 rounds. Trans H. Sc>t Ttop Med Hyg 1 991~ 85: is used in the treatment of strongyloidiasis and has Trop M~d Hyg 1997: 91: 592-3.
4. Gardon J, el al. Marked decre.ise in Lua fo~ microfilaracmia si:i1.
I J. WHO. WHO expert commitlec on onchoccrciasis: third repon. been tried in some Mansonella infections. For details and twtlve inonihs oner u siT1glc dose ('If ivcnnectin. Tnms R &,c
WHO Teclt Rep Ser 751 J987. Available st : http:// _ of these infections and their treatment, see under Trop Med H.•11t997;9t: 593-4.
libdoe who.int/1rs/WHO_TRS_752_(part I ).pdf and hllp:// S. Chippaux J.P, <.1 al. Impact of repeated large SC-."tlc ivtrn)ectin
libdoc.\\ ho.int/trs/WHO_ TRS_ 752 _(pan2).pdf (accessed
Choice of Anthelmintic, p. 140, and under the individ· tn:Mm~nlS on tb~ transmission of Loa !O.J. Trans R Soc Trop Med
16107!08) ual headings below. H.•·g 1998: n: 4S4-8.
The symbol t denotes a preparation no longer actively marketed
 154 Anthelmintics
6. Anonymous. Encephalitis (ollowin& 1rca1meo1 or loiasis. WHO 4, TIJ>IS M. flt at. EO'ec1 or mass trcauncnl ofa human popuhuion 2. Aubin f , Humben P.' lvermectin fOf crusted (Norwegian) sea~
Drug ln/1991; S: 113-14. with ivcrmcctin on lrnnsmission of Onchoccrca volvului by bin. N Eng/J Med t995; 331: 612.
7. Gudo.n J. el ol. Seriou5 rcKdons 1f\cr fl'lit$$ 1rca1mc:m of on- Simulium ythcn.se in Uberia. Wes1 Africa. Am J TtYJp Med }~)·g l. Strons M. Johnsrone PW. lnterven1i<>M for 1.reatins scabies.
chocereiasts wilh ivc:rmc(1in in an :uea t-ndemic for Loa loa in- 1990: 42: t48-S6. Available in The Cochrane Databuc ofSystcmauic Reviews: Is-
fcClion. lonccJ 1997; 350: 18-22. S. Chavassc DC. et nl. Low lc:vd ivenncctin coverage and lM sue 3. Chichwcr: John Wiley; 2007 (•cccSStd 21108/09).
t.ransmiuion o( onchoccn:iuis. TrollS R Soc Trop M~d H)'I 4, Currie SJ. McCarthy JS. Pcrmcthrln •nd ivermtctin for s.c:abiu.
8. Kamgno J. n ol, R1ndom1ud. conlroUcd. double-blind lrial with 199S: 89: Sl4-7. N En.g/J Med2010; ~62: 717-2S.
ivc:nnea.in on Loa loa microf1lartcm11: efficacy of a low dose 6. Bouni~ M, e1 al. Onchoccrca ..·olvulus: strikins decrease in S. Lcppard 8. Naburi AE. The use of ivcrmcdin in controlling an
(-2S vsJl<g) vcmis cwttnl mndud dose (I SO vtlkgj. Trans R lt'VlsmissK>n in the Vln~ vaJfey (Ca:meroon} after eight 1nnual outbreak af scabies in 1 pnson. Br J Dwrmo10/ 2000; 143:
Soc TropMedHyg2001; IOI: 777-U.
\9J;; fi~at~.nnec:lin uctlments. Tron< R Soc Trop M•d 11>'1 S20-l.
6. Ly f, •• o/. lvcmiectin vcnus benzyl b<nzoa1c tpp!icd once or
Lymphatic fbriasis. h'Crmcctin is used in the management of 1. Pond 8 . Oistribucion of i\-t:rt'lltttin by hcahh wottcrs Lotte8 twice to treat human scabies in IRkv, Seneg1t· 1 randomized
lymphatic filariasis (p.143). lo cndtmic areas mass trc3trnent of 1990: 33S: IS39. conllOllcd !rial. 8ull IYHO 2009; 87: 424-30.
Ute entire population (excludina neonates, pregnant women. and 8. De Sole G. t:t ol AdVCTK reactions after la:gc-scak lrGtmcnl or 7. MuliCre V. el al. Crus1cd (Norwq:iln) scab1tJ inductd hy u.sc:
ck:bilit•ted individuals) cao ~ucc lbc intemity of transmission onchocerciuis wi'b i~rrTl«t.in: combined results from eiaht oflopical coni:OOSteroids and treated successfully wtlh i'lcnnec-
and the incidence of disease. In countries where there i.s co-en- community lritls. Bull WHO 1989; 67: 107-19. tin. J Potllorr t 9~ US: 122-4.
9. Pacq~ M. 1t nl. Sa(c:ly or and compliance: with communily· 8. Ccok AM, Romanelli F. Jvermectin for the 1rc:atmt'nl of resistant
dcmic Joiasis or onchocerciasis, the Olob:ll Programme to Elim- based ivcnnec1in tneropy. Lonc<r 199(); 335: t377-80. scab1u. An'7Phormncolh•r2003; 37: 279-S t.
inate Lymphatic Filariasis launched by WHO, with other interna- 10. P1cqutM 1 ttal. Community-ha~ trcatmentofonchocerciasi1 9. Foucault C. et al. OraJ h·cnnectin in tM uc:atmenl o(body lice.
tional agencies, advocates a single oral dose of ivcnnectin l 50 to with tvcnncc.tin: safc1y. efficacy, and acccpu1bility or yearly J /efcc1Dis2006: 193: 474-6.
200 micrograms/kg with a single oral dose of albendazolc 1rea1mcn1. J lnftt1 Dis 1!191; 163: 381-5. 10. Mumcuoglu KY~ e1 ol. Sys.temic activhr of ivcnntctin on the
400 mg given once each year for at lc;ist 5 years. 11. S1eel C. 11 nl. Jmmunologic responses to repealed lvennec1i1\ human body louse (Anoplura : Pedicuhd11e). J Med E111omol
lrcatmenl in p1tic:nts wilh onchooer-ci3..Sis. J l11ft ct Dl1 199 1; 199(); 17: 12-5.
Mansonella infections. The response of Muim:mello infeer 164: SSl- 7. 11. Chosidow 0 , ~t ol. Oral )vermec1in vcnu~ malathion lotion for
12. Whilwort.h JA~ ,_,al. A community trial of i\'trmeclin for on· difficuh-to•Ucat head lice. N E•gl J Mtd2010; 3<\2: 896-90S.
tions (p.144) to ivc:rmeuin d<.1'CndS on lhe species. It may be ef- Correction. ibid.; 1647.
choccrc.iHis in Sierra Lc.oue: clinical a.nd paras-iloloaic1l re·
fective ai:ainst Monsonella ozumJi, bul stoclies in M. perslons sponscs to four do.ses given at six·monthly interval. Trmu R SoC'
infection have not shown· ivcrmeclin lo produce a subotantial re- Strongyloldiasis. lvcrmecrin is etfcelivc in the treaanent of
Trop M<d H;vt 1992; 86: 277-80.
duction in microfilaraemia,'.l even used with albcndazole.J.• A 13. Greene BM, <f of. A comparison of 6·, 12-, and 24·monthly dos· strongyloidiasis (p.145) and is considered by !IOme authorities to
good response to i\'Cmlectin has ~n reponed in infeaions with ing with ivennoctin for treaune:n1 ofonchocCRi ~is. J left:cr Dis be the drug ofchoice. Subcutaneous use has been investipted in
1991; 163: 376-80. patients with sc-.tte, disseminated disease.
M. srrepto<err:a."' 14. Gtrdon J,ntt/. Efrecu orsundard and high closcsofivmnec1in References.
I. Yan den Enden E, a ttl. Treatment ftilure oh single higb dose on 1duh worms of Onchoccrca volwullt$: 3 randomised control·
of i'vcrmcctin for MansantUa ptrs111ns filarinis.. Trans ll Soc led !riot Lonur 2002; ~: 203-10. I. NaquiraC~nol. Jvermectin ror human 1uonok>idi.tsis1ndoth·
TropMedlln 1993; 87: 90. 1S. K1mpio J. Dal. Adverse systemic: reaclions to treatment ofon-- tr intminal bclminths. ,(,. J Trop Mod Hyg 1989; 40: )()S-9.
chocerciasis wnh i\..:rmcctin at normal and high dos.es g;._en 1n· 2. W'tjcsundcra M de S. S.n111'1Jallllhom PS. lvermc<:tin therapy in
2. Schulz.-Key H. ~I ol. EfriCacy of iYcrmcctin in the bt\lmtnl of ~;;~nic strongyloidiasis. Tro".s RS« Trop M«I Hyg l992; 86:
conc;omit.ant Mansonetla pc.rsran1 infections in onchocerciasis ~9'~~:. three·men1bly. TTans R Soc Trop Med Hyg 2004; 98:
p0tieacs. Trtms R Soc Trop M<d lfn 1993; 87: 227-9. l . ~yaa,oub! M. e.t ol. Chronic persistcn1 stronayloldiasis cured by
I6. <;hurchill OR.~' al. A trio I of a 1hree-.dose regimen of ivennec-
3. Asio SM.~' al. MansOfttlla perstoM: .ufcty and efficacy of ivu- lln for the trtahnem of patients wi1.h onchoecrc1Hi.t in tk UK. 1vtrme<:tm. Tron1 R Soc T"'p M<d Hn 1992; 86: 54 t.
mectin alone. albcndazolc efone and lhe lwo drugs in combin3- Trons R Soc Trop M<d Hyg 1994: 8$: 242. 4. Oatry A,., ol. Tret11mefl1 orStron.gyloidcJ Sltrcoralis inf«tion
tion. Ann Trop Med Parosltol 2009; JOJ: 3.1-7. · 17. D:idzic KY, ti al. Changes in ocular onchoccrciasii af\cr iwo with ivt.'OTict.'tin compar~d with albcnduole: re.suits of an open
4. Asio SM, tt al. A randomised, double-blind field uial of jvcr- rounds orCCommuni1y-based ivetn\CCtiO 1.reo1ment in a holo·en· study of 60ca«s. Trons R Soo Trop Med Hyg 1994;88: 344-S.
mectin alone and in combination wilh albc:nduole for the treat· S. Gann PH. el ol. A randomized trlal orslnate· and IV..'O·dosc iver-
:~~~6~~~.0<erci~•is focus. Trons R. Soc Trop Med llJ'f 1991; meC1in ven:us thiabcndatole fof lrcAtmcnl or $1rOng)iloidiasis. J
mcnt ofMou'lsonella pers11ns infccrioni in Uganda. Trans R Soc
Trop Med Hyg 2009; JOJ: 274-9. 18. Abiose A, 11 al. Reduction in incklcnce of op1ic nerve disease Jefccr D;s 1994; 169: 1076-9.
wi1h annual ivermtclin 10 conlrol onchoccrciasis. ltmc~t J993: 6. M;irti H. er of. A comparaliYe trial of 1 singlc--dosc ivermectin
S. Fischer P, e1 of. Treatment of human Mansonclla streptot.eru in·
~~:::~~i~~1~~rc~,:;~::~:~i;1~dt1~~~1 ni~ ~!kc~r!~di~
341: 130-4. 1
fcction wilh h·cnncc•in. Trop Med Int H~altlt 1997; l: 191- 9.
6. fjscher P. et ul. I..ona-term suppression of MansontJla strep. 19. Cousens SN, ~t 111. lmpac.1 of annual dosing with ivnmttlin on
pror:ression of onchoccrcal visual field 10... Bull ll'JIO 1997: children. Am J Trop Med Hyg 1996; SS: 471-B I.
toccrca n>icrofiluiae af1cr lrcalmcnt with 1vcnncctin. J Infect 7. lau•l-Adell R. er ol. Efficacy •nd safet)' ofivcrmcctin and thia-
Dis 1999; 180: 140}..S. 75: 229--36. bcnda:r:olc in the trea1ment or .strongyloidiuis. Exput Op;n
20. Whi<woMJAO,•lol. Etfec:uofrepeateddoscsofiva-mec11non
Onchocerciasis. Jvcrmectin has a microfilaricidal action ocular onchoctrciuis; communily-N:scd trill in Siem LloM. P - w 200-I; 5: 261S-9.
Lonttf 1991;338: 1100-1103.
8. Matty FM~ e1 al. Treatment or human dissc:muutcd strongyloi-
against Onchocer:a voh.,Jus and is the main drug used in the diasis wilh a parrntCt:ll veterinary formubtk>n cf innncctin.
21. ~· H• ., ttl lvtn1*1in for on<-..,.1 eye dis..sc (ri•tr Clin /nf<et Du 200S; 41: tS-d.
control of onchocm:iuis (p.144). A single oral dose rapidly blindnesa). Ava1Jab!e in The Coch,..nc Oatabosc of Sysiematic
eliminates microlilariae from the skin. v.ith maximum effect ar. 9 . P1anowski J. eJ ol. Subcutaneous iVC'ftnectin as a safe salvaac
~9;(,~ Issue 2. Chichester: John Wiley; 2001 (•ccc:..sed thenpy in Slrongyloides stcrcoralis hyptrinfcction syndrome: a
ta I to2 months, 1and graduallyeliminateslhem from thecomea •-report.AMJTropMnlllnWOS; 73: 122-4.
and anterior chamber of the cye.l l~rm«tin has Jinle effect on 22, Pacctu6 M. tr al. Improve-menu in severe onchoccrcal skin dis~ 10. Salluh JI. d cl. Succe.Ssful USC or parmtcr1I ivcrmcctin in an
the adult wonns but does suppress the release of microfilariae case ar1er a sin&lc dose of j.,·c.rmcctin. Am J M«I 199 1~ 90: immun~upprnsed pc!ticnt wilh dlsscmin11ed strongyJoidiasis
S90-4. and septic shO<~. J>11ensiw Cor• Mtd lOOS; 31: 1292.
from the adull worm for several cycles wtiich accounts for its
prolonged activity. lvermectin therefore only controls the dis- Scabies and pedlculosis. Scabies (p.2182) is usually lrc;ited 11. Houbcr HP, er al, f atal outcome of• h)'l>orinfcction syndrome
with• lopiClOlly applied acaricide. However. a single oral dose despite SUt."OCSS-fUI eradicalion orStrongyloide.i; with subcutane..
ease; it does nol cure or eradicate it. Its action againsl O. vofrulus Ou$ ivcnncc1in. lnfec1fon 200S; 33: 383- 6.
has been attributed to a GA DA·agonist effect. Studies have also ofivermeclin has been reported to be effective.'" Jn a sn1dy of 12. Turner SA, et of. P:>renlcr.il odminis1nuion or ivcnn~cin in a
indicated thal ivcrmectin inhibits the transmission ofmicrotilar- I I patients with uncomplica1ed scabies, a single oral dose of J>Qlicn1 wilh disscmiMlcd ltrOn8Yloidi11Sis. Am J Trop Med Hyg
iae by reducing lheir uptake from man by the insect veclor.:i.6 ivennectin 200 micrograms/kg was effective in curing infection 200S; 73: 91 1-4.
after 4 weeks. In a group of JI patients. also infected with HIV, 13. Leung V, et ol. Case report: failure Clfsubcutaneous ivcrmcclin
lvennectin is donated by Merck through the Mcetizan Expert in trc:a1ing Stmngyloidcs hyperinfection. Aiu J Trop Med H)'g
scabies was cured in 8 after 2 wccks.1 Two of the remaining 3 79: 853-5.
Committee (MEC) for human use in community-wide mass patients received a sooond dose of ivermcctin which cured the
200$;
treatment programmes in all coun1ries in which onchocerciasis is 14. l.ichienberg_cr P. er al. HYJ>Crin(tctton s1ron..yJoid;asis in a fiver
~~~; i~Jer.': t~~~ ~1h J)Ortntcral 1vtrmectin. Tronspl
2
scabies infection by the fOUrth week. lvennectin docs not sttri-
endemic~ where it is given al a ttand~rd oral dose of
lise the scabies eggs and in order to kill newly hatched mites 3
l 50 micrograms/kg once or twice a year to all but pregnant
second dose ofivennectin is recommended, given al least 7 days Trithostrongyliasis. For mention of the use of ivermectin in
women, breast-feeding nl0lhe1'5ofrec:ently born babies, children after the first dose.• A single oral dose of ivermectin Trichostto1ig>lus infections, stt p. l 4S.
weighing Jess than 15 ~and lhose unable to walk or otherwise ISO micropmsllcg was partially effecth'C in an OUtbreak ofsca-
seriously ill. 1 Theaduh worms li'e for •bout 15 )'C'ltS. theiefore bies in 1153 Tanuniao patients.5 A systeinatie review' on the Preparations
treatment will ncedlO be continued for many years. Sevwil stud- treatment ofscabies fovnd that oral ivcrrncctin was less effective USP 33: ~ "1ld f')nntl'I Pamoate Tllllots:~ T -
ies h"-e confirmed the long-term safety and efficacy ofsuch pro- than topical permethrin, but appeared to be as etfeclive u topical Proprietary Prepuations (details arc &ivcn tn ~Ju mt B)
grammes.$." Srudies hove reported that incrc:ising the frequency
of the stan<lard doses or ivennectin to every 3 or 6 months •p-
benzyl benzo:iteand morcefiectivelhan topical lindanc. Howev-
er, a randomised, open-label study' found that one or two appli-
Arr.: 0ennope- IV: °""""""°'
Oetebc:n<I. 1""1•1, S.CVO: Austral"
Stsomectol. Bnn.: '-meet LM<rtlin: ~ Vtrmect~ CMe: Kao.
pe:irs to incr= efficacy compared with annual treatments•J.1' nol: Medodenr< Fr" Me<1izan: Stromcctot Cr.: SlrOmO<tol:Jpn: Stsome<tot
cations of 12.5% benzyl benzoale, each left on for24 hours, were Mex.: IYexlerm: N~th.: S'lomectol: NZ: Scrornectol: Thal.: Vcrmectin:
and that 3-monthly regimens may also reduce risk of adve= ef. more e1fec1ive than a single oral dose of ivenneetin of I50 to USA: MectG:an: StrOmoclol
lects.105No additional benclil was noted by increasing 1hc dose 200 micrograms/kg; bacterial superinfection also occurred more
of ivcrmcctin to 400 or 800 micrograms/kg given either 3- often in lhose given ivenncctin than in those trcaled with benzyl
monthly or annually. benzoatc.
b1 norMOndemic areas, repealed doses may be ncccssary to re- Crusted (Norn'Cgian) scabies bas also been reported to be effec- Levamisole (BAN. rlNN)
duce rcc.urrence; a SIUdy in the UK found that patients given tively treated by a single oral dose of 12 mg of ivermectin in ad-
three doses at monthly intOM1ls had fewer relapses at 6 months dition to topical application of 3% salicylic acid ointment in 2
lcvamisol: Levamisole; Levamisoli; Levami~um: levamizol. (S)·
than patients who received a single dose, but relapses were nev- palients; lhc treatment was clfcctive in under one week. 2 A single 2.3.5.6-Tetraltfdro-!rphenytimidazo{2.1-bX 1 .3)t~.
ertheless seen in 50% of patients •l 12 months. 16 oral dose of h·crmectin 200 micrograms/kg was effective for l\eeaM,o)OA
The ocular microfilarial load can be safely reduced by crusted scabies in a 2-year-old infant who had contrae1cd the dis- CttH,,N,S = 204.3.
ivermeclio'-11 and early lesion! of the anterior segment of the eye ease following Jong-term eorticosteroid usc.7 Ivenncctin has also CAS- 14769-73-4.
have improvcd. 11 A reduction in the: incidence'' and been successfully used in a small number of patients with trea1- ...re -POZCEOI.
pn>gJCSSjoo" of Of>tic nerve damage has also becl reported. but ment-ruisw11 scables.1 ATC Vet - QP52A£01.
the effect on posterior segment disease is less certain.20 A sys- lvennectin has also been inves1igated9asa pos.;bJe trealmenl for UNll - Z880D3468G.
tema1ic review of S placebo-controlled srudies, with data from pediculosis (p.2181) although, again, topically applied insec1i-
3810 individuals, found nostaliSlically significant dilference iJe. cides are d1e usual melhod of control. A study in vitro Md in
iween ivenncctin and placd:>o groups for preventing visual acui- animals showed lhat ivermectin killed nymphs and fen1alcs or
ty loss.21 lmprovements in skin lesions have been reported."' the hurr14n body louse (Pedic11/11s humanus huma1111s). Jvenncc-
I. Bas3nez MG, tt ol. EfTcc1 of sfng,lc~dosc ivc:,mcctin on On· tin was known lo be effective against other louse species that in·
chocerca volvulus: a systcm11ic l'C\'1cw and mctawanalysis. lan- feet a range of onimals. m lvcrmecrin has also been shown to be
cet lnfe<:l Dis 2008; 8: 31G-l2.
effec~ve against head lice: lwo oral doses of400 microlP"'msikg
2. Newland HS. ti al. Etrect of sinate-..dosc. ivermcc1in therapy on at an intcr.·Jl of7 days were more ctfecti,•e than applications of Pharmacopoeias. In Eur. (sec p.vii) for veterinary ll<e only.
human Onehoccrca volvulus infccLion with onchoccrcaJ ocular Ph. Eur; 6.8 (Levamsole 6:r Veterinory Use: lev¥nisole BP(Vct)
involvemcnc BrJOph1holmol 1988: 72: 561 -9. malathion 0.5% in a controlled double-blind study in peticnt.s
l . Taylor HR.~' of. Impact of mass treaunen1 of onc,hocerciasis with refractory infesations. 11 2010). A white or almost white powder. lt exhibits polymor-
with i¥Crmectin on the lransmiSStOn o( infeel ion. SciD?te 1990: I. MeinkingTL.. ~10/, Thctrauncn1ofscabics wi1h ivermeclin. N phism. Slis)>tly soluble in water, freely soluble in alcohol and in
lSO: 116-18. Ent/ J J.l•d t99S: 333: 26- 30. methyl alcohol. Store in airtight containers. Protect from Jig)it.
All cross-references refer to entries in Volume A
 Levamisole J55
Levamisole Hydrochloride (BAM\'\ USAN. rlNNA1J Precautions dose, repeated after 7 days in cases of severe hook.-
Oo6dralo de Leva:nizol: Hidrocloruro de levamisol; ICl-S9623: The use of levamisole shou ld be avoided in patients wonn infection.
Levamisole. cMo:'h)'drate de: Lcvamiscl-h)"drochlorid: Levamiso!· with pre-existing blood disorders. Patients given le- Lcvamisole infl uence.s host defences by modulating
1~,.0o·okJoc>:l: Levarr.isol; hydrochloridum; Levamisoiihydroldoridi; vamisole with fluorouracil should rn1dergo appropriate cell~mediated i:nmune responses; ii restores depressed
LevaMizal.hidroi<Jorid; Levamizol<o hidrochloridas; Lewamizolu monitoring of haematological and hepatic function. T-cell functions and has been described as an immu-
chiorowodorek: NSC-177023; R.-1256~: RP-20605: l·Tetrami-
sole Hydrochloride; 1-Tetramisole Hydrochloride. Abuse. Cases of severe neutropenia and agranulocyrosis associ- nostimulant, although stimulation above normal levels
ated with abuse ofcocaine tainted with levamisole have been re- does not seem to occur. It has been tried in many disor-
l\eBaM~30/l.a f HA.pOXAopi1.l..
C,,H, N;S.HCI =240.S. portcd. 12 Necro1ising. vasculitis has been associated with abuse
of such mixlures.3 Fatalities l1ave been repo1tcd.4
ders, including bacterial and viral infections and rheu-
o.s - 2 16595·80-5. I. K.t\owtes L. ct al. Levamisole 13in1ed eocoine c:iusing severe
matic disorders, although in these conditions results
ATC - P01C£01.
nc:utrope-nia in Alberta ~n d British Columbia. Harm Reducr J
have not been encouraging.
UNI/ - Dl 90.55K809. 2009; 6: 30. Levamisole has also been used as an adjunct in patients
Pharmacopoeias. In Chin.. Ew: (see p.vii), Int.. US, •:md JlicJ. 2. CDC. A,g.1t1nuloc:y1osis a.~ ia tcd wi1h cocaiOle: use - four sble:s. with malignant disease, although it is not clear that any
Ph. Eur. 6.8 (Levamiso!e Hydrochlondc). A white to almost March :?008-Novcmber 2009. MMWR 2009; 58: 1381-5. Also
white ciystalline powder. Freely soluble in water; soluble in al- 3vailabl(' ~I : http:!/www.cdc.g.ov/mmwr/POF/wkfmm5S49.pdf (ac· response is due to its action on the immune system.
ce,<Sed 18105/IOJ Adjuvant treatment with levamisole and nuorouracil
c'Ohol: slig)ltly soluble in dichloromethane. A 5% solution in wa·
3. Bradfor'd M. et ul. Bila1eral necrosis of c<irll..'lbo:s und ched.;s: ~n·
ter has a pH of3.0 to 4.5. Protect from light. o ther complication of cocaine contaminnted wi1h l~v<Jmisol c .
has been given to reduce recurrence after resection of
USP 33 (Levamisole Hydrochloride). A white or almost white Amthue.1·,,Mcd.10 10; 1S2: 758-9. aden(1Carcinoma of the colon with regional lymph
ciystalline powder. Freely soluble in water; soluble in alcohol; -1. Ouflou JA. cl ol. L<V3misole as an adullerant in : cocaine over· node involvement (but see Malignant Neop,lasms, be-
slightly soluble in dichloromethane; practically insoluble in dose fa13lit}'. MedJ Ami 2010: 19?: 724.
eiher. pH of a 5% solution in water is between 3.0 and 4.5: Pro- low).
toc1 from light. Rheumatoid arthritis. The presence of HLA B27 in seropos-
itive rheumatoid arthritis is an imponant predisposing faclor to OReviews.
the development ()f agranulocytosis with levaniisole: it is recom- I. Amery WKI', Bruynse<ls JPJM. f,cvamisok:., the story an~ 1he
Adverse Effects lessons. Int J lm1mmoph1m1wcol 1992; 14: 481-6.
mended that the use of levami<0le in this group should be avoid- 2. Schein re Id N • .:1 IJI. Lcv3misofc in dcm1a1ology : n review. Am J
When given in single doses for the treatment of as- ed.' Cli" Dt:rmo1012004: 5: 97- 104.
cariasis or other wonn infections, levamisole is gener- I. Micfo1lts H. Veys EM. A st\1dy of the hcmatofogic~ I side effects
Administration in children . Levamisolc may he given orally
ally well tolerated and adverse effects are usually lim- of lcvamisole in riltumatoid ~nhrit is with recom mcn~Jions. J
R'1eumatol 191S: S (su ppl 4): 77-83. to children for the ireatmeol of ascariasis, hookwom1 infections,
ited to nausea, vomiting, dian:hoea, abdominal pain, and mixed ascariasis and hookwonn infections.' Doses used arc
dizziness, and headache. Sjogren's syndrome. A sludy was slopped afier adverse ef- the same by weight as those used for 3dults (see above).
fects appeared in 9 of I0 pat.icnts with rhcum•loid arthritis and
When Jevamisole is used as an immunostimulant and SjOgren~s syndrome while receivjng lcvamisole.' Levamisole Malignant neoplasms. Le"amisole hos been iried in lhe adju-
should he given with caution, if at all. to paliems with Sj6gren's vant tream1ent of various malignant neoplasrnsl.? with conflict-
given for longer periods, adverse effects are more fre-
syndrome. ing results. Based on tlie results of early adjuvanl sludies.),< lc-
quent and diverse and, in common with other immu- vamisole was fonncrly used with lluorou111cil in patients with
nomodulators, may sometimes result rrom exacerba- I. Balint G. ~,al. SjOgrcJl'S syndrome: a contraindi<:3tion to lcv3m-
isole 1 ~alment'? BM.I J977; 2: 1386-7. colorectal cancer, panicularly in the USA. However, adjuvanl le·
tion of the prima1y underlying disease. Adverse effects vamisole alone Ms no more effective than placebo in I study.6
associated especially with the more prolonged use of and more recent studies have indicated that levamisolc is no
Interactions more effective than placebo when added to fluorouracil,7 ot to
levamisole have i1icluded: hypersensitivity reactions fluorouracil plus folinic acid.s For cunent management of color·
such as fever, a flu-like syndrome, arthralgia, muscle Alcohol. US licensed product information states that leva01isole
can produce a disu)firam-like reac1icm wilh alcnlml. eetal cancer see p.7'.?4.
pain, skin rashes, and cutaneous vasculitis; CNS ef- l . Sprcafiro f, Ust of lcvam isol;: in cancer p3licnts. Dmgs 19SO;
fects including headache, insomnia, dizziness, and Ant.i coagulants. for an increase in the activicy of warfari11 20: 105- 16. .
when given with Jevamisole and fluorouracil, see Interactions. 2. Amery WK. Buiterw<>rlh BS. Review/co1nmc1ltary: the do~ge
convulsions; haematological abnormalities such as Levamisole, under Warfarin, p.1569. rcginum uflevamisolc in rnnct-r: i!, it r:::la1ed to dlic,acy and safe·
agra11ulccytosis, leucopenia, and thrombocytopenia; 1y? /111 J l1111111111"f'lttmn<rcal l 9S3~ 5: 1-9. .
Antiepileptics. For increased phe11ytoi11 concentrations when 3. Laurie JA, l!t lll. Su1gicol adjuvanl 1herapy of large·bowcl cor<:i-
and gastrointestinal disturbances, including an abnor- norna: :Jll ~val u;ition of lc\•:i:miS(lfe and the C<'1 11\bin.:ition o( le•
given with le'·ainisole and fluorouracil. see Interactions, Antiue-
mal taste in the mouth. oplastics, under Phcnytoin, p.543. v~misole and Ouorou racil: 1hc Nonh Ccnual Cancer Tr\.·a1mcn1
Group a nd the Mayo Clinic. J Cli11 Om·ol 1989; 7: 1447-56. .
Incidence of adverse effects. In a TC".icw' (by the manufac· 4. Moen.cl Cli. et af. Levamisolc and fluorouracil for adjuvant ther-·
rurers) of 46 oootrolled srudies in which 2635 cancer patients re- Pharmacokinetics apy of re~ected C<'llon e:>rcinom..,. N Engl J Mrul 1990; 322:
ceived adjuvant levamisole treatment.. most paticntS received le- Levamisole is rapidly absorbed from the gastrointesli- ;s2-s. .
vamisolc on 3 consecutive days every 2 weeks ( 1102 patients) or 5. Mocrtel CG, t!I al. Fluorourac-il p lus lcvamisole as dfcc.ti"e ad-
nal tract and peak plasma concentrations occur within jm•:mt lhcrnpy oJtet rtsecli<'ln of stage Jll cOlon carcinoma: a ·r..
on ]. consecutive days eveiy week ( 1156 pa1ients). usually in a nal report, .4mt lt11i:rn .\,Jed J99S: 122: 321 - 6.
daily dose of 150 mg. Levnmisole caused several adverse effects. 1.5 to 2 hours. It is extensively metabol ised in the liver. 6. Chlc"')\vski RT. ct 11/. Long.·1~rm sur\'iV31 following lcvam i$Olt
such as skin rash, nausea, vomiting. and a metallic or bitter taste The plasma half-life for levamisole is 3 lo 4 hours and nr pl3ccho :1dju·t:i.nt trca11nent of colorectal cane.er: a WcMcm
in the mouth. which although t1:oublesome were relatively n·ivial for t11e metabolites is 16 hours. It is excreted mainly in Cancer SlUdy G1oup trial. Oncolof!:!· 19SS; 45: 14 t- 3.
and ofle11 regressed during therapy or disappeared on cessation 7. QUASAR Colhrbora1i,•e Grc-up. Comparison of Ou~>r<Juraci l
of therapy. A to1al of38 patients developed agranulocytosis and
the urine as metabolites and a small proportion in the wi1h addition3J lcv:.lln isok, hi'!!her-dose folinic :'I Cid. (If b<Hh. 41S
faeces. About 70% of a dose is excreted in the urine adj\J\'Ant chemoflcr~py for eol";,rc:ctal c:ance.r: a randt1fnised trial.
of these 36 had received weekly treatment. Several contracted L'mcet 2000: 355: 1588-96.
possible life-threatening infoctions and 2 died of septic shock. over 3 days, wilh about 5% as unchanged levamisole. S. Wohnntk N. e1 cl. Clinical triol to usscss the rel:i.1ivc dlicacy of
I. Amery WK. Buuecworth BS. Review/commentary: lhc dos3gc lluorourncil anC lcucC1vorin, fluorouracil ;ind l~v;'lmisole, ond
regime1\oflev:amisole in c1u1C'C'r; is i1 related lo C>flic:icy :md Slilfc- o Refertnces. Ouorouracil. leu:ovorin. :>nd le"amisole in pa1icnt:t wi1h Ouke-s·
1y? /111Jlm111111t011ltomwca/ 1983: ~·: 1-9. I. Luyckx M. l!t tJJ. Pha.rmacokinctics of lcvainisole in hcalth.y sub- Band C coircinetn3 of lite:' colon: re.:suhs from N:ilionnl Surgical
jects and cnnctr p::nicuis. Eur J Dmg M~1ob Phormal'okinet Adjuv:int BrGst;ind Bowel Project C-04. J C'liu Oncr1J 1999: 17:
Effects on the endocrine system. Rechallcngc confin11ed 1982: 7: 247-54. 3553-9.
that levainisole was responsible for inappropriate a ntidiurctic 2. Kouas:si E. (JI t1I. NQvel 3SSay Jnd ph.,rnmcokinc•ics or lcvami-
honnone syndrome in a patient receiving levamisole with fluor- Stlle :ind p-hydroxylev;:unisok in human pl3sma ~md urine. Biop·
Mansonetlainfections. Levamisole is one ofthedr\lgS thal has
ouracil.1 hmw Drug Di5pos 1986: 7: 71'""89. been suggesled ror lhc treatment of }.1ansonel/o infections
I. T1.\•Ctd)•CR. et fl/. Lev::unisole·induccd syndrome of inappropri- (p.144). There lia·1e been repons'-' of "''pon~ whe11 g.i"en with
ate an l idi u r~tic hom1onc. N Engl J Med 1992; 326: 1164. mebendazolc.
Uses and Administration I. Mn~ nens K. v.,:~y M. £ f1Cc:1 <•f mcbettdazok :ind levnmisol.;: on
Effects on the liver. Elcvalcd aspartate aminoiranslcrase con- Levamisole hydrochloride is the active laevo-isomer OnclHX"en:-:t \'Oh•ulus :>nd Oipc:1<1loncn1<1 pc.rsu111s. Trom• R Soc
centrations in 2 of 11 patients given iewmisole for recurrent py- of tetram isole hydrochloride. It is used as an an- Trop ..\-J<:J JJ,-g 19?5; 69: 359-60.
odenm1 suggested liver toxic.ity, a very rarely occu1ring adverse 2. BcrnbCr:?. HC, t!Jal, The combined 1 ru11r~n1 wi1h ll•vamiso!c :ind
elfect 1 In a later report. liver enzytne concentrations were raised thehnintic and as an adjuvant in malignant disease. It mcbcnd<lzole f()( a perswns·likt! fi lnri:il i11fcc1ion in Rhodesia.
i11 a 14-yeir-old boy tre-:ited with lev3misole for minimat change has also been tried in seveial conditions where its stim- Ttt111>· R Soc Tro;1 Mee/ H.1"g 1979: 13 : 233-1.
n<-']>hrotic syndrome.' ulant effect on the depressed immune response might Mouth ulceration. Lcvamisole miC?;hl be beneficial in severe
I. J>1;1pagcorgiou P, ttl o/. Levmnisole in chronic pyoden n a. J C/i,, be useful. mouth ulceration (p. I 849) but is limiled by its •dverse ell.eels. A
Lob /mmunol 19&'2;8: 121-7. review' of its use in recurrent :iphthous slomatitis indicated thal
2. Bvlugal13piliyn OTO. Li,•erto:\icit)• inanephrOlic P!llicnl tre-ated Levamisole is active against in1es1inal nematodes and beneficial resul1s have been reported with ll!vamisolc in open
with levamisole. Arch Dis Child 1997: 76: 289. ·
appears to act by paralysing susceptible wonns which snldies. but resultsof double-blind sllidies have been conflicting.
Effects on the nervous system. Reports 12 of inOanunatory are subsequently eliminated from the imestines. In par- Ncverthclcss, there have been patients with severe recurrcnl aph-
leukocncephalopathy were associated with the use of fluorour- ticular, levamisole is effective in the treatment of as- thous stomatitis r!frnctory to all other modes of tre.auncJlt who
acil and levamisole in 4 patients being treated for adenocarcino- have responded io levumisole. Dosage has been with 150 mg
ma of the colon. Active demyctination was found jn 2 patienl's . 1 cariasis (p.I 40). It is also used in hookwom1 infections daily in divided d~scs given for 3 days at the first sign ofuloera·
Clinical improvement occurred when chemotherapy was (p. 142). tion. followed by 11 days without treatment, repeated as neces-
stopped~ 3 patients were treated with corticostcroids. 1 A similar Doses of levamisole hydroch loride are expressed in saiy. Asmoll controlled sll1dy~ indicated that it was ineffccli,·c in
syndrome has ~n reported i11 ~ parient with a history of hepati- the prevenlion ofrecurrcnl aphthous slOm:lliliS.
tis C given levamisole alone.l terms of the equivalent amount oflevamisole. Levam- I. Miller MF. Uscoflcvamisolc in rccurrcn1 aphthous Slom:itilis.
I. Hc.nk CC, et ol. Mulli lOcal innammalory leukoenecpJ1a1opathy isole hydrochloride I.18 g is equivalent to about I g of Drugs 1980; 20: 1;1-(), . .
with S-lluorouraciland Je,•amii.ok A11nNi:11rol J992; 3J: 262-7. levamisole. The usual dose for adults and children in 2. Weck:< LLM . ~'"'· Lev3111isol n3o 1uc:vmc le~O{"S de estomn111 e
2. Kimme' OW. Scht1U AJ. Multifoc3I leukoencephalopathy: o<:- aAosa recorreme: um cn~aio clinico 1and oini~o. duplo-cego c:
currcncc d uring 5-lluol"Oliracil Md le\·amisot~ 1herl\py 30d re~o- ascariasis is 2.5 mg/kg oflevamisole orally as a single c:omrol<!do por placebo. Rev A.m1c Med Bn1J 2009; 55: 132-8.
1ution after discon1inuution of chtmolhcrapy. Mayo Clin Proc dose. For hookworm infection (ancylostomiasis) or Renal disorders. In a randomised double-blind study, children
1993; 6! : 363-5.
3. Luci3 P, et qi. Multifocal kucC'locnccphatopaihy induced b)' le-
for mixed ascariasis-hookworm infections, lioth with frequently relapsing corticosteroid-scnsi1ive and cortices·
''a1nisole. L''nct't IW<,: 34K: 1450. adults and children may be given 2.5 mg/kg as a single teroid-depcndcnt ncphrotic syndrome were given placebo or

The symbol t denotes a preparolion no longer actively marketed

156 Anthelmintics
levamisolc 2.5 mg/kg on alternate days and corticosteroid thera- wom1s. However, male fern is highly toxic and has bct:n super- counrs. Pa1ien1s with liver damage should be treated wilh re-
py was gradually withdrawn. 1 Of3l children being treated with seded by other drugs. duced doses ofbenzimidazole carbamates, if al alJ.2
lcvamisolc, 14 were still in remission 112 days after the start of Adverse effects include headache, nausea and vomiting, severe I. Davis A, el al. Multicentrt clinical trials of benz.imidazolecar·
the study compared with 4 of 30 rcccivinf placebo. An evalua- abdominal cramp, diarrhoea, dyspnoca, albuminuria. hypcrbi· bamates in human cchinQCC)CGOsis. Bull WHO 1986; 64: 383-8.
tion of 3 randomised, controlled studies, including this study, 2. Davis A. e1 ol. Muhiccnlre clinic.al 1rials uf benzimid.azolcc.ar-
lirubinaemia, dizziness. tremors, convulsions, visual disturbanc- b3mates in human cystic cchinococcosis (phase 2). 8111/ WHO
found that levamisole reduces the risk of relapse during trcal- es including blindness (possibly pcrmanenl), stimulation ofutcr· 1989; 67: 503-8.
menl bul no conclusion could be reached on its co11icos1eroid- ine muscle, coma. respiratory failure, b<adycardia, and cardiac
sparing effect. 111ere have been similar repo!IS of adjunctive USC failure. Fatalities have oecwred. Overdosage. Respiratory arr.est and 1achyarrhytl\mia associat·
in children with uephrotic syndromc,3 ·' but its place in therapy ed with continuous convulsions were reponed 1 in an 8-weeJ<-old
rcinalns to be established. For a di"<:ussion of the lreatmcnt of Preparations infant after accidental poisoning with mebendazole. Treatment
glomerular kidney disorders, including the nephrotic syndrome. Proprietary Preparations (details arc given in Volume B) by exchange translbsion and anticonvulsants was successful.
see p.1641. I. c1 Kalla S, Menon NS. Mcb~ndazo lc poisc.nins in infancy. Ann
Multi'·ingredt~nt Austria: Digcstod()(otY; Ge-r.: Digestodoron; S.A(r.: TropPoediorr 1990; 10: 313-14.
J. British Association for Paediatric Ncph1ology. Levsmisolc for Digestodoronf.
CQrticostcroid-dependenl nephroticsyndrome in childhood. Lo1r.
eel 1991; 337: 1555-7. Homoeopathic: Fr.: Diicstodorcfl< Ger.: Ag>ricus comp; O>.l;dorium Precautions·
2. Davin JC, Merkus MP. Levamisolc in stcroid·sensitivc ncphrotit con-p: PhonOc Thu~·ladiesis spag; Phoni>c UrtiCa·A"'Senicum spag: UK: D~
iyndrom~ of chi1dhood: the lost paradise? P1diarr Ncpl1rol 200S; gestodoron. Patients given high doses of mebendazole, such as
20: 11>-4. those with echinococcosis, should be supervised close-
.3 . Donia AF, er of. LevamisoJe: adjunctive therapy Ln steroid de·
pendent minima) change t1Cphrotic children. P~diotr Nephro/
ly with blood counts and liver function being moni-
2002; 17: 355-S. tored; such high-dose therapy may be inappropriiite in
4. Fu LS. et al. LevamiS<\le in s.teroid..~ensilive nephro1ic syndrome Mebendazole (BAN. !JSAN. r1NNJ those with hepatic impainnent (see under Incidence of
children wiLh frequent relapses and'or s1eroid dependency: com·
porison of d3ily and cvcry·olhCr·<fay usage. Nephro11 Clin Pr·oct Mebendatsolc Mebendazol: Mcbe<ldazolas: Mebendazole: Me· Adverse Effects, above).
2004; 97: cl37-<141. bendazolum; R- 17635. Meth)j 5-benzoyl- IH-benzimidazol-2-yl- Monitoring drug concentrations. Jn a retrospective analysis
~. SOmegi v• ., of. Long•lerm effects of levamisole treaunent in carbamate. ofpatients given high doses ofmebendazole for echinococcosi~, 1
chi ldhood ncphrotic syndrome. Ped;o1r Ncphrol 200-1; 19:
1354-60. Me6<1>1Aa30A no relationship was found between dose and·plasma concentra-
6. Al-Saran K, et al. Experience wi1h Jev~misolc in frcquctllly re~
lapsing, sicroid-dcpendent ncphrotic: syndrome. Pedlolr N~phrol
=
C 16H 13N 303 295 .3.
tion of mebendaz.ole and considerable inlra· and interindividual
variation in plasma cpncenirations was seen, emphasising the
2006; 21: 201-5. . CAS - 31431-39-7. need for repeated monitoring. Several patients appeared to have
1, Boyer O. et ul. Short- .-od Jong-term efficacy of levamisole as ATC - P02CAOI. wha! were considered to be subtherapeutic plasma concentra-
adjunctive thcrspy in childhood rephrotie syndromt. Pediatr tions.
Ntphrol 2008; 23: 575-80. ATC Vet - QP52AC09.
I . Luder PJ, et ul. Tr~atment of hydtttid disease with high oral doses
Vltiligo. In a study' involving 36 patients with limited slow- UNI/ - 8/G6/5V051. of mebcnda.zole: long-tenn follow-up of plasma mebcndttole
sprcading vitiligo, response to lev001isole treatment occurred in levels and drug in1cractions. Em• J Clin Phormocol 1986; 31:
34 within 2 to 4 moolhs. Patients re:eived 150 mg oforal levam- 443-8.
isole daily on 2 consecutive days each week. Patients who were Pregnancy. Mebendazole is teratogeriic in rats and there ·are
additionally treated wilh topical fluocinolone or clobetasol had no adequate .and well controlled studies in human preg11ancy.
higher rates of repigrnentation. A later controlled.study' involv- Mebendazole is lherefore usually contra-indicated during preg-
ing 43 patients reported less benefi~ oancy. However, it was noted lhat io a survey ofa Jjmiled number
The usual lrcalmcnt ofvitiligo is dscussed under Pigmentation of pregnant womea who had inadvertently taken mebendazole
Disorders, p.1723. during the first trimester, the incidence of malformation and
J. J>:micha JS, Khera V. Effect of prolonged l'rc-atmcri1 wi1h levam~ spontaneous abonion was no greater lhan that seen in !he general
isolc on vililigo with limited and ~low·spri.:ading, disease. /n1 J population.
Dermotol 1994; 33: 5&4-/.
2 . Agarwal s. et of. A randomized pl.a;.ebo-controlled doubl~blind Pharmacopoeias. In Chin., Eur. (see p.vii)Jnl., us: and Viet.
study of levamisolc in the treatment of limi1ed and slowly Ph. Eur- 6.8 (Mcbendazole}. A white or almost while powder. It
Interactions
spreading vitiligo. Br J Dermoto/ 2005; 153: 163-6. shows polymorphism. Practically insoluble in water, in alcohol, Antiepileptics. Phenytoi11 or carbamaupine have been report-
Preparations and in dichl<iromethane. Protect from ·1ighl. · ed to lower plasma-mcbcndazolc concentrations in patients re-
USP 33 (Mebendazole}. A white to slightly yellow, almost ceiving high doses for echinococcosis, presumably as a Tesult of
USP 33: Levamiscle H)'<lo'ochlondo Tabt?t.<.
odourless, powder. Practically insoluble in water, in alcohol. in enzyme induction; WJ/proate had no such effect. 1
Proprietary P·repara.tions (dctaiJs arc given in Volume B) chforoforrn, in ether, and in dilule mineral acids; freely soluble in I . Lu.d U PJ~ el al. Treatment of hyda1id disease wilh high oral doses
Levatr< Meglum; Austral~ Ergam6olt. Belg.: &gamisat: Broz.: 1'o-
Art-~
formic acid. of mcbcndatolc: long-1cnn follow-up of ?lasma mebendttole
~ri~11in~~: =~;~~~~::;:n~~tm~~~~t~f·'. ~: levels -and dn.ig interactions. E11r J Clin Phormocol 1986; 31:
00!;Mex.: Dewis; Rus.: Oeca..;, fAe>•P"<): $.Afr.: Ergamisolj: ~rk: 443-8.
Faraks: Sitraks: Uk/'.: Decaris (Aei<ap1-1C): USA: ~rgamisult: VencL: Decar- Adverse Effects Histamine H2 -antagonists. Plasma concentrations of meben-
~. Since mebendazole is poorly absorbed from the gas· dazofe·have been raised when !he enzyme inhibitor cimeridine
trointestinal tract at the usual therapeutic doses, ad- was also given, and this has resulted in the resolution of previ-
ve~ effects have generally been restricted to gastroin- ously unresponsive hepatic hydatid cysts. 1
Male Fern testinal disrurbances, such as transient abdominal pain 1. Bckhli A, Pirouc J. Cimc1idine i n cr~ascs serum mebcndazole
concentrations: implic.atiOns for trcatmcnl of hep3tic hydatid
Aspidium: Famwur:zel; Felce Maschio; Feto Macho; filix Mas; and diarrhoea, and have tended to occur in patients be- cysts. Br J Clin Phormocol 1981; 24: 390-2.
Fouge"" Male; Helecho macho: Rhizoma Filids Maris. ing treated for heavy intestinal infection. Headache and
Ul"1T03H11K M}?KcKOH dizziness have been reported. Adverse effects have Pharmacokinetics
CAS - 114-4 2-1 (flovospidic acid). been reported more frequently with the high doses tried Mebendazole is poorly absorbed from the gastrointes-
ATC Herb - HP02DW5002 (Dryop1eris (ilix-mos: rhi- in echinococcosis and have included allergic reactions, tinal tract and undergoes extensive first-pass metabo-
zome).
UNll - COZKORRF5X.
raised liver enzyme values, alopecia, and bone marrow lism in theliver. It is e liminated in the bile as un-
depression. changed drug and metabolites and excreted. in the
Incidence of adverse effects. In the firs! phase' of WHO-
faeces. Only about 2% of a dose is excreted unchanged
coordinated mullicentre studies on the treatment ofechinococeo- or as metabolites in the urine.
sis (hydatid disease) involving Echinococcus gra1111/osus or E. Mebendazole is highly protein bound.
mulliloc11/aris. the most frequent adverse effects in the 139 pa-
tients given high.<fose mebcndazole. generally for 3 months,
were reduced Jeucocyte count (25 patients), gastrointestinal
Uses and Administration
symptoms (22), and raised scrum-transaminase values (22). Qlh... Mebendazole, a benzim idazole carbamate derivative,
er.adverse effects were allergic conditioos such as fever and skin is an anthelmintic with activity against most nema-
reactions (4), CNS symptoms including headache (6), and loss of todes and some other wom1s; activity againsl some lar-
0 0 OH hair (7). Seven palienls stopped treatment because of adverse ef. val stages and ova has also been shown. lt inhibits or
fects.
(novaspidic acid) destroys cytoplasmic microtubulcs in the wonn ·s in·
The second phase of studies? compared albendazole '~ilh
testinal or absorptive cells. Inhibition of glucose uptake
Pharm acopoei;a.s. In Chin. mebendazolc in more prolonged high-dosage schedules for cyst-
ic E. gra1111/osus infec1ion. Adverse effecis were similar to those and depletion of glycogen stores follow as do other in·
Profile reported with the first phase. However. in !he fir~t phase the al- hibitory effects leading to death of the worm within
Male fern consists oflhe rhizome, frond-bases, and apical bud of lergic consequences of the 14 ruptured Iung cysts and !he 4 rup- several days.
Dryopttris fl/ix-mas agg. (Polypodiaccae). collected late in the tured liver cysts that occurred with mebendawle were not report-
autumn, divested of !he rools and dead pollions and carefully ed. In the second phase, 2 pa1icnts suffered anaphylactic shock as Mebendazole, being poorly absorbed from the gas·
dried, retaining tl1e internal green colow. It contains not less than a result ofrup111reof a lung cyst and a cyst in !he abdominal cav- is
trointestinal tract, used principally in the treatment of
I.5% of filicin. During storage the green colour of the interior ity. These 2 patients were with<hwn from mcbcndazole treat- the intestinal nematode infections ascariasis (round-
gradually disappears. often after a lapse of 6 months. and such ment, as were another 4 patients as •consequence of their ad· wom1 infection), en terobiasis (pinworm or thread·
material is unfit for medicinal USC. verse reactions~ although in 3 1he withdrawal was only wonn infections), hookwonn (ancylostomiasis and ne-
Filicin is !he mixtute of ether-soluble substances obtained from temporary.
male fem. Jts activity is chiefly due to flavaspidic acid, a phloro-
catoriasis), and trichuriasis (whipwonn infection); it
Although albendazole is preferred to mebendazole in the treat-
glucinol derivative. is useful in mixed infections. During treatment with
ment of echinococcosis, if either drug is used there should be
Male fem has an01ehnintic propenies rutd was formerly used as constant medical supervision with regular monitoring of serum- mebendazole, migration of wonns with expulsion
male fem extract (aspidium oleoresin) for the expulsion of tape- transaminase concentrations and of Jeucocyte and platelet through the mouth and nose has occurred in some
All cross-references refer to entries in Volume A
 Male Feno/Meuifonate 15 7
patients heavi ly infected with Ascaris. Mebendazole is 2. Oe:rnhcri; HC. er t1I. The comhincd 1rea1mcn1wilh lcv~mi~lc ~nd
mebendazok for ll pcrstans-like filarial infccli<m in Rhodesia.
also used in the treatment of capillariasis and tiichos- Trans R Soc Trop Med H)•g 1979: 73: 233-4.
trongyli3sis and has been used in strongyloid iasis. 0th· ~. Bn.~an i ER. CJ nl. Comparison or differenl an1helmin1ic drug
er nematode infections which may respond to mebe n- regimens &ga inst Man~onella rcrs1ans filariasis. Tnms R So,
dazole are infection with the fi larial nematode Trop M•d Hyg 2006: 100: 4SS-63.
4. Wahl~ren M , frolov I. Treutment of Oip~1alon ema persusns in-
Mansone//a perstans, and the tissue infections toxo- ~;~~~~s with mcbc11duole. Trans R Sor Ti'Op M~d H.vg 1983: 77;
cariasis and trichinosis. Mebendazole has also been
tried in high doses in the treatment of echinococcosis
Strongyloidiasis. Mebendazole has been used for the treatment
(hydatid disease). For discussions of these infections ofstrongyloidiasis (p.145). bul needs lo be giv¢n for longer peri-
and their b·eatmem, see under Choice of Anthelmintic, ods than alb..,,d.120le to control auto-infection. so tha~ ofthe two, NtrTr.. Thenames C)onelarsan and lmmiticidc have been used as
p.140, and under the individual headings below. albendazole is prefem.?d. 1·3 trade 1narks for rnelarsominc.
Mebendazole is given orally. TI1e usual dose for adults I. ~il50~ KIJ. Kaufftm1n CA. Persis1en1 Strongyloides stcrcoralis Profile
in a bhnd loop<:'lrthe bowel: successful 1re.o1ment with mcbcnda·
and children aged over 2 years with enterobiasis is zole. Arch /111cni Med 1983; 14~: 351- 8. Melarsomine is a u'ivalent arsenic.al derivative used in \.•ererinary
I 00 mg as a single dose, repeated ifnecessary after 2 to medicine for the control of canine heanwonn (dirofilariasis).
2. Mra~k S, r::I ol. Trcotmcnt of str0ngyloidillsis with mcbcnda-
3 weeks; for ascariasis, hookworm infections, a11d zolc, Ac-10 T1tJµ (Basf!I) 1983; 40: 93-4.
trichuriasis the usual dose in adults and children over I 3. Pcllclicr L.L. Oakc:r CS. 1·rwtnu:m failures following mebenda-
zolc thcrap)' ror chronic Slrongyloidiasis. J h!fC!CI Dis 1987; 1S6:
year is 100 mg twice daily for 3 days, although a single 532-3. Metrifonate (BAN. rWNJ
dose of 500 mg may be effective and this dose is also
Syngamosis. Mebenda20le has been used successfully' to treat Bayer·L· 1359: DCTr-; Metrifonaatt1, Metrifonat Metrifonat Met-
used in mass treatment programmes for hookwonn in- 1ifonatas; Metrifonate; MetrifQn~tQ; Mei,;fonatvm; Metriphonate:
syngamosis (p.145).
fections and trichuriasis. For the treatment of capil- Trichlonnn (l!$AI\) : Tric.hlo,.phon. Drnethyl 2.2,2-uichlorc-l-hy·
lariasis in adults and children over 2 years of age, me- I. Timmons RF, ct al. Infection of the respirtnory tn:ict wi1h Mam-
mom:inog:ainui: (Syngamus) laryna_eus: a new c;ise in Largo, droxtethylphosphonate.
bendazole is given in a dose of 200 mg twice daily for Florida, and a summary of previously reported cases. Am Rt" Merp...pot;ar
20 days; for mass treatment control programmes a dose R~spir Dis 1983; 128: 566-9.
C,HeCl304P = 257.4.
of 500 mg is g iven as a single dose 4 times a year. Toxocariasis. Mebendazole has been u.'°d in the treatment of CAS - Sl-68-b.
toxocariasis (p. 145). ln comparative studies, mebendazole has ATC - P02BBGI.
Administration in children. Mebendazole may be given
orally to children for ihe treatment of intestinal nematode infec· been reported to produ«: similar improvements to those oblained ATC Vet - QP32ABOI: QP53AF02.
lions, inctuding ascariasi~ capillariasis. enterobiasis, hookwonn with tiabcndazole' and with dieihylcarbamazine,' in caeh ease UNI! - OBF20G4G2K.
infections. trichostrongyliasis, and trichuriasis. Doses used arc with a lower incidence of adverse effecls.
the same as those used for adults (sec above). I. Magna val JF. Charle< JP. EfficacitC compartic du 1hiabcndazotc
Although licensed product infom1ation indicates that mebenda- e1 du ntCbendatole dan.s le 1rai1c:menc de la toxoearosc. Tl1eruple
1987; 41: S4 1-4.
20le should not be given to children under 2 years of age, there
have bec1; no reports of toxicity or adverse effects when used in 2. Magnavoit J.f. Comparative efficacy of diethylcarbamazinc and
mcbendazok for tht: trcetmm1 of human to:to-tariasis. Porositol-
tliis group of children.' Alier a review ofhuman and animal tox- og_" 1995: 110: 529->3.
icological data, WHO concluded that there were no reasons to
exclude children as young as 12 months from trea!ment with Trichinosis. Mcbcndazole is used for the treatment of trichino-
be11zimid'7,oles, such as mebendaz.ole ond olbendazole, and they sis (p. J45) in some counnies. Pharmacopoeias. In £1J1: (seep.vii), Im.. and US.
recommend that children from one year of age should be includ-
References. Ph. Eur. 6.8 (Metrifonate). A white or almost white, cry~ralline
ed in systematic de-\\"Onnjng programmes.2 powder. M.p. is between 76°and 81°. Freely soluble in water, in
I , Montresor A, et ol. Is the c,\cluSiQn of children under 2~ momhs I. L-tvin ML. Trcatmc:n1 of trichinosis with mcbendatole. Am J
from :mthelmintic uea1me1't juslifillble? Trans R Soc 'llop Med 'frop M•d H,vg 1983; 31: 980-3. alcohol, and in acetone: '""Y soluble in dichlorome~1ane. Prorcct
Hrg 2002: 96: 197-9. from light.
2. Anonym0\J$. Bcn:zimida?ole.o;;: u!\e in children. WHO Drug Jnf PrepaYations USP 33 (Metrife<>ate). A white crystalline powder. M.p. about
200>: 17: 29->0. 78° with decomposition. Freely soluble in water, in alcohol, in
USP 33: Mebond;izole Totle« acetone. in chlorofonn, in etller, and in benzene; vel)' soluble in
Angiostrongyliasis. Mebcndazolc was fom1erly used for the
lreo1111entof angiostrongyliasis (p.140) but current opinion is Iha! Proprietary Pr~parations ldetails are given jn Voh1mc 8) dichloromethanc; very slightly soluble in hexane and in pentane.
there is no convincing evidence to support its use. · Arg.: Oazcmet Helminc Mebu'tcc Nema:sole: Tes.a t Austral.: Ch<."misls
Decomposed by d kal.i. Store a1 a lernpernturc not exceeding 25°.
Ovm De Vilorm; Combantrin· I with Mebendazole: Vem'IO)c; Au.stria: Pan~
Echinococcosis. Mebenclazole has been uscd 1'9 in echinococ- telmh: Belg.: Oocrnebcnda; Venr~x; Braz.: Ascariobelt: Averpant: Ben- Adverse Effects, Treatment, and Precau.
cosis (p.1 42), but albcndaz.ole is generally preferred. The usual draxt: Crisduolf: Ductei'nin; Eo.sve1mt. Fcl!ert; Geophagol: Gran-Vennt:
oral dose of mebendazole in cystic echinococcosis is 40 to lbdJzclt. !(ncielmin: Mebertalt: Mebio~lf; Heciarol; Menbo!t Mober.: Mui· tions
tk!rnir'lt Multizol; Necamin: Neo Mebend: No~~ii; Panfugan: Pante&'nii: Metrifonate is generally we!! tolerated, but may cause
50 mglkgdaily for at lcasr 310 6montl1s.8 A similar dose is used Par~r:'lt; Paravcrmt; Pen~7.olet; Pluriverm: Plui·1ve:l't11ilf: Polidazolt:
as an i\dj\~vant to surgery. For alveolar ccl1inococcosis, the dose Probenduot S~fbemt: s:rt>enf; Tctrahclmint: Trotilt: Verrnben: Vermi- nausea, vomiting, abdominal pain, diatThoea, head-
is adjusted after 4 weeks to produce a plasma conc.:ntration of at nonf: Vetmeplex VcmlO"'t Venal: Zoldatx.1t Canad.: Vem>o>< Chile; ache, dizziness, and weakness.
least 250nanomoles/litre (74 nauogramsimL). although adults Dia<or. Cz.: Vermo>: Denm.: Vermo>r. Ger.: Sur<ol">l; Vermax:: Gr.: Ce-
should not be given more than 6 g daily. Treaunent is continued cu~ St'Ptr.aii~ Vcrmox; Hong Kong: Meben::c!e: Vennox; Hung.: Vt!f°- It is an organophosphorus compound and because of its
rr.cx:: India: 1'1ebex; Woi·min: lndon.: Ga·JOtj: Verl'l"OX: lrl.: Vennox Isra- anticholinesterase properties d epresses plasma-
for al leas! 2 years after rndical SllrlJel)', or indefinitely in inoper· el: Vel'TY'tOX ltol.: Vcrmox: Maloysio: Qucm())( Thetmox: Vcrmox: Mex.:
ableca~s. Amatol: ee:lSOlmin: Bes'tetar; Daben: Oi~lan:. E6.oertin: Ex;r..,ermt. Exbeo· cholinesterase concentrntions. For a description of the
I. Ammann RW, ct of. Recurrence rate after disC'Qntinu:iti(ln or zol; Extcny; Fancii1da..70I; Heda.zol: Hd milzolet: L-Omb.tix. Lurnbit~ Meb· toxic effects of organophosphoms compounds and the
Jong-1crm mcbcndazolc therapy in alveolar et:hinococrosis (p1·e- Ovct·otd; M ebelmin: Mebendicin; Mebenr.Me. Mebenti.1sis: Mcbc:ntr~ I;
liminary rcsul ~~) ..AmJ Tr-01' Mt:41 lf.'llg 1990; 43: 506-15. Nemap<es: P.,..enn;nt: Pao-.niolt: Pl·odazolf; Profen7.0i: Rev.!l'OI: S<lhrtj: n·eatment of acute poisoning. see Organophospliorus
Vermicol: Veonid~t: Vermin-Dazol: Vennox: Vcrtizole: Neth.: A.nfj.Worm:
2. Messari.akis J. ct al. High mehcndazolc doses in pulmonary and
1<ruidvat Ant:-'-"'O'TTl; Midicure: Tnt4l1eister A')lj.Worm;, Vermox; Nonv.:
Insecticides, p.2195. Atropine has been used to relieve
li1.!p3lichydatid disease. Arch D~ Child 1991: 66: 532-;. cholinergic adverse effects without affecting metri·
V<!rmox; NZ: Combantr:n-1; Vermox: Philipp.: Antiox: Hefmacon;
3. Teggi A. Cl nl. Theropy orhum:in hydatid disease w ith mi:benda- \l'/ol'mex: Pol.: Vermox; Port .: Pantelmin: Tolo:xim: Rus.: Vermox
~~~c9~~~-a~bcodazolc. An1imicrob Agents Chemother 1993; 37: (ileP"O«e): Won'f1on (llop-M): S.Afr.: Adco-Worme><; C•peo<: 0.VVo<m:
fonate's activity against Schistosoma haematobiwn.
Riov-<>nnt: Rolab-Anthe><t: VemlO>C Wormgo; Wootnstop: Spain: Lomp- Anticholinest erase effects. Metrifonale depresses
4. G6~ml!!11: .-\,et qi. Tr('.alment of hydatid disc:tsc in childhood wilh Mt..-'bc~: Sufit Swed.: Vennox. Switz.: Ven'l"'IO'X; Thoi.: .AJ..vonn;
,.,.;
mcbcnd:lzolc. Em· Respir J 1993: 6: 253- 7. A~n-Wo«Yo; Bonda; Benduole: Benfu: s;g.e.,n; o..;....,m<le: FWen: Fugao.-:
cholinesterase acLivily and there has been lhe occasional report
S. Ammann RW. ~t al. EITcc1of chemotherapy on the larval ma&S Hero-BeroSO<>< KS Bendazot.: Ma.aworm· I: Mebaf: Meben: ~P. of severe cholinergic adverse effecrs. 1 However. it do<.."S not usu-
ond 1hc lons-1crm course of a1vcolar ~chinococc:vsis. H1tpfJfl)/vgy Mccbzolc: R.id·O·Worrn: \¥~a: V\/onnob. Turi(._~ Vermazot Ver5id; UAE: ally give rise to troublesome effects al dos~s i>0n11ally used. even
1994: 19: 73H2. · Mein:ot UK: &ou Thread""-crm lablets 2 Years Pl~; Ovex: Pnpsel"( Ve<- though there may temporarily be almost complete inhibition of
6. E.rcHrn;ltr P. et fll. ·n,e role of 11)Cbcnda2ole- in the surg)c:i.1 trcal- mox; USA: Vermox. Venei.: Bendacor: Se.~<irnen; Eprofik flemdazolef: plasma cholinesterase and considcrnble inhibition of erythrocyre
m\.".nt orccmr:.I ncrvl\US system hyd:itid disease. Br J Nc?w-os11rg PMtemint: Piva!t; Tami1<ant:Verm:don.
cholinesterase~ (ool s..: also under Alzheimer's Disease, below).
1997: II: 116-20.
Mu1ti·ingredient Arg.: Aduar. ~ CompJe~o: M~but~r Con·..- TI1c cnvironmenhll aspects ofn1et1·ifo1&atc usage have been (..'00·
7. VuCO\'~ K. c1 <11, Effec1 or mebend:nole on human cvstic cchino· P'.JeStO: Tru Compuest<x Broz.: Eraverm·T t. Exelmint forvenn: He'm:t>f:
co.;c~is: the role of dosage and trcatmenl duratiOn. Am> Trop Helmibe<>: Hetm<l,.axt: Josve"1tj. Met;•benf: Ne<mrmin: Octelmnf: Po· sidered by \llHO.l
Med P,.-ositol 1999: 93: 3S7-6S. libent: Pl·oSum; Prohelmil">f; Ven'l"'IOlt. Zolesf: India: Mebe>c Plus: Mex.: I. Jamnadas VP. l'homas JEP. Mcuiplmmllc and org3nophosphate
S. WHO hformal Working Group on Echinococcosis. Guidelines Ao'!ibri,f: Amoebnz; ll<!n;olm:n Complex: Mel>ec:iclol: Vcomox./'lus; Ulcr.: poisoning. Ccnl Afi· J l-i-fed J9;9; 25: 130.
for 1re~1.ment of C)'SliC and ah·eolar c:chinococcosis in hum:ms. VC<mox t~pMoKC.). 2. Plci1ina R. c1 al. Effect of rnelrifonale on Wood cholines.ter3ses
Bull WHO 1996; 74: 231-42. in children <t\irbg the 1rea1mcn1 of ~histosomi:ts i s. BuJI WHO
9. Smego RA. et al. Percutaneous aspiration-injeclio1l~reaspi ratio n l 972; 46: 747-!·9.
drninag: plus albendazole or mcbendatolc for hepatic cystic 3. WHO. Trid1'orfon. £nrircmmental Hen/th Cti1erit1 I J], Geneva:
echinococcosis: u rne1a-nnalysis. C/in Infect Dis 2003: 37: WHO. l992. 1\v3ilable :lt: http://\V\V\\'.inchcm.o:g/documcnts/chc/
1073-Sl. . Melarsomine (rlNN) c:hc!ehc 132.htm (accessed 16/07108)
Giardiasi$. For mention of1hcusc ofmebcndazolc for the treat- Melamir.y\thioar~enhe;
Melarsomina; Melarmmine; Melarsomi. Handling, Bulk metrifonate is very toxic when inhaled, swal-
men1 of gardiasis. see p.908. num; RM-110. Bi<(2-aminoethyl) P·[(4.6-diamino·S·triazin·2·yl} lowed, or spilled on the skin. It can be rc:mO\'ed from lhe skin by
amino)dithoobenzencarsonite. "vashing with soot:> and water. Contaminated material should be
Mansonella infections. Mcbenda20le is one of the drugs tllat
immersed in a 20/c aqueous solution ofsodium hydroxide for sev·
has been suggested for the treatment of infections with Man·
Me11apco""'" eraf hours.
so11ella persta11s (p.144 ). Some patients have resl"'nded to
mebcndazole with levamiso!e,'~ diethylcarbamazine,' or to mc- C 13Hi,AsN 6S2 428.4. = Pregnancy. WHO reponcd 1 that metrifonate had not shown
bendazole alone.>A CAS-128470-15-5. cmbryotoxicity or 1cratogenicity~ but did not recommend rhe use:
I. Mac:11e11s K. Wery M. Effect of mcbcnd:izole and lcvamisote on of meuifonate in pregnant patients unless immediate intetven-
ATC Vet - QP51A006. tion was essential. There has been a report of an infant bcrn with
On ch~crca \'OIYulus and Dipctaioncma pcrstans. Trtm:l R Soc
Trop Mtd Hyg 197S; 69: 3S9-60. UN/I - 374Gj0S41A. massive hydrocephalus and a large meningomyeloccle whose
The symbol t denotes a preparation no longer actively markcled
158 Anthelmintics
mother had been ucatcd twice wilb me1rifonate during !he sec· Milbemycin Oxime USP 33 (Morante! Tar1nte). A white or pale yellow, crys1alline
ood month of pn:gnaney.2 A possible link bc.,_.'CCll eo.ittcnilol po...icr. \!:ry soluble in water and in alcohol; prac1ically insolu-
abnormalities and !he use of mc1rifonate lo cradicale fish para- CGA-179246: Mo!bemi<:fla oxoma. A mxture ol milbemycin A,, ble in ethyl acc1a1c. pH of o 1% solution in waler is bclwecn 2.8
sites has also been pos1Ula1ed.3 5-oXlflle and mibem)'con Ai S-oxine. and 3.9. Store at a 1cmpcntutc of25°, excursions permitted be·
iwcm 15° and 30". Pro<ecl from light.
J. WHO. Tbc control of schistosomiasis: iCCOfld rcpon or 1M ~H0<rnM
WHOHptrl commince. WHO TtchRtpStor830 1993. Availablc
al: hllp:/lhbdo< who.int!tr.iWHO_ TRS_~30.pd f (•cccsscd CAS - r 29496-iO-l. Profile
16107/08) ATC Ye1 - QPS4A60 1. Moran1el is an analogue ofpyrantcl. The cilratc and !he Wtratc
2. Monson MH. Aluande:r K. Mcttifon:ue in prcgn:.ncy. TrtutS R UN/I - 0502PUN0Gi (m1/bemyc1n oxome): OS3YPPl/9C arc used as anthclminties in veterinary medicine for the trcatmcnl
So<- Trop Med HJt 1984: 78: 565. (milbemycin A 1 5-oxome): 6ZWJ3 94628 (milbemycin A, 5- of gastroin1cstinol roundworms.
l. Czcizcl AE, "' ol, Environmental trichlorfon and clus1tt of con- oxime).
genital abnonnalilies. Lone.,
1993; 341 : s;µ2.

Interactions M oxidectin (BAN. USAN. ifl'JNJ

Patients treated wilh metrifona1c should nol be given a.-30 1423: Moksidelctiine Moxidectina: Moxid~ Mo><idecti-
depolarising neuromuscular blockers such as suxame- nutre Moxidektn (6R.1 SS}5-0.Dcmelhyl-28-0eoxy-25{(E)·
lhonium for al least 48 hours. The use of metrifonate R
l,3-dimethylbut-1-enyt}O~><y-23-oxomilbemycn B (E)·
should be avoided in those recently exposed to insecti- 23-0-methylCIO<M'lle.
cides or other agricultural chemicals with anti-
cholinesterase activity.
C 3,Hs~0 1 = 639.8.

Pharmacokinetics CAS - 113507-06·5.

Metrifonate is absorbed after oral doses and some is ATC Vet - QP54A802.
converted to dichlorvos which is considered to be the UNll - NGU5H3 I Y09.
active moiety. Plasma concentrations of dichlorvos are
NOH
about I% of those of metrifonate and peak concentra-
tions of both substances occur within 2 hours. Excre-
tion is via the kidney, mainly as glucuronides. milbemycin A3 R =CH3 fO'CH,
CH,
0 References. milbemycin A,. R =CH2CH3
I. Nordgren I. t!I o/. Plasma lcnls or tnc.uifon.;ite and diddorvos CH3
during 1rcatmen1 of schis1osomiasis with Bilartil. A• J7mpM#d Profile
Hyg 1980: 29: 426-30. Milbcon).:in oxime is an an1helmin1ic used in veterinary medi- CH3 CH3
::?. NClfdsrtn I. ct ol. Levels of metrifonatc and dichtorvos in pfasm• ciM.
30d erythrocytes during treatment ofschisiiosomiuis with Bitar·
eil. Acto l'lttl'mocol Toxicol tCop<nlt) 1981; 49 (suppl V):
79-$6.
>. Pcttigr~w LC. "ol. fl'harm3tokinetks, phamiacodyn3mie1. ind
safety of melrifonalc in pa1icn1s "ilh Alzheimer's disease. J Clm Morante! (SAN. pJNN)
/'hormoco/ 1998; 38: 236-0.
Morantelt Moranlelurn. (f)· l,4.5.6-Tetrahydro- l-<nethyl-2-(2·
(3-mcthyl-2-thierr,-l~idine.
Uses and Administratio n
MopaHTeA
Mctrifonate is an organophosphorus c-0mpound and is Pharmacopoeias. In Ew: (sec p.vii) for veterinary use.
converted in the body to the active metabolite dichlor- =
C,,H,•N2S 220.3. Ph. Eur. 6.8 (Moxidectil for \~leririary Use). A white or pale
vos (p.2188), an anticholinesterase. CAS - 20574-50-9. yellow, amorphOl.IS powder. !'radically insoluble in "''liter; very
ATC Vet - QP52MOI. soluble in alcohol; slightly soluble in hexane.
Metrifonatc has anthelmintic activity against Schislo· UN/I - 7NJ03 I HAXS.
soma hoema1obi11m and has been given orally as nn al- Profile
ternative to praziquantel in the treatment of schisto· Moxidectin is an anlhelmintic used in velerinary medicine. IC is
also used as a systemic vclerinary ectoparasiticidc and for the
somiasis due to S. hoemolobium. It has usually been trcaiment of int~inal roundwom1s aod lungworms. It is under
given in three doses of7 .5 to I 0 mg/kg al intervals of2 investigation for the 1reo1ment of human onchoccrciasis.
weeks.
O Refcrcoccs.
Metrifonate has also been used as an i11sccticide and is
I. Cotrtau MM, et al. The Jn1ipuas.itic mm;idcc1in: safety. tole~
used in veterinary medicine as an ectoparasiticide and bility, ind ptla.rm3c-okinetics in hun»M. J C/111Phormacol2001;
for the treatment of gastrointestinal roundworms. 43: 1108-IS.

Alzheimer's disease. Mettifonate., like some o<her cholineste-

rase inhibitors, has been 1ried in tl1e ucaunent ofAlzheimer's dis-
ease (sec Dcmenlia. p.392). Clinical sllldies produced n>Odcsl
Morante! C itrate (W<h\fJNNtv)
benefits but resc:uch was Slopped ancr n:ports of muscle weak- 01rato de morantel: Morantel Otrate de: Morante~ Citras.
Naftalofos (IW( I.MN. lfNN)
ness. sometimes requiring rcspir•ll.lfY l>Upport.1 Bay-9002: E-9:J02: ENT-25567: Nafta:of6s: Naftalofosurrc Naph-
Mopa1<Te11<1 UITTpat
I. L6pc:t·A1Tie13 JM. Schneider t. Mc-trifortale for Afz.hl'imc:r"s th31ophos; Prnhalophos; 5-940. Dietl-)! naphthafim'do-oxyphos-
or
disease. A\•ailablc in The Cochr.mc D-111bHC Sysacma1tc Rc- C , 2H 1 £N,s.c~,O;.H20 =430.5. phonate.
virws; luue 2. Chichesrer: John Wiley; 2006 (accesstd CAS - 69525-81· 1.
23!07110).
Arc Ve1 - QP52AFOI. Ha+T ""*"
Schistosomiasis. While praziquanlcl is now the muin trcUI·
mcnt for scllis1osomi•sis (p. l44), metrifona1e is an allcma1ive for
C 16H"N06 P =
349.3.
Morante! Ta rtrate (MN/I\ tJSAN. ptNNM) CAS - 1491-41-4.
infection due lo &histosomo hoe11101obi11m. Cure raics wilb
standard doses in schis1osomiasis control programmes ran&• CP-120Cfl-18: Morant~hvetyWVaattr. Morar.tel hydrogeno- ATC Vet - QPS2A806.
from 40 10 more 1han 80%, wich a reduction of more than 80'/e in tartate de; Morantel Tartnte de: Morantel-hidnr,;<!~tartanlt.
q;g counls an1ong those not cured. Allhough praziquantel and Morantel-hydrogen-t<rtzrit Monnteh hydrogenotanras: Mor- UN /I - HSIT2P8M51
mctrifonaic appeaJcd 10 be of similar efficacy a systematic re- anteli Tarvas: Mooonti!Milew-trat Tartrato de rnorm1et UK-
view railed 10 find sllldics comparing tl1e rwo drugs when used in 2964- I 8.
standard doscs.1 However, nlelrifonatc's dosage schedule of 3
doses al in1crvals of2 -•ks has caused problems ofpa1icn1 Mopa><re.-a TapTpn
compliancc;1 giving 5 maJkg lhree limos in one day has pro- c, 2H ,.N,s.c,H.o. = 370.4.
duced simijar resuhs 10 • >llll1dMd dosa~ sebcdulc.1
CAS- 26155-31-7.
I. Dan.so-Appiah A. ,, ol. Druas for uc.a1ing urinary schistosomia- ATC Ve1 - QP52AFOI.
1i.1. Available in The Cochrane D111b&sc of Systematic Reviews~
luue J. Chichester. John Wiley: 2008 (tcttSs<G 29!07110). UNI/ - 5WF7E9QC3F.
2. Aden Abdi Y. Gus1afs..~ LL. Poor paucnc compliance reduces Pharmacopoeias. In E:.1r. (sec p.vii) 311d US for '"lerinary use
the ttr'IC~C)' o( mcuifonatc lre:1t1Mnl o( SchislOs.oma h<Jcmato·
bium in Somalia. EurJ CJ;n Pltormocol 1989; 36: 161-4. only. Profile
Ph. Eur. 6.8 (Morar.tel Hycrogen Tartrate for Vetcmary Use: NaRalofos is an orgaoophospborus compound (sec Otganophos-
3': Aden Abdi Y. Qu~;aruon U.. fjcld 1rial oflhc efficacy <-fa $im- phorus Jnseclicidcs. p.2195) used as an 1n1helmintic in velcri-
plificd and s landard melrifonue trc.atmcnts orSchiltoiom.a hK· Morante! Tartrate BP(Vet) 2010). A while or pale yellow, crysllll-
matobium. £,,r JC/in l'/otirnW<Ol 1989: 37: 371-S, line powder. Very soluble in water alld in alcohol; praclically n.ary medicine.
insoluble in ethyl accta1c. A I% solu1ion in \valcr has a pH of3.3
10 3.9. PrOICCI Croon liJ1,bl.
All cross-references refer lo enirics in Volume A
 Milbemycin OXJme/Oxamniquine 159
Netobimin ~ UW( •INN) Pharmacokinetics Nitroxinil fclAN dNN)
Netobrnina; Netobimne; Netobiminu.T< Sch-32481. 2-{3-MClh- Niclosamide is nol significandy absorbed from die Nttroxini!o; Nllrol<inihJni; N1trOX)"1il. 1-H)'dr0l<)'-3-iodo-5-ni-
oX)'(4rbotl)'!·2-[2-n;tro-S-(µ<opyt1h•o)phenyfJtuanidi- gastrointestinal tract. troben2onilrile.
no)eih;mesu phonic acid. HwTpOKCJllrl~.\

He1ofA..IM1*4 Uses and Administration =

C,H1IN203 290.0.
CAS - 1689-"89-0 (n•troxin•I); 279 I 7-82-4 (nitroxioil eg-
C,.H"oN,O,Si 420.5. = Niclosamide is an anthelmintic which is active against
most tapewonns, including the beeftapewonn (Tae11ia
lumine).
CAS - 88255-01-0. ATC Vet - QP5ZAG08.
ATC Vet - QPS2AC06. saginoto), the pork tapeworm (T. soliwn). the fish tape- UNll - 9LOEXQ7 I 25.
UNI/ - U30C.54N3/\1U.
worm (Diphylloborhrium /arum) and the dog tape-
worm (Dipylidium cani11um); it has also been given for

l-AN02
OH
infections with the dwarf tapeworm, H)'meno/epis
nano. For discussions of the treatment of tapewonn in-
HO
\
~s~
O
o =< O-CH3
fections, sec DiphyUobotluiasis, p.142, Hymenolepia-
sis, p. l43, and Taeniasis, p.145. The activity of niclosa-
y
0
SL
. HN-1-9
'----, NH
CH, mide against these worms appears lo be due to
inhibition of mitochondrial oxidative phosphorylation;
anaerobic ATP production is also affected.
CN
Pharmacopoeias. In BP(Vet). Also in Fr. for veterinary use
Niclosamide is given as tablets, which must be chew~d only.
,,
·o-N• thoroughly before swallowing and washed down wilh B P(Vet) 20 I 0 (Nitroxinil). A yellow to yellowish brown pow-
0 water. der. Practically insoluble in wa1cr; slightly soluble in alcohol;
sparin¥1Ysoluble in ether; it dissolves i11 solutions of alkali hy-
For infections with pork tapeworm a single 2-g dose is droxides. Protect from ligl11.
Profile given after a light breakfast. Niclosamide is not active
Netobimin is a prodrug ~m is converted 10 albcndazolc (p.146). against the larval form (cysticerci) and, although lhe Profile
II is u.«d in ''eterinary medicine for the treaonent of nematode, Nibaxinil is an antbelmintie used in vetennary medicine for the
risk of inducing cysticercosis appears to be theoretical, treatment of fascioliasis and some gastrOintestioal roundwonns
rapewonn, ond nuke infectioos.
a laxative is given about 2 hours after the dose to expel in callle and sheep.
the killed wonns and minimise the possibility of the
migration of ova of T. solium into the stomach; an
Niclosamide {BAN. USNI. tlNNJ antiemelic may also be given before treatment.
Oxamniquine (BAN. USAN. tfNNJ
For infections with beef or fish tapeworms the 2-g dose
Anhydrous Nodosamide: llay-2353; N"JClo<.vnida: Nodosamida O>QJTriquina; Oxamriqc;r..im- UK-4271. l.23,1-Tetra~2-
of niclosamide may be divided, with 1g taken after isopropytaminomethyt-7-nitro-6-quioolylmelhanol.
Anidra; N1clo~mide 2nhydre: Niclosamd.Jm; Niclosamidum an-
hydricum; Niklosamid; NiHownid, vattenfri; Nllosamidi; Niklos-
breakfast and 1 g an hour later. OKcaMHHX'MH
a'Ylidi. vedeton; Nikloz<mid; N11doz.amid bczwodny; Niklozami- In dwarf-tapeworm infe~ions an initial dose of2 g has C,.H21N303 = 279.3 .
dls. bevandenis; Phenasale; Vizmcntes niklozamid. 2'.S-Oichloro- been given on the first day followed by l g daily for 6 CAS- Zl738-4Z-1 .
4' -nitrosali()~anifide; 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hy- days. ATC - POZBAO?.
d-oxybenzamide. ATC Y~t - QP57AAOZ
Unless expulsion of lhe worm is aided by a laxative, UNll - 00977R7ZlD.
HMAA03aM,,.~
portions are voided in a partially digested form after
C 11HaCl2N;O, = 327.1 . treatment with niclosamide; the scolex is rarely identi-
CAS - 50-65-7. fiable. 0 CH3
ATC - P02DAOI. For details of doses in children. see below. II H ~
>TC Yet - QP52AGOJ In schistosomiasis (p.144), nicloSllmide is used as a
·o,..:G(),;?" N N CH
llNll - BKK8CQ2KBG. molluscicide in water-treatment control programmes. HO ::::,..
I H 3

Administration In children. Niclosamide may be given onl·

ly 10 childreu for the treatment of most tapeworm infections. Pharmacopoeias. In Fr. •nd Int.
Children 2 to 6 years ofagc are given half the usual adult dose;
th- under 2 years of age are gi""n one-quarter the usual adult Adverse Effects
dose. Children over 6 years of age arc given the usual adult dose
(sc-c abo.,,). · Oxamniquine causes severe pain at the injection site
when given intramuscularly and is no longer given by
Preparations this route.
BP lOIO: Nr:bsomide 1'lllets.
It is generally well tolerated after oral doses, although
Proprietary Preparations (details are gjv<:n in Volume B) dizziness with or without drowsiness occurs in al least
Pharmacopoeias. In Cl1i11. and£111: (soc p.vii).
Belt.: Yomesanc ll<oL: AteN ..t; Cz" Yomc>a<lf; D•nm.: Y~t:
/111. permits the anhydrous substance or the mQOOhydratc under F;n.; Korul: Fr.: Tredt<Mc Gv.: ~ Gr.: Tredemtt: 'lbm....-c a third of patients, begiMing up to 3 hours after a dose
the title Niclosamide. Honi K.oni: i.-9'1: Indio: Nidosao: lsroek Yomeszn: ltoJ.: ~ and usually lasting for up to 6 hours. Headache and
Ph. Eur. 6.8 (N~. ~). Ydlo\\ish-white toyel- Mox" <Moroid. Noth.: Yomn.rc S-Afr.: 'fomosoo: S-4" Yomo-.v.;
lowisb, fine crys«als. PrncticaUy insoluble in water; slightly solu· Thal.: leo-9'; t'~ ~t: Shon Mesorc S«hcn: ~~ gastrointestinal effects such as nausea, vomiting. and
T......n 10pid&: u-.odirt: Uownde:; bneszn; Tu<k: .,..,..,....,. UK: Yo- diarrhoea are also common.
ble in dehydrated alcohol; speriogly soluble in •a:tonc. Store in
airtight com:iiners. Proleel from hghl
Multi-inl'edfent Thol.:Amon:~T-Z..-.d&
Hypersensitivity reactions including urtiCllria, pruritic
skin rashes, and fever may occur. Liver enzyme values
Niclosamide Monohydrate (MNM 11NNM1 have been raised transiently in some patients. Epilepti-
Nidosamida Mono-hidratada; Niclosamida monohidrato; form convulsions have been reported, esp«:ially in pa·
Nitroscanate {&l>N. WN. lfNNJ ticnts wilh a history ofconvulsive disorders. Hallucina-
Niclosamide monohydrate; Niclosamidum monohydricum; Nik-
CGA-2365~; Nitroscanato; Nl".roscanatum; Niirosl<anaatti: Ni- tions and excitement have occurred rarely.
losam;d monohyc4t; Nik105amidin1onoh)'draatu. Nildosamid-
troskanat 1·(4-Nivophenoxy)phenyl isothiocyan.ote.
monohydrat: Niklozamieas monoi-.dratas; Nildozamid-mono- A reddish discoloration of urine, probably due to a me·
hidral H1o1Tpoci<aHaT
tabolile of oxamniquine. has been reported.
C11HsNiOiS = 272 3.
H s.'U<A03af.IV-A MOl--Of\1AP3T
CAS - 19881-18-o. Effects on body temperature. A rtviC\• 1 in 11187 noted that
C11HsCl2N,O,.H,O =345. 1. ATC V~: - QP52AXOI
olthough a modest post-treatment rise in temperature h3d been
reponed occasionally, fever was not a common adverse ellect of
ATC - POZDAOI. UNll - P41ES86D6U. o:umniquine, except in Egypt where it appeared to be clw-acter-
UNll - 20ZZ5RI 1•5.
istic. The cause was not known. Increased immune complexes
Pharmacopoeias. In Eur. (seep.vii). and excretion of antigens occurred in ooly half the cases, there
/111. pcnni~< the monohy<htc or the anhydrous subs:lance Wider WllS no c\·idcnoe that Egypt~ p:itienis mel3boliscd the drug dif-
the title Niclos:unide. fete1lly to produce a pyrogenic metabolite, and the effect bad not
Ph. Eur. 6.8 (Nidosamide Monchydrate). Ycllo\\i<h, fine crys- been seen in other areas "ilcr( a similar higb-dose regimen was
tals. Practically insoluble in watet; slightly soluble in dehydrated used.'
alcohol; sparingly soluble in ace!~. Protect from light. I. FOl't" R. A rcvii:w or clinical c.iq~ri~nce with oumniquinc.
T'c"' R Soc Trop Med H.•'8 1987; 81: SS-9.
Profile
Adverse Effects Nitroscanate is an iso1hiocyuna1e anthehniniic used in veterinary Etrects on the nervous syttem. In 37 patients with Sd1is10-
Gastrointestinal disturbances may occur occasionally medicine for the treatment of gastrointestinal roundworm and somo numsoni infection lreated successfully with oxamniquinc:.1
tapeworm infections. dizziness and drowsiness "-ere most common, but 1hc most sig·
with niclosamide. Lightheadedness ru1d pruritus have nificant adverse effect was the development of EEG abnonnali-
been reported less frequently. ties in 6 or 34 patients wh0se pre-1reatmen1 EEG was nonnaf. Of
The symbol t denotes a preparation no longer actively marketed
160 Anthelmintics
the 3 patients with pre-exisling EEG abnonnalities, l suffered a O xantel E;,,bonate (8ANM. rlNNM) O xyclozanide (MN. rlNN)
tonic-<:lonic seizure during d1erapy as previously reported,' 1 did
CP-14445- 16: Embonato de oxantet Oxantel. Embon2te d'; Ox- ICl-46683; Oxiclozanida: Oxydozanidum. 3.3'.5.5'.6-P.,,.,tachlo-
not suffer seizures, and the third received phen}1oin prophylaxis
during oxamniquine therapy. It was considered prudent to give antel Pamoate (USAN); Oxanteli Embonas. (£)-3-(2-( 1,4.5.6-Tet- ro-2' -hydroxysalicylanilide.
antiepileptics before slarting oxamniquine io patients ·with a his~ rahydro-I -methy!pynmidin-2·y0vinyl]pllenol 4,4'-methyleneb- 0KC"1K/\03aHMA
tory of seizure disorder. After completion oflhis stlldy, a patient is(3-hydroxy-2-naphthoate). C 11H6Cl5N03 = 401.S.
with no history of seizures suffered a tonic·clonic seizure 2 hours 0KcaHTe.Ni 3M6oHaT CAS - 2277-92- 1.
after each of the second and third dooes of oxamniquine. C13H 16N20.C23H "O' = 604.6. ATC \let - QP52AG06.
Tiie main neuropsychiatric adverse effects seen in 180 Brazilian CAS - 3653 1-26-7 (oxontcl): 68813-55-8 (oxar.tel em- UN/I - IQS9G4876X.
patients with Schlstosoma mansoni infecrion trea.tcd w ith single bonate): 42408-84-4 (oxantel embonote).

HOn
oral doses of oxamniquine were: drowsiness (50.6%}, dizziness ATC - P02CC02.
(41 . l %}, headache (16.1%), lempcraiy amnesia (2.2%), behav· UNI/ - UPYI D732TO. Cl
ioural disturhance.< (l .7%), chills O.J%), and seizures (1.1%).'
An EEG was perfonned before and after trcaonent in 20 patients;
there we-re alterations in 3 but !hey were not associated with neu-
OH 0 ~ I
Cl~N ~
ropsychiatric changes.
I. .Krajden S. er()/, S'1fcly :md lox:icity of oxtimnjquine in the treat·
ment of Schistosoma mansoni infe.."1.ions, with p3Iticular refer·
ence to electroencephalosraphic at.n('lrm:.lities. Am J Trap Med
Hyg 1983:32: 1344-6.
2. Keystone JS. Seizure-sand electroe.cephalograph changes asso-
Ct'-Q OH
I
§ Cl
H
Cl

Cl
ciated with oxamniquinc therapy. Am J Trop Me.ti !lyg 1978~ 27:
360-2. (oxontel)
3. de Carvalho SA, et of. Neurotoxicid~de do o,.;amniquinc nO l.rata- Phannacopoeias. In BP{Vet):
mento da inf~o humana polo Schistosom• mansoni. Rev Inst BP(Yet) 20 IO(Oxydozanide). A IJ0le cream or cream-coloured
MedTropScoP011lo 198~;27: 132-42. Profile powder. Very slightly soluble in water; soluble in alcohol; freely
Oxantel is an analogue ofpyrantel !hat has be'eo used as the ern- soluble in acetone; slightly soluble in chlorofonn.
Precautions bonate in the treatment oflrichuiiasis. ll is used with pyrantel for
various intestinal nematode infections. Profile
Oxamniquine should be used with caution in patients Oxyclozanide is an anthelmintie used in velerinary medicine for
with epilepsy or a history of oonvulsive disorders. Pa- Preparations !he control offascioliasi.s in cattle and sheep.
tients should be warned that oxamniquine can cause Prop rietary P reparatio ns (details are gjven in.Volume B}
dizziness or drowsiness and if affected they should not Multf-ingredicnt: lndon.: Quantrclf; Phmpp.: Quant.re~ VeneL: Dual·
id: Quantiel.
drive or operate machinery. Piperazine
Pharmacokinetics Piperotsiini: Plperazin; Piperazlla; Piperazinum.
Oxfend azole (BAN. USAN, rfNN)
Oxamniquine is readily absorbed after oral doses and nWlepa3•H
peak plasma concentrations occur after 1 to 3 hours.
Oksfendatsolr, Oxfendazol: Oxfendazolum: RS-8858. Methyl 5-
phenylsu!phinyl-1 H-benzimidai~-2-yica<Wmate.
=
C,H 10N2 86.1 4.
The pla~ma half-life is l to 2.5 hours. CAS - 110-85-0.
0Kt~a.30A
ATC - P02CBOI.
It is extensively metabolised to inactive metabolites, =
C1sH 13N303S 315.3. ATC Vet - QP52AHOI .
mainly the 6-carboxy derivative, which are excreted in CAS - 53716-50-0.
ATC Vet - QPSZACO] . UNI/ - I RTM4PALOV.
Lhe urine. About 70% of a dose of oxamniquine is ex· UN/I - 0 MP2Ht 7F9E.
creted as the 6-carboxy metabolite within 12 hours ofa
dose; traces of the 2-carboxy metabolite have also been
detected in the urine.

()SD=N
0
II
Uses and Administration
I ~NH
Oxamniquine is an anthelmimic used in the treatment
of schistosomiasis caused by Schistosoma mansoni,
but not by other Schistosoma spp. It causes wonns to
-6- ~ . rd
0
CH3

Phannacopoeias. In US.
shift from the mesenteric veins to the liver where the USP 33 (Plperazine). White to off-while lumps or Oakes having
male wonns are retained; the female wom1s return to an ammoniacal odour. Soluble in water and in alcohol; inso1ub1e
Phannacopoeias. In Eur. (sec p.vii) and US for veterinary use in elher. Store in airtight containers. Protect from lighl
the mescntery, but can no longer release eggs. Resist· only.
ance may occur. Ph. Eur. 6.8 (Oxfendazole for Veterinary Use; Ox'.endazole
BP(Vet) 2010}. A while or almost while powder. It shows poly- Piperazine Adipat e
Oxamniquine is given orally, preferably after food. morphism. Practically insoluble in water; slightly soluble in al- Pipcratsiiniadipaatti: Piperaz. Adip.: Piperazina. acipato de: Piper-
Dosage depends on the geographical origin of the in- cohol and in dicbloromethane. PrOlect from light. azinadipat; Plperazin-adipat Piperaiine, adipate de; Piperarni ad-
fection and total doses range from 15 mg/kg as a single USP 33 (Oxfendazole). A white or olmosl white powder. Prac- ipas; Piperazino adipatas; Piperazinum Adipcum.
dose to 60 mg/kg given over 2 to 3 days. A single dose tically insoluble in water; slightly soluble in alcohol and in n...ncpa31>1Ha AA&<naT
dichloromethnne. Protect froni ligbl
should not exceed 20 mg/kg.
Profile
C,H ,0N2.C6H100< 232.3. =
CAS - 142-88-1.
Schistosomiasis. Oxamniquine is an alternative to praz.iquan- Oxfendozole is a bcnz.imidazolc carbamatc anthelmintic struc· ATC - P02CBOI.
tel for the treatment ofschistosom1asis (p. l44) due to Schisto- rurally related to mcbcndazole (p.156). It is used in veterinary UNI/ - V7P5PI 22LB.
soma mansoni, although resistance has occwred, particularly in medicine for the treatment of nematode and 1apewom1 infec-
South America,1 and it is somewhaL less effective than praziqu- Pharmacopoeias. Jn Eur. (see p.vii)J11t., Jpn, and Viet.
tions.
anteJ.2 In US for veterinary use only.
Ph. Eur. 6.8 (i'iperazine A<ipate). A white or almost white, crys-
The oral dose ranges between a single dose of IS mg/kg and tillinc powder. Soluble in water; practically insoluble in alcohol.
60 mg/kg given over 2 or 3 daysu Doses io the low range have USP 33 (Piperazitie Adipate). A white crystalline powder. Solu-
been used eJfectively in South America, the Caribbean, and West O xibenda zole (BAN, USAN rlNN)
ble in water; practically insoluble in alcohol.
Afiica while patients in Egypt, Sou~h Atiica, and Zimbabwe re- Oxibendaiot Oxibendazolum: SKF-303 10. Methyl 5-propoxy-
quire doses al !he top end of the range; intennediate doses may IH-ben:rimidazol· 2-ylc:atbamate.
be effoctivc in other pans of Africa.; Pipera.zine Citrate
QKC'15eHAa30A
H)'drous Tripiperazine Dicitrate; Piperatsiinisitraatti; Piperaz.ina,
After the appropriate therapeutic do•e ofoxamniquinc, cure rates C 12H1sN101 = 249.l.
of nl least 60%, and often more than 90%, can be expected. Egg CAS - 20559-55-1. citrato de; Piperazincitra~ i'lperazin-citr.i~ Pperazin<itrdt hydrat
excretion in those no! cured will be reduced by over 30"~, and ATC Vet - QP52AC07. Piperazine, t itrate de: Piperazini citras; Pipe1azini Citras Hydritus;
usually by over 90%, one year aftertieatrneni.1 UN/I - OZ2N I lKJOX. Piperazino citratas.
I. WBO. The cC1nttol of schistosomiasis: s.econd rtpo:t of 1he n,mepa3...1-l<l U>rrpaT
WHO expert commiucc. WHO Tech Rap Ser 8JO 1993. Avai1ub1e
ot: hup://libdoc.who.int/1rs/WHO_TRS_SJO.pdf (access<d (C, H ,0N 1),.2C4 H8 0,.xH 20 = 642.7 (anhydrous sub ·
t6/Q7/08) stance).
2. Ferrari ML, ct ol. Efficacy of oxarnniquine and praz.iquanteJ in CAS· - 144-29-6 (anhydrous piperazine citrate); 41372-
the trearment ofSchistosoma man$CJ'li infection: a controlled !ri- 10-5 (piperazine citrate hydrate) .
al. 8111/ WHO 2003; 81: 19G-6. ATC - P02CBOI.
3. WHO. The control of schislosomiasis: report of a WHO expert UNI/ - 63KP7FXF21.
committee. WHO Tech Rep Ser 728 I 98$. Available at: hllp# Pharmacopoeias. In Chin., Eur. (seep.vii). /111., US, and Viet.
lit>doc.who.int/lwWHO_TRS_728.pdf(accessed 16/07/08)
Profile Ph. Eur. 6.8 (Piperazine Citrate). A white or almost while gran-
Preparations Oxibendazole is a benzimid.<lzole carbamate antl1elmin1ic struc-
ular powder. It contains a variable amount of water. Freely solu-
ble in waler; practically insoluble in alcohol.
Proprietary Prep arations (deu1ils ore given in Volume B) turally related to mebcodazole (p.156). It is used in veterinary
medicine for the lre3hncnt of nematode infections. USP 33 (Piperazine Citrate). A while, crysUUine powder having
SroL' Man<•; Gr~ V~j.
not more than a slight odour. Soluble in water; insoluble in alco-
hol and in ether. pH ofa 10%solution in waler is about 5.
All cross-references refer to entries in Volume A
 Oxante! Embonate/Pomegranate Bad< 161
Stability. A d~~rease in the content of piperazine [as citrate] in ings. piperazine products could remain as medicines available to muscle paralysis in susceptible worms. wh ich are then
syrups or storJgt" was altributcd to interaction with fructose and the public through phcmmicic::;..1
glucos~ formed by hydrolysis of sucrose. 1 A syrup prepared with
easily dislodged by the movement of the gut and ex-
I. Anonymous. Diua sheet chang.:~ for pi1,Cr:\tin~ in prci;nancy. pel led in lhe faect:s.
sorbitol lost no potency when stored at 25° for 14 months. P/wrm J 1988: 240: 367.
I. Nielser A, Reimer P. The sc3bilil)' of pipcrazine in syrup. Arch 2. Bcflunder BTD, et nl. Ni1ros.o1ion of pipe.ruin< in 1he s-totnach. Piperazine is usually given as the citrate or phosphate,
Phnn11 ('hemi (SC'i) 19iS: 3: 73-S. L(J11Cef 1981~ ii: 31l. but the adipate may also be used. The dihydrochloride
3. T;annenbilum SR. N-nitroso compounds: a pcrspcc t iv~ on human is used in veterinary practice. The dosage of the salts of
Piperazine Dihydrnchloride exposure. Um<·q1 IQ83: i: 619-32.
piperazine is tsually expressed in tenns of piperazine
nMnepa31.1.f(l A~ntApoXl'.opv~ Abuse. Derivotives of piper:izine have been developed and hydrate: l 00 mg of piperazine hydrate is equivalent to
C,H ,,Ni.2HCl.xH 20 " 159. I (anhydrous substance). abused as 'designer drugs'- sce Bcnzylpiperazine (p.235J ).
about 44.4 mg of piperazine, 120 mg of piperazine ad·
CAS - 142-64-3. Effects on the blood. A 4-year-old African boy with G6PD ipate, 125 mg of piperazine citrate (l I0 mg of anhy-
ATC - P01CBOI. deficiency developed haenlolytic anaemia; no cause for 1hc drous piperazine citrate), and to 104 mg ofpiperazine
UNll - 17VU4Z1W88. haemolysis was found except that 2 days previously he had taken
phosphate.
Pripse11 (piperazine and seona).1 Severe thrombocytopenia with
Pharmacopoeias. epi.staxis and haemoptysis, which developed in a 61-year-old For the treatment of ascariasis, a single dose. repeated
In US for veterinary use <>nly. man after piperazine self-medication, was prohahly the result of
USP 33 (l'iperazine Dihydrochloride). A white crystalline pow- once after 14 days, has been used. In adulls and chil-
scnsi1isatio11 to piperazine 15 years earlier.-
der. Soluble in water. A 5% solution in water has a pH of 3.0 to dren over 12 years of age, a dose equivalem to 4.5 g of
I. Buchanan N. er al. G-6-PD d<:tick·ncy aod piperazine. BMJ
3.4. 197t: 2: 110. piperazine hydrate is given orally.
2. Cork MJ. et al. Pruritus ani, piperazi1\-e, and 1hrombocy1opcnia. For enterobiasis, piperazine has been given for 7 days.
Piperazine H ydYate HMJ t990; 301: tJ9S. '
A second course after a 7-day interval may be required.
Piperatsiinihydmtti: Piperazin Hcksahidrat; Piperazin hexahy- Effects on tke liver. A reacrion resenibling vital hcpalitis oc- AdullS and children over J 2 years of age are given the
drat; Pipe·azina hex.;t-idrato; Piperazinas hidra\as: Pip1kazine, hy· curred on 2 occasions in a 25-ycar..old woman after use of pipcr- equivalent of225 g of the hydrate once daily.
drate de: Piper.?Zin-hidrat; Plpe1<!Zinhydrat: Piperaiir.i Hydras: azinc; it appeared to be a hyperscnsi1ivity reaction.'
P"operazinium Hex;hydricum; Plperazinum hydricum: nperaiyna For details of doses in ch ildren, see below.
I. Hainlyn AN, et of. Pipcraiinc hepati1is.. O<J~'lf'OCnturology 1976;
uwodnk>na Piperazine he~hydrate. 70: 1144-7. Piperazine is also used as a preparation with senna in a
n...nepa3•Ha rV.APaT Hypersensitivity. A patient had a scrum-sickness-like illness single dose of 4 g oftl1e phosphate for adults and chil-
C,H 1oN;.6H 10 = 194.2. associated witl1 piperazine,t which was followed by a delayed dren over 6 years of age, repeated after 14 days for en-
CAS - !4 2-63-2. hyperscnsiti,·ity vasculitis. Oewpational asthma related to expo- terobiasis, or repeated monthly if necessnry for up to 3
ATC-· P02CBOI. sure to pipcr:tzine citrate has also been reported.' months to treat and prevent ascariasis.
Sec also Effects on the Blood and Effects 011 the Liver, above.
Pharmacopoeias. In Em: (seep.vii) and Viet. Administration in children. Pipef:)zinc may be given orally
Ph. Eur. 6.8 (Plperazine Hydrate). Colourless deliquescent crys- I. Gaitan M , Ca..:ciottolo JM. Hypersensilivity vasculilis associat·
cd wilh pipcruin:c thera1>y. OrJ D<!rnrttto/ 1994~
131: 133-4.
to children for the treatment of intestinal nematode iqfections,
tals. M.p.about 43°. Freely soluble in water and in alcohol. A 5% such as ascarias.is (roundwom1) and cntcrobia~is (pi~worm nnd
solution ir. water has a pH of 10.5 to 1 ~.0. Store in airtight con· 2. Quir« S. ~' (J/. Occupa1iom1l asthm3 due to piper3zine cilr:llC. J
bwes1ig.ilfogu/Cli11bmmmol~()()V; 16: 138-9.
thrcadwom1), altJ-ough other antl1ehni11tics are usually preferred.
t:iiners. Protect from light.
For the treatment of ascar iosis, a single dose equivalenl to the
following amount of piperazine hydrale is given, repeated once
Piperazine Phosphate Precautions after 14 days:
Piperazine is co11tra·indicated in patients with epilepsy
Pipe,.azina. fosfato de: Piperazini ?hosphas. • 9to J2·ycarsofage:3.7Sg
or severe renal impairment and should be given with
nHnepa3...3 (])o(~T • 6 to 8 years ofage: 3 g
care to patients with neurological disturbances or mild
C.,H,oN;.H;PO•. H,o 202.1 . = to moderate renal impainnent It shonld also be avoid- • 4 to 5 years ofoge: 2.25 g
CAS - I 4538-56·8 (onh)'drous piperozine phosphate}; ed or given with extreme caution in patients with he- • I to 3 years ofage: 1.5 g
18534- 18-4 (piperozine phosphate monohydrate). • under I year of age (oo medical advice only): 120 mg/kg has
patic impainnent.
ATC - P02CBO I. been suggested
UNll - 8TIF7T48FP. Breast feeding. The UK licensed product information for For entero biasi.s. piperazine has been given for 7 days in doses
Pharmac:opoe.ias. In Br.. Chin., Jpn, ::md lliet. Pripsen (piperazine and senna) states d1at piperazine is distribut· equivalent to the following amount of piperazine hydrate:
ln US for veterinary use only. ed into breast milk. Mothers should be advised to take a dose
• 7 to 12 years of age: 1.5 gdaily
EIP 2010 (Pipe1<Uine Phosph;;te). A white odourless or almost after breru;t feeding then not lo breast feed for S hours during ·
which period milk should be expressed and discarded at the reg- • 4 to 6 years ofage: 1.125 g daily
odourless crystalline powder. Sparingly soluble in water; practi-
cally insoluble in alcohol. A I% solution in water has a pH of 6.0 ular feeding ri me~. • I lo 3 years ofagc: 750 mg daily
to6.S. Pregnancy. It has been repoo1cd that pipcrazine is teratogenic in • under 1 yearof•g,e (on medical advice only): 45 to 75 mg/kg
USP 33 (Piperazine Phosphate). A white crystalline powder. rabbits and that there have been isolated reports of fetal malfor- dJily has been suggestOO
Sparinglysoluble in water: practically insoluble in alcohol. A I% mations afte1· dinica1 use, though no causal rel3tionship has been A second course of lre:ilment after a 7-d.ay interval may be re·
solution in water has a pl-t of6.0 to 6.5. Store in airtight contain- established. Two infants with malfon11ations have been de- quired.
C..'f'S. scribed briefly:' one had bilateral hare lip. cleft palate, rutd ano-
phthalmia: the other had an abnormality ofone foot Both moth· Preparations
Adverse Effects ers had take11 Prip.re11 (pipcrazinc and senna). UK licensed BP 2010: Piperazinc Gtru~ Erocir; P~..r.v:i.ne ~phale Tablcts:
product infonnation for Pripsen advises 3gainst use in pregnan- USP 33: Piperaiirle Ovate Srrup; Piperazinf' Citrate T2:ble1.s.
Serious adverse effeets are rare with pipcrazine and
cy, especially during the first trimester, unless irnmediate lr~t­ Proprietary Preparations (detttils are given in Volume B)
generally indicate overdosage or impaired excretion. menl with piperazine is essential. Braz.: Asu.rinaiet; Ortoveimrmt: Vermifiont : Vermi!ent: Fr.: Vem'!1fvse;
Nausea; vomiting, diarrhoea, abdominal pain, head- I. l~nch FN. Management or lhreaclwonn infestJlion during preg- Gr.: QX)uran; lndon.: Combidtn:.""IC: Pipel"iKyl: Upi,xon; ltol.: Citropiper·
ache, skm rashes, and urticaria occasionally occur. Se- nancy, .4rch DiJ Cltild 1990: 65: 399- 400. arina; Mex.: H-:hlif.rt: Lu-Pe<acin?.; O ...-t~ P\:icrazil; Pip~!s; Pi1"Z:ncM:
Venodj; Ve,,.,... Port.: Pipennct: Fiper<ox: S.A(r.: P.ldax: Plpr•;e<1t: PlprUle<
vere neurotoxicity and EEG abnonnalities have been SB To:x Wonnt Spain: Mimed:atl: Verni!; Thal.: So;npar; Sinperr.-iine:
report~ with symptoms including somnolence, dizzi- fntel"actions Vermexf: Turk.: Asepar~: Askaripar: Helmicide: Hefmipc.r: Oksiaskaril:
Sirop3r; Venez.: C~rina; lrquip0?1t: Ietsanf: 0.<i•lCt: Pipe1·.ito: P~oerazit;
ness, nystagmus, muscu lar incoordination and weak- The anthelmintic effects of piperazine and pyrantel Pip.?«din; P~•Lan: ve~ol.
ness, ataxia, paraesthesia, myoclonic contractions, may be antagonised when the two cotnpounds are used M ulti-ingredient: Broz.: VenTiilen COr."lpostCit: Indio: Helmaunt: lrJ.:
choreifonn movements, tremor, convulsions, and loss together. The possibility that piperazine may enhance p,;pset0t; Port.: Bi<irc.'Ot: UK: Prip;cn.
of reflexes. the adverse effects ofphenothiazines such as chlorpro-
Transient visual disturbances such as blurred vision mazine is discussed on p.1078.
have occuned occasionally a~d there were repo1ts of Pomegranate Bae-k
cataract fonnation after treatment with piperazine al- Pharmacokinetics Granado: Granati Cortex: Granatrindc: Granatvni: Grenadier:
though they do not appear to have been substantiated. Piperazine is readily absorbed from the gastrointestinal Melograno; Pomegranate.; Pomegran2te Root Bad<; Ron1eira.
Hypersensitivity reactions such as bronchospasm. Ste-
tract and is excreted in the urine within 24 hours, partly Ko pa rpa..aroeoio Aepeea
as metabolites. The rate at which different individuals UNJf - 56687DIZ4D (pomegranate): 335JQ2VHXV
vens-Johnson syndrome, and angioedema have oc-
excrete piperazine has been reported to vary widely. It (grenodier).
curred in some individuals.
is distributed into breast mi lk. Profile
(I Piperazine has been taken off the market in some European Pomegranate bark, the doied bark of the stem and root of Pimica
countries becau~ of general coocem about ils safety.' A sntdy Uses and AdministV"aticn gro11alum (Puniea¢Cilc) eontaioiing aboul 0.4 to 0.9% of alka-
carried out in Sweden on 2 healll1y subjects h•d indicated that loids,, has been used for the expulsion oftapewomis.
mononitrosation of piperazine can occur in the stomach co pro- Piperazine is an anthelmintic effective against the in-
duce the potential carcinogen N·mononi1rosopipera-zine; the testinal nematodes Ascaris lumbricoides (roundwo11n) Preparations
onore pot<m N.N-dinitrosopiperazine was not found.' However, and £nterobi11s vennicularis (pinwom1, threadworm), Propr'ietary Preparations (details are given in Volwne B}
the disease risk to m3n from such N·njfroso compoWlds has been although other anthelmintics are usually preforred (see Fr.: Hexapor;ne,
questionedl ond cenainly reports of rumours associated with the Multi·ingredient Chile: Cel~etty.
use of piJl'razine have not been b·aced. Also, in the UK the.CSM the discussions on the treatment of ascariasis and enter-
concluded that the incidence ofserious adverse effects associated obiasis on p.140 and p.142). In roundwonns piperazine Homoeopathic: Fr.: Pocorieol no 34; Ger.: My.>zCIOtfcum Nf.
with pipcrazine was low and that. with appropriate pack warn- produces a neuromuscular block leading to a flaccid
TI1e symbol t denotes a preparntion no longer actively marketed
162 Anthelmintics
Praziquantel (BAN. uSAN. rlNN) ion is thal praziquantel may be considered the safest of all an- 2. 80hrin,g KU. er (1/. Mc1abolism of praiiqu11n1el 1n man. f.:ur J
thelmin1ie drugs and lhat the risks to pregnant women or unborn Dr"g Mciab Phormocokinc1 1978; J: 179- 90.
EMBAY-8440: PratsikvM>telc Pruicuantel: Prazikvantet Prazik.iar>- or nw-sing children from use of praz.iquantel are very small. l ). Pati.schkc K. et o/. Scrum c:oneentraiions and renal excretion in
humans after OT31 admlnislratiOn o( praziquantel-ruullS of
telis; Praziquamelum l·Cydohe><ylcarbonyl· I.2.3.6.7. I lb-hex- Praziquantel is the dn1g of choice in schistosomiasis Md delay• three determination methods. Eur J DMIJ Mttob Phormocokinet
ahydtopyrazino(2.1-o)isoquinolin-4-one. ing trcatmeo1 may in fact result in more serious outcomes. h 1979; 3: 149-56.
npa3W<sa1<Te11 therefore susgeS1s that pregnanl and lactating women may be 4. Mandour M El M. er of. ?harmacokinetH:s of pra.ziqQnlel in
given the~ and should be included in national de-wonning httlthy volunteers and p11ienLS with schisaosomiuis. Tro11s R
C19H2.N;02 = 312.4. Soc Trop Med Hyg 1990: 84: 389-93.
(AS - 55268-74-1 . programmes.
5. (ioclawsk.>-Matysilt A, Ki«-Kononowia IC. Bio~ufom•ation
I. Adam '"'' ol. 11 praz.iquantd thr:rapy $3fr: during prqnancy? of p<Uiqu>ntcl by human C)10Ch"""e p-150 JA4 (CYP 3A4).
ATC - P02MOI . TraM R Soc Trop MU H>'f 2004; '8: 540-3. Acta Pol Pho,., 2006: 63: 311-S.
ATC Vet - QP5ZMOI. 2. Anonymous. UH o(prniquantcl in ~gnant and 1acuting WOfnoo.
UNll - 6490C9U457. en. ff'HO Dr11z lti/2003; 17: 29.
Uses and Admin istration
Interactions Praziquantel is an anthelmintic with a broad spectrum
Anthelmintics. For reference 10 plasma ooncenlrntions of the
of activity against trematodes (flukes) including all
active mc1>boli1c of ol/H!ndozo/e being increased by praziquan- species ofSchistosoma pathogenic to man, and ag;iinst
1el, see p.146. cestodes (tapeworms). It is used in the treatment of
Antibacterials. A sludy1 in healthy subjects found lhat oral,;. cysticercosis, diphyllobothr'iasis, hymenolepiasis,
fampicin docrcnscd plasma concentration.< after sinsle a.nd mul- schistosomiasis, taeniasis, and intestinal, liver, and
frple doses of oral pmziquantel 10 sublherapeutie levels. lung fluke infections. For discussions of these infec-
I. Ridtitid W. tr of. Rifampin markedly dca-cascs Pluma conccn· tions and their treatmenl, see under Choice of An-
trations of prat.iqu1ntel in he,a,hhy volunteers. Cli.n Phormocol
Tl"" 2002; 72: S0>.13. thelmintic, p-140, and under the individual headings
Pharmacopoeias. In Chin., Eur. (seep.vii). Int.. and US. Antiepifeptics. Ct!rlxmraupiHe and phenytoin have been re· below.
Ph. Eur. 6.8 (~el). While or almost while cryslalline poned to reduce lhe bioavailability ofpraziquantel.1
powder. JI exhibits polymorphism. Very sliglitly soluble in waler;
Praziquantel is given orally with food.
I. Quinn or. Day RO. DNg inte111elions or clinical impon>no<: ""
freely soluble in alcohol and in ctichloromc1hanc. Protect from
lighL
updot<d guide. o,.,,,
So/tty l 995; 11: 393-452. In the treatment of schistosomiasls in adults and chil-
dren over 4 years it is given on one day as three doses
USP 33 (P=iquantel). A white or practically white crystalline Antifunga ls. A crossover study in 10 heahhy subjects' $\J&&esl·
cd that the CYP3A4 and PgP inhibitor l<Lfoconti:ole elm~t dou- of 20 mg/kg at intervals of 4 to 6 hours or it is given as
powder; odourless or with a faint characteristic odour. Very a single dose of 40 to 60 mg/kg (bul see below).
slightly soluble in woter; &ecly soluble in olcohol and in ehlore>- bled exposure to, and mean peak plasma concenlJation of, prazi·
form. Protect from light. quan1cl when both drugs "'-ere given together. It was suggesled Doses in adults and children over 4 years in liver and
that standard doses of pmziquantel should be halved when bolb lung flu ke infections are 25 mg/kg three times daily
drugs were given.
Adverse Effects 1. Rid1ilid W, at ol. Phann:icokinetic intetac1ion between ke1ocona·
for two days or a single dose of 40 mg/kg. Similar dos-
Adverse effects' with praziquantel may be common but i.olc and pn.iiquantcl in heohhy volunteers. J Cli11 Ph<Jntt Thi,. es may be' used in inteslinal fluke infections (see be-
are usually mild and lransient. Headache, diarrhoea, 2007; 32: 585-93. low).
dizziness, drowsiness, malaise, abdominal discomfort, Antlmala.rlals. ChlOIYXJuine has been reported to reduce the bi· Praziquantel may be given as an oral single dose in the
nausea, and vomiting have been reported most fi-e- oavailability of praziqu:tnlel. 1
I. Masimit't1nbwa CM.#tol. The effect of c-hloroquineonthcph•r·
treatment of tapeworm infections in adults and chil-
quently. Hypersensitivity reactions such as fever, urti- rn1c;okinetics o.nd mctaboJism of pra:z.iquantcl in rats and in hu- dren over 4 years of age. For the treatment of Taenia
caria, pruriric skin rashes, and eosinophilia can occur; m1ns. /Jloplturm Drug D..pos 1994: IS: 33-43. .taglnata and r sali11m infections the recommended
they may be due to death of the infecting parasites. Cordcosteroids. Corticosleroids may be used lo reduce the in- dose is 5 to I 0 mg/kg, for Hymenalepis nano infections
Raised liver enzyme values have been reported rarely. Oamrmitory reactions tbal often occur witllin 2 to 3 days ofsuvt· the dose is 15 to 25 mg/kg, and for Diphy/lobothrium
Most patients with neurocysticercosis who are given ing cysticidal therapy. However, use is complicalcd by the fact /alum infections doses of 5 to 25 mg/kg have beeo sug-
that dcumclhasonc roughly halves the plasma ccoccnttation of
praziquantel suffer CNS eCfeas, including headache, praziquantcl It has thcn:fore been suggested that wbcn praziq1>- gested.
hyperthermia, seizures, and intracran ial hypertension, antel is given in the 2-wcck treatment regimen, conicosieroids Praziquantel is used in adults and children over 4 years
which are thought to result fi-om an inflammatory re- should not be given prophylactically but only ifan inflammatory in the treatment of neu rocystieercosis in a dose of
sponse lo dead and dying parasites in the CNS. Use reaction develops. Dcxamcthasone is then given da~y for 2 or 3
days and mos1 of Ille treatment period will be free ofphannacok- 50 mg/kg daily in 3 divided doses for l 4 days. An al-
with corticosteroids is advised in such patients. inc1ie intcraclion. When the shon cow-se pr82iquantcl regimen is lemative regimen of3 doses of25 mg/kg every 2 hours
Effects on the gastrointestlnal tract. Colicky abdominal used (3 doses given 2 hours apart), the corlicosleroid may be giv· has been proposed.
pain and bloody diarrhoea occurred in a small community in Za- en prophylaeticelly. 111c first dose of dcxamethasone is given 4
0 Reviews.
ire shonly after 1ICatmcn1 for Schistosomo monsoni infection hours after O>e las1 dose ofpraz.iquantel (when the concentration
I. Pearson RD. Guerrant RL Prn.iquankl: a m1jor adnncc in <1n·
with single oral doses ofprl%iquantel 40 mg/kg. 1 A similar syn- of praz.iquantel is slaning lo decrease and the pharmacological thclmlntic lhc-rapy. Ann Intern M~d 1983; 9~ : 19S-8. Concc1ion.
drome has been rep0ned in some patients with Schis1osomo action is usumed to have been accomplished) and 1ho:n daily for ibid.~ S14.
joponicum infection given prv.iquantel. 2 The abdominal pain 2 to 3 days. No phannacokinctic intcrnclion woukl be c::i.pccled 2. King CH. Mahmoud AAf. Drugs fh•c yc•rs Iller: p-11iquaniel.
oc:cuning in lhese palients was ''ely differen1 from the mild al>- al 1his poini. 1 Ann lnttrn Malt 989; I tO: 2~.
dominaJ disoomfon much mott commonly rcpor1ed wilh prazi- J. Sotelo J. Jun& H. Phannacokinctic op1imisa1ion of the tre11meru 3. Cioli D. Pica-Mat:.ocia l . Pratiquon~t Poro1uol Res 2003; 90
quantel therapy. ofnwrocysuccrc..is. Qin Phtmtt.,.,,kin<J t99S; 34: S03-tS. (suppl t): S3-S9.
• · Ali Blf. A >ho<! ,..,.,_. of some phannacoloaieal, therapeutic:
I. Polderman AM, ., ol. Side elT~IS o( pnz"l""'tel in the u..t. Histamine H 2·antagonists. Ometidine has been rq>ortcd to and 1oxicological propeni« or prat.iqwntcl 1n man and animals..
mtru of Schiscosom ma.nsoni in M1n1c.m1. Zaire:. Trans R Soc increase pruXjuantcl bioavailability.1.l PolJ PhormS<:i2006; 19: 170-5.
Tr0p #«I Hyg 1984; 71: 7Sl-4.
2. Wan G, •! o/. Bloody diarrhoco after pnziquontel therapy. Trons t. Metwolly A, ti ol. EITe<t o( eimctidine. bi<1rbona1e and clue°" Administration in children. Praziquantel may be given oral-
R Soc Trop MedHyt 1986; 80: 34~. on 11'¢ biolvaflabillly or difrttenl fonnulation.s of pru;quantcl. ly to children over 4 yeais of age for the rreatment of trematode
Ar.:n•lmUt<lforsthung 1995; 45: 516-18.
Effeets on the nervous system. Adverse nervous system ef- 2. June H. "'al. Phann1cokine1tc study of prariquancet adminis.. infections (including scbistosomia.sis) and CC$lode infections
fects are common in patients with ncurucysticcrcosis giv~n 1crcd alone tnd in combina1ion with ciinclidine in a singlc·d•y such os cysticcrcosis, diphyllobolhriasis, hymenolepiasis, and
praziquantel. Neurological symptoms have •lso been reported' 1herapcu1ic regimen. Amimicrob Agcms Chcm01hcr 1997; 41: tueniasis. Doses used are lbe same by weight as those used for
l lS6-9. adulls (sec above).
with the much lower doses or pniziquantcl used in the lrealment
of1aeniasis in a patient with undiagnosed ncurocysticereosis. Cysticercosis. Praziquantcl is used in 1he tre>tment of neure>-
I. Flisser A, ~' ol. Neurological symptoms in ocGull neuroe.ystice:r- Pharmacokinetics cysticcrcosis (p.J 4 J) although albendazole is also considered to
cosis after single tunicld1l do.se or pruiquantcl. Lancet t993; Praziquantel is rapidly absorbed after oral doses; more be the drug ofchoice.
342: 748.
than 80% of a dose is reported to be absorbed. Peak Rererences.
Precautions plasma concentrations occur J to 3 hours after a dose, I. Sotc1oJ, Ju~g H. Phannacoliinctic opiimimion oft.he arcatmcnt
of ncurocys.tioercosis. cu,, Ph<Jl'macoJd,111 1998t 34: 503-J S.
Praziquantel should not be used in patients with ocular but there is a pronounced first-pass effect and praziqu- 1. Del BruttoOll,<1al. SingJe-<!ay praziquonccl VctS1/S I-week al-
cysticere05is because of the risk of severe eye damage antel undergoes rapid and extensive metabolism in tl1e b<ndlzole for ncurocys1iCU1:0SiS. Newrolou 1999; 5?: 1079-111.
liver, mainly via the cytochrome P450 isoenzymes 3. Del 0Nlto OH, d al. Mou-analysis: eyst1Cidal drugs for neuro-
resulting from destruction of the parasite. C)sticercosis: .albendaz.ole and prHiquantcl. An;, lnt~rn ~d
CYP2Bl and CYP3A4, being hydroxylated to metab- 2006; 145: 43-S 1.
Patie.nts should be warned that praziquantel may cause
dizziness or drowsiness and if affected they should not olites that are thought to be inactive. It is distributed Echinoco~cosis- Praziquanlel tnay be: used as an adjWlCI lo sw--
into the CSF. The plasma elimination half-life of prazi- 11ery in echinococcosis·(p.142). Praziquanlcl has been reponed to
drive or operate machinery during or for 24 hours after ~a •colicidal eirecl in virro and in viWJ against Echinococ-
quantel is about 1 to 1.5 hours and that of the meta~
treatment.
lites about 4 hours. = gronulosus, although it does nQt penetralc well inlo mature
Breast feeding. Praziquantel is disllibuted in10 breast milk and cysts. 1 'There has been a rcporl of the successful 1rea1men1 of di,;.
mothers should not bre11s1 feed during treatment or for 72 how-s
It is excreted in the urine, maio ly as metabolites, about scniinated peritoneal hydatid disease wid1 praiiquantel and sur-
thereafter. For further infonna1ion on the usc of praziquamel in 80% of the dose being eliminated within 4 days and gcry.2 In this case praziquantcl was effec1ive against the small
breast feeding. sec below. more lhan 90% of this in lhe first 24 hours. cysts; 2 large cysts were removed siirgically, one before praziqu-
antel was staned. However, activity in 9 o01er patients given
Pregnancy. Jn a review of 637 women given pr.iziquantel in a Praziquantel is distributed into breast milk_ praziquantcl was disappointing. 3 A combinodon of prnziquantel
mass distribu1ion programme, 88 had had• single oral dose dur- with albendazole may be more effective,'·' although bener cvi-
0 References.
ing pregiiancy, including 37 in their first 1rimestcr. All pregnan· denc<: is needed for firm recommendations.'
cies ended in full·term babies and there was no evidence ofclin- t. Leopold G, <r al. Clinical phannacology in normal volunteers of
pruiqu>nie.I, a new dru& against schisros:omes and ccstodes: an I. By,ott JM, Chiodini PL. Ptu.iquantct: ntileclcd dN8? lne1Tcc-
ical abnormality. No diffetcncc was found in the rates ofpretam e:\amplc or 1 complex study eovcring both tolerance •nd ph:u· 1ivc treatment? Or tht:raptullc choice in C)'Slic hydttid disease?
delivery or abonion compared wilh a control group. 1 WHO opin- ma.cokinctics. Eul'JClinP/Jormaco/ 1978; 14: 281-91 . Acta Trop 2009; 111: 9S-101.

AIJ cross-references refer 10 entries in Volume A

 Praziquantel/Pyrcmtel Embonate l 63
2, Henrik$..cn T·H. (•((II. Treatment or diSS¢1Tiin;;ittd peritoneal hy· ail that is required to achieve a permanent cure or prevent re - Pharmacopoeias. In Chiu.. Eur. (seep.vii), /m., Jim. and US.
dutid dit'case with praz.iquantel. ltmC'el 1989: i: 272. infection, aod any treatment plan should be reassessed after 6 or Ph. Eur. 6.8 (Pyramel Embonate). /\pale yellow or yellow p<>w-
·'· Piens MA. el al. Pr:n.iqunniel dans. l'hy(fatidosc humoine: C"alu· 12 months.5·<• Such an approach with annual screening and tar·
ation par trailement mCdical prC opCratoirt. 8111/ S<K Puthul £.,·01
0
der. Practically ir.soluble in waler and in methyl alcohol: soiuble
FilinleJ 1989: 32: 503-12. · ge1cd chemotherapy can provide. at least in some endemic areas. in dimetllyl sulf°"ide. Procecl from light.
4. /\yks HM, c1 a/, A CQmbincd med i~ol and s-urgic.al opptoach 10 successful protection for children against intense infection and USP 33 (Pyrantel Pam<>ate). A yellow 10 tan soiid. Prnclically
hydatid dise:i.se: 12 years' cxpc<iencit at the Hospi!al for Tropical consequ~t hepatic disease.6 insoluble in waler and in mechyl alcohol; soluble in dime!hyl sul·
Diseases, London. Ann R Coll Surg Engl 2002: 84: 100-IOS. Several studies indicate that doses lower Lhan those recommend- foxide: slightly soluble in dimcchylfonnamide. Protect fi·om
Intestinal fl uke infectio ns. Praziquantcl, given orally, is used ed above might be effcccivc and in some control programmes lighL
in the creatment of intestinal fluke infections (p.143). In che crcat- 20 mg/kg might be enouzh for S. /laema/obiumM OT 30 mg/kg
mCJH of fasciolopsiasis, hetcrophyiasis. and metagonimiasis, the for S. mansoni. 7 The extent to which low doses contribme to re- Adverse Effects and Precautions
usual recommended dose is 25 mg/kg three cimes daily for one sistance. as has been suggested with oxamniquine, 10 is unclear,
bm refractory infections have been reported. A 4-day treatment l11e adverse effects ofpyrantel embonate are generally
day. 1 However, a single dose of25 mg/kg has also been recom-
mended 1 Single doses of 15 mg/kg. 25 mg/kg, or 40 mg/kg all course was needed to produce a complete cure in a paricnt who mild and transient. The most frequent are gastrointesti-
yielded a cure rate of !00% in a study in 72 primary·school chil- relapsed '"ice following standard one-day treatment regimens.'' nal effects such as nausea and vomiting, anorexia, ab-
dren in Thailand who were harbouring Foscinlopsis buski, sug- Hepatic i01paim1en~ specifically hcp3tic flbro~is, is a feature of dominal pain, and diarrhoea . Other adverse effects re-
ge.<ting that a single dose ofl 5 mg/kg al bedtime might be tried.~ some schistosomal infections and patients with such liver in·
volvement h3ve beneficed from treatment with praziquan1e1.•.12
ported incluce headache, dizziness , drowsiness,
In another study, 9 patients infected with the tremalode Nnnn-
or insomnia, skin rashes, and raised liver enzyme values.
p/n.,ws salmincola were lrcaled with praziquancel 20 mg/kg I. WHO. The con1rol of schistosvmiasis: secon<.I r.:porl the
three times daily for one day and were negative for eggs in their WHO exper1 commiuec. WHO Tech Rep Ser 810 1993. Also Pyrantel embonate should be used with caution in pa·
nvailable at: hllp:l/1ibdoc.who.in11trYWHO_TRS_830.pdf (ac.
stools 2 co 12 weeks lacer,' and this has become Che usual recom- c<S!ed 2511 I /09) tients with hepatic impainnent.
mended cose. 1 2. Docnh~IT MJ, Pica·Mauocia l . Praziqu:intl:I for the 1rca1mcn1
I. Al:iramowic; M, ed. Drug.f for paroJitk infections. 2nd ed. New of schistosomlasis: its use for conlrol in areas w i;h endemic dis:..
Rochelle NY: The Medical Lener, 2010. ease and prospects ror drug fCSisunoe. E.tpen Rev Ami Infect Interactions
2. WHO. WHO modelform11/a1y. Geneva: WHO, 200&. Availabl• al: 17•..·2Q06; 4: 199-210. TI1e anthelmintic effects of both pyrantel and pipera-
http:/;v.ww.who.int/selcction_medicin,c s!lisr/WMF100S.pdf (ac. 3. Docnhoff MJ, c1 al, Resistance of Schistosom3 mansoni ro
ccmd 2511lllJ9) pra2iqlJan1el: is there a problem? T1•ons R Soc Trop Med H.11g zine may be antagonised when the two drngs are used
2002; 96: 465-9. together.
"· Ho rin.::i~utn T. e1 al. £nicacy of pr3ziq~ ntel on fasciolopsiosi:>.
Arweir11it1eljorschung 1984; 34: 1214-1.5. 4. Doenhoff MJ, ct al. Pra2iquantel: mechanisms of3ction, resist·
4. f ritsche TR, et nl. Prnziquantcl for lrcatm('UI or human Nana• ance and new derivatives for schisiosomiasis. Curr Opin fl?fecr
Di.r 2008; 21: 659-61. Pharmacokinetics
phyctu~. sa lmi ~ola (Troglotrema salmincola) infection. J /nf~c1
S. Anonymous. The chcmolher:Jp)•ofschistosom iasis control. 8t11/
Dis t%9; 160: 896-9. WHO I986; 64: 23-5. Only a small proportion of a dose ofpyrantel embonate
Liver fluke infections. Praziquantel given orally is used in che 6. Anony1nous. Mass trea1mcnt of schistoson1iasis with pr82iquan· is absorbed from the gastrointestinal tract. Up to about
tel. W/10 Drug ln/1988; 2: 184-5.
treatme~tq( clonorchiasis and opisthorchiasis, and has also been 7% is excretec as unchanged drug and metabolites in
used in the treatment offaseioliosis (p.143) altl1ough in !his latter 7. Taylor P. Cl of . Effie<lcy of low dosc-s of praziquantcl for Sch is·
~~s:o~;~~~nsoni and S. h3emito~ium. J Trop Med 1/yg 1988~ the urin e but over ·half of th e dose is excreted
infection bithionol or lriclabendazole are preferred.
unchanged in the faeces.
Various studies have shown praziquanlel to be effective in 8. King CH,~' al. Dosc·finding s1udy for praziquamcl therapy of
c.lonorchiasis 1.. and opistl10rchiasis,5·' although one study in Schistosonia h<\em31ob1um in Coasl P1ovinc~. Kcnva. Am J
Trop Med H.rg 1989: 40: 507-1 3. ·
opisihorchiasis 7 showed !hat re·infection was common despite 9. Hatz c. e1al. Ullrasound sunning for detc:c1ing morbidity due
Uses and Administration
pl'llziquantel therapy, particularly in those with heavy inicial in- to Schis1osoma hsematobiuni aod i1s resolution following trtat· Pyrantel embonate is an am.helmintic effective against
feccion. A study in Tbailands confirmed that mass treatment for mcnt wi1h different doses ofpraziquantcl. Tram R Soc Trop Med intestinal nematodes including roundwonns (Ascaris
opisthorchiasis with a single dose ofpraziquantel was beneficial, l~l'g 1990; 84: 84-8.
10. Coles GC. et al. Tolerance of Kenyan Sc:histosom3 m3nsoni to lumbricoides), threadw9nns (Enrerobius vermicu/a-
alU1ough ii w-dS suggested !hoc ideally treatment should be given
oxamniquine. Trans R Soc Trop Med H)'g t9Si; 81: 782-5. ris), and Trichostrongy lus spp., the tissue nematode
twice a year. 11. MurTay·Sinith SQ, tt al. A c:i.se or r.:fractory schis1osomiasis.
While praziquantel is notthe drug ofchoice for fascioliasis, there Med.I Arm 1996; 16!': 458. Trichinella spiralis, and hookworms, although it is
has been areport9 ofsuccessful neannentofa palient wilh severe 12. Zwingcnl.H~r~cr K. et al. Praziquamel in 1.hc treatment ofhefh't· possibly less effective against Necator am<!ricanus
°'
infection. Subsequent studies 1 12 have. however, shown prazi- osplenic schis1osomiasis: bioc:hcmkal disease markers indicate hook.·wonns than against Ancylosloma duodenale. Pyr-
qua.ntel to be of little benefit. :~~~~~.i°t,.0~1~ ~b~:~~;,~~s;,~: :~~~i~9~8~g~~ ~Si~.now ob· antel embonate is one of the anthelmintics that may be
f. Soh C-J. Clonorchis sincnsi ~: experimental and <::liniCRI scudics
with pr~z i qu3ntt:I in Korea. Arz1wimiflel[cm;clumg 1964~ 34: Taeniasls. Pr:v.iquantel is """d in the creatment of taeniasis used in the tTeatment of infections with these worms, as
1156-9. (r.14.5). h has been studied in che mas.< control of1aeniasis when discussed under Choice of Anthelmintic, p.140. It ap-
2. Chl?n C-Y, Hsieh \V-C. Clonorchis sinensis: epidemiology in a singJc dose of 5 mg/kg wa.s used. 1 pears to act by paralysing susceptible wonns which are
Taiwan :md clinic31 cxperitnce with pra2iquin1el. Anneimittel-
for.ch•11g 1984; 34: I 160-2. Praziqunntel is also effective against the larval fonn of Taenia then dislodged by peristaltic activity.
3. Kuang Q·H, tu al. Clonorehiasis: trc:atmtnl with pra~iqu3ntcl in solium and is used to !real ncurocysticcrcosis (sec above).
50 cases. Ar:11timitU>/forsch1mg 1984: 34: 1162-3. I. Crut M. < '' al. Op~r.ttional studies on the conno I of Taenia SO· Pyrantd is given orally as the embonate, but doses are
4 . Lte S-.' i. l.:irgc sc~le trea1mem of clon~rchis sinensis infections limn 13c:niasislcysticc1cosis in Ecoador. Bull J.JlffQ 19S9i 67: described in terms of the base. Pyrantel embonatc 2.9 g
Wilh pr:>ziqu:>mcl under field c<mditions. Arweimi11el(or:rc/11m~ 40t- 7.
I984; l4: I 227-8. . • is equivalent to about I g ofpyrantel.
5. Bunna;t 0 . (_'f al. Opisthl'fcl1is vh•..::rrini: tlinical experience wilh Preparations Single or mixed infections due to susceptible worms
praziqt.tantcl in hospiutl for tropic~I diseases. Ar=neh11i1telfoc,·c· USP 33: Pl·;uqJ.;mtel Tabk:-1'>
lumg 19&4: 34: 1 1 73~. ' may be treated with the equivalent of pyrantel
6. Ambruise· Thom:.'s P. ti ol. Therapeu1ie rcsul1s in opi s1horch i~· Prop rietary P~parations {details arc given in Volume B) IO mg/kg as a single oral dose. Ascar iasis occurring
sis with prai.iqu:rnlel in a rcinfcction·frec en\'ironmcnt in Arf.: Praz~; Aunrol.: Bihricide: 8f'02.: Ccmt>X': Gsti-c:id; Canad. : 841tri-
France:. Arweimillclforxdumg 1984; 3': 1177- 9. cide: Chile: 0.'>ot Cisticie:t Fr.: 8iltiicid~ Ger.: Biltnc.~e: Ccsot Cystic.Ide: alone may only require 5 mg/kg; a single dose of
1. Up~tlum ES. ut ol. R~t~ orrc.. infeciio11 by01>isth.:>rchis vh·tr· Gr.: Silt:icide; Hong Kong: Sltricide; lsroel: Bilbic1de: MeK.: Cesot Cisti· 2.5 mg/kg given three or four times a year has been
ri:-ii in :m endemic nonheast Thai <;ommunity after chemothera· cid: E)(liSC<•Qt: Ttcprabo: TetWkcn; Zlartet1: Neth.: 8dtiicide; Rut.: Sttb·icid
py. /1111Poroj·ifqf1988; 18 : 64'.l-9. (6'1'>Tpv.u1A): S.Afr.: lliitricide: Cysticide; Singapore: Oistodde: Thai.: used in mass treatment programmes. Jn necatoriasis,
S. Pungpak S.. cl al, Opislhorchis vivcrrini infection in Thailand: Mycotricic:f.ef: Opticide: P:oqvantel: Pratikon; Pi-azitc: V Day Prazide: Wot"· I0 mg/kg daily for 3 or 4 days or 20 mg/kg daily for 2
~tudiei: o'n' 1he morbidity af the infection :md rcwlulion follow· micide; Ukr.: Btltricid (fu,bl"pC1lll-u}: USA: Siltricide: Vener.: Ce~ox: Cis6·
i11s, praz.iqu:lnlcl 1rea1rnem. Am J Trop M(_·d Hyg 1997: SG: ciot. days may be necessary. The response in enterobiasis
311-1 4. may be improved by repeating the I 0 mg/kg dose after
9. Schi::i1~ac'!lsse RH, ~1 al. Successful 1rc:io11e.11 of sever~ info c· 2 to 4 weeks. In trichinosis, a dose of I 0 mglkg daily
tion wth Fas<; iota hcpa1ica with praziqu~nte l . J 111/CCI Dis l 985~
1 ~2: 1139-40.
!Pyrant:el IEmbonate (Bfl.NM. rlNNMJ for 5 days has l>een used.
10 . f:i rag Hf, et al. A short no1e on pr:>ziquantcl in hmnan fascio·
liasis. / Trop Med H.•'f. 1986: 89: 79-80. • Pyrantel ta11me has been used as a veterinary an-
CP-10423-16; Embonato de pirantel: Pirafltel Pamoat Plrantel
11. Farld Z. e1 al. Unsuccessful u~c of proziquan1el to lreat :icute thelmintic.
fa$tioliosis in children. J b~fcr1 Dis 1986: 154: 920- 1. Pamoate: Plrzr.telio embonatas; Pyranteeliembonaatti: PY"-.intel,
12. Farid Z. f!I of. Tt('31Jnc111 or acute lO~ae1 nic: fo.scioliasis.. Trow; R embooate de; f')·rontel Pamoate (USANJ: P.1rantelembonat Pyr- Administration in children. Doses of pyranlel enibonate for
Soc n•p Med Hrg 1988: 8? : 299. antel·embonat Pyranteli err()ollas; Pyrantelu embonian. 1.4.S.6· the treatment of susceptible sing.re or mixed wonn infections in
Lung fluke infectio ns. Praziquantel. gi\·en o rally, is used in lhe Tetrahydi·o.1.methyi-2·[(E).2·(2·thienyt)vinyljpyrunid>ne 4,4' - children are the same by wtight as lhosl! for adul1s, see l)ses and
trcatm.,nt oflhe lung fluke infeclion paragonimiasis (p.143). med))'le.1ebis(3-hydroxy·2·naphthoate). .'\dministrntion. al>O\'C.
References.· nt.-;p<;HTeAa 3M60H3T
Preparations
I. V~11ijanon1a S. l!I al. Ptiril~Oninms het::rotremu$ and Qthcr Para- c .. H,.N2S.C23H,.o. =594.7.
gonit':llA i?P· in Tlmil3nd: p~thogcncsis clinic an<.I treatment, USP 33: tvermec-'11 and P)7·an~d P.Jmo.nc Tableu: ?yramei Pcimoate Orat
Ar-;.11ci111illelfor:~ch:mg 1954: 34: 1186-R,
CAS - 15686·83·6 (pyronrel): 22204.24.6 (pyronte! em· S...spensaon.
1. Pachucki CT. ct ol. Americ;:an paragonimiasis treatc:d with prazt· bono<e): 33401 . 94.4 (pyrontel <0rua1e).
Proprietavy Preparation5 (details are given in Volume Bl
qtoantcL N £11g/J Med 1984; 311: 582-3. ATC -- P02CCO r. Aun.ra'.: Anthet CombantJin; Ea11y Birdf: Austria: Combantrin: Bren.:
3. De NV:.C'l '!1·. Epidemiology. s ympto1ns and trealmc1H of paras· UNrt - BIBK;94ZSM. Asarial: Cdn od.: Combantrin: J;ia Pyrat Chile: Combantfint. Fr.: Com-
onimia~iS'in Sin H<' district. L:ii Chau ptovinee. Vietnam. So111h- bo.ntl'irt Hehlintoic Ger.: 1-telrnex: Gr.: Cor:iblntrin: ""ong Kong: Com·
f!os1 Asian .I Trcp Med Public Health 2000; 31 (Suppl I): 26-30. bant1'i1)J: Pyw-antinf': tndia: Nemoc:id: lndon.: ComOOntii ii': Kcn\."e~x-j ;
Schlstosomlasls. Praziquan1el is the main drngU used in the Medr.on.,vnt. Plra.<f~j: PrQWOrmt Ital.: Coinb.m.-li: Mex.: Comt>aov;r,:
Piranuir.t NZ: Ccmban-:rin: Phllipp.: Coinbantrin: Gelm;nt!iic: Port..:
treatmenc of schislosomiasis (p. 144). IC is effeccive against all Combantrin; Rus.: Helmin!OX (fe1.ti~..HTOKc): N emocid (Hcv.ou"IA):
Sp<.'Cies oi schistosomes, 1 altl1ough the possibility of resiscance S.Afr.: CornbanL,....'": Singapore: Searantet Spain: Lombriareu: Trilom-
remains a concem.H Oral doses are eilher 20 mg/kg given three oon: Swiu.: Cobanlri Thai.: S.ntet Pyn1pom: P)'lcldon: Turi<.: 1:0.d: Pi·
rantrin; USA: Pin-P.id: Pin-X: Reeo:e's Pif\'\Notm: Vene.t..: Combanlrir-:
limes in one day or a single dose of 40 10 60 mg/kg. WHO
irt;mext: Pamovalj: Pi<.'OS<IJ1t T•mo.>: Teriechat.
considers' that in the field such a single-dose treatmcnc will pro·
duce a cw·e rate of 60-<o 9001(, with a reduction in egg count in Mult i·ingred ient: India: Mebex Plus: l ndon.: Qvantrelt: Philipp.:
Q uanti¥.i: Venez.: C~bd; Qu;intrcl.
!hose not cured of90 10 95%. Good as such results are, asingle (pyromel)
dose or o'e day's sole treatment should not be considered co be
The symb-01 t denotes a preparation no longer actively marketed
 164 Anthelmintics
Pyrvinlum Embonate (t!NNMJ Santonin Profile
EmboNto dt pirw.o: f'lrvnyum P1moat f>yN!na Embonas: f')r· Santoni.'"li: Santornna; San1onoro.Jm. (3S.3..s.5&S.9bS)-:i...5.Sdb- Tc:iramisole hydrochloride is an anOlebnintic ~ in velmnlrv
W.um. Fmbonatc de. ~llOUm ~te (SAN); V'P')"IO..,, Em- Tet.-a.'>)"dro-3.5a.9·~na:>htho(l.2~Jfu~2.8{3H.4H)-d­
medicine for die control of nematode infeaions. It is 1 raccmiC
ooc. mixllll'C and tlie lacvo-isomcr, levamisolc hydrochloride (p. I SS).
bona\c; Vlfll')'Mm l'lmoatt 8's{6-drncthylamno-2-{2-{2.5·
accol.llts for mOSI of its aaiviiy.
domelhyt 1-pht~-) )4)vtrv,4l·l·mtlhylquinor.n.um} 4.4'· Ut<To.<MH
metnylenebd()·hydtol<y·2~phthoale).
Preparations
C,$H1aOi = 216.3.
Pl"Oprietary Prep:ara.tion• (details an: g;,..,.. in ~lume B)
n..pe>o..l<A 3M6oHIT CAS - 481-06-1.
UNll - I VL8)38ERO. Sto-c.1 AsariZXlllf.
C~iHs.N,.CnH,.o,. 1151 4. Multl-ln&redi•nt India: l<'tornosol.f.

.
CAS - 3546·•1·6.
ATC - P02CXOI

)~n
UNll - 310X6S84lW
Thiacetarsamide (tHIM)
~.....OC: Thiacelllnamide; Ttiacetars<rnidlffl ~c:
CH,
, 131-{ mide:
T~
l>'{Bis(arboxyrne'Jiytnerapto)arwt0~­
Tiaceurwnodo
1-~ lls{~th)'tth<>}arscrile.

0 C11H11A•NO~S2 377.3.=
CAS - 531-72-6
Pharmacopoeias. In Jpn. ATC Ver - QP52AX08.
UNll - VMF•ElY9TZ.
Profile
Santmin is a crystalline laao,,., nbtamcd from the dried unex-
panded Oowemeads of Anomsla clna (untonoca, \l<Otmwood)
and other J;pecics or Artemisia (Compositae). It was formerly
~~an antlielmintic in the U"ealmalt ofroundworm (Ascorl1)
1nfccuon. but bas been superseded by other less toxic an·
thclmintics.
It is used as a flavour in food.

Se lamectin (!AN.'-~""" ~NNJ

P harmacopoeias. In US Se!amectina; S&mectine: Sclamectinumr ~'I( ~­
USP ll (~ Pimoltc). A bright orange or orange-red to tin; UK-1241 Ii. (2aE.'\E.S'S,6S.6'S.7S.8E.11R.13A.ISS,17aR.20aR.
practically black aystAllinc powder. Pt1ctically insoluble in wa- 20bS)-6'-Cydohexyl-7-{{2.Uideo>C)l·3~meth)'l-o-1.-ootwio­
ter IJld in ether. sli&)ldy soluble in chlorofonn and in mclhox· hexopyranosyl)o")'}l".4'.5'.6.6'.7, IO. I I, 14. I5.20a.2a>-dodec·
yclhanol; freely soluble in alaci1I acetic ICid, very s!ia)llly sol1>- ah)d'o-2Qb.hydroxy-5'.6.8.19-tetran"eth~ro(l l.15-mtllwc- Profile
ble in mtlhyl ak:ohol. Sinn: in •1rli11ht c:untaincrs. Protect Crom 2H.13H.17H.furo{4.3-2·p.qJ2.6]benzo6o>eaCydcxx~- Thi1cctarsam1dc is an aneIDcal derivative used ill veterinary
ligbt 13.2'{2H}pyranj- I7,20( I7aH)-doonc ~ medicine for cawnc hcartwonn.
(.e.o.a...,KTMH
A dverse Effects
l'yrvinium occuionally CIUKS nausea, vomiting, abdominal C 4JH6 iN0 11
CAS - 165108-07-6.
=770.0.
pain, •nd dill!l'hoea. Hyperscnsian•il)I reactions IJld photosam· Thio pha.nate (SNJ)
ri~il)I have been repo11ed Headache may ocet...
ATC Ve! - QPS4AA05.
UNll - A16690WX9N. Toof;anato. 4,1'-o-~(ethyl 3-!Noallophanate).
Pyrviuium siains lite stools bo&ht red and may , ..'" clothio& if T"°4>1kaT
"omiling occurs. c,.H, 1N.o.s2 =310.1.
Pharm acokinctics CAS - 13564-06-9.
Pyrvinium cmboo1te is n0111S11ifoc:ancly abtorbed from che gas- ATC Vet - QP52AC01.
trointcs1inal ttad. UNll - SQOY960518
Uses and A dministration
Pyrvinium einbonltc 1$ an cftec11ve 1n1hclm1nhc m the 1reauncnc
or cnterobiasi< (p.142). but h•s gcnenlly been superseded by
Oilier~
P)TVinium is &J\'Cfl u the e•nbonetc but dollCS asc cbcribcd on
tctms of the base. P}"'1n1um cmbonalc 7.S ma is cquivat.!nt to
about 5 mg of pyrvinium.
It has been &ivcn orally in asillate dose cquivalcnl to pyrvmoum
5 m~g. repeated 11\cr 2 10 3 weeks.
Preparations Profile
Pha rmacopoeias. In Eur. (sec p.,;i) for veterinary use 0<1ly. ll11ophanl1e •S a prodrua that IS conveitcd 10 the bcnzimidaiolc
USP JJ: ~,..,.,_.Chi~ l')r"""""'h"'°"" l'M*ts. P h. Eur. 6.8 (Selamectil b- '4!terirwy Use). A semlsynlhctic 1nlhelmontic lobendazole. II is used in veterinary medicine for
Proprie tary Prepan tlons (de111l11re ah..,, m Volume B)
A11.: Tru: Aufttlo: l"lclewc1. 4NL: £nttr0<idf, ~-P.,,,f: P\-vom\
product derived from a fermentation prodUCL A white or almost
white. hygroscopic powder. Practically insoluble tn \\Iller; $Olu-
or
tlic control nematode infections.
O.nm.: V.nq<.-.; nn.: P\'NR tr~ """M.t c;.,_, 11a11Mc: F')<con; NO<W.: ble tn acetone and ill dichloromcthanc; f~y sol\iblc in JSOptO-
Vv-q..rc Spoin: , . . , _ Sw•d.: ~ Twl<.: Fwd< pyl alcohol; sparingly soluble in methyl 1lcdiol. S1nre in 11ni&ht
COIJtaUlCf'S.
Tiabendazole (BAN. rlNNJ
Profile
Rafoxanide (MN. USAN. f.NN) Sela~_cc1in is an avcrmee_1i!' anthclmintic used in vcl(rinary
E233: MK-360; Tho~ole ilJSAN); Toabendatsorc Toabenda·
~1c11~ as an ec.1oparas111cidc and fot chc prophylaxis of aas- zol:T~.. T~um. 2-(TNazof..4-*IH-benzim·
MK-990:~~ ~fO>Qnidum )'.Q>loto-4'-(4·chlorophe·
tro1n1cstmal roundwonns and heanworms. odl2ole
nc>cy)-3.5-d"i-oodosa~.
T ,.,.6e•~A.no.,
Pa$oo<a,..,... C,oH,N,s = 201 2.
=
C,,H 11 Cl 111N01 626.0
Tetramisole Hydrochloride (8ANh\ t.MN, tll>NM) CAS - I 48-79-8.
CAS - 22661-39·'· ATC - 001AC06. P02Cl\02
ATC Vei - QP52AGOS Hodroclot\ro de te\r.lmisot I0-50627: McN·JR-8299-11. R-
8299. Tetram1sole. Chiorll)'drate de: Tctramosoi Hydrochlori- ATC V•I - QOOIAC06; QP51ACIO.
<i.fn. (±)-2.35.6-Tetrah)'dro-6·phen)'imida~2. I ·b)lhiuole hy· UNll - NIQ45E870T
6-oc:Noridc.
TeT~H>Olla rO<APOXt.OpHA
C 11 H,:iNi$.HCI =210.8.
CAS - 5036-02-2 (tetromosole): 5086·7•-8 (tetromiscle
hydrochloflde).

Pharmacopo~las. In Chi11, Eur. (sec p.vii),/111.. and US.

Ph. Eur: 6.8 (robcndllole). A "hiteoralinost whiteC7)stalline
Profile powder. Pnctically insoluble in "atcr, slightly solli>lc in 1loohol
Rafoxanide is an anthcbnintic used ill vcte11nary medicine for Ille and in dichlQ'Olnclhane; it dissolves in dilute mineral acids. Pro-
(ierromiscle) tect fi"om light .
treatment or fa.sc10liasis in unlc and sheep.
USP ll ~).A whne to pr.1cticaUy white. odour-
Pharmacopoeias. In Fr. for veterinary ust only less or pradlcally odourtm. po\\lder. Practically insoluble in wa.
All cross--refercnocs refer to entries in Volume A
 Pyrvinium Embonate/Tridabendazole 165
tcr: sligl11ly soluble in alcohol anJ in acctoil<: very slightly solu- tivity against some larval stages and ova has also been Preparations
ble in chlorufonn and in ccher. shown. The mode of action is no t certain, but BP 2010: Tolll>enc:ado Tztieu:
tiabenda7.ole may inhibit the fumarate-reductase sys- USP 33: Tl...,.._ 0r.i Su!i;.,,..,.,: T,.abe, _ r.tle'~
Adverse Effects tem of worms thereby interfering with their source of Propriet~ry Preparations (de1:.ils are given in Volume 6)
Dizziness and gastrointestinal disturbances, especially energy. Nf" rolc!an: Austral.: Mrntczolj. 8roa.: llen:olj: Foldan; 11-'__,I. TN·
anorexia, nausea and vomiting, diarrhoea, and abdom- bosr. T"""'1xt: Tiabenzojf: io>dct T..p..: Chile: Soldrin; Gr" Mrne2ot
inal pain are common during treatment with tiabenda- liabendazole is used in the treatment of cutaneous Jar- Mu" Eprollj: Spain: Tri•""'f'. USA: ~teoolt. Venez.: Dro<cnt.

zole. Other adverse etfectS occurring occa.sionally in- va migrans, dracunculiasis (guinea worm infection), Multi-ingredient: Broz.: 0"""" En,..,.,.Tt FQlderm Pcmoda: for·
and toxocariasis. It may also be used in the treatment of """"' Htmbt. ~n: Holn'Odr»<t. Jcsvem>t: Meolb<nt Micqile¢
clude pruritus, skin rashes, headache, fatigue, N""""'"'"' 0..'telr'nlnt. Polibent: Prolun: ~. Thi•ben1t, y.,-.
drowsiness, drying of mucous membranes, hypergly- strongyloidiasis, and can provide symptomatic relief milon Coml>O><of: VwnlOlj·: Zclost
caemia, disturbance of vision including colour vision, during the larval invasion stage of trichinosis. Tiaben-
leucopenia, tinnitus, effects on the liver including dazole is also active against some intestinal nematodes,
cbolestasis and parenchymal damage (in some cases but should no1 be used as primary therapy; the treat· Trlclabendazole <aNi •INN}
severe and irreversible), enuresis, crystalluria, and ment of mixed infections including ascariasis is nOt Tnclabendalot iridabendaloUn. S·Chloro-6-(2.3-dichlcrophe-
bradycardia and hypotension. There have also been re- recommended since tiabendazole may cause the noocy)-2-(methyithio)benM'Odalole.
portS of erythema multiforrne, fatal Stevens-Johnson worms to migrate to other body organs causing serious TpocK11a6etW30A
syndrome. toxic epidermal necrolysis, convulsions, complications. For discussions of the treatment of the C.,H,Cl1Ni0S = 359.7.
and effects on mental state. above infections see under Choice of Anthelmintic, CAS - 68786-66-3.
p.140, and under the individual headings below. ATC - P028X04.
Fever, chills, angiocdema, and lymphadenopalhy have
been reponed, but may represent allergic response to Tiaben(lazole is given orally, with meals, usually in a ATC Vet - QPS2ACOI.
dead parasites rather than to tiabendazole. dose of 25 mg/kg twice daily for 2 or more days, the UNI/ - 478•C8E.030.
The urine of some patients taking tiabendazole may duration depending on the type of infection; the daily
dose should not exceed 3 g. For those unable to tolerate
have a characteristic odour similar to that after eating
2 doses daily, 25 mg/kg may be given after the largest
asparagus; it is attributed to the presence of a tiabcnda-
meal on day I and repeated 24 hours later after a simi-
zole metabolite.
lar meal on day 2. For mass treatment, a single dose of
Effects on die salivary elands. Ory mouth with swollen pa- 50 mg/kg after the evening meal is suggested although
rotid and ;;alivary iilanJs suggestive ofthe sicca ClOUlplcx ~d­
cd the development of cholestitic jaundice in a 17-year-otd boy the incidence of adverse effectS may be higher than
given tiabcnduole.1 wilh 2 doses of25 mg/kg.
I. Davidson RN. et ol. lntrabepalic cholestuif. ancr 1hlabendazole. In cutaneous larva migrans, 25 mg/kg may be given i>rofile
Ttu11s R Soc Trop M..J H,.g 1988: Sl: 620. Triclabendazole is a benz.imidaw!c anthehnintic used for the
twice daily for 2 days, repeated after 2 days if neces- trearmeot of fascioliasis. Adul!S and children 6 ycaTS orage and
Hyperse:1sitivity. Scvese Cl)the111;1 mullifoome developed in a sa1y; topical treatment with a I 0 to 15% suspension in-
i»tient 16 days after a cowse oftiabendazok:.1 Many of the lo- older may be given a single oral d~ of JO mg/kg afier food; io
sions encircled pre-existing melanocylic naevi. tended for oral use has also been advocated as an alter- ~vere infestations those I$ years of age or older m:1y be gi\'cn a
I. I lumphn:ys F. Cox NH. Thiobtnduole·induccd cryth~me n1uhi· native or adjunct to oral treatment. second dose al\er 12 to 24 hoors. It is also under investigation for
forme with lesions around 1nelaoocytic natvi. Br J Dcn11urQ/ the treahncm ofpiintsonimiasis.
19SS: 11 G: 8Ss-6
Jn dracunculiasis, 25 to 50 mg/kg may be give11 twice
da ily for one day; in massive infection a further Liver flul.. infactions. Although bithionol or praziquantel are
50 mg/kg may be given after 5 to 8 days. used to tre<lt fascioliasis (p.143), $Ome consider triclabeodazole
Precautions to be the cln:g of choice. 1 Sevei~I s!Udic$1'1 bllvc shown the effi-
Tiabendazole should be used with caution in patients In strongyloidiasis, 25 mg/kg may be given twice dai- cacy of triclabendazolc ia fasciolil!Sis.
with hepatic or renal impairment. Tiabendazole causes ly for 2 or 3 days or 50 mg/kg as a single dose; when I. Ahrunowicz M. ed. DnfRSfor pato1ilk fn/ttlions. 2nd rd. New
drowsiness in some patients and those affected should the infection is disseminated treatment for at least 5 Roch<lte NY: Th< Medical Lcllcr, 20t 0.
no< <hive or operate machinery. days may be necessary. 2. Apl W, "' ul Tm_trncnl o(hurnnn <:hronic: ra.sc,ioliuis ""ith uic:l:i·
bendazole: drug cffccocy and scrolog.ic: respon.sc:. Am J Trop Mtd
liabendazole should not be used in mixed worm infec- In trichinosis, 25 mg/kg may be given twice daily for Hyg 1995; Sl: 532-S.
tions involving Ascaris lumbriccides as it can cause the 2 to 4 successive days. 3. El-K3raksy H, er ol. Human fucioll~sis in EG.ypti~n children:
suc:c:essful 1rcatm(nt wtlh tricl.abendllzotc. J Trnp PeJ;o1r 1999;
latter to migrate; live wonns have emerged through the In toxocariasis, 25 mg/kg may be given twice daily for 4S: 135-8.
mouth or nose. 5 to 7 days. Millin JC. Cl"'· The efficacy and lOkrt'Jbilhy or triclabendnolc
in C.ab1.n pa1tcn1s wi1h Ja1en1 and chronic Fuc:iola hepitica in-
Pregnancy. Tiabendazole is teratogenic in ml« although there Tiabendazole also has some antifungal activity. It is fe<tion. _.,., J T>..,p Med H.•'81000; 63: 264-9.
are no adequ.ite and well controlled shodies in hum:m pregnancy. used as a fungicidal preservative for certain foods. S. GnMm CS, « al. Jmported Fa.sciola hep:ltica infection in the
Renal impairment. Tiabendazole nnd its 5-hydroxy metabo- United Swts and tr\!t1lmc1H with meJabcncbzok. Clin lltftc1 Oi.'f
lite did nor accumulate in an OMpluic patient on haemodialysis OroctJnculiuis. Tsabcndazolc 1.:? may be used for syn1p1omatic 2001: 33: t-5.
and haemopcrfusion who was treated for severe strongyloidia· 1reatmcnt of dracunculwis (p.142), although it has no direc:ian- 6. T3laie H, tr ol. R.audom1icd 1rinl of~ sin!lt, double and 1riple
sis. 1 However, the potentially toxic conjugated glucuronide ond lhelmintic effect. It is used to facilitate removal oftlie worm from dose or 10 1nglkg or. hum.. n formulation of tr;clabenduolc: in
subcutaneous tissu~. patients with rascioli»i.s. Cliu ~P Ph.t1rm«<1I Ph)'lioll004: ll:
sulfate metabolites did accumubte. The clearance of nll 3 metab- 777-82.
olites w.1S poor by haemodialysis; haemopufusion was much I. Mu.lier R. Guinea wonn dis.east: t~dcmioloay. con1'°', and
ue;umcm. Bull WHO 1979; 57: 683-9. 7. Marcoi LA, 11 ol Natural histor)'. <'linic:omdioloa.ic correlates,
more etrocicn~ although for rapid removal the hacmopcrfiision 2. K21c:- 00. "cl. Controlled compantivc u~I or thiabendatole
and rcspo•1sc 10 tricl.abtndazok iti ac-utc rnnssivc fa.scioliasis. .4.m
columns should be changed every hour. 3nd mdronktazolt- in the rrcatmcnl of dn1con1i:uis. Aim Trop JT,..,p Med Hyg 2008: 78: n?-7.
I. Bauer L. Cl ol. Thie ph:armaco kinctics or thi1bc-ltd•U>lc and its M<dPorot#o/1983: 77: 151-7.
mct.."lbolites an an :mcphric p:itie:n1 unduraoing bm.odialysis •md
Lun& fluke infections. Encoura~ng rcsul15 were reported
hc m nptrfu~ion. J Oin Phamtocol 1982: 22: 27~SO. Strongyloidiasis. Toabendazole may be used in the ll't3hnent of fi'om a pilot study of triclabendazolc in d1e treatment of par.ig-
strongyloidiasis (p.145), but albendazole or ivermcctin arc gen- onimiasis (p.143). Jn an open companttivc study2 in 62 1iorit111s.,
Interactions erally preferred. a more rapid p:irositological l'cspo11se was obtained with tricla·
Reference.<. bcndawle in oral doses of S 111g/kg once daily for 3 days.
Xandlines. For the elf.a of ti.>bendazole on ~m eooccntra- I. Gro,·e 01. Treatment 0(1tton1Yloidiasis with lhiabCnduole. Jn IOmg.Ike, mice on ooe day, or I 0 mglkg .. a >ingle c!Q;e, tl1an
tioos of1heophylli11•. see p.1260. :i.n.alysis or toxicity and :ffccliv~nc:ss. Trau.s R Soc Tf'O/> Mttl HJ"I with praziquantel. Clinical symptoms rewl\'•.'<I al • compor•ble
!9S2: 7~: Jt4- t8. rate in all gro11ps. A later study comp<srcd lhe two one-day regi-
Fharmacokinetics a
2. Ba.rni$h 011rkcr J. An mten"altion study usin& thiGbcndatolc mens in J54 patients.' Af\cr 3 mon1hs, the cure rates (a=ssed by
suspc:nsior\ 11aalns1 slrongyloidcs futUc:bomi 1ikc inf<c1ions in
0
clc:iruncc ofeggs from sputum) were 84.4% in those given a sin-
Tiabendazole is readily absorbed from the gastrointes- Papuo New Quine•. Trant RS« TropMM llyg 19&7: 81: 60--3. &le dose of 10 mg/kg, and 90.9".4 in those given two such doses
tinal tract and peak plasma concentrations occur after I
~~: ~,::~~~~h';~~!:~:=~n~:~:a~:rh~1:.~~~~
3 1
' on the same day. In those who were still infected at 3 months. •
to 2 hours.. It is metabol ised to 5-hydroxythiabendazole Chi• h>fe<t o;, 1993: t6: 1 23~ . second two-dose course resulted in complete parasitologie;1I
and excreted mainly in the urine as glucuronide or sul- 4. Oann PH. t1 al. A randomized trial of singk:- and (\\O·dose ivcl'· clearance al I year.
fate conjugates; about 90% is recovered in the urine lllcctin \'CrSU.S thiabenduolc ror lrtalmtnl or suon:yloidiasis. J I. Ripcrt c. ct al. Thc:npcu1ic; effect oftrid.a.bt'nduok in p;Jticnl5
Infect Dis 1994; 169: t076 9. with par.11'°nimtAsiJ in Cameroon: a pilot study. Tt·o11s fl Snc
within 48 hours of ingestion, but only 5% in the faeces. S. l'itisuui1hwn P, ti ol. A randomized comp.aratiYc saudy o( alben· Trop Mtd 11.•'t 1'192; 66: 417.
Absorption may occur from preparations applied to the daz.ole and 1hi1bmduole in chronic s1rong.ylok11aSJS. Somb«lst 2. Calvopfl\a M. tt t1I Trealmcm of human rulmOMry P"raeonim-
Asian J Tiop Af•d 1'11/Jhc lf<al1h 1995; 26: 73S-8.
skin or eyes. iasi~ whh trida.bcnd~rrolc: dinical 1ulcnmcc and druc efficacy.
6. Sc:haffrl R, tt t1I. TI1i~bt-ndnolc for 1M trct>\rntnl orwongytoi·
d1uis in pa1icnts with htnvtologic m.alig.nandcs. Clln Jn/«1 Dis Tran.1 R Soc Trop Mt'd H,1·g t99S: 92: 566-9.
ORcfcrcnQCS. l . Calvopil\a M. ~t ol. Comparison of two sin&lc..d.t)' regimens of
2000: 31: 821-2.
I, TOC<'o DJ. ti ol. Absorp1ion. mcllbohsm. and uc:rc1ion o( thia· iriclabenduolc (or the trcalmcnt o( hum11l J>ulmoMry p:an.~­
btndnolc: 1n mon and labotatory anim:a1s. Toxkol .<f.ppl Pharma· Synsamosls. Tiabendazole has been used successfullyl.2 to onlmlasls. Tro11s R Soc Trop Mtd l(>'t 2003: 97: 45 I~.
""' 1966: ,, 31-9. tre.it syngamosis (p. 145) when it has OCCWTcd in man.
I. Gttll QAC. <1 al. Syn1aonus in 1 West Indian. BMJ 1978; 2:
Preparations
Uses and Administration 146-4. Proprietary Preparations t\ktails arc gi~n in Vol\1mc 0)
Tiabendazole, a beozimidazole derivative, is an anthel- 2. Leers W·D. et ol. Synaomosis, an unusual case of asthma: the Fr.: Egiten
l'irs-r repor1td ca.se in CAnRd:t. Cnn Med Anoe J 1985~ 132:
mintic with activity against most nematode wonns; ac- 269-70.

11lC $)mbol t denotes a preparation no longer actively marketed

Antibacterials
Dru;: Groups. p.166 Ucherichia coli ~ritis. p.t8t Pregnancy and the neonate. p.202
Asmoglycosides. p. 166 Eye infections. p.181 Prematu"' labou: p202
Antmycobacterials. p.167 Gas pnvene. p. t81 PtoctM. p203
Cephalosporins and re.ted bela lacums. p.167 ~p.18t Proslatitis. p.203
CNoramphe1"CO!s. p.167 Anlbiotic-auoc>ilteCI coWs. p.182 ~p.203
~p.168 umpylobacw ententi!. p.183 Q"-p.203
li>c~p.168 Cholera and other vilrio ~ p.183 ReQpWig ~ p.203
Maaoides. p.168 Esct>erich:a coll enteri1is. p.181 Reipntory-tract infections. p.203
PeOO!i>s. p.168 ~enlenx:olitis. p.t81 Rhel.matic re-e; p.204
Quinolooes, p.169 Safmoncla enlerilis. p. t85 Rickettsial ~ p.204
5'Afonamides and~"'~ p.169 SNgellosis. p.185 Salmonella enteritis. p.204
Tetracyer.~ p.170 Yeninia enterills. p.185 ~iis.p.204
Miscellaneous Antibacterials. p.1 iO Gonormoea. p.186 Septicaemia. p.204
Choke o( Asr.ibacterial. p.170 Gr4111Aoma i°"'inale. p. t 86 Sexually transmitted d;seases. p.205
Abscess. abdominal, p.170 Haemophilus 1nnuenzae infections, p 186 Chancroid. p.205
Abscess. bcoin. p.170 Heticobacter pylori infections. p. t 86 Gononhoea. p.206
Al»::ess. liver. p. 170 lnf~ons in irrvrunocomprom4sed patients. p.186 Grar>Joma inguinale. p.206
Abscess. lun~ p.171 lntensM! care. p.187 Lymphograruloma vei>eteun\ p.207
Actn:lmycosis. p.171 Legionnaires' d'isem. p.t88 5yphilis,p2D7
Anaerobic bacterial intect>OnS. p.17 I Leprosy. p. t 88 Shigellosis, p.208
Antlr.!x. p.171 Leptospiros.s. 189 Sickle<ell disease. p.208
Mtbiotic-mociated colits. p.172 Listcriosis. p. t~ ~p.208
Artmtis. bacterial p. I 72 4me dsease. p.190 9cin i*ctioos. p.208
Batlary~ p.172 L~~p.l'><l Spleen <ison:len. p.109
Ba..'1Ctial ~ p.172 Mdoido5is. p. t90 Spotted~ p.210
Biery-tract~ p.172 ~p.191 s~~p.2to
Bites and sliigs. p. I 72 Menr..,cot'al nfections. p.192 S<rgial infection p.2 t I
Bone and joi'll rlecticn p.17 3 MolAh rlections, p t92 S~is.p.21t
Botul5m. p.174 Mycetoma. p.193 l'eianus. p.21 t
8ron<hitis. p.174 Necrotisi'c enteroco111Js. p.193 T~itis.p.2 1 1
Brucelosis, p.174 Necrotising fascitis. p.t93 To><ic shock S)<\dromc. pl I t
Campylobocter enteritis. p.175 Neonatal conjunctivitis, p.193 Trachoma. p.212
Cat watch disease. p.175 NocordiCYA, p.194 Trench fever. p.212
Cei.Jlitis. p. 175 Nontubcrculous mycobacterial infectiol"llS. p 194 Tuberculosis. p.212
Cervicitis. p. 175 Obstetric dsordeN, p. t95 Tular6emia p.2 14
Chancroid p.175 Osleomyelrtis, p.195 Typhoid and paratyphoid fever. p.2 14
ChlaITT/dial infections, p.175 Otitis extema. p.t95 l'yj>hus. p.215
Cholera and other .,jbno infections. p.176 Otitis media. p.196 . Urethritis. p.215
Cystic ~brosis. p.176 Pancre.nitis. p.197 umar-,..1ract infections. p.2 t5
Diasmoea. in<ecto.e. p. I 77 Pelvic inf.ammatory disease. p. t 97 Catheter-related. p.216
D~p.177 Peptic ulcer disease. p. t98 The~p.216
Ear i>fec1io-ls. p.177 Pemml svep:occxal inlecl>ons. p. t98 Wants """ children. p.216
EMdliosis. p.177 Perit<riti<. p. t 98 Mcn.plt6
Endocarcilis. p.178 Per1wis. p. t99 f>regNncy. p.216
Endamelrilis. p.179 ~p.t99 Womenp.216
Enterococcal illec1io<>s. p.180 PS1ta. p.200 Whipple's dse.ase. p.2 t 5
~p.180 l'lague. p.200 Yaws, p.216
Epiglottitis.p.181 Pniumcnio. p.20 I Yenini.l crneritis. p.2 t6

This chapter includes antimicrobial drugs whose main aminoglycosidic aminocyclitols. The sulfale sails are gen- duction product of streptomycin, is only rarely used be-
use is the treatment and prophylaxis of bacterial infec- erally used. cause of its toxic ity. The neomycin comp lex of
tions. In practice 1he tenn 'antibiotics' is often, and in The aminoglycosidcs have broadly similar toxicological aolibacterials were the next lo be isolated; neomycin itself
some instances erroneously, used to encompass all of features. Ototoxicity is a major limitation to lhcir use; is mainly a mixture of the Band C isomer,;; neomycin Bis
these drugs. ln Martindale the term antibacterial is pre- slTeptomycin and gcotamicin arc generally coosidcred to considered to be identic~I with framycetin. Because of
be more toxic to lhc vestibular branch oflhe eighth cranial their toxicily they are not given syslemically. The related
ferred for the drugs in this chapter. The groups into
nerve and neomycin and kanamycin lo be more toxic IO the compound paromomyci11 (p.931) also has antiprotozoal
which these drugs may be categorised are described and anthelmintic properties and may be used in the treat·
auditory branch. Other adverse effects common to the
below. Antibacterials described elsewhere in Martin- group include ncpltrotoxicity, neuromuscular blockade, mcnt of intestinal amoebiasis, cestode infections, crypt-
dale include metronidazole (p.924), nitazoxanide and allergy, including cross-reactivily. osporidiosis, and leishrnaniasis. Konomyci11 is less toxic
(p.930), and tinidazole (p.937), which, as well as being The phannacokincties of the aminoglycosides arc very than neomycin and can be used systemically. Although it
antiprotozoals, are used in the treatment of anaerobic similar. Little is absorbed from the gastrointestinal tract has been used in penicillin-rcsiswit gonorrhoea, it is not
bacterial infections. but Ibey arc generally well diSllibuled in the body after active 1tgiiinst Pseudomonos oerugtnosa and has generally
pl\Tenteral dosage although penetration into the CSF is been replaced by gentamicin and other newer aminoglyco-
Immunological approaches 10 the treatment and proph- sidcs.
poor. They are excreted unchanged in the urine by glomcr-
ylaxis of bac1cri1tl infections are discussed under Vac- ular filtration. Gentomicin was isolated from Micromonospara pwpurea
cines Immunoglobulins and Antisera, p.2406. The aminoglycosides have a similar antimicrobial spec- in 1963 aod, being active against Ps. ae1uginosa and Ser-
Jn addition, disinfectants and preservatives (p.J 765) trum and appear to act by interfering with bacterial protein rotia marcescens. is widely used in the treatment of life-
are used to kill or inhibil the growth of micro-organ- S)'Tlthesis, possibly by binding irreversibly to the 30S and lhreatening infections. Tobramycin is one of several com-
to some extent the SOS portions of the bacterial ribosome. ponents of the ncbramycin complex of aminoglycosides
isms.
The manner in which they bring about cell dcalh is not ful- produced by Stl'eptomyces tei1ebrarius. It has an antimi-
ly understood. They are rnost active against Gram-ncga- crobial spectrum very similar to that of gcntamicin and is
Drug Groups ti ve rods. Staphylococcus aureus is susceptible to the reported to be more active against Ps. ae1uginoso. Ami-
Although antibacterials are very diverse compounds aminoglycosidcs but otherwise most Gram-positive bacte- /cacin, a semisyntheticderivative ofkanamycin, has a side-
they are often classified and discussed in groups. They ria, and also anaerobic bacteria, arc naturally resistant. chain rendering it less susceptible 10 inactivating enzymes.
may be classified according to their mode of accion or Aminoglycosides show enhanced activity with penicillins It has a spectrum of activily like thal of gentamicin but
spectrum of antimicrobial activity, but generally those againSI some enterococci and streptococci. Baclerial re- Gram-negative bacteria resistant to gcntamicin, tobramy-
with similar chemical structures are grouped together. sistance IO streptomycin may occur by mutation, whereas cin, and kanaroycin are often sensitive. Sisomlcin is close-
with the other aminoglycosides it is usually associated ly related structurally IO genlllmicin. Netllmicin, the N-
with tbc plasmid-mediated production of inactivating en- cthyl derivative of sisomiein, may be octive against some
Aminoglycosides zymes which are capable of phosphorylation, acetylation, gentarnicin-resistant strains of bacteria although not to the
Theuminoglycosidcs arc a closely related group of bacte- or adenylation. The aminoglycosides have a postantibiotic same extent as amikacin. Other aminoglycosides include
ricidal antibacterials derived from bacteria of the order Ac- effect, that is an1ibacterial activity persisting after concen- opramycin, orbekacin, astromicln, bekanamycin,
tinomycetales or, more specifically, the genus Strep/Om)~ trations have dropped below minimum inhibitory concen- dibekacin, elimicin, isepqmicin, and micronomicin.
ces (framycctin, kanamycin, neomycin, paromomycin, trations. Aminoglycosides should in general only be used for the
streptomycin, and tobramycin) and the genusMicromono· Streptomycin was the first aminoglycosidc 10 become trcabnenl of setious infections because of their potential
spora (gentamicin and sisomicin). They are polycationic avai lable commercially and \VdS isolated from a slrdin of toxicity and antimicrobial spectrum. Doses must be care-
compounds that contain an aminocyclitol, usually 2-dc- Strcptomyces griseus in I 944. Its use is now restricted fully regulated 10 maintain plasma concentrations within
oxystrcptamine, or strep1idinc in sll'Cptomycin and related mainly to the treatment of tuberculosis when it is always the therapeutic range but avoid accumulation, especially in
compounds, with cyclic :unino·sugars attached by g)yro- given with other antitube:culous drugs because of the rap- patients with renal impairment. Neomycin and li-amycetin,
sidic linkages. Therefore, they have also been termed id development of resistance. Dihydrostrep1omyci11, a re- which arc considered too toxic to be given parenterally,
All cross·refcrcnces rercr to entries in Volume A 166
 Antibacterials 167
have been given orally to suppress the intestinal flora . The acre111011/11m. The nc1ive nucleus, 7-aminocephalosporanic their broad spectnun of activity. Cq/lobiprole is active
1opi.:al use of neomycin and gent:amicin has been associat- acid, is ve1y closely r~lated lo the penici llin nucleus, 6- against meiicillin-resistanl staphylococci.
ed with allergic reactions and !he emergence of resist:ant aminopenicillan ic acid, and consists of a beta-lact:am ring The semisyntllClic cephamyclns are chemical modifica-
bacteria. Gentamicin or tobt11myci11 are the dnigs ofchoice fused with a 6-membered dihydrothiazine ring and having tions of cephamycin C, a beta-lactam antibacterial pro-
in the treatment of life-threatening infc1:tions due to an acemxymethyl group at position 3. Cephalosporin C duced naturally by Slrep1011~vces spp. They differ from the
aminoglycoside-sensitive organisms and arc often used has a side-chain at position 7 derived from o-o.-amino- cephalosporins by the addition ofa 7-o.-methoxy group to
with other antibacterials. With the continuing emergence adipic acid. Chemical modification of positions 3 and 7 the 7-aminocephalosporanic acid nucleus. Stcric hin-
of resistant strains, amikacin and netilmicin should be re- has resulted in a series of drugs with different characteris- drance by this methoxy group is considered to be respon-
served for severe infections resistant to 2entan1icin and the tics. Substitution al the 7-amino group tends to affect anti- sible for their greater stability to beta l:ictamases. For prac-
other aminoglycosides. - bacterial action whereas at position 3 it may have more of tical purposes they are generally classified witl1 the
Desc:nb<d in this chapter arc an effect on phannacokinetic properties. second-generation cephalosporins, but arc more active
Amikacin, p.216 Gen1an1icirt, p.306 The cephalosporins are bactericidal and, like the penicil- against anaerobic bacteria, especially BacteJYJidesfragilis.
Apramycin.p.223 lscpamicin.1>313 lins, they act by inhibiiing synthesis of the bactctial cell Cefo.tilin was one of the first cephamycins available; ce-
Arbekacin, p.:!23 Konamycin, p.316 wall. The most widely used system of classification of cc- fmetazole and cejo1eton have been intrOduced more re-
Astromicin, p.223 Mieronomkin, p.326
Ockanamycin, p.229 Neomycin, p.33 1 phalosporins is by generations and is ba.~ on the genera I cently. Anoiher is cefininox. All these cephamycins must
Oibekacin, p.288 Nctilmicin, p.333 features of tl1cir antibacterial activity, but may depend lo be given parenierally.
Dihydros1rep1omycin, Sisomici11. p.360 some extent on when they were introduced. Succeeding lmipenem was the first of tl1e cnrbapenern group of anti-
p.289 Strep«>mycin, p.362 generations generally have increasing activity against bacterials to become available; it is the N-fonnimidoyl de-
Etim1cin, p.300 Tob111mycin, p.384 Gram-negative bacteria. Cejalo1i11 was one of tJ1e first cc- rivative of tltienamycin which is produced by Srreptomy·
framycetin, p.303
phalosporins to become available and is representative of · ces cauleyo. It is bactericidal, and, siinilarly to the
the first-generation cephalosporins. It has good activity cephalosporins, acls by inhibiting synthesis of the bacterial
Antim ycobacterials against a wide spectrum ofGram-posi1ivc bacteria inchid- cell wall. le has a vezy broad specn'Um of antimicrobial ac-
The antimycobacterials arc a miscellaneous group Qf anti- ing pcnicillinasc-producing, but not meticillin-resisUJnt. tivity including Gram-positive and Gram-negative aerobic
bacterials whose spectrum of activity includes Mycobocte- staphylococci; enterococci are, however, resistant. Its ac- and anaerobic organisms; it bas good activity against bolh
riu111 spp. and which arc used in the trearrncnt of rubercu- tivity against Gram-negati\IC bacteria is modest. Cefalotin Ps. aen1gi11osa and B. frogilrs . lmipcncm is given
losis, leprosy, and other tnycobacterial infections. They is not absorbed from the gastrointestinal tract and must be parentera11y with cilastatin, a dehydrnpeptidAse I inhibitor
include the rifamycins, also known as ansamycins or rifo- given parcnterally although intramuscular dosage is pain- that inhibilS the renal metabolism of imipenem. Simil:!rly,
mycins, a group of antibacterials isolated from a strain of ful. Cefalotin has generally been replaced by cefozolin or the carbapenem panipenetn is given with the renal protect-
Amycolotopsls medilerronei (Nocardia medite11"011ei; cefi·odine. Cefaloridine is now rarely used because of its ant betamipron. Two other carbapenen1s, erlOpe!1em and
Streptomyces 111edi1e1·ranet). The main antibacterial in this ncphrotoxicity. Cefiadine is absorbed from the gastr0in- meropenem, are relatively st~blc lo renal dehydropepti-
group, rifamplcin, is a mainstay of regimens for the treat- tcstinal tract and can be given both orally and by injection. dase and can be used without such an inhibitor. Enapenem
ment of tuberculosis and leprosy, and is increasingly being Cej11dl'oxil. cefarrizine, and cefale.rln are a II giv~n orally. has a narrower spectnim of activity than othe~ catba)len-
used for other infections. TI1e related drug rifabutin is also All of these drugs have a very similar spectrum of anti mi- cms, including no activity against Ps. ae111gh1asa. Dorip-
used in mycobaeterial disease, especially nontuberculous crobia l activity to cefalotin. Cefaclar is also given orally. It enem is a carbapenem claimed to have particular activity
mycobacterial infections due to Mycabacteriwn aviu111 has similar activity to cefalotin against Gram-positive coc- against Ps. oeruginosa.
complc>t (MAC). Other rifamycins described in this chap- ci. but because of its grealer activity against Gram-nega- 111e monobactams were fir.;L identified as monocyclic
ter include rlfapemine, rifaximi11 which is poorly absorbed tive bacteria, panicularly Haemaphilus injluenzae, it is of- beta laccams isolated from txlcte1ia; they arc now produced
and is mainly used for a local effect ou the gastrointestinal ten classified as a se<:ond-genet11tion drug. Cefprozil is an synthetically. Azlreonam was the first commercially avail-
tract, and rifamyr:in sodium, a rifamycin rarely used as it oral cephalosporin with a longer half-life than cefaclor. able monobactam. It is bactericidai with a similar adion on
has been superseded by more effective drugs. Ctfa11101ido/e was tlie first available second-generation bacterial cell-wall synthesis to the cephalosporiris. Its anti-
Another antimyoobacterial widely used for wbctculosis is ccphalosporin. It has similar or slightly less activity than miaobial activity, however, differs from imipenern and
iso11iozid, a derivative of isonicotiuic acid; it is invariably cefolotin against Gram-positive bacteria, but greater stabil- the newer cephalospoiins in that it is restricted to Gram-
used with other drugs to avoid or delay emergence of re- ity to hydrolysis by beta lactamases prod11ccd by Gram- negative aerobic organistns. It has good activity against
sistance. P)~·azmamide. a nioo!inamide derivative, is also ncsntive bacteria and enhanced activity against many of Ps. oeruginosa. Aztreonarn is given parcnterally. Other
· an imponanl component of regimens for tuberculosis. the Enterobacteriaccae and Hoe111op/1ilus i11jlue11zoe. It is monobactams include ctwumonam.
while e1i10111bu1ol and the aminoglycoside slrep1omyci11 given parentera!ly. Ceji1roxime has a similar spectrum of Carbacephems arc structurally related to the cepha-
are added when resistance to first-line drugs is likely, TI1e activity to ccfamandole although it is even more rcsistan1 losporins. but the sulfur atom of d1c 7-aminocephalospo-
thiosemicarbazone derivative 1hioace1ozo11e is now less to hydrolysis by beta lactamascs. It is gi ven parenterolly ranic acid nucleus is replaced hy a methylene group. Lo-
widely used in tuberculosis because of its toxicity and be- but, cejino.rime a:retil, the acetoxyethyl ester of cefuroxi- mcarbefis an 01'31 earbaccphcm.
cause more effective drugs arc available, but is sometimes me, is given orally. Otht:I' dnigs classified as second-gen-
used in developing countries. Otll<:r drngs that have been eration cephalospooins and given pare111e111lly include ce- ~ribed ill d1ls cl~ph!r are
Aztrcono.m, p.226 C~IOtiam, p.149
used to treat ruberculosis including aminosolicylic acid fomcid, ceforunide, and cefotiam; these all have spectra of Be~mipron, r.234 ('cfovetin, p.249
and its salts, capreomyc/11, cycloserine, e1hio11amide, pro- activity similar to cefamandole. Cephamycins (see below) Biapeil<ln. p.234 Cefoxitin, 1':?49
1io11amide, and kanom)'Cin arc regarded as secondary are also classified with second-generation ccphalosporins. C•rumonam. p.23S CefOl1lprall. p.250
drugs and are reserved for patients in whom resistance or Ccf.>clor. p.236 Cefpirdlnidc. p.251
The third-generation cephalosporins, sometimes referred Cefodro.,il. p.236 Cefpiroom. p.251
toxicity to first-line drugs is a problem. to as extended-spectrum cephalosporins, are even more Ccfpocloxime. p.251
Cefalcxin, p.237
The sulfones have been used since the 1940s in the treat- stable to hydroly.c;is by bela lactamases than ccfamandole Ccfaloniuin. p.238 Cefprozil p.252
ment ofJcprosy, but the only one widely used now is dop- and ccfuroxime. Compared with tlie earlier generations of Cefalotin, p.238 C'cfquinome, p.252
sone. an lmponant component of mullidrug regimens. Its ccphalosporins tliey have a wider spectnim and greater po- Ctfamandole, p.239 CelDdine.1>253
action is thought to involve inhibition of folate metabo- tency ofactivity against Gram-negative organisms, includ- Ccfilpirin, p.240 Cefsulodin, p.253
Ccfatrizine, p.240 Ccft:izidi111t, p.254
lism, similarly to the sulfonamides, and dapsone is also ing most clinically important Enlerobacteriaceae. Their Cefazolioi p.241 CeAeraon. p.255
used for the prophylaxis of malaria and for prophylaxis activity against Gram-positive organisms is said to be less C<lbopcrazonc, p.242 Ceftt7.ole, p.255
and trcaf111ent of pneumocy~tis pneumonia. Also impor- than that of the first-generation drugs, but they arc very Ccfcap<nc, p.242 CeAibuten, t~256
13111 in the lreallncnt of leprosy is the phenazine dye c/ojoz- active ag:iinst streptococci. Cefataxime was the first of this Ccfdinir. 1>.242 Ceftiofu<. p.256
imlne. Additionally, it has a role in tlie treatment of type 2 group to become available and it has relatively modest ac- Ccfdi1orci1, p.242 Cef\i1.oxime, p.256
Cefepime. p.243 Cefiobi11role, p.257
lcpra reactions and has been used in 01her mycobacterial tivity against Pseudomonav aeruginosa. Cefimmoxi111e, ce- Ctfcl3mct, p.244 Ceft.ri3.'<one. p.25/
infections. The thioamidcs ethionamide andprotionomide fadizime, c~fiizoxime, and cejlriaxone are all very similar Ccfixime. p.244 Cef\iroxime. p.259
hav( been used in the treatment of leprosy and tuberculo- 10 cefota.'time in their antimicrobial activity. TI1csc dmgs Cefinent,.ime, p.244 Ci la<-l~ tin. p.'164
sis, but hove generally been replaced by less toxic drugs, are all given parenterally and differ mainly in lhdr phar- Cefmeuzol<. p.24S Doripenem. p.2S9
for example clarithromycin. ojloxocin, minocydin~. or pe· m3cokinetic characteristics. Cefrxime is n third-generation Ccfminox. p.245 Er1llpcnem. p.292
Ccfodizimc, p.245 f aropc:nnn, r.300
floxocln, in alternative antilepro1ic regimens. cephalosporin given oral!)~ others includece/dinil', cefeto- Flomo.xcf, p.300
Ccfonicid. p.246
O<scribed. on this ch:IJl(cr or< meJ pivoxil. cefpodo.time proxe11/, DJld cefiib111en. Cefiazi- Cefope=one. p.246 lmipenem, p.31 I
.'<mmosahcyhc Acid. Me:lwliazide. r.l24 dime is typical ofa group of parcntCl'llf third-generation ce- C<for.111iclc. p.247 L.atamoxcf. p.317
p.218 Morin:unidc, p.328 ph a losporins with enhanced activity against Ps. Cefooelis, p.247 t.oracarbef. p.m
Caprcoon)«in. p.234 Protionamidc, p.3'48 aer11ginasa. Cefoperozone is similar in its activity to Cef0taxione. p.20 Meropcnem, p.323
C'lofWminc. p.276 Pyrazinamide, p.348 ceftazidime. Cefpiramide is structurally related to cefoper- Cefo1otan, p.249 Ponipencm. p.340
C'ycloserine. p.283 Rifobutin. p.351
Dapsone, p.284 Rifampicin. p.354 azone and has comparable activity. Although cefsulodin is
E1hambu1ol, p.298 Rifamycin, p.358 classified as a third-generation ccphalosporin it~ activity Chloramphenicols
1:.1hionamide.1>.29\I Rifopen1ine, p.JSS against Gram-negative bacte1ia is confined to Ps. oerugi- 01/oramphenirol is on antibacterial which was fu-st isolat-
F1ivazide. p.303 Rifaximin, p.358 nosa. Latamoxef is an oxace.phalospor in which difters ed from cultures ofSireplOn(~'Cf!S ve11ezuelae in 1947 but is
lsoniozid, p.313 Thioacel320nc. p.381 from ihe true cephalosporins in that the sulfur atom of the now produced synthetically. It has a relatively simple
7-aminocephalospornnic acid nucleus is replaced by an strucrure and is a derivative of dichloroacetic acid wilh a
Cephalosporins and related beta lactams oxygen atom. It differs from ccfotaxime mainly in its en- nitrobcnz.cnc moiety. Chloramphenicol was the first
1l1c cephalosporins or ccphem antibacterials are semisyn- hanced activity against /Jacte1vides fi·agilis. broad-Spectrum antibacterial to be di.srovered; it act~ hy
thctic antibacterials derived from cepbalosporin C, a natu- The newer cephalosporins cefepime and cefpirome are interfering with bacterial protein synthesis and is mainly
ral antibacterial produced by the mould Cepha/osporium generally consi<kro:I to be fourth-generation because of bacteriostatic. Its ronge of octi\'ity is similar to that oftct-
168 Antibacterials
racycline and includes Gram-positive and Gram-nega1ive Lincosamides cin have activity against protozoa including Toxoplasmo
bac1eria, Rickettsia spp., and Chlarnydiaceae. The sensi- Lincomycin is an antibacteria l produced by a strain of gondii.
1ivities of Salmonella ryphi. Haemaphi/us injluenzoe, and Srreptomyces li11cal11ensls and was fin.'! described in I %2; Flurithl'Omycin is anolhcr newer macrolide in use.
Bocf6J'Oidas fi"ogilis to chloramphenicol have diclated the clindamycin is the 7-chloro-7-dcoxy derivative of linco· Other macrolides include spiramycin, which has been
principal indicalions for its use. mycin. used extensively in Europe and has also been used in the
Shortly afier its introduc1ion chloramphenicol was found Although not related structurally lo crythromycin and the treatment and prophylaxis of toxoplasmosis. It may be
to have a serious and sometimes falal depressant effect on other macrolide antibacterials, the lincosamides have sim- useful in the treatment of cryptosporidiosis. ·
the bone marrow. The 'grey syndrome', another potential- ilar antimicrobial ac1ivity and act at the same site on the 0/eondomycin has been used orally and parenlerally as the
ly faial a"dverse effect, was reported later in neonates. As a bacterial ribowme to suppress protein synthesis. phosphate. Its ester, troleandomycin, is better absorbed
result of this toxicity the systemic use of chlorampbenicol The lincosamides arc bactcriosiatic or bactericidal, de- from the gastroin1cstinal tract but, like erythromycin es-
has been restric1od in many countries; ii should only be pending on the concentration, and are active mainly tolate, has proved hepatotoxic and more effective antibac-
given when there is no suiiable al1emative and never for against Gram-positive bac1cria, and against Bocteroides terials arc generally preferred. Josomycin. kitasamycin,
minor infections. spp. They also appear to have some anliprotozoal activity. midecamycin, and rokitomyci11 have been used in Europe
Chloramphcnicol is active when given orally and, unlike Clindamycin and lincomycin have qualitotively simi lar ac- and/or Japan. Meleumycin has been used in China.
most other an1ibac1erials, it diffuses into the CSF even tivity but clindamycin is more active than lincomycin in 1ilmicosin, tulothromycin, and rylosin are used in veteri-
when the meninges arc not inflamed. nie majority of a vitro. Cms.~-resistance occurs between the lincosamides, nary practice.
dose is inactivated in the liver, only a small proportion ap- maaolides, and strcpt.ogramins. The streptogramin group of antibacterials are also de-
pearing unchanged in the wine. The lincosamides have been used, l!Jce erythromycin, as an rived from Streptomyces spp. and include pristinamycin
Chloramphcnicol is widely used for typhoid fever, al- alternative to penicillin, but reports of severe and some- and virginlomycin. They consist of two components that
though resistance is a problem in some countries. For Hae- times fatal pseudomembranous colitis with lincomycin act synergistically and arc therefore also known as syner-
mophilus injlue11:r.ae infections, cspcc.ially meningitis, the and clindamycin have led to the recommendation that they gislins. One of the components is structurally related lo the
emergence of ampicillin-resistan1 strains led to a reap- should only be used when there is no suitable alternative. macrolides, and they ba\'C a similar spectrum ofantimicro-
praisal of the use ofchlorurnphenicol, and suggestions that Botli lincornycin and clindamycin can be given orally Md bial activity to ciythromycin. Semisynthetic derivatives
ampiciUin and chloramphenicol should both be given em- parenterally, bu1 clindamycin is much better absori>ed such as q11inupristin/da/fopris1in may be useful in the
pirically 10 patients with meningitis un1il the sensitivity of froro the gastrointestinal tracl and less affec1ed by !he pres- treatmenl of infections with multidrug-resistan1 organisms
1he infecting org;inisms was known, but the newer third- ence of food in the stomach. They both penetrate well into including mcticillin-resistant Staphylococcus aureus and
gerieration cephalosporins are increasingly preferred be- bone and have been used successfully in osteomyelitis. vancomycin-resistant eoterococci.
cause of resistance. For proven H. injluenzae meningitis, They have also been used topically in the treatment ofacne Cross-resistmce often occurs between the macrolides, lin-
chloramphenicol is used as an alternative to the third-gen- vulgaris. cosamides, and streptogramins. The ketolide antibac1cri-
era1ion cephalosporins, which are now regarded as 1rea1- The main indication for tlie use oflincosamides is now in als 1eli1hromycin and cethromycin are semisyuthetic deri v-
ment of choice. Chloramphcnicol is also effective against the treatment of severe anaerobic infections, although met· atives of crytbromycin A !hat have been developed to
many anaerobic bacteria and may be valuable in such con- ronidazole (p.926) or some beta laciams may be a more ov.crcome macrolide resistan\'e in respiratory-tract patho·
ditions as cerebral abscess where anaerobes such as suiiable choice in such infections. Clindamycin also has a gens.
Bacte1'0idas fi·agilis arc ofien involved, although metroni- role in the prophylaxis ofendocarditis in penicillin-allergic Described in !his chapter arc
daz.ole may be preferred. patients and has been used, usually with other antiprotoz.o· Authromycin, p.224 Quinupristin/Dalfopristin.
Cbloramphenicol sodium succinale is used parenterally als, in babesiosis, chloroquine-resistant malaria, toxoplas· Cclhromycin, p.260 p.350
Cl>rilhromycin, p.270 Rokitamycin, p.3S9
and the palmiiate is given orally. Ophthalmic and other mosis, and pneumocystis pneumonia. Diri1hromycin, p.289 Roxithromycin, p.3S9
topical preparations ofchlorarnphcnicol are used widely in Described in this chapter are El)'lhromyein, p.293 Spiramycin, p.362
some countrie1i. Clindamycin, p.272 Pirlimycin, p.344 Fluri~iromycin, p.302 Telilhromycin, p.37S
Lincomycin, p.3 I8 Josamycin, p.316 Tilmicosin, p.384
Thiamphenicol is a sernisynthetic derivative of chloram- Troleandomycin, p.387
Kiwamycin, p.317
phcnirol in which the nitrO group on the benzene ring has Mcleumycin, p.323 Tulalhromycin, p.387
been replaced by a methylsulfonyl group, resul1ing, in gen- Macrolides Midecamycin, p.326 Tylosin, p.388
eral, in a loss of activity in vitro. It has been claimed that The macrolides are a large group of antibacterials mainly Olcandomycin, p.338 Virginiamycin, p.39 I
tbiamphenicol is less toxic than chloramphenicol and there l'ri$tin&mycin, p.347
derived from St1·eptomyces spp. and having a common
have been fewer reports of aplastic anaemia but reversible macrocyclic Jac1one ring to which one or more sugars are
bone-marrow depression may occur more frequently. ii is attached. They are all weak bases and only slightly soluble Penicillins
also less likely to cause the 'grey syndrome'. Unlike cblo- in water. Their properties are very similar and in general Penicillin was the first antibacterial lo be used therapcuti·
ramphenicol, thiamphenicol is nOI metabolised in the liver they have low 1oxicity and a similar spectrum of antimi- cally and was originally obtained, as a mixture of penicil·
to any extent and is excreted largely unchanged in the crobial activity with cross-resistance between individual !ins known as F, G, X, and K. from the mould Penicillium
urine. It has been used similarly to chloramphenicol in mem~ oftl1c group. Tiie macrolidcs are bacteriostatic or 11()/arum. Better yields wuc achieved using P. chrysoge-
some countries. bactericidal, depending on the concentration and the type m1m and benzylpcnicillin (penicillin G) was selectively
Azidamfenicol is another analogue of chloramphenicol of micro-organism, and are thought to in1erfere with bac- produced by adding the precursor pbenylacelic acid to the
!bat has been used topically in the trcatment of eye infec- terial protein synthesis. Their antimicrobial spectrum is fcrmcntalion medium. The term 'Jlctlicillin' is now used
tions. similar to that ofbenzylpenicillin but they arc also active generically for the entire group of natural and semisynd!et-
0<$<ribcd in lhis chapeer .,. against such organisms as Legianella pneumoplrila, Myc- ic penicillins. Penicillins are still widely used; they arc
Azidamfenicol, p.224 florfC<licol, p.300 oplasma pneumo11iae, and some rickettsias, chlamydias, generally well tolerated, apart from hype1SC11silivity reac-
Chloramphcnicol, p.260 Thia"'l'h<nicol p.380 and chlamydophilas. Macrolides and related drug.1> have a tions, and are usually bactericidal by virtue of their inhibi-
posiantibiotic effect: lha1 is, antibacterial activity persists 1ory action on the synthesis of the bacterial cell wall.
after cooccntrations have dropped below the minimum in- Penicillins all have the same ring structure and are mono-
Glycopeptides hibitory concentration. basic acids that readily form salts and esters; 6-aminopen-
Vancomycin has a glycopeptide structure; it acts by inter-
E1y1hromyci11 was discovered in 1952 and is die macrolide icillanic acid, die penicillin nucleus, consists of a fused thi-
fering with bacterial cell wall synthesis and is very active
used mosl widely. h is destroyed by gastric acid and must azolidine ring and a bcta-lactam ring with an amino group
agains1 Gram-positive cocci. Jnll'avenous vancomycin is
therefore be given as en1eric-coated fonnulations or as one at the 6-position.
reserved for 1he trC3nnent of severe staphylococcal infcc-
of its more stable salts or esters such as the stcaratc or ethyl Thccatlieror so-called 'natural' penicill ins weceproduced
1ions and for the treannent and prophylaxis of endocarditis
suceinate. Hepalotoxicity has been reported afier tlte use by adding different side-chain precursors to fermentations
when olber antibacterials caMot be used, either because of
patient sensi1ivity or bacterial resisiance. It is the treatment of e.ythromycin, most corrunonly as the estolate. Erythro- of the Penicilli11m mould; benoylpenicil/in, with a phcny-
mycin lactohionate or g}uceplale may be given intrave- lacclamido side-chain at the 6-position, and phenaxymeth-
of choice for infections caused by mcticillin-resisiant Sia·
nously. Cardiac arrhythmias have been reported occasion- ylpenicillin (penicillin V), with a phenoxyacetamido sidc-
phylococci. Vancomycin hydrochloride is poorly absorbed
when laken orally; it is used in the treatment of pseu- ally ufier intravenous use. Erythromycin is used as an chai11, were 2 of the first and are still widely used. Ben-
domembranous colitis. Teicoplanin is a glycopeptide with altcmalive to penicillin in many infections, especially in zylpenicillin can be considered the parent compound of
similar properties to vancomycin, but a longer duration of patients who are allergic to penicillin. It has similar uses lo 1he penicillins and is active mainly against Gram-positive
action. It can be given iniramuscularly as well as intrave- tetracycline in tl1e treatment ofinfections due to Mycoplos- bacteria and Neisseria spp. It is inactivated by penicilli-
nously. Telavancin also has similar properties to vancomy- mo pneumoniae and Chlamydia n·acl1omatis, and in acne nase-producing bacteria and because of its instability in
cin and is given intravenously for complicated skin and vulgaris. lt is also used in tl1e treatment of infections gastric acid it is usually injected. Long-acting preparations
skin Slructure infections. Ramoplanfn is under investiga- caused by Legionel/a pneumophila. . include p1'0col11e benzylpe11ic:illin and benzalhine ben-
tion, especially for the treatment of Closll'ldium difficile- More recently developed macrolides include azirhromy- zylpenici/1111, which slowly release benzylpenicillin aftec
associated diarrhoea. Jt has also been investigated for the cin, clarithromycin, dirithromycin, and roxithromycin. injection. Phcnoxymethylpenicillin is acid-stable and is
prevention of infection due to vancomycin-rcsistanl ento- These drugs all appear to have similar propenies 10 eryth- therefore &ivcn oraUy but i1 is also inactivated by pcnicilli-
rococci. Also under investigation are tlalba11c111cin and ori- romycin although d1c:y may differ in their pharmacokinet- nase. It is gczicrally used foe relati~-ely mild infections.
tava.11c.in. ics. Cl~rithromycin and, to a lesser extent. ai.ithromycin When no sidc-dlain precursor is added to lhe fermentation
arc more aclive tl1an erythromycin against opportunistic medium, 6-aminopenicillan ic acid itself is obtained. A
Descn"bed in this~ are mycobacteria such as Mycabacterium avium complex. range of penicillins has been synthesised from 6-ami-
A"°"""'in,p.223 R.amoptanm. p.3SI
Oalba...ncin, p.2&3 Tcicq>bnin, p.373 Clarithromycin is also used in the treatmenl ofleprosy and nopenicillanic acid by substitution at the 6-amino position
N""'2nComycin, p.337 Tclavancin. p.374 in regimens for the eradication of Helicobacter pylori in in an effort to improve on the instability of benzylpenicil-
Oritivancin. p.338 V..nc:an)'cin, p.389 peptic ulca- disease. Both azithromycin and cla.rithromy- lin to gastric acid and penicillinases, 10 widen its antimi-
All cross-refetences refer to entries in Volume A
 Antibacterials J 69
~robial spectrum, •nd to tcduu its rapid me of renal and pipemidic and puomidic acids, pyndo-pynm1dme de- use in the treatment of urinary-traet infections. The so!u-
e.'<cretion. Phcnoxypenicillins with 111 o.-phenoxypropion- rivatives, are 6,8-diaza..4.<juinoloncs. btlity in urine of earlier short-acting sulfonamides. such as
amido (phc11et1cillit1) Of <1-phenoxybutyramido (propicil- Nalidixic acid is ac:ti\-e against Gram.ncg11uve baclma but Ju(fup.i•rrdmr, and their aceryl metaboliles i.s low and
lm) side-dlain are more stable 111 ec1d than benzylpcnicil- has little activity against PSl!Udomonos ond Gram-positive hence crystolluria has been reponed frequently. Of the
lin but offer no advantage over phcnoxymethylpenicillin. organisms. Because bacltricidal conccnl11ltions can only short-acting sulfonamides most commonly used, s:ulfodi-
Mr11ctllm has a 2,6-<limethoxybcn.wnido group at the be achieved in urine its use has generally been lim11ed to o:itre also has low solubility in urine whereas sulfod1m1·
6-110Siuon and was the fim penialhn fouod to be resistant the treatment of urinaty·ll'ICI infections. dmt! and StJ/fafara;ole lllCI their acctyl conjugatesare'ay
10 dcS1J'Udion b) staphylococcal pemcillinase.. However, it Modification of the structure of nalidixic acid has pro- soluble. Three short-actmg sulfonamides (biple sulfona-
is not acid-resistant and has to be injected. The isoxazolyl duced related antibactertals such as axolmic acid, mides) have been given together to reduce the risk ofcrys,.
penicillins. c/0¥DCJ/lm. d'teloxocillin, j/uclaxoc1Uui, and cinc=cin, and rosoxoci11. Although some of these have a talluria, as the oonstituent sulfonamides can co-exist in so-
txrocillin, are resistant to penicillinase and gastric acid. ~ct acrivity rn vitro against Gram-ncalti\'e oq:;inisms
lution in unne without affecting each ocher's solubility.
They have very similar chemical structures and differ and activity against some Gram-positive orpnisms, none Preparauons of mixed sulfonamides have, however, gen-
mainly .in their absorption characteristics. Nafcillm is a has been considenxl to represent a significant chnical ad- erally been replaced by the more soluble sulfonamides.
similar penicillina~resistant antibectcr1al but is irregular- The medium-acting sulfonamides such as sulfametho.w-
vance over nalidixic acid; rosoxacin is only used in the
ly absorbed when la.ken Ofllly. trea011ent of gonorrhoea. Addition of a piperazinyl radical zoll!, the lon~ting sulfonamides such as sulfodimt!thox·
Ampicillin has a D(-)~-ammophenylacetamido side- inc, s11/fametho:rypyrida;illt!, and sulfometoxydionnc. and
at position 7, as inpipemidicocid, appcars to confer some
chain and a broader spectrum of activity than benzylpeni· activity against Pseudomonos. Fl11meq11ine was the first the ultra-long-acting sulfonamides such as sulfotlonne
cillin; although aenmlly less active against Gram-positive fluorinated 4-quinolone to be synthesised, but has no pip- and sulfame:topyrazlne do oot attain such high conoentra-
bacteria, some Gram-negative organisms including Es- ttODS m the urine and rarely cause crystalluria. Sulfona-
erazinyl group. Addition of the 7-pipcnzinyl group and a
cherichia coli, Hocmophilus inj/11enz~. and Salmonella mides that are slowly excreted from the body do appear,
fluorine atom at position 6 has produced a group of fluori-
spp. arc sensitive although resistance is being rcpo~ in· however, to have been more commonly implicated in the'
nated piperazinyl quinolones or nuoroqulnolones with a development of reactions such as the Stevens-Johnson
creasingly. P.w:udomonos spp. arc not sensitive. Ampicil· broader spectrum of activity than nalidixic acid and phar-
lin is acid-sl!lble ftnd can be given omlly but is destroyed syndrome.
macokinetic properties more suitable for the treatment of
by penieillinase. Prodrugs such as bocampicillin and pi- systemic infections. They include c/pmj/oxocin, e:no:rocm, The sulfonamides are usually bacteriostatic, and interfere
vomplcl/lln are also said to be better absorbed and are hy- j/eroxoci11, gatij/o:rocin, gemlj/oxacln, levoj/oxaci11, /om.- with folic acid synthesis of susceptible o~nisms; their
drolysed to ampicillin In .,fvo. Amoxicillln, with a o(-)-o.- jlaxacin, moxijlaxacm, nadljlo.•acl11, norjloxacln, broad spectrum of antimicrobial activity has. however,
aminohydroxyphenylRCctamido side-chain, only differs ojloux:in, pozuj/oxocit1, pcjlo.tocin, ruj/oxocl11, and spa,... been limited bythedevelopmentofresistance. TI1eclinical
from ampicillin by the addition of a hydroJtyl group, but is jloxodn. Besif/oxoci11 is used topically. Several fluoroqui- u.~ ofsulfonamides has therefore been greatly reduced; in
bener absod>ed from the gasttointestiml tract. noloncs have been witl1drawn because of t0xicity includ- general they arc indicated only in the treaunent ofurinary-
Carbenlcrllln, w11h an o.~rboxyphenyla<leumido side- ing: a/a1rojloxacln, clinaflaxacfn, grrpajloxacin, tnlct infections and a few other disorders such as nocardi-
chain, has marked activity against Pseudomotros oerugi- temajloxacin, and n-ovajloxocin. Donoj/oxacm, enro· osis. Sulfonamides such as sulfaguonidine, succinyls11l-
11osa and some Proteus spp. but otherwise is genaally less .floxocin, ibojloxocin, marbof/oxacln, orbiflo.racin, and fa1hio-.olr, phihalysulfacetamide, and phrhalylsulfothia-
active than ampicillin. It has to be gh'Cn by injection and sorojloxocin are used in veteiinary prac1ioe. Development zole are poorly absori>ed from die s-strointesrinal tract and
laise doses are required. Carlndoc1llm is the indanyl es1er of dijlaxocin for human use W3S suspended because of the have been used for the treatment of gasirointestinal infec-
of Clrbenicillin and is hydrolysed to carbenicillin in "'"" high incidence of adw:rse effec:ts, but it is used 1n "eleli· tions although they arc now rarely indicated. Su/fodiazine
\\Jten taken Ofally. Sulbt:mc1/hn has tn a•phenylsulfo- l12J)' practice. s1/v~r. sulfathia-dJit! silver. and mofenide are applied topi·
aoetamido side-chain end trcomllm an o.-carboxythten)'I· cally for their anobedcrial action in patients "1th bums.
The fluoroquinolones are very active against aerobic Sulfasoloime (p. I 92g), a conjugate of 5-aminosalicylic
acetamido side-chain and both have similar activity to Gram-negative bacilli :ind cocci including the Enterobac-
cari>enicillin, uc:arcillin is more active against Ps orrugi- acid (mesalaiine) and s.ulfapyridine, is used in the llCal-
teriaceae, l/ae111ophi/11s inf/llt!llZ«, Momulla ~a1annalts menl of inflammatory bcM'el diseases and in rheuma!oid
noso. The weidopenicillinsa:/oei//i11 and malocillin, and (Bronhome/ID cotarr/10/is), and Nt!lssrrla gonnn-hMOe
the cl0$Cly related drug pi~rocillin are more .ctive than anhntis.
and are also active against Pse11domanos «ruginosa.
carbenicilhn against Ps. acniglnosa and have a wider They are generally less active apinst Grarn-posuive org- Trunethopnm is a diaminopyrimid1ne lhll also inhibits fol-
range of aaivity against Gram-negative bacteria. anisms such as Slaphylococci and much less active apinst ic acid synthesis but at a dilfemn stage in the metabolic
Tvnoc11/i11, a 6-o.-methoxy derivative of ticarcillin, is re. streptococci such as S/rq)tococcu.r pneumonzat!, althou&h pathway to thal inhibited by the sulfon:mtides. Jt has a sim-
s™4!11 to many beta lactamascs and b active against must some 6uoroquinolones now de-.'Cloped have increased ac- ilar spectrum of antunicrobial activity to sulfonamides and
Gram-~ive aerobic baclma, but not Ps. aer11gmosa. tivity against these organisms. They also ha\'C actl\llty often shows synergy m wtro with these drugs. Trimetho-
Mwlli11am is a pcnici111J1ic ac:id derivative with a subsri- against mycobacteria, m)'coplasmas, and ricketts11s. prim was initially available only in combination with sul-
lut::cl amidino ~oup 111 the 6-position. Unlike the 6-arni- Some, for example oOoxacin, have useful activity apinst fonamides, most commonly ...;th sulfamethoxazole as co-
nopenicillanic acid derivatives it is ICIJve mainly against Chlamyclia trochomolis. Activity as-inst anaerobic bacte- tnmoxazole. It is now used alone particularly in the treat·
Gram·nepuve bacteria, although Ps. atrugilrosa, and ria is generally poor. There is concern that the emergence mcnt of infections of the urinary and respiratory tracts. An-
Bacteroldt.• spp. arc considered 1esistant. Mecillinam it· of resistant strains of org;misms may ltmit the usefulness alogues of lrimcdioprim include boqui/aprim, brodimo-
..elfis not active orally; it is aiven as pfrmectllinom, which 'ttf fluoroquinolooes. pnm, 1claprm1, annctoprim, and letraxoprim.
is hydrol)'Sed to mecillinam on absorption. One disadvantagt of the quinolonc antibacttrials is thor Co-rrm1axa:ale generally replaced use of sulfonamides
The beta-lactamasc inhibit()($ clav11kmic acid, sulboclom, they are generally not recommended for use in children, alone in the treatment of systemic infections, although its
and 1owlx1G·tu111 me used to extend the antimicrobial range adolescents, and pregnant or breast-fccdin11 women be- use has also been restricted in some countries and lrinierh-
of certain bcta-lact11111 ant1bacterials. cause of their propensity to cause joint erosions in imma· oprim may be preferred. Co·trimoxazole is however indi-
ture animals. cated for pneumocystis pneumonia and nocardiosis and
Dc>cnhtd in 1h1' chnpm nrc
Amo.,icilhl\ p.219 Meciltlwn. p.323
may Ix: useful in protozoa! infections such as toxopla~1no­
Docnbed on this choptcr 11e sis. Other sulfonamides which have been combined with
Am~1Uin. p.22 1 Mcticlllil\ p.32$ lblofloxoein, p.229 MOK1fl0KKIO, p.32$
Aspoio~illln, p.223 Mctloc1tlin. p.)26 Ba1floxacin. p.234 Nod1no..c1n. p.330
trimethopri m include sulfadiazinc (as co-/rimazine), sul-
A1.idoclllin, i>ll4 Nafcilll1\ p.330 Cinoxxin, p.264 Naloclvcte Ac>CI. p.JJO fomethoxypyridazine, sulfametopyruine, sulfametrole,
Az.locillin. p.n6 Oxocillio\ p.339 C1pn>lloucin. p.265 Norllol<lcin. p.336 and sulfamoxole (see c1>-1rifamolt!). Sulfadiazine has been
Bacampicollin. p.22ll Pcncthanute, p.341 l)anofloxacip, p..283 onoocin. p.ll7 u~ with tetroxoprim (sec co-ft!lmXozine:).
Benctlumine Penic1Qm, Phcnctieitlin. p.341 DiOoxocin, p.28& Oib1floxac:in, p.338
p230 Pt..noxy1ncthylpcruo1ll1n. Eno.ucin. p.292 Oxolinic Acid, p.339 Sulfonamides h~ve also been used ";th pyrim~thamine
Renzalhinc Bcneylptll<Cllll'I, p.341 Enrofloxacin. p.l92 Pm1floxac1n. p.340 (p.664) in the treatment or prophylaxis of some protowal
p.230 Pipmc1Uin. pJ42 Fleroxacin, p.lOO Pefloxocin, p.340 infections. Common combinations aresulfadoxine and PY·
lleiu;Miline Ph<1>0Xymcih)'t~ PMmpicitlin, p.344 Flumequi,.,, p.301 Pipcmichc Acid, p.342 rimethamme for m3laria, and sulfadiazine and pyrimc1h-
natl"" p.23t PMnoc.IJin&m, pJ4S ~n.p.30S Poromidic Acid. p.344 1m1ne for the treatment oftox.oplasmosis.
Dml)-lptnteolto\ p.231 P1VIUlboclan>, p.363 O...llo.ucin, pJOS Pru11no..c11~ p.348
C'wtlcnoalhe, p.?;S " ' - Bauylp<nic:illin. Gem1floxacin. p.306 ~p.3S9 Oncnbcd m this chapter . .
Cwvldlat1.., p.?lS p.l-47 lbofloucUI. p.311 Rufloxac,n, p.360 Baqu1lopn1n. p.229 Sulfadimdlo.,;,,., p.J66
Ccllcill-. p.264 ProplCJtlnl, p.347 LCYOlloucin, p.3 t 7 S>nlloxaan. p.360 Btodimopriln. p.lJ.4 Sult.dimidinA:. p.367
c.lawlanoc AC'ld. p.ln Slllblcuim, p.J6l ~p.321 ~p.361 c~.p2so Sut:'adoioino. p.367
Ckmi1olc P<nociOin, SutbcniclUin. p.J64 Martiolloxxin. p.323 Tosunc.c..cu.. p.l&S CcMnfaonolc, p.280 SulS.finmk, p.367
p.272 Sultamtetlhn. p.373 C~p.:?80 Sul~idint. p.3GB
ClomdOCiltm. p.27' TlllOlleaam. p.373 F'<xn_.tfllhmolt. p.3o:? Sul&m.azint, pJ68
Cloxacdltn, p.27' Tcmoctlltn. p.li6 Sulfonamides and dlaminopyr imidines lcllpm1.pJll Sul~.p.361
Oiclo.ucillin, p 218 TICll'Cithn. pJ81 The sulfonamides are analogues ofp-ammobenzoic acid. Mofen>dt, p.)22 Sulf~p.369
Fluclouctlhn. p 300 Ormetoprim.1'.338 Sulfat~id:mnr
The fUSI sulfonamide of clinical importance was f'rot>.
Phtllalylsulfacaamidt, p.371
IOSil, an azo dye !hat is metabolised In 1•tvo to su/fonllo- p.342 Sulfamelh) llhiaznl<,
Quinolones mide. It was synthesised in Germany in 1932. Many sul- Phcllolyl•uttllh1oz.olc, p.371
The qu1nolonecarbo.xylic acids. carboxyquinolones, or 4- fonamides have since been synthesised; they differ only p.342 Suliameropyrazine, p.371
quinolones are a group of synthetic anllbacterials structur- slightly in their antimicrobial activity, but vary in their Succinylsutf:olhiUJOlc, Sulf.-trote, p.371
nlly related to nalidixic acid . 11ic tcnn 4-quinolone has pharmacokinetic propenies. The sulfonamides have been p.J6l Sulf.OlmonomClhoxinc, p.371
been used as a generic name for the common 4-0xo-1,4- classified according to their rate of excretioo as short-, me- Sulfabcnumidc, p.364 Sulfamoxo4e, p.37 t
Sulfacatblm1~. p.304 Sulfonilimidt, pJ 7 r
dihydroquinoline skeleton. Undc1· this system nalidixic ac- dium- or intennediate-, long-, and ultra-long-acting. The Sulflt~ide. p.364 Sulf;p)'ridme. p.372
id, a naphthyridcne derivative, is an 8-aza-4-qumolone, short-act ing sulfonamides are excrered in the urine in Sulrachlorpyndaiin•. Sulraqu1nonhrie. p.372
cinoxacin, n cinnoline derivative, is a 2·aia-4-quinolone, high concenlJ'lltions and have therefore been of panicular n.364 Sulfalhiuolc. p.372
170 Antibacterials
Sulfacluysoidin•, p.365 Sulfothiazole Silver, treatment and prophylaxis of malaria; it is also used in the F~nginc, p.303 Terizidone, p.376
Sulfaclozine, p.365 p.372 management of antl1rax. Fusidic Acid, p.303 Thcnoic Acid, p.380
Sulfadiazine, p.365 Sulfauoxazole, p.372 Gramicidin, p.310 Thiostrcpton, p.382
Sulfadiazine Silver, Sulfisomidine, p.372 Described in ~1is chap1cr arc Gramicidin S, p.3 t I Tiamulin, p.382
p.366 Tetroxoprim, p.380 Chlorte1racycline, p.264 Melhacycltne, p.324 HalquinoL p.311 Tigecy<:line, p.383
Sulfadicr.unidc. p.366 Trimc1hoprim, p.385 ~mcclocycline, p.287 Minocydinc, p.326 Lincwlid, p.319 Tyrodvicin, p.388
Doxycycline, p.290 Oxytettacyclin<, p.339 Mai;ainins, p.322 Valnemulin, p.388
L)1nccycline. p.322 Rolitetracyclioc. p.359 MIU!delic Acid, p.322 Xibomol, p.391
Tetracyclines Mcclocychnt. p.323 Temcycline, p.3n
The tetracyelines are a group of antibacterials, originally Choice of A ntibacterial
derived from certain Streptomyces spp, having the same Miscellaneous Antibacterials Ideally, antibacterial treatment of infeclions should be
tetracyclic nucleus, naphthacene, and similar properties. Spectinom)ICin is an aminocyclitol antibacterial with some chosen after the infecting organisms have beeo identi-
Unlike the penicillins and aminoglyoosides they arc usual- similarities to Streptomycin although it is not an aminogly- fied and the results of sensitivity tests are known. In
ly bacteriostatic at the concentrations achieved in the body cosidc. Spectinomycin is active against many bacteria but practice, empirical treatment is often necessary initial-
but act similarly 10 the aminoglycosidcs by interfering its clinical use is resoicted to the treatment of chancroid
with protein synthesis in susceptible organisms. ly, bearing in mind local patterns of infect.ion and re-
and gonorrhoea. Trospectomycin, a water-soluble deriva-
sistance. Other factors such as site of infection and tis-
Tetracyclines all have a broad spectrum of activity which tive, bas been inves1igated.
sue penetration are also important in deciding which
includes Gram-positive and Grom-negative bacteria, M11pirocin is an antibacterial produced by Pseudomonas
chlamydias and chlamydophilas, rickettsias, mycoplas- j/11oresce11s with activity against most strains of staphylo- antibacterial to give.
mas, spirochaetes, some mycobac1eria, and some proto- cocci and slrt:p1ocucci and also some Gram-ncgalive bac- The prophylactic use of antibacterials is restricted
zoa, but ttW emergence ofresistant strains and the develop- reria. It is applied topically. mainly to patients undergoing some types of surgery.
ment of other antimicrobials has often rcdU<:Cd their value. Fosfomycin is a derivative of phosphonic acid; ir is active Other groups requiring infection prophylaxis include
Adverse effects have also restricted their usefulness. Gas- against Gram-positive and Gram-negative bacteria and is patients at special risk of developing endocarditis and
trointestinal disrurbances are common and other important given orally or parenterally. those who have had rheumatic fever, who are splenec-
toxic effects include deposition in bones and teeth, pre- The fusidanc antibacterialfasidic acid is derived from Fu- tomised, or who are immunocompromised.
cluding their use in pregnancy and young children; anti- sidium coccineum and has a narrow spectrum of antibacte-
anabolic effects, especially in patients with renal impair- rial activity, but ii is very active against Staphyloccccus uu-
mrot; faUy changes in the liver; and photosensitivity, espe- reus and has been used both topically and systemically in Abscess, abdominal
cially with demeclocycline. Allergic reactions are relative- the t=tment of staphylococcal infections. Resistance de- See under Abscess, Liver, below, and under Peritonitis,
ly uncommon. Because of these adverse effects velops r~adily and it is often used with other antibacterials. p.198.
tetracyclines sbould be avoided in pregnant women, chil- The polymyxins are basic antibacterials produced by the
dren, aod, apart from doxycycline and minocycline, pa- growth of different strains of Bacillus polymyxa (B. aero- Abscess, brain
tients wilh renal impainnent. sporus). Polymyxi11 Band colistin have been used clinical- Brain abscesses can result from otitis media, sinusitis, trau-
The first 1etracycli1ie to be introduced was chlorten·acy- ly, but their systemic use has been more or less abandoned ma, or dental sepsis, or they may be mctaStatic secondary
cline in 1948 and, like chlommphcnicol which was discov- because of their toxiciiy, notably to the kidneys and nerv- to, for example, lung abscess~s. Opportunistic infections
ered at about the same time, it was found lo have a broad ous system. They are not absorbed when taken orally and in immwiocompromised pa1ients may present as brain ab-
spectrum of activity and to be active orally unlike ben- have therefore been given in gastrointestinal infections for scesses.
zylpenicillin or streptomycin, the only other antibacterials their bactericidal activity against Gram-negative bacteria. Treatment of brain abscesses entails removal of pus or ex-
then in use. The discovery of chl0r1etracycline was fol- They continue to be widely used as components oftopical cision and use of high doses of antibae1erials. Ideally the
lowed closely by that of oxytetracycline and theo tetracy- preparations. choice of antibac1erial depends on the infecting organisms
cline, a reduction product of chlortctracycline which may Bucitrocin. gi-amicidin. gramiciam S, and f}7'0thricin are and penelrarion by the an1ibacterial into brain tissue and
be produced semigynthctically. All three have very similar polypepc.ide antibacterials also produced by certain soains abscess pus. Until org;misms can be cultured empirical
properties, although chlonctracycline is less well absorbed of Bocill11s spp. but they are acti~ against Gram-positive treatment should be given.
and 0).)'tetracycline may cause less staining of teeth. De- bacteria. Like the polymyxins, they are IOXic when used There is vety little good quality published information on
meclacycline, dernetl1ylaled ehlortetracycline, has a longer systemically and"are therefore mainly used lopically. the treatment of brain abscess. For many ye&IS, combined
half-life than tetracycline but is more often associated with The halogenated hydroxyquinoline clioq11inol has antibac- treatment with ben.zylpcnicillin and chloramphenicol was
phototoxic reactions. lt has been used with some success terial, anti fungal, and antiprotozoal activity. It was former- the mainstay ofempirical therapy, but a repon by the Brit-
in pa1ients with the syndrome of inappropriate secretion of ly used in gastrointestinal infections including amocbiasis ish Society for Antimicrobial Chemotherapy,' based on
aniidiuretic honnone, but is ofli11le value and can produce severe nt:t1ro1oxici1y. published information and the authors' expertise, recom-
TI1ese four tetracyclines are all naturJI products that have It is now mainly used locally for superficial infections of mended the following regimens for first-line empirical
been isolated from Sn-eptomyces spp. The more rcccnl tet- the skin and external ear. Chlorq11ina/dol and ho/quinol are treatment, according to the site ofthc abscess and origin of
racyclines, such as methacycline, doxycycline, minocy- used similarly. the infection:
cline, lymecycline, meclocycline, and rolitetracycline are Urinary nnlimicrobials such as ni1rofumntoi11, and also • for frontal lobe abscesses originating from infection of
semisynthetic derivatives. Methocycline, like demeclocy- metltenomine which has generally been given as the hippu- the paranasal sinuses or tccrh, a combination of metron-
cline, oos a longer half-life than 1c11aCycline and has been ratc or mandelate, may be used in the treatment and proph- idaz.ole with one of ccfuroximc, cefoiaxime, or ccftriax-
given twice daily. Doxycycline and minacycline are both ylaxis of infections of U1e lower urinal)' traet. TI1ey are one
more active in vitro than 1ettacycline again.~\ many species. concentrated in the urine, but do not 11SU3lly achieve anti- • for temporal lobe or cerebellar abscc:sses originating
More importantly, minocyclinc is active against some tet- microbial concentrations in the blood. from infection of the middle car or sphenoidal sinuses,
racycline-resistant bacteria, including strains of staphylo- The oxazolidinone linezolid has activiiy ag11ins1 Gram- ampicillin and meuonidazole with either ceftaz.idime or
cocci. Both are well absorbed and, unlike tbc other tetracy- positivc organisms including vancomycin-resistant entc- gentamicin
clines, absorption is not si11nificantly affected by the rococci and meticillin-resistant Staphylococcus aumis. ll • for abscesses associated with penetrating trauma, flu-
presence of food. They can be given in lower doses than is used in infections of the skin and respiratory tract due to cloxacillin, cefuroxime, cefo1a.,i1ne, or ceftriaxonc
the older members of lhe group and, having Jong halt: these orsanisms.
lives, doxycycline is usually given once daily an.d minoc- • for metastatic abscesses, usually in the area supplied by
The glycylcycline tigecycline has activiiy against Gram- 1he middle cerebral artery, one of cefuroxime, cefotaxi-
ycline twice daily. Also, they do nol accumulate signifi- positive bacteria, including meticillin-rcsistant Stoph. ou-
cantly in patients wi1h renRI impainnent and can, with me, or ceftriaxone, witl1 or wi1hout metronidazolc, or, if
reus, and also against some Gram-negalivc and some 3$SOciated with endocarditis or cyanolic congenital
care, be given to such patients; however, usual doses of anaerobic bacteria. It is u.~ed in the treatment ofcomplieal-
minocycline can lead to higher serum concentrations re- heart disease, bcnzylpcnicillin
ed skin and skin structure infeciions, complicated inira-ab- Similar suggestions have been made by a more recent re-
sulting in possible liver toxicity. Both doxycyclinc and mi- dominal infections, and community-acquired pneumonia.
nocycline arc more lipid-soluhle than the other tetracy- vicw,2 which also suggcsred the use of oxacillin with rnct-
TI1c pleuromutilin amibacterial retapamulin is deri•cd ronidazole and a tliird-generation cephalosporin for empir-
clines and they penetrate well into tissues. The use of from the fungus C/itapilus passeckcrianus; it has activiiy
minocycline may, however, be limited by its vestibular ad- ical management of abscesses associated with pcnetJ-ating
against Stophylococcus aureii< and Streptococcus pyo- 1rauma, and vancomycin plus a third-generation ccpha-
ver.;e effects. genes. II is applied topically. losporin for abscess occurring postoperative!): Another
Tc1I11Cyclincs are not generally the amibacterials ofchoice Oc$cribed 111 du• rnoj)(tf..., revicw1 suggested the latter combination for abscesses
in Gram-positive or Gram-negative infections because of Acedmulfone, p.2 16 M•lheoaminc; p.324 both after neurosurgery and trauma.
the emergence of resistant organisms and the discovCI)' of Alsanihc Acid, p.223 MupiJocin, p.329 I. lnfcClion ill N=owrg•ry Workina Pony of1he Bnllsh Society
drugs with narrower antimicrobial spectra. However, they AviL•m)1"n. p.223 Nil\Jroxazide, p.334 (c>r AntimicroblaJ Chemotherapy. The r:itiottol use or antibiotics
have a place in the treatment of chlamydia! infections, Bacitr.aein, p.228 Nifurpirino~ p.334 in the 1rca1mcnt or a,.
bC3in :tbsccss. J Ne11ros,,rg 2000'; 14:
a~mbermycin, p.229 Nifunoinol, p.334 525-30.
rickcttsial infections such as typhus and tbe spotted fevers, Broxyquinoli11•, p.234 NifurLide, p.334 2. Lu C-11, el ol. St.rategics for the manaacmtnc ur b3ctrrial br.iin
mycoplasmal infections such as atypical pneumonia, pel- Carb4odox, p.235 Nisin, p.334 ab5C't:$S. J Clin Ncurrud 2006; 13: 979-8S.
vic inflammatory disease, Lyme disease, brucellosis, tu- Chlorquirnildol, p.264 Ni1rofuran1oin, p.334 3. Hakan T. Management of OOclcriGI broin 1b~CCl$CS. N1uros11rg
laraemia, plague, cholera, periodontal disease, and acne. Clioquinol, p.276 Nitrofurozone, p.336 PQc11s 2003; 24: E4. Availahle al: h11p://1hcjns.orgldoi/pdf/
Clofoctol, p.217 Nitroxolinc, p.336 10.3 t 7 llF0Cf.?008/2416/E4 (3CC<. .ed 31/03/10)
The tetracyclines have also b«n useful in 1hc treatment of
penicillin-allergic patients suffering from sexually trans- ColiS1in, p.278 Novobiocin, p.337
D•p•omycin, p.286 Polymyxin B, p.345
mitted diseases, actinomycosis. bronchitis, and lcptospiro- Foofbmycin, p.302 Retapamulin, p.3$ 1 Abscess, liver
sis. Minocyclinc may sometimes be used in multidrug reg- f'urahadone, p.303 Spcctinomyc:in, p.361 Bacteria commonly responsible for pyogenic liver ab-
imens for leprosy. Doxycycline may be used foe the fwaiidin, p.303 Tawolidine, p.373 scesses include Enrcrobacteriaceae, especially Es-
All cross-refercn= refer to entries in Volume A
 Amibacterials 171
che,-ichia coli and in some countries' Klebsiel/a p11e11mo- sponded to a prolonged course of ciproOoxacin;' in ge11s. The emeigence of multidrug-resistant anaerobes has .
niae; anaerobes, especially Bacteroides fragi/is; aud another, actinomycosis was eliminated with a 4-month been noted.5
Streptococa1s milleri (these can be microaerophilic). As course of lcvoOoxacin.5 There are also rcpons of success I . Sl)'rl O. Oorbxh SL. Rcttni <kvetopincn11in1hc undcrSt;:anding
elsewhere in the abdomen (see under Peritonitis, p.198). with imipenem, first generation cephalosporins, cellriax- o( 1h~ raihogt:nes.is and trttt.ment of anaerobic inf«.iions cfirsl
infections are often mixed. Treatment involves percutane- one, and piperacillinltazobactam. 1·1.6 Actinomycosis is not of1wo pans). N EnglJ Akd 1989: 321: 240-6.
ous aspira1ion and drainage of pus and the use of rugh dos- susceptible to metronidazole, aminoglycosides, co-tri- 2. Styrt B. Corbach SL. Recent dcvelopftlents in lhe understandU\I
es of antibacterials. ?.l Broad-spectrum empirical therapy moxazole, peniciIlinase-resistant penicillins, or cefalexin.2 of the pathogenesis :ind 11'CIU'llttlt of ~naerobit infocrions (S«·
ond oflwo paris). N E•t&IJ Med 1919: 32 1: 298-302.
should be started immediately; more specific therapy may Most patients can be managed with medical therapy alone; 3. Finegold SM, W<Xlcr HM. Pr<S<nl Slaws ot1het1py for onocro·
be possible when the results ofcullw-es following diagnos- however, drainage or aspiration ofabscesses or excision of bic infectionL Clln In/eel Dis 1996; 23 (suppl I): S9-S l4.
tic percutaneous aspira1ion of the abscess are known. Gen- fistulas may be appropriate, and occasionally ex1ensive 4. Brook t Anaerobic infc:clic:ms. R("t· Alttl Mic't'ol>iol 1999; 10:
tamicin with clindamycin has been commonly used° but surgery is indicated, especially if medical lherapy fails or a 137-53
other antibacterial combinations, involving cefoxitin, critical location is involved.1J S. 80)'ll'IOVt L. d al. An1jmicrobi ~I rc:$iSltncc and the m;magemcnl
chloramphenicol, carboxypenicillins, third-generation cc- 1. Sudh1kar SS, Ross JJ. Short-term Utahncnt of ac1inorn}'CQSi$.: of anaerobic tnfttlions. E.:rµrt Re,. A111; ln/m Thu 2001; S:
phalosporins, and meironidazolc, might be appropriate.5A two cues and a review. Clin lr1/«t 011 2004; 38: 444-7.
68~701.

regimen of ampicillin, gentamicin, and metronidazole has l . Brook I. Actinom)'·c.osi$: diaanorit ond management. South .M~d 6. Turner P. ~' al. SimullaMOUS rcs.islttn<t to mc:1ronldazolt. co-
become standard in some centres, but may be hazardous in JlOOS; IOI: 10 19-23. amoxiclav. and iinipcntm in clinicol isolate of Bacle:rotdti <ras·
llis. Ltmcei 199S: 345: 127S-7.
patients \vim Klebsiella-rclall!d liver abscess, in whom a 3. Chaudhry SI. Crccr1$p1tn JS. Actinomycosi.s in HIV infection: a
combination of an aminoglycoside ,~;th either an extend- review of~ nrc complication. Int J STDAJDS2000; 11: 349-S.S.
4. Macfarlane DJ, ti of. Treatment of rcakiinnl 1c;tinomycusis
ed-spectrum beta-lactarn such as piper..cillin or a second- wilh cip«>llon<in. J Jnfec1 1993; 1 7: 17i-30. A nthrax
or third-generation ccphalosporin, may be preferred.' An- S. Ferreira 0 de FG. ~ o/. Treatment of pulmoruwy ac:cinomycosis Anthrax is caused by Bacillus aniltrocis, a spore-forming
tibacterial therapy has been successful without surgical in- with lcvonoxacin. J Br& Pneumo/ 2008; 34! 20·-L Gram-positive aerobe found in the soil It most commonly
tervention, but may not be consistently so,6 although this 6. Vt F, tf nl. Actinom~ infection of 1hc: abdominal wall mim 4
infects herbi•·orous mammals. Humans can become in-
might be due 10 inadequate acatment against enteric anaer- ic)cin& n malian~nl neoplasm. Surg "1/tcl (l,,archmt) 2008; 9: fected by contact with infected animals or infected or con-
SS-9.
obes, especially B. ji-agilis.5 taminated animal products, or by inhalation of anthrax
For the ireatment of amoebic liver abscess, see under spores. Person-to-person transmission has no! been report-
Amoebiasis in Antiprotozoals, p.906. Anaerobic bacterial infections ed. Ahhough rare in western countries it remains a prob-
I. Lcdcnna~ ER.. Cru.m NP. Pyogenic lh-er abscts.s wilh a focus on Anaerobic bacteoia (or anaerobes) are part of the normal lem in many areas, including Africa, Asia, some southern
Klcbsiclla pn~wnoniae IS n pritnary pathogen: an cmcr,in1 dis· microbial Oora of the skin, mouth, gastrointestinal tract, European countries, the Americas, and parts of Australia.
case with u.niquc clinic:al ch;;,racltristies. A.01 J C011rotm~rol and vagina. If their commensal relationship is disnipted by Anthrax has also been used as a weapon for biological
2005; JOO: 322-31.
1. Barakatc MS.~' ol Pyogcnic liver abscess: a review of 10 years' surgery, trauma, immunosuppression, poor blood supply, waifare.
experience itt m:mascmcni:. A1is1 NZ J Surg 1999: 69': 2o.s-9. or tissue necrosis, some anaerobes can cause potentially In humans anthrax presents most often in the cutaneous
3. Alvarez. l'~rez JA.. t'tt1I. Clinical C»Ursc, trt-Dlmenr, and mullivar- serious infections. They often cause infections in the pleu-
iatc: on11lysis of risk factors for pyoscnic livtr1tbKcu.AmJSl.u-g form. Gastrointestinal or inhalation anthrax can also occur
2001: 181: 177-86.
ral spaces and lungs, upper respiratory tract, gasnointesti- and in 1hese types the prognosis is poor without prompt
4. HC'Tbert DA. er al. Pyogcme liver abscnscs: suc<.-tssful non·1ur· nal tract, CNS, skin, and vagina; haematogenoos spread treatment. In cutaneous anthrax symptoms may develop
Jical oh<r.>py. LLmc<t 19S2: I: 13•-6. c~m occur. Common anaerobic pathogens include Bactei~ within hours, or up to 12 days, after contact and initially
j. Hcri>en DA. er ol. Medic.:. I mon1.iemen1 of p)'(lgcnic li\'CT ob- aides, Prevote//a (formerly non-fragilis Bacteroides}, F11- involves a painless, pruritic papule, which enlarges to an
<Cesses. /J>nctJ 1985; I: I)S4.
soboclerium, Pa171hyro111anas, Clostridium, Pep1ostrep10- ulcer. Later (2 to 6 days) a vesicle with a black eschar de-
6. McCO<ltcll SJ. Niles NL. Pyo:;enic lh'CT absceSSc&: 1nothcr look
a1 medical manalC'f'H::Ot. Lancet I 9BS; i: 80l-6. coccus, and Actinamyces spp. Apart from single species velops. The i11cubation period for inhalation anthrax is
infections such as tetanus, gas gangrene, pseudomembra- usually about 10 days. Initial symptoms are non-specific
nous colitis, and actinomycosis, most anaerobic infections and resemble a Ou-like illness with fever, non-productive
Abscess, lung are of mixed aetiology. Abscesses are often a fearure. In-
Lung abscesses are ofteo secondary to aspiration pneumo- cough, dyspnoea, fatigue, headaclie, malaise, sweats,
fections include: brain abscess; acute necrotisinggjngivitis weakness, abdominal pain, aud vomiting. This initial stage
nia and are discussed under Pneumonia, p.201. The organ- and other periodontal infections; chronic otitis media and
isms involved are commonly anaerobic bacteria. may last from a few hours to days end is followed in some
chronic sinusitis; aspiration pneumonia and luog abscess; patients by a shon period of recovery while Olhers progress
peritonitis and intra-abdominal abscess; bacterial vagino- directly to respiraiory failure. Gastroinres1i11al anthrax has
Actinomycosis sis and pelvic inflammatory disease; cellulitis, ulcers, an incubation period of up to I week (usually 2 to S days)
Actinomycosis is a rare, chronic, slow-growing, on~n pol- bites, and other wound infections. 1 and initial symptoms are fever, abdominal pain, nausea,
ymicrobial infec.tion caused mainly by Gram-positive Management of anaerobic infections usually includes sur- vomiting, gastric ulcers, haematemesis, and diarrhoea
anaerobic or microaerophilic bacteria of the genus Actino- gical procedures and antibacterial therapy. Sensitivity test- (usually bloody). Systemic disease progresses rapidly and
myce.r (usually A. israe/i1) and sometimes by others such ing 111 wtro is often inipractical and ifdone results may not bypotension, shock, and death may occur 2 to 5 days after
as Propio11ibacterium or Bifidobacterium. Such organisms be available for several days. Initial antibacterial treatment in11ial symptoms.
are parf of the normal flora of the oral cavity, gastrointesti- is therefore usually empirical,1'5 should COYCr aerobes and
The treatment of naturally occurring anthrax has tradi-
nal tract, female genital iract, or skin. They are oflow path- anaerobes, and take into account local resistance rates and
the site of infection. Antibacterials are usually given tionally been witl1 benzylpenicillin with ciproOoxacin or
ogenicity and require a break in the mucosa! barrier to
parenterally, in high doses, and for a prolonged duration doxycycline (or other tetracycline) as alternatives. Other
cause infection; foreign bodies also appear to facilitate in-
(weeks to months).:i.s drugs with in 1•itro activity are aminoglycosides, arnoxicil-
fection. Actinomycosis occurs worldwide and at My age
but it is most commonly seen in men and those in the mid- lin, chloramphenicol, clindamycin, imipcncnt, linczolid,
The antibacterials of cl10ice are metronidazole, carbapen- the macrolides. meropenem, rifampiciu, and vancomy-
dle decades of life. Any site in the body can be involved; ems, combinations of a beta lactam with a beta-lactamase cin.1 .. There arc currently no clinical study data on the op-
the most common are oral-cervicofacial and are usually inhibitor. and chloramphenicol as they have the highest ac- timal treatment for anthrax and treatment recommenda-
associated with dental pro<.:odures or poor oral hygiene. tivity (more than 95%) against obligate anaerobes. Tigecy- tions and gu idelines1·2·• are based laigely on the
Less commonly, thoracic, abdominal, or pelvic regions arc clinc is also highly active and considered a promising new experience gained during !he 1979 incident in Sverdlovsk
involved (the latter usually associated with the use of intra- agent for anaerobic/mixed infections with multidrug-re- (accidental release of biological warfare agents), the 2001
uterine contracepli"e devices). Rarely, CNS, cuuneous. or sistant bacteria. Cefoxitin and clindamycin are often effec- attack in the USA (deliberate release), isolated caserepoits
dissemin?ted infection may occur. tive, except for infections caused by Bacteroides. Penicil- of narurally occurring disease, and in vitro data. Because
The iutcction is characterised by single or multiple indura- lin alone is no longer recommended for mixed infection of the risks of engineered drug-resistant strains of B. a11-
tions !hat spread regardless of tissue planes. I.,ocal S\Vell- because of increasing resistance in Gram-negative anaer- 1/waeis, inducible beta-lac.1amases, and i11 w110 resistance
ing. inOammation, abscesses, woody fibrous tissue, and obes, but may still be used for giis gangrene and actinomy- 10 otloxacin, guidelines•·H for the treatment of anthrax
draining sinuses that exude characteristic yellow aggre- cosis. Other antibacterials with low to modcrdte resistance (occurring after deliberate release) recommend the use of
gates (sulfur u-mules) may de\•elop. Oi3gnosis is di fficult; rates include moxiOoxacin and garcnoxacin. Other drugs 2 or more antibacterials which should be s1a11cd as soon as
~ie lesions may be mistaken for neoplasms. with po1ential for therapy may include oral nitazoxanide, possible. Co11icosteroids may be given as adjunctive ther-
Actinomycosis responds slowly to antibacterials, and ramoplanin, rifaximin, intravenous dalbavancin, and for apy. For the treatment of mha/arkm and gash'Oinleslinol
long-tcnn treatment is required 10 prevent recurrence. 1•3 topical use, retapamulin.$ anthrax intravenous cipronoxacin or oral doxycycliue plus
The treatment of choice is high-dose intravenous ben- Surveys of susceptibility pattems in. clinic:il isolales of one or two additional antibacterials with i11 vih'O activity
zylpenici llin for 2 to 6 weeks atld then an oral penicillin anaerobic bacteria have shown increasing resistance oftbe are recommended until antimicrobial susceptibility is
(e.g. phenoxymethylpenicillin or amoxicill in) for 6 to 12 B. ji-agilis group (including B. distasonfs, B. .frogilis, B. known. Trea1men1 should be given for 60 days. For c1110-
months,!.2 although complicated cases may require up to avatus, B. 1he1alo1oomicran, and B. mlgah1s) to clindamy- 11eaus anthrax, oral ciprotloxacin or oral doxycyclioe is
18 months oftherapy.2 Some patients may be successfully cin, continuing penicillin resistance in non-!Tagilis Bacter- generally recommended. A change to amo:><icillin, paiticu-
treated '"ith less prolonged regimens of penicill in, espe- oides spp. (now rcclassifioo as l'l'eVOtello spp. and includ- larly in pregnant women and children, may be ~nsidercd
cially ifthe disease burden is light;1 uncomplicated oral- ing the type species P. 111eloninage11ica), and rare beta- irthe or~anism is found 10 be susceptible or first-hne dlugs
cen~cofacial disease is particularly responsi,•e to shorter lactamase-mediated resistance of F11saboc1erium to peni- caMOI be taken. Treaunen1 for 7 to I0 days is usually rec-
trcaorn~nt courses. Short-course regimes an: generally not cillin.5 A clinical isolate of B..frogilis, simultaneously re- ommended for cutaneous anthrax, but in the event of a de-
advised for patients with large ll!Sions and/or abdominal sistant to metronidazole, amoxicillin with clavulanic acid, liberate release or if concurrent inhalation is suspected
disease unless surgical debridcment is performed. and imipenem, was reported in the UK,..6 treatment with then treatment should be cominued for60days. lftherean:
Alternatives to penicillins include the tetracyclines, eryth- clindamycin was successful on this occasion. Resistance signs of s)'Slemic involvement, extensive oedema, or le-
romycin, chlor~mphcnicol, and clindamycin.2.l In one pa- of some C/ostrldium spp. to penicillin and clindamycin sions on 1be head or neck., intravenous, and a multodrug
tient, actinomycosis resistant to conventional therapy re- had declined, but no changes were notod for Cl. peifrin- approach is recommended.
172 Antibacterials
Anthrax can be prevented by controlling and eliminating intravaginal mettonidawlc S g of a 0.7S% gel once daily for and Bocleroides spp., are cultured in about 15% of cases,
infected animals and \'accinating livc:stock. In humans, S days, or usually as part of a mixed infection and are more common
chemopropbylaxis may be given when exposure to an- intravaginal clindam.Yc;n S g of a 2% cn:am a\ bedtime foc 1 in those with bile duct-to-bowel anastomosis or fistulas,
thrax is suspected. USl and UK' guidelines recommend days the elderly, or seriously ill patients.'"
antibacterial prophylaxis with oral ciprofloxacin or oral alternatives are: lo most cases of obstruction, definitive treatment depends
doxycycline for 60 days. UK guidelines suggest that • oral clindamycin 300 mg twice daily for 1 days on restoring drainage of bile by surgical or medical treat-
amoxicillin may be coosidered ifthe organism is found to • intravaginal clindamycin 100 mg at bedtime for 3 days ment of gallstones (p.2647). Antibacterial therapy for
be susceptible. Anthrax vaccines may be used for active A systematic review~ of 24 clinical studies to assess the cholecystitis and cholangitis is similar and nims lo control
immunisation and are recommended for persons working effects ofantibacterials on bacterial vaginosis in non-preg- bacteraemia; treatment may be complicated by the fact
with potentially infected animals or animal products (in- nant women found clindamycin preparations (creams, !Ital biliary obsliuction prevents adequate concentrations
cluding laboratory workefli). The vacxine may also be giv- ovules, and tablets). oral metrooidazole, and oral or intra- of many antibacterials being achieved in the bile. Choice
en wilh antibacterials as part of a postexposure prophylax- vaginal tablets of lactobacillus probiotics to be effective. of an antibacterial is detennined by the severity of the dis-
is regimen. 24•6 In such situations, antibacterial prophylaxis For further information on the use ofprobiotics in rite treat- ease, the suspected pathogen, antibacterial activity, and lo·
may be reduced to 4 to 6 weeks.4•6 In the USA, specific ment of bacterial vaginosis sec Urological Infections, on cal antibacterial resi~1ance pattems.~s
guidelines6,7 for the use of anthrax vaccine, in<:luding its p.2606. Patients with mild illness may be treated with oral antibac-
use in response to terrorism, have been developed. An association has been reported between bacterial vagi- terials; fluoroquinolones (levofloxacin and ciprofloxacin},
1. CDC. Update: investigation of bio\c.rrorism.relatc:d antl\ru ind nosis and advefliepregnancy outcomcs, including miscar- first-generation cephalosporins (cefotiam, cefcapaie, and
interim auulclinu ror exposure manaie:ment and an1imicrobi1I riage and premature births of low-weight infants, and
1herapy, Oc1obcr 2001. MMWR 2001 ; SO: 909-t9. Cortection. cefazolin), or a broad-spectrum penicillin plus a beta·
ibid~ ; 962. Also available at: hnp:/lwww.cdc.gov/ mmwr/
some have advised ITeatment early in !he second trimester lactamase inhibitor (such as ampicillin with sulbactam) are
prcview/mmwrh1ml/mmS042al.htm (oe<:.,sed 22105/07) of p(egnancy.5 •6 A systematic review7 of clinical studies options. s Broad-spectrum intravenous antibacterials that
2 . lnclmy TV, II ol. AJ11hrax as a biologic.I weapon, 2002: updll· has concluded that tltere is little evidence that screening achieve high coocentrations in both bile and blood are pre-
cd rccommendatiot11 (or managemenl. JAMA 2002; 287: and treatment of all pregnant women for bacterial vagino-
2236-52. ferred for initial treatment in those with moderate to severe
3. Baillie LWJ. Pas.1. imminent and ru1urc human medical c:ountcr- sis would prevent premature birth and its consequences, illness.3•5 Antibacterials used for moderate illness and of-
mcasurc.s for anthnx. J Appl Microbiol 2006; I 0 I: S94-606. but there is some suggestion that treatment before 20 ten, io combination, for severe infections, include the ce-
4, Hc11lh Ptottction Agency. Anthrax: gwidelinu for oc.tJo,, /11 flit weeks of gcswion may reduce the risk of pretenn birth. In phalosporins, fluoroquinolones, and ureidopenicillin
ew"' of o tkliberore relco10. Vcnion .S.9; issued 16/04/07. women with a history of a p-evious premature binh, ITeat-
Available at : hllp://ww~.hp• .ora . uklwcbc/HPAwcbFilc/ (preferably mezlocillin and piper.icillin).'J,• Secood-gen-
HPAwcb_C/1194947401128 (a«<Ssed IWS/08)
ment of bacterial vaginosis may reduce the risk of prcterm eration cephalosporins may be given for moderate infec-
s. CDC. Upclarc: investigation ofanthn>. usociarcd with in1e:n1ion· birth.2 Symptomatic pregnant women should be treated tions, while third- and fowth-generation cepbalosporins
· al cJtpo,ure and interim public health guidelines. October and the following regimens bave been recommended: and aztreonam are given for more severe illness.5 Metron-
2001.MMWR 2001; 50: 8S9-9J. Also available u :
http:/iw-.-.-w.cdc.gov/mm-..,/prevkw/mmwrh1mllmfn5G.ilal .htm •WHO: idazole should be addC4l if anaerobic infection is consid·
(ae<csscd I J/OS/07) oral metronida.zole 200 or 250 mg throe times daily for 7 ered lil(ely. •.J.S In penicillin-resistant cases (particularly for
6. CDC. Use of anthrax vaccine in rcsp0nsc to tcnori.sm: supple· days, after tile first trimester, or infections with E coli or Klebsiella spp.} piperacillin with
mc:nt•I rccommmcbtion1 of the Advisory C.ommitte:c on Jmmu-
niuhon Practlc~. MMWR. 2 002~ SJ: 1024-6. AIM> available at:
of
• single oral dose mcuonidazolc 2 g. if treatment is needed tarobactam may be considered. If patients have recently
in the first trimester unclergone nonsurgical biliary tract procedures or received
h1tp~1~w.-Cdc.gov/mmwr/prcvicw/mm"'ThtmVmmSJ45o4.htm
(ace<ssed 11/05/07) alternatives are: a broad-spectrum antibacterial, it may be useful to add an
7. CDC. Use of anthrax vacci1'C in the Unucd Stalt's: rccommtncb· oral clindamycin 300 mg twice daily for 7 days or aminoglycoside to cover Pseudomonos ex En1erobacter
ttons of 1he Advisory CommiHH: on lmmuni1..ation PTletice-s • intra\'aginal metroniduole S g of a 0.7S% gel twice daily f0< spp.'·3 In those with more severe illness, antibacterials
(ACJP). MMWR 2000; 49 (AA-IS): 1-20. Also availahle at: 7 days
htt'p://www.c.de.s~'V/mm,,-r/prcvie w/minwrhtmVrr49JSa1 .htrn with pseudomonal and entcrococcal activity (such as imi-
(occe.scd I J/OSI07) USA: peDCID, rneropenem, or piperacillin with tazobac1am)•.S
• on1I mdronidazole SOO mg twice daily or 2SO mg three times and fluoroquinolones may be considered.5 Antibacterial
cbily for 7 days or treatment is usually given for S to 14 days.t.l.•
Antibiotic-associated colitis • oral clindamycin 300 mg twice daily for 7 days
See under Gastro-enteriris p.182. Antibacterial prophylaxis is common in biliary swgcry
Treatment of male sex partnen does not prevent rite recur- (see Surgical Infection, p.211) to prevent acute cholangitis
rence of bacterial vaginosis. 1-3 and wound infections. A single dose of an intravenous ce-
Arthritis, bacterial Patients co-infected wiih HJV should receive the same phalosporin {cefazolin, cefoxitin, cefuroxime, or cefotaxi-
See under Bone and Joint Infections, p.173. treatment as those who are HIV-negative. 2 rne), piperacillin, or ciprofloxacin is often used for this
I. Clinical Etrec11"entss Group (Brilish AssocratK:>n for Sexual purpose. •J .
He.Ith and HIV). NOlionol guidclinc for the ,.. ,,..cmenl of bac-
Bacillary anglomatosis terial v1ginosis (2006). Av1ilablc at: http:/lwww.bubh.org/ Maintenance antibacterial Uicrapy to reduce the number of
See under Cat Scratch Disease, p.175. doeumcnts/62/62.pdf (1cccucd 1S/OSI03) episodes may have a role in those with recurrent c.holangi·
2. CDC. Sexually •ronsmintd disusn uta1mcn1 guidelines 2006. tis. Oral co-trimoxazole is the drug of choice, although
MMIYR 2006; SS(RR·ll): 1-94. Also available ai: hup://
www.cdc.gov/mmwrll'OfmhTSSI l.pdf(acccssed 22/0J~7) there are also a few reports of oral ciprofloxacin being
Bacterial vaginosis 3. W110. OuidcHnH ror the manRaemcnt or sexually Cf'2Mm1ntcl used;t.3 a further alternative is a.moxicillin (or :unpfoillin)
Bacterial vaginosis (anaerobic vaginosis; non-specific in(cc;tions. Geneva: WHO. 200J. Also available 111: plus a beta-lactamase inhibitor (clavulanic acid, sul-
vaginitis) results from a reduction of the normal vaginal hup://whql•bdoe. who.int/publications/20031924 I S46263.pd f
(accessed 22/0l~7) bactam; or tazobactam).' An attempt is usually made after
bacteria (loCJobacilhtS spp.) and an overgrowth of anaer- 4. Oduyebo 00. ti al. The effects of ancimicrobiaJ therapy on bac- 3 to 4 months to stop tl1is treatment l.l
obic bacteria (in<:luding Gardnere//o voginolis, Mycoplos- lcrial vag.inosis fn non·prcg.nant women. Anitablc in Tiic Co- I. van den Ha~I SJ. et al. Role of a1mDiotics in lht ucatment and
mo hominis, or Mobiluncus or PrewJt~//o spp.). ll is a com- chr.mc Database of Systcmo.1ic Rcviewa; Issue J. Chichesler: prevention· of 3cutt. and rc.cum:nt e-holangitis. Clht lnf«t Dis
Joltn Wiky; 2009 (•cocmd 2•!02110). 1994: 19: 279-86.
mon and often distressing condition that is not thought 10 S. Hey PE. Therapy ofbac:tctial "·aginosis.J A111lmlcrob CJ1ttt101htr 2. Pdla C, Oudiol F. Chot«ys1itis and cholangitts: 1pec:1rvm of
be sexually transmitted but is gencnlly associated with 1998; 41; 6-9. boc1tri1 and rok of antibiotics. Diii Suf11 19%; 13: ) 17-20.
sexual activity. Infections may be asymptomatic or result 6. Anonyrnous. Man~gcmcnt o( bacteria.I "aginosis. Dn¢ Thcr 3. Wes1ph1I J-f. Brogard J.M. Biliary lract infections: 1 guide to
in a fishy-smelling vaginal discharge. B>lfl 199S; 36: 33-S. druglr<>lrncnl.D'11gt 1999;57: 81-9 1.
1. McDonlld HM. r1 ol. An1ibio1ic:s !Or lrea1ing bacterial va1inosis 4. J~in MK. Jain R. Acute ba~teria l cholanai1i.s. c,,rr Trrot Op1/0111
Various antibacterial regimens for the treatment of bacte- iri pregn;.ncy. At.-ailable in The Cochl'1nc Oita base of Systematic GtutTOmtrro/ 2006; 9: I lJ-21 .
rial vaginosis are recommended in guidelines issued in the Rcvicwsi Issue l. Chichester: John Wiley; 2001 (accessed S. Yoshida M. ti al. Antimicrobial lherapy («acute cholccystitis:
17/03107). .
UK, 1 and in rite USA2 and also by WH03 but relapse is Tokyo Guidelines. J Htpotobiliory Po,,cNot S11rg 2007; 14:
IJ-90.
common after any regimen.
•WHO : Biliary-tract infections
Altliough the biliary-tract is normally free of bacteria. in- Bites and stings
• oral metronida:.:ole 400 or SOO mg twice daily for 7 days
fections may follow partial or complete blockage ofpart of Dog, cat, or human biles are the most commonly encoun-
altcmativcs are: the biliary tree; the part blocked determines 1he clinical tered bilt wounds. The resulting injury depends oo the an-
a single oral dose of1ncnonidazolc 2 g condition. imal species and dentition, the ferocity of lhe attack, and
inua»aginal 111C1Toniduole S g of a 0.1S% gel twice daily for Acule c/rQ/e<:ystitis results from blockage of the cystic the anatomical locatioo of the bite. Dog bites most oflcn
Sclays duct, mostly caused by gallstones (ac:alculous cholccystitis cause crush iltjurics, lacerations, and abrasions, whereas
oral chndamyein 300 mg twice dally for 7 days refers to cholecyslitis without gallstooe:s). Bile stasis oc- the sharp pointed teeth of cats usually cause puncture
ino-avaginal clindamycin S g ofa 2%cream at bedtime for 7 curs after the blockage and leads 10 inOanunation of the wounds and lacerations. A major concern in all bite
days gallbladder and possibly secondary bacterial infection, wounds is the risk of infection; it can be caused by nearly
•UK: which is mostly polymicrobial. lnadcquale drainage in- any group of pathogens {bacteria, viruses, rickeu.sia, spiro-
• oral mctronidazole 400 or 500 mg twice daily for 5 to 7 days creases the pressure witltin rite bile duct, resulting in reflux chcies, or fungi). Paticnl~ presenting more than 8 hours af-
or a single oral 2·& dose of bacteria into the blood and lymph (bacteraemia). Com- ter a bite injury often have infected wounds, with cat bites
alternatives are: plications can in<:ludc gangrene, hepatic or inrraperitoncal developing infection more rapidly than dog bites. Human
intra•aginal mellOnid•zole 0.75% gel once daily for S days abscesses, periton itis, and septicaemia. Cholang/1is is bites have a higher complication and infection rate than an-
caused by infection in an obsuucted biliary system, usual- imal bites.
oral clindamycin 300 mg twice daily for 7 days
ly the common bile duct. Suppurative cholangitis is asso- Animal bite wound infections conmin a mix of aerobes
inlra\'aginal cJindamyein asa 2".cr.am onoe daily for 7 days ciated with a higher niortality rate. and anaerobes rrom both the skin of the patient and lhe
a single oral dose oftinidazolc 2 & The organisms most commonly involved in bolh these mouth of the animal, although certain organisms are asso·
·USA: conditions arc Esch<!richia coli and Klebsiella spp.; En1e- ciated with particular animal species. Cat bites are most
· oral menonidazole SOO mg twice daily for 7 days. or rocacci are less common. Anaerobes, mostly Clostridium often associated with Postcun!lla mullocido; other organ-
All cross-references refer lo entri"l' in Volume A
 Antibactenals 173
isms include PorphpY1mo11as and Maraxella spp. Bnr- la~is it should be considered in high nsk human bite inJU- with a higher dose of antibacteri31, has been evaluated in
101>ello henseloe can be uansmittcd "1a a saatch or bile of ries (see HIV Infection Prophylaxis, p.947).: children with bacrerial anhritis.s
an infected cat or cat flea. Sec also under Cat Scratch Dis- Among the more unusual 111fections acquired from ani- • Empirical u-catmcnt regimens for bectcnal arth1itis (as
ease (p. l 7S). A common can111c urganism is P. canis. 0th· mals is seal finger, caused by an as yet unidentified organ- foros1comychtis) usually includeantibactenalswith ac-
er common organisms associated with cat and dog bites ism and treated with lell'acycline.~TI1c Gram-negative ba- iivity against staphylococci and streptococci. These in-
are Streptococcus, Stophyloc0«11s, F11soboc1erium, and cilli Splrillmn 111/1111.s (or minor) and Strt!p1abaclllus clude flucluxacillin, nafcill in. o~acillin, or cepha-
Bnc1eroides spp.'.2 A more unu511al organism is Cop11ocy· mon//ifarm1s are both causes of rat-bite fever. In each case losporins t•,u Clindamycin is an ahema1ivc in patients
1ophogn ro11imorsus (fom1erly called dysgonic fermenter the treatment of choice is benzylpenicillin;7 a teuacycline "ho arc penicillin-allergic.'·' Benzylpemcillin and
type 2 or OF-2) which has mostly been associated wilh or s1tq>tomyein an: altemati\'CS. ccfiriaxooe are also actl\'C against streptococci.• Altcr-
dog bites.H It is an opportunistic pathogen especially hu- Emcnomation afier bites and stings by snakes, SCOl'pions, nativel), gentamicin can be added 10 an antistaphyloco-
ardous 10 chronic alcohol users and immunocompromised spiders. and some marine animals is usually~ symp- ccal drug_l.• \lancomycinl.4 or teicoplanin• arc used if
patients; including splenectomised patienis. 1J Infection tomatically and with specific antivcnoms and antiscra (sec mcticillin-rcsiStant Staph. nureus is suspected; a sccond-
with C. cnmmt)r$u.t after dog bites has led to fatal septicae- Jellyfish Slings, p.2427, Scorpion Stings, p.2446, Snake or third-generation cephalosporin,3 rifampicin, fusidie
mia, disseminated imravascular coagulation, meningitis, Bites, p.2447, Spider Bites, p.2448, and Slone Fish Venom acid, or doxycyclinc• have also been added. Jn patients
or cndocarditis. 3 Antiscra, p.2448). unable to take vancomycin, line:zohd has been used as
an al1emativc.6 Coagulasc-negath·c staphylococci are
lnfectcdJ1uman bites are usually polymicrobial, however I. Odller RL. ff ul 811c-rcl>1<d ond S<plte syndrom.. au..d by
n1> aod dop. w"""' lnfttl Dis 2009: 9: 439-47. tre3ted similarly.6
Eikt11>ella con-adl!lrS has caused septic arthritis after a pen-
etrating injwy ofthe hand, and this may be complicated by 2. =~,;,;~7l~:~~f~"1ofmal'l'lrruilianb1tts. A11JIF"'" • Empincal anti00ctcrial treatment for infections caused
infccti"e cndocorditis. Hepatitis B and C can be tmnsmil· by Gram-negative bacteria include a third-generation
). Pc-rs C. ~ ol Capn~ophap c~nunorsus upticcmea in Dtn·
tcd by human bites and HIV tra1umission has occasionally mark. 1982·199S; .....w of39 CIS<S Clm lnf«I DiJ 19')6: lJ: ccphalosporin or ciprofloxacin.6 Ccftriaxone may be
been reported. 2 71-S. used for empirical treatment ofoocterial arthritis where
.f Loe Moal G. ~ ol Mcn1n;ai1is due to Capnocyt0phap anonorsus infection is lhought 10 be caused by N go1101rlloe~"
Ma nagement of cat and dog bites should include treat· af1crrecript of 1 dog btlt: cue re.port 3nd ftV~\\' of aht htcroturt. or N. menmgiud1s.J Young children should be given a
Clm lnfeN Di• 20Cll: J6: t42-e46
mcnt of.the wound 10 reduce the risk of acute infection. s. MorpnM.ralmnJ Oo1b11cs 8Wl007;3.l4:413-7. ccph3losporin such as ccfocaximc because of the likeli-
Prompt and thorough inig;ition of the wound with tap wa- 6. Medeiros 1. SacooMo H. Anob4ocic: prophylu11 ror memmalia.ft hood of H. i11j/ut1rzoe infection.•
ter or nonool saline aims to dislodge foreign martcr and b1ttt. Available in The Cochrane Oatabosoe of Sysiantic ll.,. • Infections caused by anacr~ can be treated \\•1th clin-
bacteria inoculated into the wound, and reduce the trans- v1t¥t.•s: 1s.iut 2 Ch1chutu: John Wiley: 2001 hcccsnd
1611\SIOS). damycin; ampicillin-s11lb.1ctam or mctronidazoleare al-
mission of rabies virus. Established infection usually re· tematives.7
7. Abramo,.tei M. <d The thao« of •n11ha<ten•I dnip. In· /1mHI·
quires hospital admission for surgical dcbridement and ~ ofonlimicrubiol th""'P.'' ISlh cd I\.,. Rocll<tlc NY: The In the treatment ofoste01ny~li1is similar drugs are typically
drainage. A systematic review' concluded thal there was M<doul t.euu. 2oos· 10 chosen 10 those listed above for treatment of bacterial N·
insufficient evidence that prophylactic antibacterials given H31'\ky JW. P11chtr D. Sul fins'-"' tttrx:ycl1ne iJ f'im lint J
/efttl 2002: 4S: 71-S 1hritis. Howe\ er, because penerration ofantibacterials into
for dog bites were effective. 1nere was evidence that anti· bone may he ''•liable and ~low, paiticularly where there is
bactcrials given al\cr bites to the hand reduced infection necrosis 01· poor vascularisation, treabnent, al least in
and "cak evidence to suggest that propbylaciic a11tibecte· Bone and joint infections adults, has often been 11101-e prolonged.2·6.1 Treabncnt is
rials after human bites rcduoed infection. l'rophylact1c an- lnfectious anhritis (septic or pyogcnic anhritis) is an infec- generally given by the intravenous route but with some
tibacterials are therefore not recommended for superficial tion of the joints charactcnsed by pain, fever, inflamma- drugs. ~11ch as the quinoloncs or clindamycin, an early
and casil)' cleansed bite wounds; I.I prophylaxis should be tion, and swelling. Bactcna arc the most common cause of switch to oral therapy is possible.u Dcbride1ncnt of
reserved for the bites most likely to become infected (such infectious arthritis, although fonl!,i ond viruses can also in· necro1ic bone is important in Ille management of chronic
as cat tll1d human bites), where adequate debridemcot can- feet joints. In acute bacterial arthritis, joinls are com- ostcomyclitis.t.7Children with ostcomyelitis may respond
not be achieved, and in immunocompromised patients at monly infected from a contiguous source via the blood or more rapidly to trtatmcnl becllu~ of the greater vascular-
high risk of infection.~ If given, antibacte1ial prophylaxis from direct inoculation during a surgical procedure, injec· ity of developing bone; sho11er courses. and initial ora12 or
should be given for 3 to S days~.S it is initially empirical tion, bite, or trauma. Infecting organisms include staphylo- an early switch from intravenous to oral ircatn1C0t' may be
and should be directed toward the organisms that usually cocci, streptooocci, cnterococci, Enterobactcriaocac, Pseu- possible.
colonise the oral cavity of the animal until cultures results do111011as at!ruginosa, and anaerobes, although the Antibac:1crials which have a good activity against surface.
can direct treatmCllt.1 commonest is probably Slaphyfococcus aurtus. In pros- adhering and biofihn-pcoducmg badcria arc required for
Pastt11irello spp. cause rapidly progressive sl<m and 501\ thetic joint infections coagulase-ncgntivc staphylococci prostlre1ic joim mfection; rifampicin is commonly used
tissue infection and are generally resistant to d1cloxaollin, 3rc often implicated. Hoemop/11/us mjluen:oe is a com· with a fluoroqumolooc.9 ln one sludy10 ~ ufrifampicin
llucloxacillin. fim-gencration ccphalospo1ins, clindamy- mon cause in young children, as is Nelsstria ganorrhoeoe with ciprofloxacm improved control of staphylococcal in-
cin, and crythromycin. 1.2 Bcnzylpenicillin is not effective in sexually active young adulis. In addition to gonococcal fections related to Joint prostheses or fracture fixation de-
against S. aureus, anaerobes, or £ike11tlla. Oral amoxicil- anhritis, other specific types of b..~crial arthritis include vices in comparison wi1h ciprofloxacin 3Jonc. Rifampiein
lin with clavulanic acid has excellent acuvity a.gains! Pas- Lyme disease and meningococc;il, sabnonellal, and ruber- has also been used with a penicillinase-resismu penicillin,
te1wtlla spp . <...'apt1oo'fophaga spp., anaerobes. and sus- culous artluitis (sec under the appiopnatc disease for fur. .ancomycm, or 1eicoplan1n9 for initial intravenous treat-
ccpt i blc S. n11re11s, and is the drug of choice for 1hcr details). ment of prosthetic joim infections; fusidic acid. 7·9 co-tn-
propl1yl3.,is. 1.l.S Tettacyclioc or doxycycline with or with- In reactive at1hritis (aseptic arthritis) joint inflammation moxazole. or minocycline9 have been added to rifampicin
out mctronidazolc is an alternative in penicillin-allergic followll infection elsewhere in the body. II is geocrally sec- for continued oral treatment. As in osteom~elitis pro-
JXtticnts.'.l.s. 7 Other alternatives include metronidazolc ondary 10 sexually transmincd, especially chlamydial, in- longed intravenous therapy may be needed; 1 debride-
\\1th co-trimoxazole or a nuoroquinolone,2 clindamycin ti:ction.s, or to cnleric infections with organisms such as mcnt and removal of the prosthesis is important.14 For ref·
wid1 a Huoroquinolonc, or clindamycin with co-trimoxa- Salmo11ella. Slugtllo, Yers1111a, Campylobocter, and ercncc to infoction prophyla'QS m orthopaedic patients. sec
rolc (in'children).' Pllrentcral ccftriaxone can be used 111 Closrridium atflidlt!. The term Re11er's $Yndrome is usual- under Swgical Infection, p.21 l.
pregnancy; 1 ·~ cefuroximc and cefpodoximc are oral ahcr- ly reserved for reactive arthritis associated with extra-anic- In reoctt"t! or1hn11s the role of antibacterials 1s less cct·
oaiives.1 In areas where community-<1cquircd MRSA 1nc1· ular fcarures such as urcthn1is and COllJUOCtivitis. ttin.' 1 Resulls 1n ortlvit1s associated with chlamydia! in·
dencc is high the choice of antiba<:terial may need to be Acute osteomyelitis, an infccuoo of bone, is also charac- fa:tions have been more promising than in that triggered
modified. Dox)cycline and co-trimoxazolc a1c effective terised by pain, fever, and inflammation. 01ronic infection by cnieric infections. 11 Long-teim treatment with a tetra·
oral ahemati•~s for coverage ofMRSA; clindamycin may can develop, with long periods of latency and recurrent ie· cyclinil in add11ion to an NSAIO has been reported to
be a lilrthcr ahcmali\'e. 1 Antibacterials should ~given lapse. and is associated with necrosis of the bone. Ostco- shorten the durallon of reactive 3rtlu1tis rcsulling from
p:ircntcrally \\hen rapidly spreading ccllulitis or si~s of myelitis is most often aiused by spread from a oontiguous Chlamwiio 1rod10111a1/s infcciion.U For reference to tl1e
sepsis develop, or involvement of bone or joint 1s likely. source of infection such as a penetrating wound, soft tissue symptomatic trcaunenl of rcac1iv.: arthritis, se;: Spumly·
Antioocteri3IS for more severe established infectioos (as infection, or surgery, but can also be disseminated by the loorthrop.11h1es p.14.
inpatient 1m11mcn1) include combina1ions of a belll l3Ctom blood or secondary to 'ascular insufficiency such as dia- For mention of the use of tetracyclines. usually minocy-
nod a bet~·lactamasc inhibitor(such as ampicillin '~ith sul· bc1ic foot infection. With the cxccpiion ofN. gonorrhoe.oe, dinc. in till: ll'l:<llnH:nl of rhe11mataid or1liritis. sec Wldcr
bectam, piperacillin with tazobaciam, or ticarcillin with infecting organisms arc simil~r to those in bacterial arthri- Musculoskelctal and Joint Disorders, p.379.
clavul~nic acid), A caJbapcnem (such as cnapenem, mero- 1is. I. Stcna;d O.~u/ St'1tma11c "·""icw ~hd ~b-ruUl)'$tSof~ub~
pcnem, doopcnem, or imipcnem). ccfiriaxooc, aztreonam. A systematic review and mcta-analysis1 of antib3ctcrial ooc thttlpY (Clf hfw'lf and jotn1 infections. l.n:nrd ln(ttt Vi•
or a fluoroquinolonc with mem>nidazolc arc alternauvcs.1 t reatment of bone 3nd JOinl infections concluded that ?OOt. I: 1is-&1 CCHftttion. 1l>td. 2002; l: 1?5.
?. O;,rk)' ESR. Mle(io-.-,n AP Anubiotic 1tt;1tmtt1l ofP"'"SK"'"
For very severe intCcl.ions. empirical imipcucm plus clin- there was linlc high-<iuahty C\'1dcncc to support use ofany mw tow aAd ~~• 1n(cc1ions. J ..1,,11111Krob LM1110tMr 20U4:
damycin has been given.~ Treatment is usually &i\'cll for one drug. In practice, treatment is usually started irurave- SJ: 921-J~ .
10 10 14 days for established ccUulius, 3 "-CCII.$ for te110- 3. tookky 0. r1 #I Bnu•h So<o<ty for Rliawot<>IQSY S""'4>rds.
nously; if hig)t bone concentmtions c:in be acl1ieved "ith Guo<ltl1,... tnd A11d1t Worltong Grwp. BSR & BHPR, BOA.
synovi1is, and 6 weeks for ostcomyclitis.1 an appropriate oral ant1bactenal, patients may be switched RCCP anJ BSAC suokhnn for "''""J."""""I oflht hol •"oll<n
to ornI therapy. j0in1 on adul1> ""'"""""'"~ri().r/ort/1200!':4S: 1039-41. Abo
If necessary, prophylaxis or tn.-atment for nibics (p.2443) ,,..-fable ae
~ould be instinned. A combined telllnus and diphtheria Treatment for boctennl artlirtl/s is usually Started intrave- h11p;t;-.,,wrhc1o1ru:uo1<1t:Y·Of'J·°"'inc1udts.'doc;umcn1slcm doctl
vaccme(Stt p.2415) should be gi\•en to patientS" hose pri- nously, althou~ it need not be given parcmcrally for the 2009/M11·unaftincn1 _o( ho1_s-w0Hcn_ioinu_in_adu1ll .pcTr (l('o
<W<d 261021 0)
mill)' tttmus nnmunisation is incomplete or unknown, or whole course.-.1• Synovial penctt'ltion for mOSt antibacte- .-. Anouyn\Ol.IS Tiw m~l\OIC'nlCnt of septic anhrius Drnt. Tl"'1"
boosters are not up-to-date. For hwnan bites hcpatuis B rials is gtnendly good, although peak concentrations tend Bull 2003. 41 : 6S-I
prophylaxis should be considered if the patient is not im· 10 be lower and slower 10 achieve than those in plasma. S. Pthol1 H cl ,;I PrQSOCC:t1''· raftdomiz~ triaJ ~f JO d1ys \•trsu•
30 d1)'t of 1n1imicrob1al treatment.. 1nch.id1ng a shorMCfm
munc (see Hepatitis B Vaccine, p.2421) and alrhougll lhcrc ·1ypically, the recommended duration of trC."ltment is SllN· counc of rercntml th<~py. for childhood septic ar1hnu1 Clm
1s limited c~1de11cc to support HIV postexposurc prophy· era I weeks.~·· A shorter treatment oourse ohbout I0 days, lefm Di• 2009 48: 1201-10.
174 Antibacterials
6. Abran'tOwiCZ M. ed. The ch<1ice ofanlibaC1cri&J drugs. Jn: Hand· p.1224). The valueofan1ibacterial treatmenl in AECB has 12 Saints. et ol. Antibiotics in chronic obstructive pulmonarv du-
book ofonti•k'robto/ rltcr<>p:.1. 18th~. New Roche Uc NY: The easc exaccrbatioru.; • mcll4 ntlysis. JA MA 1995: 273: 9Sf-60.
Medical 1,,tner; 200R: 39. beeft controversial and early studies were difficult 10 as-
' · Lew DP, W.ldvog<I FA. Osieomydi1is. Lonce1 2004; 364: sess. ;-9 After a comparison of a brood-speclrum antibacte- 13. Bolter M, Weiss K. Treatins 1w1c exacerbations of chr<>t1ic
369-79. bronchitis and communi1y-acquired pneumonia: how cffcctl\•c
rial (amoxicillin, co-trimoxa:zolc, or doxycyclme) with are r~spiratory Ruoroquinolones? Co11 Fom Phyiirion 2006; 51:
I. Zaoutis T. ~t al. Prolonged .1tnra'llet10Us 1herzipy vcnus eat'J placcbo,1° ii was considered that antibacterials were justi- 1236-42.
tnnshion to oral an1imicrob11I therapy for acute 051eom)-cli11s
in children. Pediatrics 2009; t1J: 636-42. fied in paticnlS wilh AECB characterised by increased 14. Dimo~&o.s c;. 11 ol. Comparison offint·linc wilh sccond·linc
9. Trampuz A, Zimtricrli W. Antimicrobial agents in orthopM'd1c dyspnoca, sputum production, and sputum purulence, a 1ntib1oaic1 (or aculc exacerbations of chronic bronchitis: a
~~S\~~~O/'ophyl~xis and lrn tmcnl. Ontg1 2006; 66: mctaa041Jysis or randomized controlled trials. ChtSf 2007; 132:
conclusion supporled by a later systematic review. 11 An •~7-SS .
10. Zimmttli w. ~' ol. Role of rifampin for lrfftmcnt of orthopedic earlier meta-analysis of randomised studies also indicated 1$. Global ini1ia1h.-c for chronic obsuuctivc lung dise1sc (GOLD).
impla.ni.rclaecd staphylococcal infections· a nndomized con· a small improvement due lo lherapy in patienlS with AE- Global strategy for lhc diaposi.s. manaigcment, ·~ prc,uaion
ironed trial. JAMA 1998; 279: lS37-41 . of chronic: obstruetivt pulmonary disease. Updaled 2009. Avail-
t I. Toivanen A. Bac1cria~ri~gered rexti~e anhri1is: implications CB.12 Amoxicillin, ampicillio, letracyclines (such as dox· able at: hnp:/lwww.goldcopd.con>/dow•load.up?intld•SS4
for on<ibactcrial <re•tmen1. Drugs 2001; 61: 343-S I. ycycline), brood-spectrum macrolides, second- or third- (•ccest.ed OS/08/10)
12. Sv~ung.'\SOn B. ReacliYe anhri1is. BMJ 1994; 308: 67 l-2. generation cephalosporins, or co-1rimoxazolc have tradi- 16. Rodrfsuez•Rolsin R. COPD exacc.rbations..5: mafl3gcmcn1.
13. l.auhi.o A. Reactive anJvn1s; consider combination ll'Cllmtnl tionally been used for treatment of AECB, 13•.. but recent Thorax 2006; 61: S3S-44.
RMI 1994; 308: 1302-;.
14. M~thcws CJ. et ol. Bacterial sc:ptic arthritis in lduhs. Lonc~r reports ftom the USA and Canada show reduced efficacy 11. Stsykova T, t1 al. Prophylac-tk •ntibiocic therapy ror chronic
2010; ;1s: &<~SS. 10 penicillin, macrolides, and co-ttimoxazole; however, bronchi1is. A\•uilablc in TM Cochr.inc 0111ba.s~ of Sys1emaric
Reviews; ls.sue 2. Chichetter: John Wiley~ 2001 (accessed
antibacterial ac1ivity for the newer fluoroquinolones and 05/02110).
Botulism combinations of a beta lad.am and a bcta-lactamase inhib-
For a discussion of botulism and iis management. see itor have remained high. 11 Furthennore, a meta-analysis"
to evaluate the compara1ive efficacy and safety of first-line Brucellosis
p.2413. Brucellosis (also known as undulant or Mediterranean fe..
antibacterials (considered to be amoxicillin, ampicillin, pi-
vampicillin, co-trimoxazole, and doxycycline) and sec- ver) is caused by Bruce/lo spp., aerobic Grain-negative
Bronchitis ond-line antibacterials (ronsidered to be amoxicillin wilh bacteria found mainly in livestock and domestic animals.
Bronchitis may be defined as inflammation oflhe bronchi clavulanic acid, macrolides, second- or third-generation Humans can become infected by direct contact with infec1-
and is associated wilh excessive spurum produc1ion and cephalosporins, and fluoroquinolones) for lhe trealmenl of cd animals or anima1 material (such as the placenta), indi-
coug)l. II may be either acute or chronic and may be as a patients wilh AECD, reported that second-line antibacleri- rectly by consuming infected and unpasteurised milk
result of infection or may be niggered by irti1ants such as als were more effective, but not less safe, compared with products, or by inhalation of contaminaled dust or drop-
tobacco smoke, pollution, chemicals, or dust. the flrst-line anlibacterials. le1s. Rarely, hwnan infection has been reported from expo-
Acute bronchitis is a common, self-limiting. respiratory in- sure to some live vet~nary vaccines. 1) The principal Bru-
Guidelines for the management of AECB were developed
fection that manifesis mainly as a cough wilh or withoul by die Canadian Chronic Bronchitis Working Group,9 and ce/la spp. affecting humans are IJ. melilensis, from sheep,
spurum production and Iasis for up lo 3 weeks; iflhe cough lhe lopic is also covered by general guidelines for the man- goats, camels, and sometimes cattle; B. abonus, from cat-
persists for more than 3 weeks other dia811oseS should be de, buffalo, camels, and yaks; B. suis, from pigs; and rarely
agement of COPD available in many counlries (see
considered. Respiratory viruses, such as those lhal cause B. canis, from dogs. Allhoug)l rare or controlled in coun-
p.1224), and internationally tluough the Global Initiative
colds and influenza, are lhe most usual cause of acute tries such as !he UK brucellosis remains a problem in
for Chronic Obs1ructive Lung Disease (GOLD).15 These
bronchitis; less lhan I00/o of cases have a bacterial cause. many areas. including eastern Europe, the Mediterranean
guidelines sll'atify patienis according to risk to identify
Bacteria associated wilh acute bronchitis include Myco- region, South and Cen1r.1l America, Mexico, the Carih-
!hose needing antibacterial therapy or more aggressive
plasma pneumonfae, BordeJella pe1·t11ssis, and Chlamydo- bean, the Indian subcontinent, parts of Africa and Asia,
treabnent. Generally, 1reatment is detcnnined according to
phila pneumoniae. Acute bronchiolitis affeclS the small and the Middle East
the infecting palhogcn, patterns of local bacterial resist-
bronchi and bronchioles and in infants is usually caused by ance, and severity of symptoms. The oral route is preferred Symp1001s usually develop 2 to 8 weeks after infection
RSV (see Respiratory Syncytial Virus Infection, p.949). and treatment is usually given for3 to !Odays.•S.16Broad- and resemble a flu-like illness wilh anorexia, fever, head-
Chro11ic bronchitis is defined as coug)l and spurum pro- ly, oo antibacterial O'eatment is needed for mild exacert>a- ache, letbargy, malaise, depression, myalgja and back
duction occurring on most days and lasting longer lhan 3 1ions. lftreaunent is needed lhen ampicillin, amoxicillin, pain, sweating. and weakness. Uibora1ory findings include
mon1hs in each of 2 consecutive years; other causes of doxycycline, or co-uimoxazole may be considered. Alter- anaemia, leucopenia, lymphocytosis, pancytopenia, and
cough should also have been excluded. Chronic bronchilis natives include combinations of a beta lactam and a beta- thrombocytopcnia. Brucellosis may be acu1e, relapsing. or
is often a fea!llre of chronic obs11Uctive airways disease lactamase inhibitor such as amoxicillin with clavulanicac- chronic (disease duration of more than I year) and can af-
(COPD-p.1224). Patients w ith chronic bronchitis or id, a second- or third- generation cephalosporin, a second- fect any part of lhe body, includingjoinlS (peripheral ar-
COPD may suffer acute infective exacerbations character- genention macrolide, or a ketolide such as tclithromycin. thritis, sacroiliitis, and spondylitis), hean (cndocarditis),
ised by increased dyspnoea, sputum production, and spu- PatienlS needing hospitalisation wilh moder.lie 10 very se- liver (hepatitis), the CNS (meningitis, encephali1is, menin-
tum pW11lcnce. These may be viral in origin, but bacteria vere COPD, but wilhout risk ofPseudomonos ac1-uginasa goencephalitis, meningovascular discase, brain abscesses,
are often present in purulent sputum, the commonest being should be treated with a lluoroquinolone or amoxicillin and demyelinating syndrome), and the reproduclive sys-
Streptoe0«-us pneumoniae, Moruxella catarrhalis, and with clavulanic acid. Those at risk ofP. aeruginosa should tem (epididymo-orchitis). Relapses occur in aboot I 0% of
Haemophilus injluenzae. be treated wilh a fluoroquinolone. patients, usually in the first year after infection, and typi-
Treatment Long-tenn prophylaxis in patients with frequent exacerba- cally cause milder symptoms.l
ACUTE BRONCHITIS. tions ofbronchilis is controversial. A systematic revicw 17 Treatment of brucellosis shortens the dwation of illness,
Antibacterials are not recommended in most cases ofacute of the value of antibacterial prophylax.is in chronic bron- and reduces complications and the risk ofrelapse. Tetracy-
bronchitis.1.2 A systematic review1 and mcta-analysis4 of chitis concluded that ii did have a small but significant ef- clines, although hig)lly DClive against Bruce/la spp., arc as-
clinical srudies in pa1ients with aeule bronchilis suggested fect in reducing tl1c number of days of illness, but I.hat it sociaLed wilh high relapse rates when given as monothcra-
diat althoug)l they may reduce the duration of symptoms, had no place in routine lherapy because of concerns over PY and therefore combination therapy is now used.
lhe benefit is modest. Similar findings were reported when adverse effects and the development of resistance. Guide- Common regimens are:
amoxicillin was gi~·en for lhe treatment of bronchitis in a lines for COPD management do not advoca1e prophylactic • doxycycline and rifampicin botl1 Or111ly for at least 6
community with a high prevalence of HIV-infected pa- use of antibaclerials. wceksU
1ients.' However, patients with acute bronchitis suspec1ed I. We nu I RP, Fowlu AA. Acute bronchitis. }l Eltgl J Med 2006:
or confinned to be caused by pertussis infection should be JSS: 2125-lO. • doxycycline orally for 6 week$ wilh a parenteral
treated with a macrolide orco-trimoxazole.1 For further in- 2. BnuNn SS. Chronic cough due to acute bronchitis: ACCP cvi. aminogl'ycoside (slreptomycin,6.7 gentomicin,s.s.9 or
dcncc-bas~d clinical practice guidelines. Chest 2006; 119 (I
formation oo lhe treaunent of pertussis, see p.199. aaJllllJ: 9$S-1o;s. netilmicin 10) for the fiJ'SI I to 2 weeks
Beta agonist bronchodilators are sometimes used to relieve 3. Smiih SM, ~I of. An1ibiotic.s for acute bronc:hi1is. Available in Fewer relapses have been reponed witb doxycycline and
The Cochrane Ontabuc of S)'S.tcrn11tc Rt\'iews: Issue. 4. O.lch-
the coug)l even in people who do not have asthma. A sys- tller: John Wiley; 2004 (1eeessed Ol/02ll 0). streplomycin than wilh doxycycline and rifatnpicin, per-
tematic review6 on the use oforal or inhaled beta agooists 4. Benl s. er of. Anli'bio1in in acute bronchitis: a mcJwnalysi.s. haps due lo rifampicin reducing plasma concen1ra1ions of
concluded that they should not be used for the treatmenl of Am J Med 1999; 107: 62-7. doxycycline. 11 Higher relapse rates have been reported
uncomplicated acute brondlilis. However, in paticnlS with S. Nduba VN, ~'al. rt:iccbo found c9uivalcm to .amoxktlfin (or wid1 netilmicin than with gentamicin.' 0 Srudies12•1) have
trca1mcn1 of acute bronchitis in Noirobi, Ktny:i: a tripSe blind,
airflow obstruction and wheezing at lhe onS'CI of die illness randomised, equivalence trial. n101'0X 2008; 63: 999-IOOS. sho1'·n that treatment wilh a fluoroquinolone plus either
some benefit was seen, but the evidence is nol well sup- 6. Smucny J, «I"'· 8eta·2·agontsts for acuce: bronchitis. Av.,ilobte
in 'The Cochrtnt Dat3b1sc of Systematic Rclficws; Issue -4.
doxycycline or rifampicin is effec1ive allhoug)l fluoroqui-
ported. The American College of Chest Physicians (AC- Cbich<11er: Jolm Wiley; 2006 C•=ssed 26/0211 0). nolooe monotherapy is not A review of the li1£ra!Ure on
CP) suggcsis that in selected aclul1 patients wilh wheezing 7. Anonymous. Antibiotics ior etac:crbation! of chronic bronchi- Ouoroquinolone-bascd combination trcaunent did not sup-
and a cough, treatment with a bela agonist bronchodilator tis? lonaf 1987: ii: 2)-.44. pon their use as f~-line treatment, 1l bu1 they can be con-
may be useful. 2 Inhaled antimuscarinic bronchodilators 8. Sealey H. <I ol. ls an objective as:ses:sment of 1nubiotic therapy sidered as part of an alternative regimen for J>31ients who
tn cu~rbatians of chronic hronchilis possible" J Antimic.rob
have not been studied for acute bronchitis and are dierefore Cl1omu1hrr 1993; 31: 19}-7. have relapse or toxicity problems with the usual first-line
not recommended.2 Antitussives containing codeine or 9. Baher MS, rt ol. Chronic Bronchitis Working Group. Coned tao antibacterials. Co-trimoxaiole when used is usually given
in triple-drug regimens.3
~~~f~1=~r~~~~=~a~[~;~~u!r :::cS::d::l;~~~:d~f
dextromethorpban are occasionally useful and can be giv- 0
en for short-term symptomatic relief of coug)ling; howev- chronic bronchitis.: executive 1um1niry. Can RapirJ 2003; 10: A systematic review and meta-analysis 14 of 30 ran-
er, expec10r11nts and mucolytics are not recommended.2 248-S& domised conb'Olled studies on the O'catment of brucellosis
ACUTE EXACERBATION OF CHRONIC BltONOllTlS (AEC6). 10. Anchoniiten NR, et al. Antibiotic lhenpy in exacerbations of
chronic obstructive putmonary disease. Aun /111cr11 Mtd 1987: found _thal a triple drug regimen of doxycycline, gen-
Treatment of AECB includes bronchodilators, systemic 106: 1 9~204 . 1amicin, and rifampicin was better than doxycycline plus
corticosteroids, antibacterials, and oxygen as necessary. 11. Ram FSF. #I ol. An1ibi0tics for C)Cacertx11ions or chronic ob· an aminoglycoside. It also found ihat 6 weeks oftreatment
Treatment with antibacterials is discussed below, while 1uuc1ive pulmonary disease. Availahlc in Tht Cochnne Dua·
base of $Y51c-matic Reviews: Issue 2. Chichester John Wiley; was associated with a lower rate of relapse thon treatment
treatment with oilier drugs is discussed under COPD (see 2006 (>ca:ss<d 26/04110). regimens of30 days or less.
All cross-references refer 10 cnlries in Volume A
 Antibacterials 175
Tel1aCyclines should be a"Oided in young c·hi/dmr (usual- Campylobacter enteritis moma. p.201), but has since been assoctatcd w11h other
ly specified as below 8 yea:s of age in the US 811d below Sec under Gastro-cntcritis p.183. cli111cal presentations including pharyngitis (sec p.199)
12 yan in the UK). The preferred regunens forthesechi!- Md has been implicated in the pathogenesis of ischaemic
<Len 1ppear to be co-trimoxazole w11h rifampicin both hean disease (sec Atherosclerosis. p.1276).
orally for at least G weeks or OCHnmolUl.ZOle orally wilh Cat scratch disease
Cat SCt8teh disease usually occurs in humans after a cat C. psi11oci is transmitted to man from birds and causcs psit·
pa1cnteral gentamicin for tl1e first 2 "'eeks. i.6 Alternative tacosis, which also affects the lungs (see J>sitt1cos1s,
regimens include rifampicin orally for at least 6 weeks scratch or bite. The condition is characterised by regional
Jymphadcnopathy and i~ often self-limiting, but may be p.203).
with either gcntamicin or netilmicin for the first 5 days.6
disseminated in immunocompromised pa1ients. Dissemi- C. 1rochoma11s cnuses a wide range of discas~s. Many RrC
F'o1· the treatment of brucellosis dulingpregnoucx WHO sexually transmitted and u1e spectrum is similal' IO that
recommends rifa.mpicin monothernpy for 6 weeks as the nated disease l)'pically involves the nervous system (in-
cluding the retina). visceral organs, or bone. wid1 Nek<trta go11arrflae.ae (sec Gonorrhoea, p.206): in-
drug of choice and that co-lrimoxazole or tetracycline fections with the two organisms often occur together. In
should only be given if rifam;>icin is unavailable; SlrCpl<>- In die 1980s a Gram-ncg111ive bacillus presumed robe re-
sponsible for cal scratch disease was isolated and subse- women C. trocho11101is may cause Clldomelritis, pc.Ivie i11-
mycin is contra-indicated. Co-trimoxuole with rif- flamm1t~· disease, ectopic pl'egnancy, and infertility In
ampiCln for 4 weeks has also beat med.6 quently named Afipiofelis. However, it has since become
apparent that Bor10nella hcntf'/oc (fo~ly Rocholimoeo the USA 1 routine scrcaung for C frochomafis infection
No one antibacterial combin1tion has been found to be su- is recommended in all sexually active women aged 25
perior for the treatment of spontJ;.~11is althoug)l a 3-mooth herudoe) is the main cause orcat scratch discase. •·J There
has bec:o no specific ant1baclenal therapy and treatmcot yean or less, whether or not they are pregnant, and in
course of doxycydine with ciprollox.acin has been pro- women aged over 25 years if they are considered to be at
posed based on an evaluation of the li1e1111.11re." In the with antibacterials is aenenlly OOl recommended in pa-
increased risk ofinfection.
treatment of neurobrucelloslr, the length of therapy ap- tients with mild to moderate infection.1.l There are, how-
ever; reports of successful treatment wctb gentamicin, co- Guidelines IJl"Oduced by WH0,3 b)' CXP'fl groups in the
pca~ to be of ait1C1I impo11ance; relapses may occur after
trimoxazole, aod ciproOoxacin.1 Azithromycin has also UK,"-' and by the CDC in die USA2 for the treatment of
irea1men1 lasting only 2 to 3 weeks and it is recommended
been found to be ofbem:fit in adults" and a S-day oral reg- uncomplicated anogenillll infection wilh C. rrod10mar/s
that doxycycline be given with 2 or more other drugs (rif- are as follows:
ampicin, an aminog]ycoside, co-tiimoxazole, or cefiriax- imen is considered the treatment of choice in both adults
and children with extensive lymphndenopathy. Oral doxy- •WHO:
one) for~veral months depending on the response. Coni-
costeroidsare often given but their efficacy is unproven. A cycline with oral rifamp1cm may be given as an alternative • oral doxycycline 100 ma twice daily for 7 days."''
similar treatment regimen is used in the management of for lhcsc patients and this combination, given for 4 10 6 • asinglc oral dose ofazhhromycin I g
paediatric neurobrucellosis and a 3-drug reghnen (doxycy- weeks, is dic recommended trcauncot for complicated cal ahematives, aivcn for 7 days, are:
cl in~. rifampicin, and an aminoglycoside) given for 3 saatch disease. I • cnl tmoxoc111in SOOmgdvtttimcsdaily
months has been sho"'11 to be effective. In young children Bacillary an&lomatosis, in which both 8. Mnseloe and B. • cnl ct)'lhroinyc1n SOO mg four umcs daily
doxycycline should be replaced with co-tr1moX1Zole.16 qu1111ono (lhe causati~'C organism of trench fever) have • oral olloxlCut 300 nig IWIO! daily
Treatment of endocarditis in adults generally ~uires been implicated, and bacillary peliosis bep:itis (caused by • oral 1c1ncyclinc SOO mg iOur tones dolly
long-term uiplc or quadruple drug regimens (a lelraey- B. henstlae) occur mainly in inununocompromised pa- •UK:
cline. an aminoglycoside, rifamptcin, and/or co-lrimox.a- tienlS, especially in those with HIV. Bacillary angjomato- • first-line rhcnpy is lhc same as WHO
z.ole) usually with surgical \'llve replacemenL n.11 Treat- s1s is generally cbaraacnsed by cutaneous or subculane- alternatives arc:
men1 should be continued for 3 monlhs or longer and some ous vascular lesions. Symptoms of bacillary peliosis,
where lesions affect the liver, arc non-specific, with or • oral erythromyc1n SOO mg "'-iecdaityfor 10 lo 14 days
recommend the addition ofceftnaxonc and/or o Ouoroqui-
without cutaneous invoh•cment IJ Disseminated disease • or.ii ollox.an 200m11rwice dailyo.-400 nia onccd111ly for 7
nolone 10 reduce the need for suigery. Cardiac complica- days
tions in children are generally less severe than in adults and in immunocompromised patients has responded to treat-
ment with doxycyclinc. erythromycan or azithromycin.1 •USA:
treatment with 1ettacycline for 3 weeks with streptomycin
for 2 weeks has been found lo be effcctive.1 * Oral Cf)1hroo1ycin for 3 monu1s is the drug of choice for
bacillary angiomatosis; it should be i:ivcn intravenously in
• firsl·hn< lhcrapy is rhe same as WHO
alternatives, given for 7 days, are:
Brucellosis can be prevented by controlling and elimina1-
1ng infected animals, pasteurising milk producu, and vac- severe disease. Oral or intravenous doxycycline may be • oral erylhromycin 500 mg four times daily
cinating cattle and o!hec Ii~ There is no human vac- given as an alternative. lmmunocompromised patients • oral erytbromycin erhylsuecinate 300 mg four times doily
cine curTCntly available for brucellosis, although many with acute, life-threatening infection should be treated • oral o1loxxin 300 ma twiec daily
have been tested and so~ hs\'C been available penod1cal- with rifanipicin p!userytluornycin or ri&mpicin plusdox- • or1l ICYOno.ocm 500 mt1 once daily
ly in various countries.3 ycyclinc; the laucr choice is preferred in CNS disease..1.J Pregnn111 women infected with C irochoma11s may be at
I. Bluoo JM. Olu R. BNeClla ....- . . Rev-I v0«1ne ti 1 Care is required in p1tients wilh AIDS since the lesions of nsk of premal\lre rupeurc of membranes and preterm la-
._of.._n bnlccllosis. Lnncn 199J, JO: &OS baallary angJomatosis closely resemble those of Kaposi's bour (sec J>reJTmture Labour. p.202). They niay also infect
l Alhfotd OA. d J Ad"'tnc" ~Vf'flts jp h\19UM u.ocj11tcl w1d1 sarcoma, and if the diagnosis IS missed, life-saving anti- their offspnng to cause ophthahoia nconatorum (sec Neo-
OC:<od<otal C\_.,e to lhe liv..1oclt bnottlloolo vxc1no RBS I.
J~l("C'1M2004. 22: )4)~. bacterial therapy may not be gi>cn.' nacal Conjunctivitis, p.193) or pneumonia (p.201 ). lnfecl-
l l'lrp.. G. <t nl Brua:llOlis.1V £"$/ J M<d ?OOS. l5l: 2325-36. 1. Rolatn JM, sol Recon11ncnd~uons f« •rnMtit111 of hcman in- cd ptegnant "-Otncn sbould be treated and the followmg
4 FAO/WllO. Joint fAOr"WHO expert eomm1Hcc oct bn11tcdos1s. fections C:tUSf'd by S-tonclln tpc(ifl A1'1u•K't0b Agna ClwJR· regimens have been recommended:
11\lh report WHO T""" R•p X, 740 19ft6. AIM> ...,la~I• 11' Othtr'.!00-l; 48: 1921-lJ.
h11p;l/hbdoc.who.inll1r11WHO_TRS _740 pdr (ICCUl<d l. Florin TA. n of. Beyond cal acrotch d11use: w1dcnq spc:clrum • WHO: treatment for 1 days with:
21/05/07) of B2r1onclla hcnnfac infection. Ptdio1r;o 200S. 121: • oral erythromycin 500 ma four 1imes daily..,.
$. Ht:ahh Prot.ecti«'t1 A'tncy. Gutdt-fi.nn for action in ~he f'\'C'nt of •1413-25.
a dchbeta1h: ttlcasc: bruc.~tlo1is. 'kn~1 I,,, IS June 200'1 • oral 81110.'(o<dhn 500 mg thr<c times daily
3. English R. CM·!<rllth d1...,. Ptd101r R<v 2006; 27: IU-8.
~;.~~~~~h"i'l 9~91~~~sooi·~~~u1k~:J:,~,HPAw•bFilct 4. D:w J w. ~r t1I. Prospttli\oe 1111ndo1:nizcd duublc blind plaotbo-
•UK:
6. Solm J. ff ttl Rceoa.1lition ;md op11mw• trc:J1nwnt of brucclk>- controllcd ev11t111ton or 11.1chromyc11\ lor treatment or ctl· • as for WHO.,,..
111 Drwp 1991; SJ: 24S-56. t1Cmcto dlKO$•. P<dlntr hl/tct 0., J 1991: 17; 447-Sl. • oral crythroiny<in 500 ms twice daily for 14 days. tx
7. Soter• J. ""' Doxytydine-rif.lmpin versus do~)'Clino-Jt.rcp-- S. l:tyk:Jr AG. ~,DI. Cat·~cnnch. l(apol.1"1 W"Mmt. i'lnd bacillary • a Jina!• oral dosc of 11%Jlhron1yc1n I i:
1omycln •n trntcncnt of hum:tn bruull051s dt.te 10 Brucclla an1.om:111oei11. la,K.:t 1993; 342: 6&6
mch1C'fl'4L A1111M'iaobAgent1Chtmnth«199S. lt: 1061-7. •USA:
8. Solcr1J,.,#. T-n<ofhu1nonbnl«llos>1,.i1flclo'<)'C)<hnc • a sioglc oral dose ofu11hromycin I g ..-
and &tntamtcin. Art11M1C1'0ti Aa1n11 Chi>IM>th#r 1991: •I: Cellulitis
I0-*4 • oral amo.·ucilhn SOO 1111 lh1tt tunes daily for 7 da)'1
9 Sokr> J. <I ol. A .-,,ZJ<d. doubk-t>l:nd Rudy lO - doc
See under Slcin Infections. p.208. altcmati\llCS arc;
opomaf d11r.nt0d of dol:)'C~l.nt lttatmmt for huNn bnecdJo.
..._ Cf,,. Jnj«1 Dll 200<. lt: 1776-S?. • ~t11111narcgimens
10 Solen J. ttl ttl. Tttat.men1 ol 111.....an ~tlo1i1 w11lt n«1lmicld Cervicitis Sexual partners of those infected "'ith C 1mchoma1is
Md clo>)<y<hM Clm lnf«I Di> 1996, ?l: 441-S. Gmorrhoc-<1 in women occws mainly as ctrvicitis, but mu- should be tested and trcalcd.2 "'
11 C~ro JO. <t ol. PO$$il>lc ""p/>CIO-s of do•y<)'<lme-r.. copurulent ~ervicitis 1s frequently c¥used by sexually
fampin •ritnachon for l'rcaoncn1 o( bfw'cllo,11. Arui111Jc1vb For further reference to sexually iransm11tcd C 1rochomo-
Al""' 0-,,,1M. 1994; JS: 27911-2802 transmiued Ch/am)'d•a rrochomart.r The two infections 1is uifections, see under Epididymiiis (p.180), Pelvic b1-
'2. ~i':w•t:f.t~pk,~'ii.O~~x~,~~,~~u:t r~;:/:!';.;;.~u! ~:,ro~i~:
often occur together and should be 1reated concurrently. 0ammatory Disease (p.197), and Urcth1itis (p.21 S)
cllno<1l 11ial [ISRCTN 11871179). DMC /llfttt 1>112004; 4: 18. Guidelines for tl'ea1111em are ll\'Cll under Gonorrhoea, Specific serotype.s of C. trocltommis are responsible for
tu~~~:!': ;~~~~~/www.biomcdc:cnrral.com/l 41t-2334/4/l8 p.206, and Chlamydia I J11fcc11ons, below. a1101hcr sexually 1runsmi11cd disease. lymphogranulolllR
13. F'al;,g.as MU.. Bht1ou1 IA Qu1noloncs for crcalmtnt of h\lrn1n vencreum (p.201).
hrvctllo.sis: c.rit~al revliC.., of I.he evidence fr<uo 1n~oloai· Chancroid Reactive arthritis (see Bone and Joint lnfoctions, p.173)
cat and clinical stvdits. An11Mkro6 Agcms Cbcnt0th• 2006; may be secon<bry to chlamydia! infections.
SO: 22-33. See under Sexually Transmitted Diseases, p.20S
14 . Sltall~y K• ., of. Trc•.....,I ofhwnaa bn1ccllos1s; '>"''""'I>< Olhcr C. 1rochomotis infections that are not sexually trans-
R"...- Md mtta-inatysis o(raDdcMti:wd co..1rolled trials. IW 1111Ued include trachom3 and inclusion COllJunctivitis in
200I. 136: 701-4. Chlamydia! infections adults (sec Trachoma, p.212).
I~ ,.....ClnM Trcatmcntofb:uccltatprtndyhhs lusonsfrom
The chlamydia organism belonp to the f~mily Oilamy-
" •lrliPOl"bJc f'ON•.aRll)"sis •nd •r'llt.tlt ~ or ctr.cocy or. US Prcvcn11n Sc:I"\ K'C1 Tasl. r orc-t $cf'f't!:ntng for chlamydGI ...
n~~iA•lg rcsuntn. /,., J ""'*~ lfUnt:I diaceac. Species that are po1tllQGcn1e in man are Chlom;:d<>- l<d1... (JllllC :?007). A\01blok II li\1pJl,.-ww.,hqw.JO'IJ>111C/
~.14:~-7. phila pneumon~. Chlomydoplt1/a F•fto<:i, and Chlamy- -•t'usp1<htm him (ll«Ul<d 0l.o(llt()7)
16. Mtbttb YKR• ., ..t Pxd..,rK "coorolonac<lloo3- . - r<pon and dia frachomatis; they arc generally scnsilive to l. COC. ~....uy ir•nmo111<d d - ll'ftlmen1 &••dclincs 2006
lil<nN« ,,.,... J ltl/ra t99&; 37; 5M2. M#ll-R 2006. SS(RR·ll): 1-9~. Abo a.11bbl• •I. hllp://
11. R,:f'~• JM. <.t ol Brv«lb ~rditls: d1na•. d1.1~. tetracyclines or erytl1romycin ,."'" c:dc.aovt"'m"r/POF/1rlrrS511.pdf (11C.CCSJ<d 23JOJ/07)
;l: ~;.:ro~oc approach. £,,, J CHn 1\.ficn:>hlol ln/«t Du 2003 0 C pneumonioe (fom1erly classified as a TWAR strain of l. WHO wldcl- for •he IOtlllg<al«ll o( scw;olly 1ronsn1111ed
tn(cclions. Gtnevt : ·wuo. 2003. Also nailtbfo 11:
IP Al Oel)Quk S. 111 ol. Brucclb cndonrditis in prollhtt•C valws. C. p.•irux:i) is a respiralOf)' pathogen. It was fim described h11p./lwhqhbdoc who inlfpublirnioosl:?OOJ/92' I 546263.pd r
CM J Con/lol 2006; ll: 971-4. as a cause of coll\munity-acquired pneumonia (see Pneu- (OCC<J><d WOJJ07)
176 Antibacterials
Airway cle2rance by manual chest percussion and me-
4. Clinic:al Efftctiveniess Group (British Associa1ion for Stxuat those with gastrointestinal risk factors. 22 Systematic
Health and HIV). 2006 UK nilional g_uideline for the mana;e· chanical techniques including cheSt-wall or airway oscilla- reviews23.Z• and the US guidelines9 concluded there was
mcnt of gc.ni1al Incl infection with Chlamydia tnchomati1.
Availabtc at: hnp:/iwww.blshh.ora/dOC'umen1.s/61/6J.pdr (ac· tion helps to loosen secretions and aid their removal.6 Dor- insufficienl evidence to support a role for either inhaled or
ce~d I Ml811!8) nase a.lfa; is given by aerosol inhalation and reduces lhe oral corticosteroid therapy, except in the management of
S. Sconub lntcrco11egial~ Guidelines NcO••'Ork. Managcmcnl or viscosity of the sputum by breaking down the large quan- patien1S who develop allergic bronchopulmonaJ)' aspergil-
tenieal Chlomydin troclJOmm/1 infection <issued March 2009). tities of DNA ·released by degenerating inflammatory losis.2 However, a retrospective analysis of observalional
AuibbJe u: hllp;/lwww.sign.ac.uk/pd011gnl09.pdf (accessed
lS/02110) cells. The use of domasc alfa has been associated with dalll collected for 2978 children, 6 to 17 ~ofage, who
some improvement in lung function and it might be a use- were given inhaled corticosteroid therapy reported a slow-
ful adjunct 10 bronchial drainage, although it is unclear er decline in lung function as detennined by the FEV1.2s
C holera and other vibrio infections whether it preven1S the development of progressive lung
See under Gastro-eoteritis p.183. Aggressive management of exacerbations with appro-
damage. However, a randomised, multicentre, placebo- priate antibacttrials is cruciat.'.2.26.27 Treatment should be
controlled study in children sbowed that dornase alfa based on recent culture results, but there appears to be no
Cystic fibrosis maintained lung function and reduced the risk of exacerba- additional value in combination antibacterial sensitivity
Cystic fibrosis is a genetic disorder associated with the tions over a 96-week period.1 US guidelines therefore also testing. 28 In patienlS with Ps. aeruginosa infection a com-
production of abnonnally viscous mucus. The underlying recommend the long-tcnn use of domase alfa to improve bination of intravenous antibacterials, typically an
defect is mutation in the gene that codes for cystic fibrosis lung function and reduce exacert>ations.9 Nebulised or oral aminoglycoside such as tobramycin and a beta-lactam
transmembrane conductance regulator (CFTR), a protein mucolytics, such as acetylcysteine, carbocysteine, am- with antiPSeudomonal activity such as ceftazidime, is fav-
that functions as a chloride channel. Mutations result in de- broxol, glutathione, and mesna arc ~enerally nOI consid- oured.l.26.27.29.lO Ooce~ily dosing with the a.minoglyco-
fective ion tronspon with reduced chloride ion secretion ered to be effective in cystic fibrosis.1 Inhalation ofhyptt- side is as effective as giving it in divided doses, and may
and accelerated sodium ion absorption, and related chang- tonic saline has. however, been shown to be of benefit11 be associated with less nephrotoxicity in children.31 Migh
es in the composition and properties of mucin seaeted. (see p.1833) and has become part of management in many doses are necessary because of the poor penetration of
Now that patien1S with cystic fibrosis usually survive into cenires. •-3 Inhaled mannitol is also under invcstigation. 12 these antipseudomonal antibacterials into the si1e of infec-
adulthood, it is increasingly seen to be a multisystem dis- The time required for such therapies and their associated tion and their increased renal clearance in palien1S with
ease. However, the main clinical manifestations are still monitoring may prove challenging to patients and !heir cystic fibrosis.32•33 Treatment is generally given for 2 10 3
pulmonary disease, with recurrent bacterial infections and families. 1 weeks although there is no good evidence 10 support a par-
the production of copious viscous sputum, and malabsorp- In young patients with early disease, prevention or erad- ticular length oftherapy.JOJ4 Intermittent elective intrave-
tion due to pancreatic insufficiency. Other complications ication or infection for as long as possible is a reasonable nous therapy has become more practical with the develop-
include male infertility and hepa~biliary disease. There is aim, in order to maintain good lung funclion.2 Staphyloco- ment of regimens that enable patients to be treated at
inaeased salt loss in sweat. ccal infections commonly develop during the first decade home.19·" US guidelines3° reconunend that airway clear-
Pubnonary disease is the main cause of mortality. Cystic of life, and while some clinicians start an1isiaphylococcal ance should be increased as part of the treatment of an
fibrosis is an underlying cause of bronchiectasis (chronic antibacterials on diagnosis of cystic fibrosis, ()(hen wait acute exacerbation and cluonic maintenance therapies be
dilatation of the bronchi) as a result of excessive secretion until the first clinical infection occurs. Once started, continued; there is no clear evidence for or against contin-
of mucus and recurrent infections. Cough and CJ<cessivc· antistaphylococcal therapy is continued indefinitely in ued useofinhalcd antibacterials in patients given the same
production of sputum arc characteristic of cystic fibrosis some centres, while others only tn:at when symptomatic antibacterial intravenously.
and the IW1gs are generally colonised with bacferial patho- exacerbations or positive sputum cultures occur. Systemat- Infection with B. cepacia complex is difficult to treat be-
gens, especially mucoid strains of Pseudomonos oervgi- ic reviews confinned that antiStaphylococcal treatment is cause most antipseudomonal antibacterials are ineffective.
11oso. Pseudomonal pulmonary infection is the main cause effective and also concluded that prophylaxis is likely to Co-trimoxazole has been suggcsted 36 and can be given
ofmorbidity and mortality in cystic fibrosis. Monitoring of be beneficial in young childicn with cys1ic fibrosis. 13·14 lo orally;l 7 meroperiem and ceftazidime have some in-vin-o
bacterial pathogens in the sputum, including their sensitiv- the UK, flucloxacillin or co-amoxiclav arecom.monly giv- activity, and temocillin has been tried.27 Other problems
ity, is necessary for rational 1reatment. Apart from Ps. oer- en.2 Jt is unclear whether in1ennittent or continuous thera- may include meticillin-resistant Staph. 011reus infections;
ugi11oso, Staphylococcus oi1reiis is often present and may py produces the best clinical outcome. Other potential dis- intravenous tcicoplanin has been used, as have oral dox~­
be the main pathogen in infants. Dw*holdcria cepocia advantages to prophylaxis are the possible early cycline or linezolid where sensiti,ity patterns permit. 1
complex (Pse11domo110S cepocio) has been recognised as a acquisition of Ps. aeruginoso infection•S (this seems to be The possibility of fungal or viral infections should also be
cause of rerious lw1g infection in cystic fibrosis and is a risk mainly if broad spectrum cephalosporins are given) considered27
readily transmitted by social contact. Jn a proportion who and an increased incidence of drug-resistant staphylococci Nutritional management of cystic fibrosis should ensure
acquire it, B. cepocia has been associated with rapid deter- with continuous lherapy. 16 Jn view of this risk of earlier or adequate calorie intake from a balanced diet in order to
ioration and death. Other bacteria isolated include Haemo- more frequent Ps. aervgi11osa infection, guidelines devel- counteract malabsorption due to pancreatic ir1suflicicncy
philus injl11enwe and atypical Mycobocteria spp. oped in the USA, by the Cystic Fibrosis Foundation, do and the increased metabolic requirements of patients with
Various diagnostic methods are available1·3 and clinical di- not support the prophylactic use oforal antistaphylococcal cystic fibrosis.37.lt SupplemcntS of the fat-soluble vita-
agnosis of cystic fibrosis may be conlinned by establish- antibacterials.9 mins A, D, and E, and sometimes vitamin K, may be nec-
ing tha1 chloride concentrations in sweat arc rdised. This' Management of chronic infection is aimed at control of essary. lovestig.ation of bone mineral densiry.19 and direct
may be done by using the pilocarpine sweat tes1 (see Pilo- bacterial lood,2 (since permanent eradication is impossi- assessment of vitamin status• 0 ~uggest that current supplc-
carpinc, p.2048). Identification of gene mutation is possi- ble), improving lung function, and reducing exacerba- mcn1S may be inadequate. Pancreatic enzymes, as pancre-
ble and may be used for further confirmation of the diag- tioos.9 Select.ion ofan antibac1erial must be individualised, atin or pancrelipase, are taken before or with each meal or
nosis and identification of carrier status. In some areas and will depend on the infecting organisms.2 and local pre- snack.41
neonatal screening programs 10 measure immunoreactive scribing policies and availability. Long-tenn intermittent Many other interventions have been tried.4 2,•3
trypsinogen concentrations (a marker associaled with pan- treatment with inhaled antibacterials, pnrticu larly to- Bronchodilators including both beta agonists and antimus-
crea~ic in~ury) have been inslituted, to allow for early in1er- bramycin, is favouroo;•-l.9 Olhcr nebulised anlibacterials cariiiics may be useful in selected patien1S altho~ there
ven11on. that may be of benefit include aztreonam and colistin.'·17 are few meaningful rcsul1S from clinical smdics A ther-
1bc reduced morbidily and improved survival in patients A systematic review confim1ed that inhaled antipseu- apeutic trial is often justified in individual patients since it
1~ith cystic fibrosis arc largely due to the management of domonal antibacterials improved lun11. function and re- is difficult to predict which patients will respond.•? While
pulmonary disease with antibacterials and physiotherapy duced the frequency of exacerbations. 1i Although there is use by nebuliser is regarded as most effective, inhalers
and to nutritional management. Several reviews have dis- some evidence ofan increase in resistance with such treat- may be more practical where compatibility with otl1er neb-
cussed both established and experimental thcrapy. •·S De- ment," it is claimed to be less frequent than fcared. 1How- ulised drugs cou ld be a problem.0 Alpha1-proteinase in-
spite the successes, the evidence base for some procedures ever, US guidelines concluded that there was insufficient hibitor, the main inhibitor of neutrophil elastase in the lung
is scanty,2 and there may be variations in management be- evidence to recommend for or against the long-te11n use of has also been investigated's as has pentoxifylline,46 a drug
tween ccnires. However, 1he comer.;tones of current man- ncbulised antibacterials other than tobramycin, including with anticytokine activity. Although cysteinyl leukOlrienes
agement are: 1·3 colistin, gentamicin, or ceftazidirne.9 Oral antipseudomo- have been found in increased concentrations in airway se-
• mechanical airway clearance, with the use of adjuncts nal therapy has not been conclusively shown to be of ben- cretions of paticn1S with cystic fibrosis and thought to con-
such as dornase alfa and hypc11onic saline efit in chronic infection, 19 and is generally avoided be- tribute to lung disease, there is insufficient C\~dcncc to rec.
1
• prevention or eradication of pulmonary infections in cause of fears of resistancc. ommend the routine use of leukotriene inhibitors and
early disease The macrolide atithromycin is, however, used orally in antagonists (such as montelukast) to improve lung limc-
• suppression of bacterial load through antibactaial ltcat- chronic infection, but may be acting as an irnmunomodu- tion and reduce exacetbations.9
ment of chronic infection in more advanced disease lator to reduce inflammation rather than specifically as Experimental treatment aimed at modifying the pulmo-
13 20 nary disease process has also included ion transport thera-
• use of ibuprofen or azithromycin to contr0l lung inflam- an antibacteriaJ. • ·9· A systematic re~iew1 on the use of
1

macrolides in cystic fibrosis found evidence of a small but py. This involves the use of aerosolised drugs that either
mation
significant improvement in respiratory function at 6 inhibit sodium ion absorption across airway cpithelia (for
• aggressive antibacterial treatment of pulmonary exacer- example the sodium channel blocker amiloride) or induce
months with azithromycin compared with placebo; the
bations chloride ion secretion. However, nebulised amiloride was
role of other macrolides was unclear. A small anti-inflam-
• nutritional support to ensure an adequate iniakc of calo- matory benefit has also been reported from treatment with not found. to be a useful adjunct in paticn1S on optimal
rics and salt, with supplementation of pancreatic en- high-dose oral ibuprofen,12 and this is used in some cen- treaunenL47
zymes and the fat-soluble vitamins A, D, E, and K tres, f:rticularly in the USA to slow the loss of lung func- Jn patients with severe lung disease, oxygen therapy may
• maintaining regular physical activity tion. ·9 1Jowever, there are some concerns about the polen· give some relief of symptoms but its cffoct on mortality
Guidelines for the management of infants with cystic fi- tial for adverse e1Jec1S; it has been recommended that if and morbidity is uncertain.4 8 At present the only available
brosis have been developed by the Cystic Fibrosis Founda- used, such therapy be stopped in patients who require in- treatment for patients wi1h end stage pulmonary disease is
tion in the USA.~ travenous aminoglycosides, and should be avoided in lung transplantation. Although individuals witl1 cystic ti-
All cross-references refer 10 entries in Volume A
 Antibacte1ials 177
brosis do as well as those referred for lransplantation with 33.10uw OJ.,., (I/. Pharmacokinctic optimisa1ion or 3ntibatteri:i.I be treated for a further I0 days. Infection with diphtheria
od1er lur.g diseases, lhe 5-year survival rate after the pro· 1rcatmcnt in patlents with cystic fibrosis: current practice and
~ugg~tions for fururc directions. Clin Phormacnkinet 1998; 35: does not always confer immunity, therefore those recover-
cedure is reported 10 be only 50%. 1 437-59. . ing from the disease should also receive active immunisa-
Somatic gene therapy refrescnls the nearest approach to 34. Fem:andes B. et al. Duration of inU'avcnous antibiotic therapy in tion. 3 Cutaneous in1ec1ion is treated similarly, allhough ao-
people wid1 cystic fibrosis. Avaifable in The Cochrane Database
a cure for cystic fibrosis.• It aims to introduce the normal of Systcm:itic Reviews; Issue 2. Chichester: John Wiley; 200S titoxin is of benefit only if very large ulcers are present.
CFTR gene sequence into cells of affected tissue. Most ef. (accessed 25!06108). Close con1acls ofprimary cases of diphtl1eria, and those in
fort has been directed at gene delivery to-the lungs using 35. Woller JM. er al. HQme intravenous therapy in cystic fibrosis: a the community identified as asymplomatic carriers, may
prospec1ive randomized 1rial examining clinical, quality of life
adenovirus vectors or liposomes, but resulls have been and cost osptcts. Ew· Resplr J 1997; 10: 896-900. be given a 7-day prophylactic course of erythromycin orai-
variable.50•53 Difficulties encountered include inefficient 36. Abramowicz M. ed. The choice of antibactcrill drugs. In: Haud· ly or a single intramuscular dose of benzylpcnicillin,1 in
book oftmtimicrobiol 1hemp)'. 18th ed. New Rochelle NY: The
gene transfer, immuniry to viral vectors, and a systemic in· Medical Ltttt:r, 2008: 67. addition to boosters or primary inununisatio11 with diph-
flammatory reaction provoked by plasmid DNA. For a dis- 37. Bowler IM, et al. Resting energy c:o.;pcndirure and subscrale ox- theria vaccine. Cultures should be taken 24 and 48 hours
cussion of the general principles of gene therapy, see id1t1ion rates in cys.tic fibtosis. Arch Dis Child 1993 ; 68: 754-9. after stopping tl1erapy to confinn eradication.1 Epidemics
p.2530:·: 3S. Green MR, e1 ol. Nu1ritional management of chc infam with are most effoclively controlled by mass immunisation of
cys1ic: fibrosis. Arch Dis Child 1995; 72: 452-6.
I. Boyle "'11'. Adul1 cysiic fibrosis. .!AMA 2001; 298: 1787- 93. 39. Haworth CS. e1 ol. Low bone mineral density in aduhs with the entiJe population.2 ·~
2. Davies JC,., al. Cystic fibrosis. BMJ 2007; 33S: 1255· 9. <.-ystic fibrosjs. Tlu1rax 1999; 54: 961-7. r. Bonnet JM~ Begg NT. Control or diphtheri~: guidance for con-
3. O'Sullivall BP. Freedman SD. Cystic fibrosis. 1Amcc1 2009; 40. Femnchok AP. et nl. PJospcctive, long•term study of fat-soluble sultam.s in com1nunicablc diseas..: controt Commu11 Dis P11blic
373: 1391-904. vit:unin status in childrGn wi1h cystic fibrosis identified by new- .'fro/th 1999; 2: 242-9.
4. Ooull' UM. Rtccnt idvanccs in cystic fibrosis . .·frdr Dis Child born screen. J Pediarr 1999; 135: 601-10. 2. Vitek CR. Oiphrhcria. C11rr Top Microb;o/ lmnumol 2006; 30.f:
2001 ;:~5: 62-6. 41. Stallings VA, Cl ol. Clinical Ptactice Guidelines on Growth and
71-94.
S. ToncHi MR, Ai~ke~ ML.. New a~1d cmcrg!ll! therapies for pul- Nutrition Subcommittee. Ad Hoc Working Group. Evide1•ce-
hased. practice rccommenc:btions for nutti1ion•rclated nianage- 3. \VHO. Dip<he.ria vt1ccine. Wt/)' Epidem Rte 2006; Sl: 24-32.
monary comphtattons of cystic fibrosis. Dn1gs 200 1; 61: 4. Abramowicz M. ed. The choice ofantibac1erial drugs. Jn: Hand-
1379-85. !"C•Ho~ children and adult~ with c~lic fi_brosis and p:incre3tic
msuffic1cncy: rcsulls of 3 sys1emat1c re-\•1ew. J Am Dic1 AJSoc book ofa11rimitrobial tlier·opy. 18th ed. New Rochelle NY: The
6. f lume PA. et ol. Clinical Pl'ac1ice Guiddines for Pulmonary 2008; 108: 832-9. . Medical Letter, ?008: 6 1.
Therapies Committee. Cys1ic fibrosis pulmonary s:uidclines:
airway clearance lhcrapies. Re.'ipir Cor~ 2009; S4: 522-37. Also 42. ConWily SP. Walson A. Ncbulise<I bronehodilators, conicostor-
available at: h11p://www.rcjo urnal .com/ conten1s/04.09/ oids. and rhDNase in adult pa1ien1.s with cys1ic fibrosis. Thorax
04.09.0Sll.pdf(aceeued 281()4/10) 1997: S2 (suppl 2): 564-8. Ear infections
43. Spencer O.'\. Nebuliscd bronchodilators, an1ibiolics 3nd rhD-
7. Jones-AP, \Valli:;; C. f.'>ornase alfa for cystic fibrosis. Available in Nasc for children with cystic fibrosis. Thorax 199i; 52 (suppl See Otitis Extema, and 01itis Media, p.195.
The Cochrane O:uabu:re ufSyslcmatic Reviews; Issue 3. Chich- 1): S89-S91.
ester: John Wiley; 20 10 (accessed 2S/08/J 0). 44. H:llthide C. el ol. Jnhalcd bronchodilators for cys1ic fibrosis.
8. Quail JM, el ol. A 1wo-year randomized. placebo.controlled 1tial Available in The Cochrane Database of Systematic Reviews; Is- Ehl'lichiosis
or dornasc'alfa in young paiicnts with cys1ic fibrosis with mild sue 4. Chichester: John Wiley; 2005 (accessed 1$106!08). Ehrlichioses are a group of diseases produced by infection
lung ful'lction abnormalities. J P~dlotr2001; 139: 813-20. 4S. McElvancy NG. 111 al. Actosol Ct-1 -antitrypsin treatment for
9. Flume ?A, et nl. Cystic Fibrosis foundation. Pulmonary Thtra- tyStic fibrosis. lonce11991;337: 392-4. with rickertsia-like bacteria of the family Anaplasmatace-
piC$ ~.~rntuiuce . Cystic fibrosis pulmonary guidelines: chronic 46. Aronoff SC. et of. EffecLS of pentoxifylli.ne on sputum ncu- ae, a family tl1at contains lhe genera Anaplasma, Ehrli-
medications for maintenance of lung health. Am J Respir Crir trophil elastase and pulmonary function in patients with cystic
Core Med 2007; 176: 957-69. chio, Neoricketlsia, and Wolbachia. At one time such or-
librosis: preliminary observations. J Pediotr 1994; 125: 992-7.
Also available at: http://ajrccm.atsjoumals.org/cgi!reprjnt/J 76/ 47. Burrows E, 41 ol. Sodium ch:it1nel bl1>ckers for cystic fibrosis. ganisms were considered to be only animal pathogens but
I0.'957.pdf (accessed 28104110) Available in The Cochrane DBlabaseC1fSystem .. tic Reviews; Is- it is now recognised that humans may also become infect-
10. Nash. EF, ~t al. Ncbulized and oral thiol deriw1tives for pulmO·
nary disease in cystic fihrosis. Avairahlc in The Cochrane Data-
sue 3. Chichester: John Wiley; 2006 (aac:cesSt:d 25/-06/08).
48. Elphick HE, Mallory G Oxygen lher:lpy for cystic fibrosis.
ed. 1-8 One of the earliest human forrns ofehrlichiosis iden-
b3SC of Systematic Reviews; ls.sue I. Chichester: Jolin Wiley~ A\•ailable in The Cochrane Oal8hasc of Systcma1ic Reviews; Is- tified was Sennetsu fever, a disease found in Japan and
2009 (accessed 02/03/10). sue I. Chichester: John Wiley; 2009 (accessed 25if12110). Malaysia, and which is caused by N. se1111etsu (E. smmet-
11. Wark P. McDonald VM. Nebulised hypertonie saline for cystic 49. JJ.ffe A, Cl 11/. Prospecls for senc therapy in cystic fibrosis. Areh
fibrosis. Anilable in The Cvchrl"n< Dmabase ofSys1ema1ic Re- D;s Child 1999: 80: 286-9.
su). Subsequently Anaplasma phogocy1ophi/11m (E.
v i ews~ Issue 2. Chichester: John Wiley~ 2009 (accessed 50.Collcdgc WH, Evans MJ. Cystic fibrosis g~ne therapy. Gr Med phagocytophila), E. chajfeensis, E. ewingii, and possibly
02i03/10j. Bull 1995; SI: 82-90. E. ca11is have emerged as tick-bome human pathogens.
12. Jaques A. er of. Inhaled manni,ol improves lung fune1ion in 51. Coutelle C. Gene therapy approaches for cystic fibrosis. Biolog·
cystic fibrosis. Chest 2008; 133: 1388-96. icol• I 995; 23: 21-5. E. chajfeensis mainly infects mononuclear cells and in hu-
13. Mc:Caflery K. et al. Sys1ema1ic review ofaruistaphylococcal A.n· S2. Sou1hern KW. Gene therapy for cystic fibrosjs; current issues. mans the resulting disease is commonly called human
tibiotictherapy in cystic fibrosis. Tl1ora,Y 1999; 54: 380-3. Br J Hosp Med 1996; SS: 495-9.
14. Smy1h A, Wailers S. Prophylactic antibiotics for cyslic fibrosis. S3. Flotte TR, Laube OL. Gene therapy in cystic fibrosis. Chest
monocytic (or monocytotropic) ehrlichiosis (HME)
Av:iilatle in The Cochrane D•uabJse of Systematic Reviews; Is· 2001 ; 120: 1245-1315. whereas A. phagocytophilum mainly infects granulocytes
sue 3. Chid1cs1cr: John Wiley; 2003 (accessed 16/0S/OS). 54. Borowiti. D. et al. Cys1ic Fibrosis Foundation cvidenc.e-ba$.!d and in humans produces human granulocytic (or granulo·
15. Stutman HR, ~1 of. Antibiotic prophylaxis in infan1.s and young guidclii:tcs for manBgcmcnl of infnnls with cystic fibrosis. J cytotropic) ehrlichiosis (HGE), now also known as human
chilclre" wich cys1ic fibrosis; a randomized controlled 1riaJ. J Pctliotr 2009: I SS (6 suppl): S73-S93.
Pedl01r 1002; 140: 299-305. granulocytic anaplasmosis (HGA). E. ewingii and E. c<mis
16. Elbom JS. Tre.atment of S1:iphy1ococc:u.s aurcus in cystic fibto- mainly infect granulocytes and mononuclear cells respec-
sis. Tl1<.ni.Y 1999; 54: 377--8. Dial"l"hoea, infective tively.
I7. Beringer r. The clinical use of cofislin in patients with c:yslic See Gastro-enteritis, p. 181.
fibrosis. C11r1' Opin I'11/m M~d 2001 ; 7: 434-40. Some patients with HGA may also be co-infected with
18. Ryan Get ol. Ncbuliscd ami·pseudornooal antibiotics for cys1ic Borrelia burgdorferi, tl1e cause of Lyme disease, ·and/or
fibrosis. Available in The Cochmnc D:n.abl\SC oCSys1cmntic Re- Diphtheria Babesia microti, the cause of babesiosis, as. they are all
views: lssu.! 3. Chichcs1er: John Wiley; 2003 (:lccessed
25/06/0S). Diphthe1ia is an acute infection with the Gram-positive transmitted by tick bites from the samelxodes spp. Forde-
19. Rcm1nirig1011 T. ct al. Oral an1i-psc:udomonal an1ibio1tcs ror aerobe Co1y11cbacteri11m diphtheriae, some strains of 1ails on tlie o·eatment of patienls wi1h HGA co-infected
C)'!'tic rbrosjs.. Avail:able in The C0<hrane Dat3b3se of Svstcm- which produce an exotoxin. lt occur.; worldwide and is en- wilh Lyme disease, see p.190.
a1ic Rc•:ic:ws: lssoc 3. Chiches1er: John Wiley; 200i (ac"cessed
~5/06/!IS). demic to many countries. TI1e efficacy of immunisation Human ehrlichiosis is characte1ised by tever, headache,
20. Giamarellos-Bourboulis EJ. Macrolidcs beyond 1hcconve1uiol'•· (see Diphtheria Vaccines, p.2415) has rendered the disease myalgia, and malaise. Laboratory findings include leuco-
al antirr.icrobials: a class of Pottnt immnnomodulators. /nl J An-
1imicrob Agt11ts 2008; 31: 12-.20.
rare in mos1 developed countries, but infection is sti ll com· p¢n ia, thrombocytopenia, and elevated liver enzymes.1·2
2 1. Southem KW, ct al. M:acrolide :lntibio1iC$ for cystic fibrosis. mon io parts of the world with low rates of immunisatiqn. Symptoms morecommonly seen in patienls with HME are
Available in the Cochrane Oatnbase of Sys1ema1ic Reviews~ Js. Although tlie risk to travellers is said to be low, diphtheria gastrointesti.nal disturbances, cough, confusion, and skin
sue 2. Chichester: John Wiley; 2004 (a«esscd 02/03/07}. should be considered in patienls returning !Tom endemic
22. Lands LC, Stanojevic $. Oral non-steroidal anti·inflammatory nish. HME isa relatively severe infection and patients may
drug thnapy for cystic fibrosis. Available in The Cochrane Oi· areas with a sore throat; most cases occur in those who are require hospitalisation for complications such as acute res·
taOOsc of Systematic Reviews~ Issue 4. Chkhe~ter: John Wiley: unvaccinaled or inadequately immunised. piratory dislreSS, coagulopathy, hepa1itis, hepatic failure,
2007 (aocosscd 25/06/0$).
23. Chen£. K, e1 ol. Or31 steroids rorcyslic fibrosis. Available in The
Diphtheria has an incubation period of about I to 5days;1-3 meningoencephali1is, acute renal failure, aod shock. Ful-
Cochr:ioe Database ofSys1cmatic Rc\'iews: Issue 4. Chichesccr: onset of symptoms is gradual. These range from a moder· minant infections may give rise lo other opportunistic in-
John Wiley; 1999 (acccSs<d 16/05105). ately sore throat, low-grade fever, and swollen gla11ds, lO fections, particularly in immunocompromised patients.
~- B:atrour-Lyrrn JM. Welch K. Inhaled corticosteroids for cy.stic
fibrosis. Available in l11e Cochrane Database ofSys1em111ic Re·
more serious manifestations caused by the exotoxin from Fatalities have teen reported in 2 to 3% of patie111s with
''icws; Issue I. Chichcs1cr: John Wilev; 20-09 (accesu:d toxigenic strains. The exotoxin causes local destruction of HME. Clinical symptoms of infcclions with E. ewingii or
2S/02!10). • mucous membranes and epithelium, leading to the forma· A. phagocyfophi/11111 are generally similar 10 those of E.
2S. Rtn CJ., r.1 nl. Ref31 ion ~hip belween inhaled conicosteroid ther· chaffeensis'-4 although usually Jess severe. Cough, confu-
apy 3nd ratt of lung fun..:ti<m dcdinc in children with cystic fi-
tion of a characteristic adherent pseudomembrane that
bt'Osis. J Pedialr 2008; JS3: 746-51 . coats the tonsillopharyngeal region and may obstruct the sion, and skin l"dSh have not been seen wilh infections
26. Ferkol 7. '-''al. Cys1ic fibrosis pulmonary c:-:accl'b.i1io11s. J Pcdi- upper airways. Swelling of the neck occurs in severe cases. caused by E. ewingii and most cases have been diagnosed
oir 2006; 148: 259-64.
Toxin can be absorbed systemically, resultinB in damage lo in irnmunocompromised patienls; no deaths have been re-
27. Smyth A, Elbom JS. E:x::1cerba1io11s in cystic fil:lros is: 3. Man-
agement. Tlwra."t 2008; 63: lS0-4. cardiac, renal, hepatic, and neural tissue.? Respiral-Ory porled. HGA is generally a mild, self-lim iting disease, but
28. Alron ~O. er ol. Combimuion ancibiotic susceptibility te-.sting to diphtheria has a mortality rale of 5 lo 100/o even when treat· may be severe in about 5 to 7% of patients and reported
trc:n eucc:rbations ofcyslic fibrosis a:isocia.tcd wi1h multiresist- ed. Cutaneous diphtheria, characterised by chronically in- fatalities are less lhan l %. MosI severe cases have been
:m bacll!ria: a randomised, double-blind, controlled cli11ica:l 1ri-
al. Lancet 2005; 366: 463-71. fected skin lesions, is usually caused by non-toxigenic diagnosed in immunocompromised patients. Skin rash,
29. 83ncrjce 0. St3blcfonh 0 . The: 1rea1men1 or respiratory PS.Cu• strains and bas fewer complications. gastrointestinal and respiratory disturbances, and CNS in-
domonos infection in cys.tic fibrosis: what drug and which way? Diphtheria is higWy contagious and paiienls should be iso- volvement are less frequent with HGA. 1
Drugi 2rn10: 60' 1053-64.
30. Flume PA. e1 ol, Clinical J>ra~tice Guidelines fot Pulmonal)' laled.1 Treabnent of respiratory infection is mainly with Prompt treatment is r~commended9 due to the potential
Thcrapi~s Comminee. Cy.slic fibrosis pulmonary guidelines: antitoxin (see p.2415).1.• Parentera l benzylpenicillin or for serious complications. Treatment for all infections is
treatmern of pulmonary exacerbations. Am J R.espfr Cl'i1 Cort el)1hromycin are also given to eliminate C. diphtheriae, wid1 a tetracycline, preferably doxycyclinc, given for 7 <o
Med 2009; 180: 802-8.
31. Smyth AR, Bhaa J. Once·daily versus multiple-daily dosing thereby tern1inating toxin production and preventing lhe 10 days or for al least 3 days after the patient has become
with inlravenous aminoglycosidcs (or cystic librosts. Available spread of infection to contacls.'" Penicillin or erythromy- afebrile. Chloramphenicol has been used as an allemative
in The Cochrane OiHabusc or Sys1ema1ic Reviews; Issue J. cin may be given orally once the patient is able to swallow for HME, ahhough its efficacy is controversial and it
Chichester: John Wiley; 2010 (acccss..:d 25i02JIO).
32. Rey E. ir nl. Drug disposition in cystic fibrosis. Clin Pharma· comfonably. Antibacterials should be given for a total of should not be considered as a first-line n·eatment 1.5 It is
cokinet 1998: 3S: 313-29. 14 days; those who continue to harbour the bacteria should also not effective againsl A. phagocytophilum in vitro. De-
178 Antibacterials
spite the known adverse effeCIS ofdox~cycline in children, predisposing conditions such as hean defects or intrave- Once the causative organism and its antibacterial suscepti-
the American Academy of Pediatrics 0 and the Infectious nous drug use, are also considcred.4•5 bility have been identified, appropriate parlrogen-directed
Diseases Society of America (JDSA) 11 state that a short· VlltUally any organism can cause endocarditis but strcpto· therJpy may be begun.
ened course may be given lo those who are Jess than 8 cocc~ cnterococci, and staphylococci continue to be major • Streptococcal endocarditis. Streptococci vary in theif
years of age who are severely ill and not co-infected with culprits. susceptibility to penicillin, and guidelines generally di-
L)me disease; the dose is 4 mg/kg daily in two di\'ided vide regimens according to whether the organism is of
doses (to a maximum of 100 mg/dose) and should be giv- • Among the commonest causes are the alpha-haemolytic
srreplococci origina1ing mainly from the mouth and low; intermediate, or high penicillin resistance, although
en for at least 3 days after the patient has become afcbrile. at what MIC these categories are defined varies between
Successful 1reatmcnl of HOA with rifarnpicin has been re- throat; they have been called viridans streptococci or
even 'Strrplococcus >•iridans' (although this is not a uue guidelines.
ported in pregnancy (gestational age of I 0 to 36 weeks) 12 For uncomplicated cases ofinfedion with the most pen·
and in 2 children with non-life-threatening infection. u The species) and include Sir. mitis, Sir. mutans, Sir. oralis, Sir.
salivarius, and Sir. songuis. Other streptococci originate lcillin s~sitive_ srrep1ococci! ~n~lpcni~imn. may be
IDSA 11 recommends that patients with mild disease who used, w1lb or without gentarnicm7•1 or neulm1c1n.9 Typ-
cannot be given a lCtracycline may be given rifarnpicin in the gut and include Str. bovis.
ically, if used alone in native-valve infection it would be
300 mg twice daily for 710 I0 days; children may be given • Also increasingly common i.s endocarditis due 10 sta· given for 4 weeks, whereas the combination regimen is
IO mg/kg twice daily. Antibacterial susceptibility testing plrylococci such as Staphylococcus aureus, a common given only for 2 weeks.7•10 Indicative doses would be
has suggested that rifamycins and fluoroquinolones are cause in intravenous drug abusers, bul endocarditis may 1.2 to 2.4 g of benzylpenicillin every 4 or 6 hours, and
promising alternatives in the ireatment of HOA. 14 also be caused by coagulase-negative stap/rylococci,
gentnmicin I mg/kg every 8 hours or as a sin~e daily
particularly Staph. lugdunensis. Prosthetic valve infec-
I. Padclock CO, Childs JE. Ehrlichi1 ch1ffeensis: a pro101ypical
emerging pa1hogcn. C//t1 Mlcroblol R•• 2003; t6: 37-64. dose of3 mg/kg. Ceflriaxone"10 or vanoomycin •10 may
tion is often caused by Staph. epidennidis or other sta· be considered as an allernative, although these are more
2. Dumler JS, ct al. Human granulocytic anaplasmosis 1md Ana· pbylococci.
plasm• phagoc)'lophilum. Em•rg /n}rct Dit 200S; JI: 182&-34. often given to treat less sensitive strains, or in patients
3. Blanco JR.. Oteo JA. Human i::nnulocydc e.hrliebios;s in Eu· • EnterotXXXi (faecal streptococci) origfaate in the gut unable to tolerate penicillin.
rope. Clfo Ml~robiol 1"/«t 200)j 8: 7'3-72.
4. Bu.lier RS.~' ol. Ehrlichia ewin;.ii. a newly ~iud 1gen1 or and include Enteroaxcus foecolis and, to a lesser ex· For sn-eptooocci le.ss sDisilive 10 penicillin benzyEi·
human dulichiOSi'- N &,ti J Mod 1999; 34 t: I 4S-5S. tenl, E.faecium. Endocarditis due lO any of these bacte- cillin maybe given as above but for4 l0 6wee1cs,•· usu-
5. Schaffn<r W, Standacn SM. Ehrl!ChiOli>-in pursuit or >n ria is commonly subacute or insidious.
<m<rginginf<dion. N EJ.tlJ Mod 1996;334: 262-3. ally with gentamicin for al least the first 2 weeks. Aller-·
6. Dumler JS, <l al. EhthchlOOH in humans: cpidemiok>e.,y, clinial Less common causes ofendocarditis incJudc:l...6 natively, 4 weeks of lrealmenl with cefiriaxone or
prcsenl.atioo. diagnosis.. end ucatmenc. Clm lrt/ttl Di.r 2007; 45 vancomycin may be consideredS. IO Typical doses are
(suppl t ) : SO-S5 I. • Gram-negative bacteria such as the Entcrobacteriaceae
7. Bakken JS, OumluS. Human aronuloc)'lic anapwmosis./n[ecr and 2 g daily of ceftriaxone as a single injection, or
Dis Clin Nortli Am 2006; 2?: 433-48. 30 mg/kg of vancomycin daily (up lo a u.sual maximwn
8. inom~ ru. el al. Oment mon•gement or hu.man granulocytic • Pseudomonas spp. of2 g daily). in 2 divided doses.
anaplasmosis, human 1nonocytic chrltchjosis and Etvlichia cw· • the HACEK group of slow-growing organisms (Hae-
ingii el1rlH.:hiosis. E~JHfl RC"\1 An# ltr/«t 1'1ter 2009; 7: 109-22. For penicillin resislanl streptococci treatment is similar
9. Hamburg BJ, el al. The impcrtancc of early ueatment with dox· mophilus, Aclinobacillus, Cardiobac1erium, Eikenel/a, 10 that for enterococcal endocardilis.7 •9 A combination
ycycline in human chrlich1o~i~. Mttll~fnt (Bommore) 2008; 87: Kingella)
S3-60. of vancomycin and gentarnicin may be given for 4 lo 6
10. Amcricnn AC-:jdcmy of Pccti:urics. 1009 R~d BooJt.: Rcp<>rt ofthe • the rickettsia Coxiella burnetii (the cause of Q fever, weeks. Streptomycin is a possible alternative lo gen-
Commilfet on Jn.ftttio"s Disaosu. 28th ed. Elk Grove Village, p.203) tarnicin for gentamicin resistant isolates.8
Hlinois, USA: Americ-.n AcaOctny of .Pcdia1rics, 2009.
11. \Vonnscr GP, ti al. The clinie1il usessme.nt1 ire~tment.. and pro- • Ba11onella spp. (also formerly classified as rickensia) For streplococci in pe11icillln-allergic t:',tie111s, vanco·
ventioo of Lyme disea,c. humt l' ar•nulocytic .anaplasmosis. aod
• fungi such as Candida and Aspergil/11s (see p.564). mycin for 4 to 6 weeks may be given;9• 0 UK guidelines
babcs-ios:is: clinical Pf'Clicc auidelincs by 1he fnfedious Diseas- ad\•ise 4 weeks of treatment combined with gentamicin
es Sociny of Am<:rica. Clin lnfw Di• 2006; 43: I 089-113-4. Guidelines for the treatment and prophylaxis of endocardi-
fol':'o:;;~:=7•(~t~7~s)ats.uchicago.edu/doilpdt7 for the first 2 wccks.8 Teicoplanin, typicaUy in doses of
tis have been issued by bodies in many countries. Al- 6 to JO mglkgdaily(higher loading doses should be giv-
12. Dhand A. et al. Hu.man gr.11nu~c an.aplasnxasis during prcg~ though some conunon principles can be identified, rccom· en initially to establish a suitable uou~ concentration)
nancy: case .series md litct1ture review. CJin ln/«1 Dis 2001;
~S:S89-93.
mcndations must be localised because of differences in is a possible alternative 10 vancomycin.8
13. Krause PJ. el ol Sucuuf'ul ueaunc-nt of human 1nnulocyric patterns of infection and drug resistance, variations in the For patients with piruthelic valve endocardilis, a regi-
chrlichiosJs in children u&il't fifampm. AbSIJad.; Pediatrics availability of antibacterials and local policies for 1heiruse,
2003; 112: 667. Full version: ht1p;//w-.-w.pcdiatriC$.org/cg.i/ men similar to that for less sensitive streptococci
conten1/full/l l2/31t2Sl (1cceastd 09/10!06) and differences in medica I practice. Countries also vary in
(above) has been suggested, given for al least 6
14. Klein MB.~tol. AntibiOfic ~ibdi1yof,hc newly cuhivat· the degree 10 which such guidelines are accepted in prac· weeks.S:io
cd agcot of human granulocytic dvlichiosis: promising activity ticc.
of quinok>nes and rifamycinl. Afllln1icrob Agents Clremother • Staphylococcal e,ndocarditis. The treatment of staphy-
1997; 41: 76-9. Endocarditis treatment. lococcal endocarditis is based on the use of an isoxa-
Treatment of endocarditis relies on prompt identification zolyl penicillin or a glycopcptide. In contrast to strcpto-
Endocarditis of the infecting organisms and their sensitivity to antibac- cocca l or enterococcal endocardilis, the benefits of
Infective endocarditis 1·3 is un infection ofthe eodocardium terials. Throe sets of blood cultures, each froro a separate adding an aminoglycoside arc uncertain, and guidelines
after invasion of !lie bloodstream by bacteria or fungi, and venepuncrure, should be taken before antimicrobial treal· differ in whether they recommend this. Combination
particularly affec1s the heart valves. Infection has tradi- menl is started; MlCs for the causative organism should be therapy is recomrnended where prosthetic valves or oth-
tionally been classified as acute or subacute; however, rneaswed. As already mentioned. guidelines vary,7•10 but er intracardiac prostheses arc present.
changes in the clinical $pectn1m of infection have meant in general: For mericillin sensitive srap/rylococci, typically an isox-
!hat some now prefer lo cla.ssify it into the calegories:1•4 • a microbicidal antibacterial, or combination of antibac- uolyl penicillin (such as flucloxacillin) is given in a
• native-valve endocarditis (often associated with con- terials, should be used for lreattncnt; many regimens are dose of2 g every 4 to 6 hours for at least 4 weeks. 1· 10
genital or chronic mcumatic hean disease, and classical- based on a beta-lactam or glycopeptide plus an Some guidelines continue lo recommend addition of
ly due lO streptococci although cases due lo staphyloco· aminosJycoside geotamicin for the first 3 to S days of therapy.9•10 Pa·
ccal infection are increasingly frequent) • treatment should be given at high doses, and by the in- lients with right-sided endocardi1is due to intravenous
• prosthetic valve endocarditis (which may occur early, 1ravenous route drug abuse may respond to shorter courses of 2 weeks
within 60 days of surgery, which is often due to ~"tapby­ of combination therapy with an isoxazolyl penicillin
• except in !he most sensitive infections, treatment should plus gentamicin.8•10
lococci, or late, in which case it is often due to streplO·
be given for al least 4 weeks (or al Jea~1 6 weeks if the
cocci or .more exotic organisms such as the HACEK For staphylococci resistant lo me1icil/inloxocillin, van-
pa1ien1 has prosthetic valves or other prosthetic material
group) comycin may be given alone for 6 weeks,7· 10 or with ri·
implanted in the heart)
• endocarditis in intravenous drug users (u~-ually associat· fampicin or perhaps gcntamicin or sodium fusidale (de-
ed with infection by ski11 pathogens, especially Staphy- • ideally, it is preferable lo wail for the results of blood pending on scnsiti\'ity) for al least 4 woeks.8•9 Such
lococcus aureus) culture before starting tberapy; however, empirical combinations may also be appropriate in patients with
treatment is given to patients presenting with acute or pe11icillin allergy. Teicoplaoin should nol be used as the
• nosocomial endocarditis (related lo catheter implanta-
severe disease rcponed incidence of treatment failure is unacceptably
tion or other invasive medical or surgical procedures; it
is usually due to slaphylococci or enterococci and has a • associated complications such as beart failure should be high.'
high mortality rate). An increa~ing incidence is also managed appropriately; management may include n> For staphylococcal eJ1docarditis 111 tire p1ese11ee ofilll-
seen in patients undergoing haemodialysis feml for early swgical intervention racardiac prostheses either an isoxazolyl penicillin or
Treatment of infective endocarditis is essential, as infec- If empirical treatment is to be given until the laboratory vancoo1ycin may be used with rifampicin or gentamicin
tion can result in heart failure, embolisation and infarction results are known, then it is most likely 10 be with gcn- or both; an indicative regimen might be intravenous
of major orgims, and death. Diagnosis is ol\eo difficult as 1.amicin plus benzylpcnicillin, ampicillin, or amoxicillin.1 doses of2 gofthe penicillin every4 to6 hows, or I gof
many of the symptoms (which include fever, ma laise, An isoxuolyl penicillin (cloxacillin, dicloxacillin, flu· vancomycio every 12 houTS, plus rifilmpicin 300 mg
headache, petechiae, and splinter haemorrhages under the cloxacillin, or oxacillin) may beadded,7 or used instead in orally every 8 hours, bolh given for at least 6 weeks,
n~ils) are non-specific. A set of diagnostic crileria known more severe or acute presentations;' ampicillin with sul· plus gcntamicin I mg/Jc~ intravenously every 8 hours
as the Duke criteria have been developed, and some mod· bactam or amoxicillin will1 clavulanic acid have also been (or as a single daily dose of 3 mg/kg) for the first 2
ifica1ions subsequently proposcd.4 •S TI1e Duke cri teria rccommcnded. 9 Vancomycin with 9 or without weeks.8·IOGentamicin may be given for the entire peri·
identify endocarditis mainly on the basis of microbiologi- ciprofloxacin7.AI is likely to be the antibacterial of choice in od of treatment if the infection is due lo more recalci-
cal data (blood culture of the infecting organism) and ana- penicillin-allergic patients requiring empirical trcabnent. trant strains of meticillin-resistanl Staph. aureus or co-
tomical lesions ofthe valves (identified by ecliocardiogra· Vancomycin may be used empirically witl1 an aminog)y. agulase-negative staphylococci.'
phy or the development of new valvular regurgitation); oosiclc and rifampicin in patients with prosthetic valves8.9 • Entcrococcal endocarditis. Treatrocnl of entcrococcal
minor crilCria such as development of fever, or presence of or where penicillin resistance is suspected.1 endocarditis is based on combinations of an aminogly·
All cross-ref~rencc~ rerer lo c:ntnes in Volume A
 Antibacterials 179
coside with another antibacterial, usually a beta laciam Patients generally considered to be at risk of developing • For infected skin, skin stmcture, or musculoskele10/ tis-
or a glycopcptide, depending on the sensitivity of the endocarditis include those wilh: sue p~ures a penicillin such as amoxicillin is usual-
isolated organism. • acquired valvular heart disease, including valve disease ly given in a single oral or intravenous dose of2 g, or a
For ge111amici11 sensitive, peniallin se11sitive ente1'QCQc,- in patients who have received a cardiac transplant cephalosporin such as cefalexin is given in .a single oral
cl: intravenous bolus injections of ampicillin or amoxi- dose of2 g. Vancomycin or cUndamycin may be given
• some types of congenital heart disea.o;e to patients allergic to penicillin or who are known or
cillin 2 g (or benzylpenicillin 2.4 g) every 4 hours and
gcntamicin I mg/kg every 8 or 12 hours (or as a single • hypcrtrophic cardiomyopathy suspected of having an infection caused by a meticillin·
daily dose of 3 mg/kg), both given for at least 4 • prosthetic valves or pulmonary shunts resistant strain of staphylococcus.12.1•
weeks.7.8.IO • a history ofcndocarditis
I. Mor~illon P. Que Y-A. lnrec.1i,·ecndocardilis. Ltmctl 2004; 363:
139-49
lf the patient is allergic to penicillin, or the isolate is Procedures that were thought likely to produce bacterae- 2. Sc)'TIO<I RP• ., al. tnfecth·e endocard~is. BMJ 2006; 333:
penicillin 1·esis1ant but gentamici11 sensitive, then a com- 334-9.
mia and therefore to require prophylactic treatment includ- 3. Prcndcrs:>st 80. The changing face of infective endocardi1is.
bination of vancomycin or teicoplanin with gcntamicin ed any dental intervention likely to cause bleeding. other Hanrr 2006; '2: 879-85.
may be given for at least 4 weeks.7·10 oral or upper-respiratory tract operations such as tonsillee- 4. llill GE. e1 al, Evolving trends i11 infective cndocarditis. Clbt
Mlcrobiol lnfec12006; tl: 5-12.
For enteroc:icci with high level gentamicin resistance, a tomy, cenain gastrointestinal procedures such as sclero- ~. Li JS, Cl al. Proposed n1ochr1«1ians lo the Duke criteria ror the
penicillin as above may be used with streptomycin therapy for oesophageal variccs or bilia1y-tract surgery, ~~f-'8.si s of infccun mdocardili$. Clin Jnfect Dis 2000: lO:
7.5 mg/kg twice daily (intramuscularly or intravenous- and some urinary-tract surgery. Whether prophylaxis is 6. Brouqui P. Raoul1 O. Endocarditis due to rare and fascidious
ly) for at least 4 weeks.a.io If there is also penicil/i11 re- truly needed before denial procedures is a subject of con- badeti). Cliu Mlc,'Obiol R~r 2001: 14: In-207.
sistance, or the patient is penicillin allergic, streptomy- troversy. A systematic review 16 concluded there was no 7. Antibiotic Expert Group. Titerapeutic Guidelines: An1ibiotie
cin as above may be given with vancomycin or (>'<Tlion 13) Melbourn<:: The12p<:utic Quidtlinu Lid.; 2006.
evidence that antibacterial prophylaxis was effective or i11· S. l!llioct TSJ. ~I ol. Guidelines for the ~tibiocic treatment of en-
teicoplanin.8 lfstrq>tomycin cannot be used then more effective against bacterial endocarditis in people at ris)\ un- doeard1tis in adults: repOrt. of the Wortina Pl~ of the B.ritish
prolonged treatment courses should be given for at least dergoing an invasive dental procedure. US guidelines12-14 !~~:'f~; ~~i~i~4~~al Chemotherapy. J An1l1rricrob Chtm·
8 weeks.8•9 recommend antibacterial prophylaxis only, for dental pro-
Endocarditis due to multiply resistant enrerococci nOl cedures that involve manipulation of gingival tissues or
:,!]7
1
~;;;~~~h:~~)'rordjouriu1$.orglcgilr<p<inV54/

· !::~,i~c~ :~ j~~cc~i'!:::~':ac:di1 i~(te~v:;.=~ 2~~~T::

pcriapical region of teeth, or perforation of oral mucosa in 9 1
susceptible to penicillin, gentamicin, or vancomydn, is
still,infrequent and there seem to be no established reg- patients considered to be at the highest risk of developing Force on the Prcvcnuon. Oiaposis, and Trutmen1of Infective
imens; options may include the use of Jinezolid, dapto- adverse outcomes from endocarditis (such as those with a Endocardi1is oflll< Europttn SocieoyofCardiology (ESC). £.,.
mycio, tigecfoline, or quinupristin/dalfopristin where history of infective endocarditis, cardiac valve replace- H,.,,.. J 2009; 30: 2369-413.
Full version: hup://curhcartj.ox(ordju...rnals.org/contcnt/30/
available.7· 0 A combinat ion of ampicillin with ment surgery, or some patients with congenital heart dis- 1912369.rull.pdr•hlml (oec.....S 2 l/04110)
cefii'iaxone9•10 or imipenem,1° given for at least 8 ease). US guidelines also recommend antibacterial proph· 10. 8Addow LM. ti ttl. American Hean Assoc:'8hon. lnfcclivt C'n·
weeks, has been suggested for multiply rcsista11t £.foe• ylaxis for high-risk patients for proccdW'CS on infected docardui:s.: diain0$is, anlimicroblal 11\crw.py. and managemcnl of
compliC3t.ions: a state1ncnt ro,- he1hhare p«>fcssionils from the
co/is infection. skin, skin structures, or musculookclctal tissue, but do not Committee on Rheumatic Fever. Endoc:arditis. and Kawis.aki
• HACEK cndocarditis. The HACEK organisms are recommend standard prophylaxis for rcspiratocy, genito- Oi1ease, Council on Cardiovascular Disease in the Young. and
urinary or gastrointestinal tract procedures.1• Similar rec- 1hc Councils on Clinical Catdiology, Stroke.. and Cardiovascutar
slow and difficult ~o culture and treabltent must often,
therefore, be empirical. Traditionally, treatment for this ommendations were made in the UK by the British Society ~~l~rrnf~ti~~~~:~;~1~~~~~:!ri~:,~
group of organisms was based on ampicillin and gen- for Antimicrobial Chemotherapy (BSAC) in 2006 11 for mary. Circula1iol1 2005~ Ut: 3167-84. Con-ce1ion. 1lnd.: Ill:
2373. Full l'trsion: hup://ci~.ahajoum~ls.org/e&ilrcprint/ l a I/
tamicin. However, bc¢ause of the emergence of beta- high-risk patients undergoing invasive dental procedures,
lactamasc producing strains, empirical treatment is now but the BSAC was more cautious in modifying the guid· a1. ~~fJ~·~~~~';,~~~e~!~)thc prc,·cntion of endoc.arditis:
ance for respiratory, gasll'Ointestinal, and genite>-urinary r~pon of1he Worklna Panyof1heBri1ishSociccy ror Antimicro--
based on beta-lactamasc-stable ccphalosporins. bial Chemotherapy. J Anrimicroli C/11mo1her 2006; S7:
procedures. Subsequerit guidelines issued by NICE13 and tOJs-42. Also a'llailablc at: hnp://jac.odordjoumals.orgtcgi/
Prefen'Cd treatment for native-valve endocarditis due to adopted by the BNF essentially abolished the requirement rcpnnt/dld 12 t \' l.pdf (•<e<SScd 06107/06)
HACEK or~anisms is therefore with inttamuscular or for standard antibacterial prophylaxis in any pcoccdure. In 12. Wilton W, er oi. Prevention of infccti\e Mdocarditis: guidelines
intravenous ceftriaxone (usually in a dose of2 g once 2009 the Task Force on Infective Endocarditis of the Euro- from iM Amc-ricaJ\ Hean Association: a guideline from the
daily) for 4 weeks,7• 10 althou2h cefotaxime7 or other pean Society of Cardiology' also reduced the number of
American Hean Association f\heumatic Fner. Endoc:ardj1is.
Jnd Kawasaki Oi$ctSc Committee, Council OQ Cardio,·a.scuhlr
third-generation cephalosporinY:1o may be used instead. indications for prophylaxis. Their guideline for antibacte- Disease in lht Young. and the Council on Clinical CardiolOJ)'.
UK guidelines recommend addition of geniamicin for Council on Cardt0\14.>CUl-.r Surgt:ry tmd Ancs\huj"' ind the
rial propbylaxi~ before dental procedures is similar to that Qua1ily or Care end Outcomes Research lntcrdisciphn~ry
the first 2 weeks of therapy.1 Alternatively, if the isolate for the US and UK (BSAC) and standard prophylaxis is Workin£ Omup. Ci~1dotkm 2007; 11 6: 1736-54. Also aY11il::i-
is penicillin sensitive, ampicillin plus 2 to 4 weeks of also not generally recommended for rcspimtory, genito- ~~~~~!J'f~78t~t1hsjoumst..orglcgi/rcpr;nv1l611 S/1736 pdf
gentamicin,1•9 or ampicillin-sulbactam10 have been sug- urinary, or gastrointestinal tract procedures. Most guide- 13_ NICE Prophyla:ds ag:1inst infmivcendocim.Htis: anli1nicrobi:ll
gested. Some guidelines consider that a fluoroquinolone lines still recommend appropriate antibacterial prophylax- prophyl1x1s ag11ins1infective codoc:atditis i.n adults and children
such as ciprofloxacin for 4 weeks, orally or intravenous- is for high-risk patients undergoing invasive respiratory, '"'der:oing in1erven1i0n21I pr<'Cedures (issued March 2008).
ly, may also be effective.9•10 Available at; h1tp ://www.n1cc.or1.uk/niccmedi aipdrt
gastrointestinal, or genito-urinary procedures to treat an CCi64NICEgu;dancc.jXlr (aec:u.ed 16I06/0S)
• Endocardilis due' to other Ofianisms. Treatment of established infection or where pre-existing infi:ction is sus· 14. Nishi1nura RA. ti ol. ACC/AHA 2008 $Uideline upd1t1c on val·
endocarditis due to other organisms depends greatly on pcctcd.'·12-1• vulsr hart diSCO$c: focused update on infective endocardilis: a
rep<>rt of the American College of Cardiology/Amcric::in Hean
the organism and its susceptibility; early surgery is often Assodalion Task Force on Prtclicc GuidcJint":S: cndortt<I by the
Antibacterial prophyla>.is is aimed mainly at viridans
required. For cndocarditis due to Pseudomo11as spp. a Society of Cardkw1.scular Anesthesi0Jo1ists. Society ror Cardi·
srreptococci and liACEK organisms before dcnllll, oral,
combination of an antipseudomonal beta lactam with
respiratory, and oesophageal procedures, and at enteroc:oc- ~~i~cS~"r' ~~°t?:-":! 106S~~~~sa;_nt6~~:,tYa\~.~i~
tobramyein has been suggested.9 Endocarditis associat- al: hUp:~clrc.ahajoumals.org/cttilrcprinll It &r&r887.pd( (•<-
ed with the intracellular pathogen Cc.<iella burnetii re- ci, Strep. bcvis, and the Enterobacteriaccae before gas- cmcd OS/05110)
quires very prolonged oral therapy (sec Q-fever. p.203) trointestinal and genito-urinary procedures. Drugs should U. lnftc1h·e Endocarditis Prophylaxis Expim Oroop. Prevention of
with doxyeycline, 8 ·9 in cotnbination w ith be given in a regimen that assures adequate blood concen- endocarditis. 2008 update from Then~u1ie guidelines: antibi·
OhC (version 13) ond Thc~peudc auidclines: oral and dent.al
trations throughout the procedure. Titey arc generally giv-
hydroxychloroquine9 or a fluoroquinolone (such as cip· (veriion I). Mclboumc: Thmpeu1ic GuidcHncs Ltd.; 200S.
en as a single dose before the procedure; die oral route is 16. Oliver R. ti al. Antibiotics for the prophylaxis or bacterial CO·
rotloxaein or ofloxaein). 8•9 Regimens suggested for docorditis in dentistry. A\•Oil:ible in 'The Cochrane 0:11abase or
used if possible.
Barionella endocarditis have included a penicillin (or Syncma1ic Rt"iews: Issue 4. Chichester: John Wiley: 200$ (ac·
ampicillin with sulbaclain) or cefiriaxone in combina· • A penicillin such as amoxicillin is the basis for prophy- C<>Sed 2MWIOI.
tion i.•ith gentamicin or netilmidn, or doxyeyclinc plus lactic therapy, typically u1 a single dose of2 to 3 &orally
gentamicin. 8•1° For other potential causes of culturc- or I to 2 g inll'3venously or intramuscularly.9·11 • ,ll For
Endometritis
ncgativc endocarditis, empirical treatment with a peni- dental procedures it may be replaced, in patients allergic Endomcaitis (or endomyomellitis) is an infection of the
cillin or vancomycin plus gentamicin, sometimes in to penicillin or who have received more than a single e1xlometrium and can be divided into obstetric and non·
combination with a third antibacterial such as rifampicin dose in the previous month, by clindamycin 600 mg obstetric, acute and chronic endomelritis. It is thought to
or cipronoxacin, has been suggested.'0 orally or 300 to 600 mg inuavcnously, or by azilhromy· result from an ascending infection fiom the lower genital
Endocarditis prophylaxis. cin or clarithromycin 500 mg OC8lly. Doses should be !Tact. Spread occurs fiom there to the tubes and ovaries. In
given 30 to 60 minutes l>efore the procedure.9· 11 •14 non-obstetric patients it may be a part ofpelvic intlamma·
Because of the potentially severe consequences of end<>-
carditis, antibacterial prophylaxis was widely practised in • For gastrointesrinal or ge11iro-uri1101y procedures the t01y disease (p.197) or due to invasive gynaccologic pr<>-
patients considered to be at increased risk when Ibey were penicillin is usually combined with a single dose of gen· cedurcs. while in obstetric patients it may be a pootopera-
exposed to procedures likely to produce bacteraemia. tamicin l .5 or 2 mg/kg intravenously or intramuscularly tive complication ofcaesarean section. Symploms include
Much"<lf the evidence to support the practice was circum- before the procedure; a second dose ofamoxicillin (typ- uteline tenderness, abdominal or pelvic pain, dysparcunia,
stantial and the benefi1:> and risks were lherefore hard IO ically half the initial dose) may be given after6 boUJS. In dysuria, fever, malaise, and abno1mal vaginal bleeding or
calculate. Revision of this practice in recent years has patients allergic to penicillin, or who have received discharge (including foul-smelling lochia in obstetric pa·
resulted in a major shift of emphasis away from giving more than a single dose of penicillin in the previous tients).
antibacterial prophylaxis to all at-risk patients, to recom- month, amoxicillin ma)' be substituted with an infusion Endornetritis is a polymicrobial disease usllillly involving
me.ndi.n g f.ro~hylaxis for ~i!\h-ris~ patients. only. of I g of vancomycin over I to 2 hours before the pro- 2 to 3 Ot'ganisms some of which are found in the no1mal
Guodehnes ·11 •1 have been pcnod1cally issued to guide the cedure,1~ or i11jection of 400 mg ofteicoplanin immedi· vaginal flora. Co mmon causati,·e organisms include
selection of patients considered to be at high risk for endo- ately beforehand.7•9· 11 Gram-positive cocci (such as Staplrylococc1Lr spp. and
carditis, the high-risk procedures requiring prophylaxis, • For nasal pocking and i111uba1ion Oucloxacillin I g in· SoTtptocoocus spp.), Grom-negative bacteria (such as Es-
and the antibacterial to be used; recommendations may mwenously is gh'ell; in penicill in allergic patients clin- cherichia coli, Klebsiel/a spp., Proteus spp., E11ter()bacter
\'aty considerably between counaies. damycin 600 mg intravenously may be used. 11 spp., Gardnereila 110ginalis, Nei.1seria spp.). anaerobes
 180 Antibacterials
(such as Bacreroidc>s spp. Pep10streprococc11s spp.), and sically resistant tl1an others.3.6 Enterococei are intrinsically
other organisms such as Mycoplasma spp., Ureaplasma resistant to beta Jactams (particularly cephalosporins and
B. ~~~ki~~~~I~; f~ ~~eli~~i~~i~~~~J~~~ j•·i~~~~~~bretJ::mO:,~~.~
2002: 50: 74)-6.
spp., and Mycobacrerium h1berculosis. pcnicillinase-resistant penicillins), low concentrations of 9. Kaiocr MA. e1 ol. Rcspon~ 10 cmctging io(cction lcadin.g to
Women undergoing caesarean section arc reported to have aminoglycosides, clindamycin, co-trirnoxazole, and Ouor- oUlbreak of finczol id ~res.is1an1 ertterococc::i. Emtrg l11/e.c1 Dis
a 5 to 20-fold greater chance of infection than women who oquinolones.1J They also have acquired resist8nce to high 10. 2007; 13: I 024-30.
Lons JK. eJ al. Daptomycin-rui1t1n1 Enicrococcus faecium in
give birth vaginally and the incidence of cndometritis for concentrations of beta lactams and aminoglycosides, the a palien1 \\.<ilh acute mycloid teuktmia.. /.la)'O Cli'n Pf'OC 2005~
glycopeptides (vaneomycin and teicoplanin), chloram- 80: 1215-6.
caesarean deliveries ranges from 20 to 85%. Antibacterial MK. tt al Ocvclopmcnl of Oapcomycin rcsigancc in
prophylaxis may be given at caesarean section to prevent phenic:ol, erythromyein, Ouoroquinolones, fusidic acid, ni- 11 . llaydc:n
\'iYo in methicillin·reris11nl Staphytococca.s aureus. J Clin
postparrum endomelritis as well as wound and urinary- trofurantoin, rifampicin, and tetracyclines.1 At least 6 M•crobiol 200S; 4): S28S-7.
trad infections. A systematic literature rcview 1has shown types of acquired vancomycin resistance have been 12. Mun~·Pricc l.S. e1 al. Emcracncc of rcsillln« 10 4aplomycin
during cttaunent of v-anc:omycut-rctiSlltlt Enccrococcus fatta1is
prophylaxis to be beneficial after both elective and non- described' (see also p.390); those causing concern arc in(ec1i0<1. Clin Jnf«t DiJ 200S; 4t: S6~
VanA enterococci as they show high-level resistance to
elective caesarean section; endometritis was reduced by
two-thirds to three.quarters irrespective of whether the an- vancomyein and cross-resistance to teicoplanin and VanB 13. ~c~l~~i:e!/(~JC:,~~ ~:~:~:,;,~n~;o!n':,~:fJ~~~~:i:~~
tibacterials were given before or afiecclampingofthe um- organisms, which are resistant to a range of vancomyein ~~~:.~;;~s~vPn~~·~~~~~~~~t~°&tti'O~~~c~~~e~b;J~~f
bilical cord. Traditionally prophylactic antibacterials for concentrations but retain susceptibility to teicoplanin.3.s.G (occ..,.d 05f08/08)
caesarean delivery have been given at cord clamping, but The e))idcmiology of vancomycin-resistant enteroeocci
a meta-analysis provided evidence that prophylaxis given (VRE)3·S and resultant antibacterial prescribing practices Epididym it is
before skin incision significantly decreased the incidence differ between North America and Europe; 3 the USA has Epididymitis is often associated with urethritis, and in
of postpartum cndometritis and other infectious morbidi- much higher rates ofVRE than anywhere in Europe.3,S-7 young men (less than 35 years) occurs mosl conunonly as
ties, without affecting neonatal outcomes.2 Unusual patterns of susceptibility and drug and multidrug a complication ofsexually transmitted infection withNeis-
Many different drug regimens have been reported to beef- resistance make treatment of an infcccion difficult. Anti· seria gonorrhoeae and Chlamydia trochomatis, but may
fective in reducing postoperative infection but it is not bacterials must be chosen according to local patterns of re- occur in homosexual males as a result of infection with en-
clear if there is a drug of choice. Furthermore, differences sistance and antibacterial sensitivity tests.1-3 In general, un- terie organisms, particularly Escherid1ia coli.
in how prophylactic antibacterials have been given have complicated mt<!rOCOCC31 infections, such as urinaiy-tract In men over 35 years and in ehildten, epididymitis is not
been noted. A systematic review1 to evaluate prophylactic infections, tend to be treated with ampicillin, benzylpeni· usually sexually transmitted but generally results from
antibacterial regimens used for caesarean section found cillin, or vancomycin.1.S For more serious enterocoeeal in- bacteriuria serondary to urinary-tract infection \\.ith Pseu-
that ampicillin and first-gencrati<?n cephalosporins were fections, including bacteraemia, meningitis, and cndocar- domonas oeruginosa and other Oram-negative bacilli, uri-
appropriate. Extended-spectrum penicillins, second· or d itis, an aminoglycoside (such as gentamicin or nary-tract instnnnentation or surgery, systemic disease, or
third- generation cephalosporins, and combination regi- streptomycin) is added unless there is high-level resist- immunosuppression.
mens were not more effective; there was also no evidence ance.s For penicillin-allergic patients or in treatment of Guidelines produced by WHO,1 by an expe11 group in the
to suggest that a multiple-dose regimen was more effective ampicilliil-resistant strains of bacteria vancomycin is giv- UK,2 and by the CDC in the USA 3 for the treatment of
than a single-dose regimen. Clindamycin w~s consider- en with an aminoglyeoside.1·l.<.6 epididymitis are as follows, although recommendations
ered to be an appropriate alternative for penicillin-allergic Benzylpenicillin and ampicillin are an option for patients may need to be localised because ofdifferences in patterns
women. infected with VRE isolates that still retain susceptibility.2 of infection and drug resistance:
Patients with endometritis should be treated with broad. However, most are resistant to benzylpenicillin and ampi· •WHO:
spectrum antibacterials. For postpartum endomelrilis (also cillin and the choice ofantibacterial is therefore limited to for chlamydia! epididymitis:
known as puerperal fever), intravenous gentamicin and those introduced more recently into clinical practice such • oral doxycycline JOO ms twice daily ror 1 days,.,..
clindamycin are appropriate.• A second· or third-genera· as quinupristinldalfopristin or linezolid. Both these drugs • asinglcdo5cofornt~1hromycin t g
tion ccphalosporin plus metronidazole; or amo.~icillin (or have activity against vancomycin-resistant E. faeciuni alternatives, given for 7 days, are:
ampicillin) with gentamicin and mctronidazole are alter- infections and linezolid also has activity against non-£.
onil amoxicinin 500mgthroe1im<S daily
natives; .co-formulated ampicillin with sulbactam can be foecium species, but most £. faecolis and non-£. foecium
• oral t:f)1hromycin 500 mg four times daily
used as monotherapy. Doxycycline should be used if isolates arc intrinsically resistant to quinupristinldalfopris-
• oral olloxacin 300 mg twice daily
Chlamydia is suspected to be the causative organism. In tin.1-J.6 Acquired resiStance has been reported to quinupris-
• oral lctracycline SOO mg four times daily
most cases improvement is usually seen within 48 to 72 tin/dalfopristin 1 and linezolid-resistant enterocoeci have
emergedl.8.9 and spread nosocomiaUy.2 Daptomycin and Unless it can be excluded, patients should also be treated
hours. Parenteral therapy is continued until the patient has
tigecycline have in- vitro activity against VRE but clinical eoncwrently for gonorrhoea (p.206).
been afcbrile for longer than 24 hours; oral therapy is not
ncecssary af\er successful intravenous therapy.4 data on the treatment of VRE infections are lacking;2 re- •UK;
I. Smail) FM, G)1e GML. Amibio1ic prophylaxis \fersus no proph- sistance to daptomyein has been reported.10· 12 The second for probable chlamydia! infections or infections with
ylaxis for pre\·e:n1ina lnfccllon 1ner ce'3rcan scc1ion. Avail3hle generation glycopeptides, oritavancin and telavancin, are other non-gonococcal, non-coterie organisms:
in The Cochrane D111basc of Systematic Reviews; Issue I. also often bactericidal against enterococci and although re- • oral doxycycline JOO mg 1wicc d•ily for JO 10 14 day' is rt~
Chiches:er: John Wiley; 2010 (DCCO$kd 21/04110).
sistance to these newer drugs is rare, it has been docume.nt· ommended
2. c.o~1antine MM, d al. Tim in; of pe:r1oper:uive antjbiotics force-
sarean delivery: a me1aan.alysis AmJ Obstcl Gyn~col 200S: 199: ed.0 Many VRE isolates are susceptible to nitrofurnntoin, for infections with enteric organisms:
JOI.cl~. which has been used to treat lower urinary-tract infection • oral ofloxacin 200 mg twice daily for 14 days, or
). llc-pkins L. Smaill FM. AnlibtOlic p!Ophylaxis regimens and but is not suitable for treating other VRE infections.1.l Dal- • oral ciprofloxacin 500 mg twice daily for 10 days
drugs for ccsarrtn section. Av1ilahte in Tht Coclva.nc 03tabasc
ofSystemali<: R.-iews; ,...,. 2. Chichc5tcr. John Wiley: 1999 bavanein is active against glyeopeptide-resistant entcro- for disease most probably due 10 gonococcal infection:
(accessed 21/04/10) cocci with the VanB phenotype, but has little activity • a single intramuscular do5c of ccl\rioxone 250 mg,.,..
4. French L.'1. Smaill FM. Anhbt<Kic rc&imcns ror endomctritis .r- ag~inst the more common v.mA phenotype. 2 Chlora1n- •• single oral dosie ofciprono=in 500 maplw Orll doxycy-
ter ddivery. Awilable in Tht COC'hnne Oalabasc o!Systnnalic cline IOOmgtwia:dailyfor IOto 14days
Re\'itws: Issue 4, Chichester: John Wiley: 2004 (accessed phenicol may be effective against VRE (see Entcrococeal
18/08/05). Infections, p.263). Rarnoplanin, ketolides,; and the rrwn- in patients allergic to cephalosporins and/or tetracy-
nopep1imyci11s (a new class of glycopeptides)2 are being clines infections from all causes may be treated with:
studied as further treatment options. In general, there arc • oral onoxacin 200 mg twice daily for I4 ~a}"-1
Enterococcal Infections
no effective antibacterials available to eradicate VRE in • USA: empirical treatment recommended:
Although enterococci arc part of the normal intestinal Oora 2
those colonised with the organism.1. likely cause gonococcal or chlamydia! infection:
d1ey may also be responsible for serious infections. The
genus Enterococc11s includes at least 12 species with Ente- A few cases of horizontal transfer of the vanA gene from • a single inlrnmuscular dose ofccfirfaxonc 250 mg plus oral
rococcusfaecolis (fonnerly Srreprococcusfaecalis) and £. vancomyein-resistant E. faecalis to MRSA, crealing doxycycline 100mg1wicc daily for 10 days
foecium being responsible for the majority of human infec- MRSA wilh high-level resistance to vancomycin, have likely cause an coterie organism or in patients allergic to
tions. Infections commonly caused by enterococci include been documented in hospitalised patients mainly in the ccpbalosporins and/or tetracyclines:
urinary-tract infections. endocarditis, bacteiaemia, cathc- USA,•·7Tiie lack of effective antibacterials has placed em- • oral onoxacin 300 mg twice daily for I0 days, or
te<-rclated infoctions, surgical wound infections, and intra· phasis on measures to prevent the spread of vancomycin- • oral leYOlloxacin 500 mg once daily for 10 days
1
rcsist8nt entcroeocci; without extensive control meas- Sexual contacts should also be treated if ~ididymitis is
abdominal and pelvic infections; less commonly entero-
cocci may infoct the bone, joints, and the meninges. ures, large-scale emergence ofvancomycin-resistantS. 011· caused by a sexually transmitted pathogeo.
reus (VRSA) may occur.• Patients co-infected with HJV should receive the same
Despite not being particularly pad10genic in humans, in-
l.~iJJJ :&'3Tl:"~';'~i~~nl cnlaococcal inf«1ions. N treatment as tbose who are HIV-negative.3
fections due to enteroc:oc<:i are of increasing concern be-
cause of drug rcsistance1·' The most significant types of
2 I. WHO. Guidelines for ~ man3gcment of scxuaUy uansmjn.ed
2. Zin.k.u&h A, h lel R. Yoincomyc•n·resist.a:nt cn1crococci: colo-- infections. Gcne,·a: WHO, 2003 . Aho aY•ilablc at:
resistance in the enteroc:oc<:i arc: niuti011, infection, detection. and rre.atmcrlt. Mayo Clfn Prrx hnp://whql ibdoc.who. int/publ icationsf200ll924 t 546263. pdf
2006; 81: S29'-l6.
• high-level resistance to the aminoglyeosides (occcsscd :2/03/07)
3. Gold HS. V:ancomycl,...resis1ant cnttrococci: mei:h3.nisms :tind 2. Clinical Effecti,·cness Group (As50Ciecion for Gtnilourin.ary
• ampicillin resistance caused by bcta-lactamase produc- clinical oh$crv;itiont... C/in h(OCt DiJ 2001; 33: 2 10-9. Medicine and the Medico: ISociety for the Study or Venereal Dis..
tion 4. Willems RJ, cl of. Global spread of va.ncomycin·rcJistant Ente· cues - no~· British Assoc:iation fOr Sexul'I Ht:3hh 11ind HIV).
rococcus raccium from distinct nosocomial genc1ic complex. 2001 Nation3l guideline for the managcmen1 of cpididymo-or-
• glycopeptidc resistance including vancomycin resist- Ema'8 l11fttt Dit200S; 11: 82 1-8. chi1is. A\•ailable a1: hnp://www.bashh.org/documcnu/31/3 1.pdf
ance 5. Sood S, ti ol. En1crococcal infections and aotimicrobi1I n:siH· (1cctssed 18/08/08)
ante. lndlo11J Mtd Ru 2008: 128: 111-21. 3. CDC. Sexually tranS:mittcd diseases trc:31mcn1 auidelincs 2006.
• multidrug resistance to ampicillin, aminoglycosides
6. Woodford N, L.ivcnnorc OM. lnfec-1ions caused by Grem·posi ~ AfMWR 2006; SS( RR- 11): 1-94. Also •"•il•blc at: hUp://
(high-level resistance), and glyeopeptides tivc h:lc1cri1· 1 rc\'itw of 1he gloMI c.h3llmge. J /nfrct 2009; 59 www.cdc.gov/mmwr/PDFtrr/rrSS 11.pdf (attcssed 22103/07)
Enterocoeci have bod1 intrinsic resistance and the ability to (<uppl I): S4-Sl6. Updated r~commended tre:n~nt res-1men1 for gonococcal in-
1. Lech:n:q R. Epidemiological and rtsist31>Ce issues in muJ1idrv1~ fections and associated conditiont-Uniicd S&.11e1.. Aprjl 2007.
acquire new mechanisms ofresistance to antibacterials; al-
though some species (such as E. foeci11m) are more intrin- =:•ri:'~"f.'?~'f°"i and emcmcocci. Cfin Miaobiol lnftt1 AvaiJable at: http://www.cdc.1ov/s1d/tre11ment/2006/
GonUpdAleApnl2007.pdf (accessed 12/04.'07)
All cross-references refer to entries in Volume A
 Antibacterials 181
Epiglottitis ogens include s~phylococci, streptococci, Pse11do111011<is positive, Gram-negative, and anaerobic bacteria. Regi-
EpigloUitis (or supraglottilis) is an inflammation of the ep- spp.. and Entcrobactetiaceae. Bactcriul kcratitis is poten- mens that have been used include:
iglouis ond adjacent structures that may occur at any age. tially sight-threatening and requires prompt aggressive • a penicillin plus gentamicin and metronidazole
h is a potemially life-threatening condition in which previ- treatment with broad•spec1runi antib3cterials. It is custom- • a second-generation ccphalosporin (such as ceft1roxi-
ously healthy persons may develop sudden upper airway ary to oblain material for sensitivity testing. but increas- mc) plus metronidazolc
obs1roction within hoUTS. Symptoms include severe sore ingly, empirical treatment is then begun without delay.
1hroat. fever, dysphagia, drooling. distress, and inspiratory Frequent or continuous topical application of drops or the • clindamycin plus a fluoroquinolone in penicillin-aller-
stridOI·. It is often due lo bactctaemic infection with Hae- use of local drug delivery devices have been used to ensure gic patients
mophilus i11fluenzae type b (see p.186); other bacteria im- prolonged elevated drug concentrations. Suboonjunctival • vancomycin or linczolid should be considered in those
plicated include H. parainj/uemae, S11vp1ococc1<r pneu- or systemic therapy may occasionally be necessa1y. Topi- at risk for MRSA
maniae, Pas1eure/la mu/1acida, Srophylococcus aure11s, cal treatment with ccfazolin and either gcmamicin or to- Other antibactelials used have included combinations ofa
bcta-h.aemolytic streptococci, Branlramclla catan-lwlis, bramycin has traditionally bec:n us.:d when Pseudomona.f beta !act.am and hcta-lactamase inhibitor (such as ticarcil-
and K)cbsiella pne11111anfaa. Epiglottitis may also be is not suspected. More recently, fluoroquinolones or lin with clavulanate, ampicillin with sulbactam, or pipera-
caused by viruses, fungi, and mechanical injury. Tradition- ceftazidime have been used, and semisymhctic penicillins cillin with tazobactam). third-generation cephalosporin,
ally epiglottitis has occurred mainly in young children. and or vancomycin are other altcmatives. For the treatment of chloramphcnicol, and tetracycline. Hyperbaric oxygen is
although the incidence has decreased in this age group Aconthamoeba kcratitis, see p.906. used as an adjunct to surgical debridcment although its ef-
since the introduction of a vaccine,1 cases due to H. i11j/11- ficacy has not been established. Gas-gangrene antitoxins
e11zae.still occur in young unvaccinated children, particu- Endopbthalmitis is a de\•astating ocular disease resulting are now rarely used.
larly in resource-poor countr·ies. Acute cpiglottitis is being from infection of the ocular cavity. usually after peuetrat-
ing trauma or surgery. Depending on the route of i11fcction, References.
increasingly seen in adults. 1-< • l. W:ms C. t1 al. Hyper~ric o'(ygcn for 1rca1ina wounds: :i system~
causative organisms often include staphylooocci, strepto- ~tic rie\"iCl,I. of1ht li1tr11urt. Arch SHIJ 2003: 138: 272-9.
Treatment and prophylaxis is similar to that for Haemo-
cocci, H. inj/umuM, Bacillus cereus, and Propianibac1eri- 2. R:kha A, C'IQC'Mtta.n TH.. Civilian .gas pn;,rene: a clinical chal-
philus in Ouenzae meningitis (see under Meningitis,
11m acnes. Fungal infections occur less commonly. Bacte- lenge. JmJ lo•· Extrrm 11'01111'4 2007; ': 98-101 .
p.191 ). lnunediatc management includes the maintenance 3. Dylcwski I. ~1 t>I A ~e or Clt):ilridium 1t<pticum spontaneous
ria I endophthalmitis requires im mediate aggressive
of an adequate airway and the intravenous use of antibac- treatment witl1 antibacterials, usually given intravitreally. gos S""ll'""'· CJ£M2007; 9: 133- S.
terials aetive agai11stH. i11j/11enzae type band other likely The value of concurrent parentera l antibacteri3ls is
causatiVe organisms. Chloramphenicol has been the drug unclear. The choice of antibacicrial for intraviucal use
of choK:e, but second- or third-genmtion cephalosporins Gastro-e nteritis
depends on the most likely pathogen. Third-generation Diarrhoea is a symptom of simple gastro-enteritis and of
such as cefuroxime, cefotaxime, and ccftriaxonc with or
cephalosporin.~ or vancomycin arc used, but aminoglyco- most intestinal infections. It is a major problem in develop-
withoul.metronidaiole arc increasingly used.•.i.•-7 Other
sides may produce retinal toxicity. Clindamycin may be ing counuies, but is common world1vide. Although viruses
intravenous antibacterials that have been used include effective if 8. ccreus is suspected. Adjunctive treatm..->n1 in- are often responsible, d1e severest forms ofinfectious diar-
2moxicil lin with clavulanic acid, ampicillin with S!Jl- cludes vitrectomy, surgical removal of infected lens struc- rhoea are generally those due to bacteria. Conunon bactc·
bactam, am inoglycosides, and erythromycin;2•4 •6 oral tures, and corticosteroids to control inflammatory and im- rial pathogens include Campylobac1erjejw1i, Escherichia
amoxicillin with clavulanic acid has been given as mainte-
n~nce therapy.• Co11icosteroids have been given to reduce
mune responses . . coli. Salmo11ella enteritidis, Shigello spp., Vibrio choferae,
mucosal oedema, although there are no data to prove any and Ycrsinia emerocolilico. Intestinal protozoa also cause
For a discussion of fungal infections ofthe eye, see p.565; diarrhoea and are important in AIDS-associated diarrhoea.
benefit6.7 Prophylaxis with ri fampicin may be given to in- for cy'tomegalovinis retinitis and ocular herpes simplex in- For discussions of viral and protozoa! gastro-enteritis and
dex cases and cont:acis (see Meningitis Prophylaxis under fections, see under Cyromegalovirus Infections, p.94 I , their rceatment, see p.938 and p.908, respectively. Many of
R.ifampicin, p.357). and Herpes Simplex Infections, p.942, respectively. these organisms are easi ly transmitted through food or wa-
I. franu 1'0, 111 al. A~utt eptato11i11s "' :aduhs: an~lysis: or 129 ttS·
<'-JAMA 1994; 272: DS~l. Some genernl references are given below. ter, or from person to person, and some may be particulal'iy
2. Pino Rhtru V. e1ol. Epialouus 11uda en atluJlos: nucmra expc- severe in immunocompromised persons or those with
ncnc:Q. c1iniea en 30 c::isos ..(cw., Otorrinoluringol Esp 2007: $8: I. B:AumJ. lnfcctiC'lns o(thecyc. Clm hif«t Dis 1995: 21: 479-81.
soucrural abnormalities of the gastrointestinal tract.
~63-S.
~- Lecinill; JP. Tre31mcn1 of oa.lar 1.nfec'lior.s with 1opic.al antib:1c- Treatment of acute diarrhoea ofany aetiology includes flu-
3. Ames WA. et ol. Adult tplglonitis: an undcr-rtt<'fµ'bcd, lift- 1criab. Clm Plrormocokluct IM: 37: ;; 1-()().
thrc:uenift11 condi1H>rt ,,. J Anui:.1Jh· ~OOO; 85: 19S-1. id replacement, antidiarrhoeal drugs, probiotics, vitamin
-I, Ng. HL~ ~f-al. Acu1t epigtouilis in odulu: a TC'trospcctivc tt\'icw 3. Koben P-Y. Adenis J.P. Co1npantii"e revit"'A• o( topical opluhal- 3nd mineral supplementation, and antibacterials. Treat-
of I06 pa1ien1s in Hong Kong:. Em<"rg M~f.12008; 15: 15~5. mic antibatttrial prcpar11ion.s.. Dn1gs 2001 ; 61: I7S-S.S.
S. Sawyer SM. t1 nl. Successful trc-;tmenl or ~pialonitis \\-ilh l\\>O ment with antibacterials is discussed below, whi le the clas-
doscsof ccfuia!\onc. Art:h DiJ Child 1994: ?(I: 129-32. 4. Sheikh A, Hurv.i1z 8. Ant1bio1ic.s vcr.sus placebo for acute bac- sification of diarrhoea and other treatments arc discussed
~ Alcaidt' ML Bl!mO AL Phary11;,tcis tind eplglottitis. ln/«1 Dis terial conjuncio II•"- A\·ailable in The Cochr1nic 01tabascofSys.--
1c111a1ic Rt'vicws: lss,uc 2. ChichtSlCr: John Wiley: 2006 (ac· under Diarrhoea (see p.1842). WHO' recommends d1at di-
C/in Nnrth Am 2007: 11: 449-69 Concction. ibid.~ 847-8.
7. Su~I SE. Z.1pat;'); S. Erisk>uillJ nnd croup. 01(>/m)'ngol Cit,, e<sscd t =/06/08). an11oea be managed with ora l rehydration therapy and
.'lorth 4.. ~008; 41 : 551-66. 5. s~an~:.pichon O. er ol. Top1c:ol conicostcroids as odjuncth·c
continued feeding and that antibacterials should not be
1hcrapy ror baclerinl kcratiliS. Av11bble in The: CochrMc 011&· routinely given as it is often difficult to distinguish whether
ba._~ or S)$lca1131ic Rcvit\\s: lss.ut 4, Chic~cr: J<ilm Wiley: the diarrhoea is caused by an organism responsive to anti-
Escherichia coli enter itis 200710<«...-d t;JO(J08). bacterials. Furthermore drug sensitivity of die causative
Sec p.184.
organism is not always known and use of antibilcterials
could promote the devdopment of resistam bacteria. 1
Ey<i! infections Gas gangrene However, diagnostic capacities are more widely available
Conjunctivitis is a common superficial eye disorder and Gas gangrene (or closllidial myonecrosis) is a life-threat- in the developed world and some clinicians consider such
may be caused by infection with bacteria, viruses, or, less ening bacterial infection caused by exotoxin-producing an approach to be unncccs.sarily conservative in adults
often, fungi. Acute baclerial conjunctivitis is often caused Closlridium spp., which invade muscle tissue and cause with severe acute diarrhoea in developed coun!ries1 in
by stophyloc::oc:ci or strcplococci in adults, aod Haemophil- tissue necro:;is, gas production, and systemic toxicity. whom empirical 1reatment with fluoroq11in'olones can re-
us injluenzae and Mora.tel/a calarrhalis (BraJ1hamella ca- TI1ey are anaerobic, Gram-positive bacteria normally lieve symptoms and shorten the illness wilhout significant
1on11alis) in children. Other causes of bacterial conjuncti- found in soil and the gastrointestinal tract of humans and adverse effects. In the USA, empirical lherapy is consid-
vitis include gonococci (see Gonorrhoea, p.206) and animals. Infection usually results from deep trauma or sur- ered for any patients with moderate to severe, febrile, com-
Chlamydit1 tmch<m1atis (see Trachoma, p.212). Neonatal gery. and more than 80% ofaises are caused by C. pei:fri11- munity-acquired dia1Thoea, especially if invasive disease
chlamydial and gonococcal conjunctivitis are disc,ussed ge11s. Spontaneous or nontraumatic gas gangrene is rare is suspected; stool samples should be obtained for identifi-
under Neonatal Conjunctivitis, p.193. Uncomplicated bac- and is almost e)(clusively caused by C. sepllcum. The t)IJ>- cation of the causative organism.J.4 Empirical thctapy may
terial conjunctivitis may be self-limiting but empirical ical incubation period is usually less than 24 hours but may also be given to those with severe nosocomial diarrlloea
treatment with topical antibacterials is often given. In the r.mge from 6 hours to 6 weeks. However, once symptoms while waiting for results of assay for C. diflicile toxin (see
UK, topical chloramphenicol remains the treatment of stan clinical detetioration occurs within hours and is char- also Antibiotic-associated Colitis, below), and for moder-
choice despite COIK.-.:rllS over the potenlial risk of aplastic acterised by rapidly increasing pain, fever, and muscle ate to severe travellers' diarrhoea (below).'
anaemia (see Ocular Use under Precautions of Chloram- swell ing. Systemic toxicity may c~use altered menial sltl-
In infants and children oral rehydration therapy isw1iver-
phenicol, p.26 1). Allematives include gentamicin, to- rus. and the progression to septicaemia, shock. and death
can be rapid. C. peiftingt:m alpha toxin has a ncgi1tive in- sally reco~1ised as approptiate initial treatment of acu1c
bramycin, crythromycin (especially when infection wid1 diarrhoea,- but it has been underutilised in both developed
Gram-positive organisms is suspected~ nuoro<1uinolones otropic effect on cardiac myocytes causing severe, refrac-
toiy hypctension, while the release of theta toxin leads to and developing countries.6 and a preference for the use of
including ciprofloxacin and onoxacin, framycetin, fusidic inuavenous rehydration therapy with Ringer's laaa1e so-
shock through peripheral vasodilatation; renal shu!down
acid (especially for staphylococcal infections). and poly-
due to m)"OllCCTosis may occur. Mortality from traumatic lution or nonnal saline was noted in the USA.7 Nubitional
myxin B in combination with bocitrncin, lrimethoprim, or support and management of secondary compl ications, in-
neomycin. gas giingrene is about 25% and for spontaneous gas gan-
grene ranges Ii-om 67 to 100%. cluding systemic infections, is also particularly important
Blepharitis is an infection of the lid margins. It usually in this age group. Antibacterials ha~e little place in man-
presents as a chronic condition and may require prolonged Mortality can be improved by rapid diagnosis and early agement in most aises1·5 WHO' has stipulated that anti-
treatment.. typically involving local hygiene lo remove en- treatment, which involves aggressive surgical exploration bacterials should 011'y be used in children with bloody di-
crustlltionsand topica l application of a broad-speccrum an- and debridement, and intravenous antibacterial lherapy. arrhoea that is probably caused by Shigella (see below),
tibacterial oinunent. Amputation may be needed in 15 to 20'% of patients. Ben- suspected cholera with severe dehydraiion (see below), or
Kcratitis may be caused by infection ofthecomea by bac- zylpenicillin is the drug of choice; adding clindamycin is diarrhoea associated with serious non-inresiinal infec1ions
teria, fungi, viruses. or protozoa, usually after trauma to the considered beneficial. However, it may be difficult to dis- (such as pneumonia or urinary-tract infection).' Treatment
surface or tlie eye, including that due to contact lens wear tinguish gas gangrene from other soft tissue infections and ofprotozoa I infections such as giardiasis and amocbiasis is
(see Contact Lens Care, p.1765). Common bacierial path- so empirical anlibactecial treatment usually covers Gr.un- rarely indicated.'
182 Antibacterials
Persistent or prolonged diarrhoea may no1 have an infec- fcctive and not recommended against in,·asive agents, The term antibiotic-associated diarThoca is usually used
tive cause and antibacterial tteatmcnt should not be started such as Cmnpylobac1cr and Shigella. Jl.JI A systematic re- for milder disease that is not caused by C. d/{ftcile or its
unless a pathogen can be identified Tropkal sprue is a view and meta-analysisJ 9 found that combination treat- toxins.
syndrome characterised by acute or chronic diarThoea, ment with an antibacterial and lopcramide, gjven early in Exposure to antibacterials is the most significant risk fac-
weight loss, and malabsoiption of nutrients. It occurs in the course of the illness was superior to treatment with ei- tor for development of disease. Antibacterial use alters the
residents of or visitors to the tropical and subtropical re- ther agent alone; combination therapy could be considered norTnal bowel flora, predisposing to the overgrov.,h of C.
gions. The exact pathogenctic sequence is unknown but it for people who need prompt rcsoluJion of symptoms. 13 difficile and the production of its toxins. The incidence of
is thought that bacterial oveigrowth, disturbed gut motility, When the infecting bacteria are known, specific therapy AAC varies considerably but is increasing worldwide due
and honuonal and hiSIOpathologic abnorTnalities conlril>- may be ncccssa.ry, as described below. to broad--spednlm antibacterial use.J.l AAC has been as"
ute to its development in susceptible persons.1 Treatment The risk of developing travellers' diarrhoea can be reduced sociated with the use of most antibacterials, but panicular"
with teuacycline and folate is effective in some patients, by avoiding possibly contamina1ed foods as embodied in ly with clind3mycin, lincomycin, arnpicillin, amoxicillin,
although relapses after treatment are common.1 the advice to •cook it, boil it, peel i~ orforget it'. Prophy- and cephalosporins (especially second and third genera-
HJV-associated diarrhoea. Dianhoca is common in HIV lactic drug regimens have been suggested, including vari- tion); and, less frequently, with Ouoroquinoloncs, tetracy-
infection and AIDS (p.944) and causative organisms may ous antibacterials, in addition to bismuth salicylate and cline, carbapene111s. trimelhoprim, the macrolides (esylh-
be bacterial, protozoa!, or viral. 1bc most common bacte" probiotics. However, routine antimicrobial prophylaxis is romycin, clarithromycin, azithromycin), and other
rial cause is the Mycobocterium ovium complex (see N°"" not generally recommended because of the danger of drug penicillins. Antibacterials occasionally reported to cause
ruberculous Mycobacterial Infections, p.194); others in" reactions, supcrinfections. and increasing bacterial resiSl- the disease include aminoglycosides, co-trimoxazole, and
elude Campylobacte,., Salmonella, and Shigella spp. ance;JO, JJ,Jl it should be reserved for those at special chloramphenicol. The perception that Ouoroquinolones
Supportive care and appl"opriate conven1ional antibacterial risk. J0,11.lO Many authorities prefer early treatment. includ- are low risk for AAC has been challenge& and studies•-6'
therapy may be adequate, as described under the specific ing self-medication (with an antibacterial), with clear in" have shown a significant association between cipro-
infections, below. structions on when medical help should be sought, If floxaein usage and AAC, with the risk increasing with
'Food poisoning' is the !CITO used when a preformed toxin prophylaxis is given it should be started at the SIMI of the longer courses of therapy.6 It bas also been suggested that
in food is ingested, resulting in un intoxication rather than at-risk period, and continued for 2 days after the risk stops; the newer fluoroquinolones (such as moxifloxacin and
an enteric infection. It is gener.illy a self,limiting form of prophylaxis should be limited to 3 weeks.Jo A Ouoroqui- gatifloxacin) may have different effects on intestinal Oora
gastro-cnteritis and most people recover from a case of nolone is the drug of choice when travelling to lllOst areas and therefore be more likely to cause AAC; preliminary
food poisoning within I to 2 days,9 although serious out" of the world; azithromycin can be considered an altema" data from 3 studies appear 10 support 0Jis hypothesis.2 An"
breaks offoodbome illness have been associated with bac- tive and rifuximin may be considered for regions where E tibacterials usually used to treat AAC such as vancomycin
teria such as Salmonella enteritidis. Staphylococcus au" coli predominates, such as Latin America and Africa. Sul- and melronidazole have also been shown to cause disease.
reus can produce a heat-stable toxin that causes vomiting fonamides, CO·trimoxazole, and telracyclines should not The role ofaeid suppression in AAC is unclear.7
within 2 to 7 hours of eating improperly cooked or stored beused because of widespread rcsistance. 10.J) Symptoms usually develop 5 to 10 days after starting anti"
food containing it. while Clostridium peifringens toxin I. WHO. The lrtMJliMnl ofdlorrh<>10: o m.onu:1/for plryslclon1 ond bacterial therapy, but may develop after a single day of use
orM.r unSor Ilea/th work,rs. •th ~d. Gencn: WHO, 200$.
causes watery diarrhoea without vomiting within 8 to I 4 A\•ailablc at: hllp://whqlibdoe.who.intlpubtications/200S/ or can occur up to JO weeks after Slopping treatment. Col-
hours after eating contaminated meat, vegetables, or poul- 9241s9:;180.pdf (accened I 3/04/J 0) onisation generally occurs after ingestion of the acid-re-
try. Bacillus cereus may cause vomiting or diarrhoea, de- 2 . Oorbach SL. Trealing diarrhoea. BM./ 199•: 314: 1776-7. sistant spores that are common contaminants from patients
l . Oucmnl RL,. rt ol. Infectious Diseases Socitty of America.
pending on the toxin produced, after eatiog contaminated Pnccice &uidtlincs for the managcmenl of infectious dfanhc:t. who harbour C. difficile. Hospitalised patients and resi-
fried rice, vegetable sprouts, or other food items.9 Clin Jnfact Dis 2001; 32: 33 1- SO. AIJO available at: hnp:// dents of long-term care facilities arc at higher risk of colo-
www.joumal.. uehicogo.edu/doilpdOI0.1086/3IBS14 (aecessed
TraveU~rs' diarrhoea. JO.J 4 is acquired by ingesting con- 18/08/08)
nisation with C. difficile although coloniS11tion can occur in
taminated water or foodstuffs. Although it occurs world- 4. Thielman NM. CYCn'1n1 R.L. Clinical pr.1c1icc. Acuit infectious the outpatient setting. The clinical presentation of AAC
wide, the highest rates (20 to 60".4) are in travellers from diarrhea. N E11g/J Mtd2004: 350: 38-47. can range from mild self-limited diarrhoea to severe colitis
developed, high-income couotries visiting developing, 5. Kolc:t2ko S, Ostcniedu S Acute infectious diarrhce in children. with pscudomembrane fo1TDation complicated by devel"
DISch An1•/;I /1112009; 106: S39-47.
low· income regions. JJ.J 4 Travellers diarrhoea is most com- 6. The United Na<ions ChildrClls Fund (liNICEF)IWHO. Oiar"
opment of toxic megacolon or colonic perforation. The
monly caused by bacterial enteric pathogens, ofwhich the usual presentation is cramping and abdominal pain with
commonest bacterial pathogen is entcrotoxigenic E. coli, ~~~c~~d, ~gg~;~~i:~'i~:i:i~ •h1~p~t!!~1:!:~h~~~~j profuse, mucoid, greenish, malod0t0us watel)' stools.
public111ons/2009197&924 JS984 JS_ens pdf(oce<ss«l 13!04/J 0)
although enteroadherent £. coli is also sometimes in- 7. HH'tlin&: l, et of. Or.11 versus intravcnouJ rehydration for treat- n
Diarrhoea resolved within 48 to hours in 20 to 25% of
voJved. Other bacteria include Compylobocter jejuni, and ing de:hydrt•io.n due to gastrocnlttitis in children. Available in patients after stopping the offending drug, J and giving flu,
Salmonella and Shigello spp., Jlibrio chalerae, and non- The Cochrane Database ofS)'St.crn1tic Reviews; lu uc 3. Chieh-
($Jer. John Wiley; 2006 (acccssc:d 29/04110~ id and electrolyte replac:emcnt. If it is not possible to stop
cholera vibrios such as V. parohoemolyticus are rare in
traveller.;. VJTUscs and the protozoa Giordia inlestlnalis,
S. Nalh SK. Tropical •prve. c,,,,. Gost,.,,.nMol /fop 200S; 7: antibacterial treatment, a drug less likely to p.-omote AAC
343-9. may be given.J.J In the past early specific antibacterial
Entamoebo histolytica, and Cryptosporidium may also be 9. DuPont Hl. Clinical pracuce. 8ac1erial diarrhe,a. N Etttl J Mrd therapy was only given to patients wi1h severe illness
2009;361: 1560-9.
responsible. Recommendations for the management of 10. Al·Abri SS, c1ol, TrawllC'f's diarrhoea. Lunctt ln/«I Das 2005; characterised by high fever, marked abdominal pain, and
travellers' diarrhoea are published by national and interna- 5: 349..;)0. marked leucocytosis and to elderly, toxic, or debilitated
tional bodies including WHO, 15 the DOH in the lJl<, J6 and 11. DuPont HL. Tra"eJlcrs' dt-Jrrhoc>1: <:on1crnpur.uy approaches ro patients, or those unrespon~ivc to supportive therapy. 8
1hcnpy and pn:ven1ion. Dn•gs 2006; 6': 303-14.
the CDC in the USA.'7 Clinica l features depend on the 12. DuPont HL. Therapy for and prevention oftrncle:r's di:mhea. However, with the increased incidence of fulminanl AAC
pathogen responsible and treatment varies :iccording to se- Clin /nf«J Dis 2001; 45 ( suppl I): S7S-SS4. and the rapid clinical deterioration of some patients, delay"
verity and duration of diarrhoea. Onset of diallhoea is gen- 13. Hill DR, Ryilln ET. Management of traW'Urtt' diarrhoea. 8MJ ing specific AAC antibacterial therapy is no longer ad-
erally delayed with Gio,.dio and En1amoeba because of01e 2008; 337: 11746. Full vttsfon: http:J/www.bmj.com/cgi/
S«lion..]'df/l37/oct06_21al746.pdf(aece""d 29/04110) vised. J.J Antibacterials are probably unnecessary in mild
incubation period. 14. Baldi f. et al. Focus on acule clia~\ disenc. Wutld J Gos· discasc9 and chemooroohvla.xis for asymptomatic carriers
Diarrhoea is often mild and $elf-limiting and increased Ou. troenluo/2009; 15: 3341 · a. is not recommend~.J."7 Antidiarrhoeal and antimotility
JS. WHO. /nlarnt1rlonal fl't1'"#'l ond lr~n/Jh. 2010 rd. Available ti: drugs should be avoided since they may aggravate the con"
id intake (in adults) or oral rehydration therapy (for infants, hup://www.who.intlith/ITH20 IOchaptcr3.pdf (:1cc.cned
young chi ldren, the elderly, or those with cholera-like diar" 12/04/JO) dition and may occasionally increase d1e possibility of tox-
rhoea) is usually all that will be required. Symptomatic 16. OoH. Hco/Jh infonwW11/oro•·crs•Ds trn ~I. 2001 ed. Avail•· ic megacolon.1 A literature review, Jo however, concluded
treatment with antimotility drugs such as lopcramide may hie a1: hup:J!www.udtive.omclal documcnts.eo.uk/doe\J1nrnt/
0
lhat antimotility drugs, used with an active antibacterial,
_ doh/hinfo/lrl\'dl9.hon (accessed 12/04110)
be of benefit in mild to moderate diarThoea. However, an- 17. CDC. Tn1vtlets Dionhca. In: Th• lellowllo<JA; CDC Htolth M· may provide safe and effective symptomatic relief and ns-
timotility drugs may worsen diaJThocal illness caused by /ol'mt1tlo11,fiN lnl~nalinnol Traw!I; 1010. sist in reducing the passage of infectious stools in the hos-
invasive bacterial pathogens aod should be used with cau" Available 11: hnp~f/wwwnc.cdc.govhrawllyc.llowbook/2 0101 pital environment.
ch>ptcr-2/lravelcrs· dianheuspx (accessed 12/04/JO)
tion in those with high fevers, chills. or bloody di3!Thoca. JO IS. Sanders JW. 11 al. Aiithromycin and Jopenmidc ate compuablc The choice of initial antibacterial therapy depends on the
Bismuth salicylate may be used to reduce the ITequency of to l cvoflo~acin vnd foperamM.lt forthe treatment of 1ravclc.r 1 0

severity of disease and different regimens are used to treat

diarrhoea lnfo1TDation on the value of probiotics in the diarrhea in United Slllct miliury personnel in Turkey. Cl/II/,,.
/ttt Dis 2007: 45: 29-1-301. first or secood episodes of AAC, recurrent episodes, and
treatmcnt of travellers' diarthoea is insufficient. 13 19. Riddle MS. e1 al. Effect of ldJunc1in lopcuunidc in combi.na· very severe or fulminant disease. J Vancomycin or 1netron-
Studies have shown that antibacterials are effective and a 1ion whh antibiotics on lrtatmcnt outcomes in travckr"s di· idazole are widely used when antibacterial treatment is
srrhu: a Jy!itcma1ic revit-w ind mc1a-analysis. Oin lnf«'t l>is
single dose (or for up to 3 days of treatment) ofan appro- 2008: 47: 1007-14. necessary.J.3.7.S Mettonidazole can be giveo orally or intra-
priate antibacterial will improve symptoms within 20 to 36 20. ~;~~~~:'.a~;::r ~~ia;fo:l~~)~;'6~f~~~J.1yl1xi• ror
venously as appropriate. Vancomycin is given orally or via
hours and shorten the duration of diarrhoea by I to 2 1 U;>>elcrs' a retention enema; it should not be given intravenously
days..13 Fluoroquioolones are effective in most areas oftl1e Antibiotic-associated colitis. Clos1ndi11m difficile is since it does not give rise to adequate concentrations of the
world, except whete potentially resistant Compylobacter an anaerobic Gram-positive organism; 2 toxins (A and B) drug in the bowel lumen.1 Metronidazole tends to be the
is common (as io South and South East Asia). Azithromy- fomied by the organism are responsible for an infectious drug of fust choice and vancomycin is reserved for thC>SC
cin may be given as an alternative in Oiese areas; it can also colitis that affects about 20% of hospitalised patients tak- who do not respond to, or wbo cannot tolerate, mCIJ'Ooida"
be used in the treatment of pregnant women and young ing antibacterials. Synonymous temlS used to refer to the zole; for those who are severely immunocompromised,
children with travellers' diarrhoea. Co-trimoxazole was sp:ctrum of disease due to C. difficile are: and for those with severe illness. J.?,S 11JiS view is also en"
the drug of choice for many years but widespread bacterial dorsed by expen bodies in the USA whose aim is to pro-
• antibiotic-associated colitis (AAq
resistance has now limited its usefulness. J0,J2 It may still vide guidelines for preventing the spread of vancomycin
be used in th~ who fail to ~d to a fluoroquinolone • C. diffici/e-assodated dianhoca (COAD) resistance. JJ The severity of the dianboe:I often decreases
and antiprotozoal drugs (such as metronidazole) in areas • C. difficile rolitis, and within 48 to 72 hours, but may not stop for a week or more.
where cyclosporias.is is suspected. JORifaximin has been • pseudomcmbranous colitis (which specifically de- Treattneot is usually continued for I0 to 14 days. J Other
found to be effective treatment of mainly E coli associated scribes the formation of a membranous exudate in the drugs that have been investigated in the treaunent of AAC
travellers diarrhoea in Mexico and Jamaica, but is less ef- colon and occurs in about 500/o ofcases of AAC) include teicoplanin,J2·J• fusidic acid,J•.Jl and bacitracin,J 6
All eross·rcfcrenccs refer 10 entries in Volume A
 Antibacterials 183
altht>ugh experience with their use remains limited. A sys- .J. McCusker ME, t.'/ ul. Fluoroquinolonc use andl C/ru1ridt1liitilif· a:rrhoea, p.1842). 1·2 Antllacterials arc gen~rally not re·
)idlt"·:JSSOC:i:i.tcd diarrhea. Emtn'g In/tel Di~ 2003: 9: 730-3.
tematic review9 found that metronidazole, bacitracin, ri- 5, Loo V(\ <U ol. A rredominanlly clonal rnulli-in~1i1nc iona l out·
q:uired but can be co11siicred for patients v.it!h severe or
faximin, nitazoxanide, or .fusidic acid seemed to be as ef- brc01k of Clo~m'di11m d~ffecil~·3SS()(;iatcd d iarrhctti wi1h hig.h prolonged symptoms or •ho are irrununocompromised."-;
fective as vancomycin in tenns of symptomatic cure, and mor'bidity 3nd OlQrtal ily. N E"gl J Med 2005; 353: 2442-9. Those that have been usd include crythromycin, azilhro·
6. Pt:pin J, ~I t1f. Emefl!:enc:e of Ouor~uino l ones 3S the predomi· mycin, tetracycline, andciprofloxacin. However, due to
teicoplanin might be slightly more effective. Bacitracin mm1 tisk factor for Closrridium dlf/ici/e-ussoc:iatcd dtan-hc:i: a
and fusidic acid seemed to be less effective than vancomy· cohorl study durin~ an epidemic in Quebec. Clin Jn/cc' Dis widespread use of these miibaccerials in veterinary prac-
cin in tenns of bacteriological cure and ros:olution.9 Ram- 2005: 4 1: 1254-60. tice and as additives to ruimal feeds (particularly poultry)d
7. lf'ffitr r;>A. Lamoni JT. Tre1u1nent of Clostridimn difficilt:·USO-
oplanin and tiacumicin B (also known as OPT-80, Jipi- e,.ted d""'"'· Gasi't>en/ero/ogy2009: 136: 1899-912. selection for resistant O,,py/obacter spp. has occwred4·
armycin, fidaxomicin, or PAR· I 0 I) have also been S. Malnick SDH. Zimhony 0 . Trc~trm:nt orClo5'ridium difficile· and increasing numbersof ci~rofloxa_cin·resistant _cases
investigated. 1.3 assot.•iated .Jiarrtica. Amr Phorn1txolhf!r 2002: 36: l 7Ci7-7S. are being reported worlO>nde.-•6' 8 Resistance rates m the
9. Nelson R. Antibiotic treatment ror Clostridium diffici!e·assC1Ci·
The anion-exchange resins colcstyramine and colestipol au:d diarrl'ca in adults. Available in The CQChi-.tnc: Oa1abasc or USA and Canada are rep.rted to be about 19 to 47%, while
hydrochloride have been shown to bind the Cl. difficile Systematic Reviews; lssue l . Chichester: John Wiley; 2007 (ac· 17 to 99% of Campylobcfer isolates in Europe are resist-
lox.in ;,;·_ vitro, and colestyramine has been used to treat «S«d 05/08108). a;nt to tluoroquinolones.8 fhis has prompted the witbdraw-
10. Koo H L, c1 nl. An1imo1ili1y ai cnis for the lrC3t.mcm of Goslrid·
pseudomembranous colitis 17 and recurrent AAC.1The use ium diQidlr: diarrhc3 and colitis. Clin hifr:ct Dis 2009; 48: a I of tluoroquinolones tom use in commercial poultry
of vancomycin together with colestyramine has been sug· 598-66S. farming in the USA.9 Rt:es of macrolide resistance have
11. Hospiul Infection Control Pr-acticcs Ad\'isory Comminec stayed stable·and low inmany countries, but an increase
gested, 1 ~. but the value of the combioatiol\ is uncertain.
Colestyrainine binds to vancomycin, resulting in a reduc- ~~c:c~;~~~i~:~e~~;;~s rir9~~c~n(t~l~~~)rr,c~J~f~~~ has been reponed in hwian strains in some coumries,5·6
tion of bfoiogic activity in stool and in general, the use of available al: http:l/www.cdc.gov/mmwrfPDF/rr/rr4412.pdf (ac- particularly in the develqiing countries.5 The prevalence
e<s•cd IS/05/04)
colestyramine and colestipol is not recorrunended.'-19 An 12. de Lilla F, "al. Tr<otlllcol of,ctomidium difficil<->UOtiMcd
of erythromycin resisl:m.e in C. jejimi has remained low
experimental toxin-binding polymer, tolevamer (or Gr dittase with 1eicoplanio. Amlmit:n>b Agents Chemo1lr1tr 1989; (below 12% ofisolatesput a higher frequency of resist-
10\J-L'IOI) nas atso oeen mves11ga1ea.·~ ,:,,:, . 1 1..c..1-1.
"'""" (UJJ w 7070) t> •cvvt.ed in C. coli. Globally, multiple
13. de Lalla F, ti ol. PtO.SJ)(!Clh·e study of 0ti1.l '1eicoplanin \·enus
It is thought tliat patients who develop recurrent AAC are oral vancomycin for l hempy of pscudomc:mbranous colitis and antibacterial resistance (t:sistance to three or more differ-
unable to mount a r,rotective immune response to C diffi- CJosuidium difficilc-·associ;itcd diarrhea. A'1timic-rob Agenrs e:nt classes ofantibacteri~) is emerging in Campylobncrer
cile and. its toxins; ·7•19 oonnal immunoglobulin products Clt1mo1litr 1992: 36: 2192--6. clinical isolates.6 .
14. Wenisch C 1 er al. Comparison of vancomycin, rteicoplanin, met·
that contain lgG have been shown to neutralise the toxins ron•d:n:ole. and fusidi:c add for the treatment o f Clostddium dif·
fic ile-associntt:d diarrhe3. Clin hifl!Ct Dis l 996; 22:: 813-18.
Erythromycin is consideed to be the drug choice for of
A and B,3 and may benefit patients with severe and/or.re· treaunent of Campyloba:ter infections; the newer mac-
IS. Cronberg S. et ul. Fusidic acid for lhe lrt3lmcnt of :mtibioticr
Japsin~ /\AC when no otl1er therapeutic options are avail- associialed colitis ind\1ccd by Clos•ridium difficile. !ofection rolides, azithromycin aid claritl1romycin are altema-
able.1· 9 Oral inunu.noglobulin A, used with vancomycin, 1984; )2: 276-9. tives.2·10 Compylobacrerpecies also arc generally suscep·
was effective in controlling severe diarrhoea in a child who 16. Oudlc:y MN, et nl. Oral bal!ittacin vs vancomydn therapy for tible to aminoglycoside~ chloramphenicol, clindamycin,
Closrridium di0icile-fr1duced dianheri: s rondornittd double-
had not· responded to other therapies.20 Normal immu- bliod trial. .~rch Jnte1-,, Mt:d 19&6; 146: 1101-4. nitrofurans, and imipenen,2•6 but high rates of resistance
noglobulin given intravenously was also effective when 17. Pnsks.ammondi.! P. Powell KR. Muhiple rela~es of Clos.!-ridium make tetracycline, amoxi:illin, ampicillin, metronidazole,
added to vancomycin and meb·onidazole tl1erapy in 2 eld- diflicilc-3ssoei'11td diiarrh~ responding 10 an e~1end«I course or cephalosporins a poor :hoice.2
orcholeMyrn.mine. Pedicur fllf~N Dis J 19X9; 8: I 7S-K.
erly patients unresponsive 10 antibacterials alone.21 Vac- IS. Shwed JA. Rodvold KA. An i o~exeh;nge re~ins •nd o~I ,.,•. 1. Skirmv MB. foodl>omc ilness: Campylobacter. IA»ect l990;
cines against C. difficile have a)so been investigated. 1 A comye in in pseLido111etnbf3nous colitis. DJCP Ann Plrormaco1h~ 336:92H.
single infusion of2 monoclonal antibodies against C. diff- ... 1989; 23: 70-1. 2. Allos BM. Carnpylobactcr.ejuni infections: update 011 emerging
t 9. Johnson S. Rt'cum::nl Clostridium difficile lofectiun; ._review of . i$sues and trends. Clin Infer Dis 200) ~ 32: 120 J-6. ·
icile toxins A and B was reponed to significantly reduce risk' f~ctors, treAlmenlS. ~nd outcomes. J ln/~C'I 2009; SS: 3. G::alanis E. Campyloboic•erand boctcri31 g:1.s troenteritis. CMAJ
the recurrence of infection when ~iven with either metro- 403-1 0. 2007; 117: 570- 1. . .
nidazole or vancomycin therapy.~- 20. Tjdbu-Om B, ct al. Or.st immun~lobu l in A s-upph.-rncnt in treat• 4. Scnok. AC, Bette: GA. Canpylobacter enteritis in tl1e Arabian
menr of Clostridium difficile cntcri1is. Lancer 1993~ 341; Oulr. J Inf<CI Dei· C.ries 2!09; 3: 74-82.
Trearment and prevention strategies aimed at colonising 701-2. S. Oibrecl A, T.!ylor DE. Mzrolidc resistance in C~mpy!ob4cttt
the gut with non-pathogenic organisms have included use 21. Salc~do J. et t1f. lntro...~ennus ioimurio~lobul in tl1erapy ror severe ~~~~~~~ ~ampylol\acter:oH. J Antimia'Ob Chemothqr 2006;
of lactic-acid-p~oducing organisms (probiotics) such as Closuidium difficile colitis. Gm 1997: 41: 366-70.
22. Lowy I, t!.f al. Treaument with monQCIQn{ll antit;iodies against
5
Lactobacillus,813 and ~1e yeasts Saccharomyces boular- Clostrldiirm diffit:Ht.• loxi11s. N Enx.JJ M11.cl2.0JO: 3Ci2: 197- 205.
6. Quinn T. f!I of. Antibiouic•rtsistant Campylohactcr: c:ould emu."
pump inhibi1ors control itfcction? J Antimicrob Chemo1/ie,.
dii,6 and S. cerevisi:Oe. 14 A systematic rcvicw25 of studies 23. V:inde:rhoof JA, cl a.'. Lactobacillus OG i:l lhc: prc,•ention ofan· 2007: 59: 1230-jj.
tihirn.ic-asS<X:iatcd diarrhea in childttn. J PeJiow 1999; 135: I . Campyloba~er Sentinel ~urveillancc Scheme Collabom1ors.
that used probiotics as adjunctive therapy to antibacterials 564-8.
(vancomycin or metronidazole) for treatment of an initial :?4. SchcHenbetg D, c.1 al. T~attncnt of Clostridium difficile diar· Ciprofloxaein rcsistanicc n C:unpylobactcr jcj uni: case-case·
rhoea with brewer's yeast. Lancet 1994; 343: n 1-2. analysis as a 1001 for e lucdating risks at horyic and :ibroad. J
episode of C. difficile colitis orrecwrent infection in adults Amimicrob Chenv;1he1~ 200~ 50: S6 l-8.
25. Pillai A, Nc:lson R. Probiotie1 for tratmcot of Clo~1riclt"i1m diff-
found there was insufficient evidence to recommend ad- icile-associated colili:s in adults. Av;iilable in The Cochrane Da- 8 . Luanglongkum T, et o!_ AnibiotH::. ruistnncc in Campylobactcr:
jwictive probiotics. However, another systematic review26 l:tbaS! of Systematic Revie:ws: l~$UC I. Chiche.~tcr: Johs-. Wiley; emergence. transmissfon 111d persis1e11cc. F111ure Microbiol
2008 (•cce~ 03/05110). 2009; 4: I 89-200.
on the use of probiotics in children reponed that they may 9. Nelson JM, e1 al. Fluor1quino!one·rcsistanl Campylobae<cr
26. Johnston BC, rtt al. Probiotics for lhe pre\·ention of pediauic
be effective for preventing AAC. Data on regimens con- an1ibia1iMssociaied <limhea. Available in Th• Coehrane Dm· specks and the witl\dra~•I or fluoroq~fr1ol~11es fo'"om use in
taining Lactobaci/l11s organisms or S. bo11/a,.dii for the ha.se of Sr,1cmatic Reviews: Issue 2. Chichtster: Jobn Wiley; poultry: a public healtb sucess story. Clm lnject Dis 2007; 44:
Ar -:ll r f.' JV'!ll'u- -:ll11rl 977-80 .
n-........ 1,,,...n t nf r11>r11n"lll'1~1' A
~~~~~sc~(.si~o~~~~\~nous ugecycnne as 3GJut\Cuvc or aner·
11"1\nflil"'ti no J.J
.!. I . 1v. J\U1~111uw1i.;_L 1~·1, cu'. 1 m: l.:ll;iice of an1ibacceriril drugs.
In: Hand·
Some experts, however, consider probioti cs to be a safe native lher"'PY for sc>arcrc refractory Chntridhrm di/fi~il~ infec- book ofc111r11nl(:.1'0b10/ 1Jrenpy. I 81h ed. New York: Tl1c Mcdic.Oll
and reasonable option for prevention of iuitial infections 1ion. c1;,, /11/ec1Dis 2009: 48: 1732~S. l.efltr. 2008: 62.
<ind possibly for treatment ofrecurrent infections.7 Campylobacter enteritis. CampJ1obacter spp.H are Cholera and othe1r "!brio infections. Cholera' re-
For patients with severe or fulmioant infection who have a the most common cause of bacterial gastroenteritis in both sults from infection with be eoterotoxin-producing Gram-
functioning gastrointestinal u·act, oral va1icomycin is the di:veloped and developing countries. In developing coun- negative bacillus Jlib,..io <lto/erae, which causes acute se-
preferred therapy.1 However, treaunent of patients with a tties, disease occurs mainly in youug children, while in de- c.reto1y diarrhoea. Outbreiks are associated with two sero·
compromised ga~u-ointestinal tract is difficult because re- veloped countries the highest rates are seen among chil- groups of V. cholerae, Q and O 139. Serogroup 0 I can
liable c'<.inceritrations of orally administered drug at the site dren less than 5 years ofage and young adults, particularly then be divided into twc biotypes (classical' and El Tor)
of infection cannot be assured. 1 Vancomycin given via a men from 20 to 29 years ofage. Ii is also a common cause
nasogastric tube or by retention enema plus intravenous of diarrhoea in travellers to developing countries. Al-
and each ofthese has !hr--~'°.,-.,.. (I.oGb- , 064~-.
Hikojima). Other strains)f V. cholerae can_cause _mild.di-
-"
mctronidazole have been tried. 1•3· 7 Jntravenous tigecycline though about 16 Sj>ecies of Coinp)'labacter have been arrhoea but such infec'liM do not develop mto. epidemics.
has been successfully used in 4 paiienl~ with severe refrac- identified, more than 90% ofcases are caused by C. jejuni Cholera is considered to Je endemic in many countries and
to1y AAC27 and most oftl1e other infections are caused by C. coli.5•6 lhe pathogen causing i1cannot currently be eliminated
About 15 to 30% of patients develop a second episode of Campylobacter enteritis is a zoonosis and me main route from the environment.
AAC after successful n-eatment of the first episode; treat- of transmission is thought to be foodborne, via under- Transmission occurs rna~ly duough i11gestion of contam-
ment with the same drug used to treat the first episode is cooked meats and meat products. Other routes of transmis- inated water and food, bit may also be spread tlu-ough di-
recomme\ided. 1·3 ·7 • 19 Higher recurrence rates of up to sion include raw or contaminated milk, contaminated wa- rect faecal-oral contamin1tion. Severe disease is character-
65% occur in patients who have had 2 or more previous ter, contact with pets and fann animals. and from doorstep ised by a sudden onset o· acute watery diarrhoea that .can
episodes.'·! Vancomycin is usually preferred for the treat- deliveries of foil-topped bottled milk that have been lead to death within holll' in previously healthy adults, due
ment of recurrent infection1·3·7· 19 because long or repeated pecked by birds. to severe dehydration. rflntreated, as many as 500~ ofpa-
courses of metronidazole have the potential to cause pe- Symptom~ usually occur 2 to 5 days after exposure, but tients may die, but with •ro~er treaunent, the _fatahty rate
ripheral neuropathy.1.7.i9 Management strategies used can range from I to 11 days. Some patients may be asymp- is about 1%. Individuai with lower 11mnumty, such as
have included tapered or pulsed dosed vancomycin fol- tom3tic while others may have dianhoea (sometimes malnourished children o; people infected with HIV, arc at
lowed by course of rifaximin, 1•7 •19 nilazoxanide,7 or ri- bloody), abdominal pain, fever, headache, nausea, and increased risk ofdeath. ne incubation period is usually 24
fampicin:19 If episodes of recurrent AAC continue, other vomiting. Illness usually lasts for 2 to 6 days but may last to 72 hours but can 1'311!.e from 2 hours to 5 days. This
treatment options such as alternative antibacterials (nita· up to several weeks. Significant post-infection complica- short incu~tion period eihances the potentially explosive
zoxanide or rifaximin), probiotics, immunological tllera- tions may include irritable bowel syndrome (15%), reac- pattern of outbreaks, as ne number of cases can ~se very
py, faecal reconstitution (slool transplantation), and toxin- tive arthritis (1%), Guillain-Barre syndrome (0.1%), and <iuickly. Abo\l\ 7~% Qf p:ople will not develop any symp·
binding products may be tried.7·19 tox.ic megacolon. Fatalities due to dehydration are rare and toms. However, the path~ens stay in the faeces for 7 to 14
I. Gerding ON. et ol. Trea1mcn1 of Clostridium di Olcilc infection. usually occur in the very young or elderly patients, or in days and are shed back oto the environm~nt, potentially
Clin lu/«I Dis 2003; 46 (suppl 1): S32-42_
those already suffering from another serious disease such infcctinR othern. Amon: people developing symptoms,
· ~~a"9.~ ~iA.~-,~~ ~J~,~~a;:;; ];,~-~~~i=~~mj.~r~~~:i~J
2 01 1
as All.J:S. 80% orepisodes are of llild to modet"ate severity and the
Anfimk,.ob Chemotl1~r 20W~ 63: 238-42_
;, Williilrns OM. Spcnocr RC. The man3gemcnt of Clostridimn Infection is usually self-limiting and in most cases fluid remaining cases may d\Velop severe watery diarrhoea
diffidl~ illfcc1io11. Br M~d 8111120(1)~ 91: 87- 110. and electrolyte replacement is generally sufficient (see Di- with signs of dehydratior.
184 Antibacterials
A guldcluic f<ll" the prevention and control of cholera out- 4. WHO. .,,,.,,.,,,_,,,of~<NrltoH o-·""'~plryHt:... owd lhrombocytopenic purpura; 1 ~ the non-antibacterial treat-
other se1tior hulltlt 'CIO'•vs 41h cd OcMva. wno. 200S. ment oflhcse two lauer oomplications is discussed u1 Plas-
breaks has been developed by WHO. 2 Individuals can re- Available: at: hnp:/lwhqhbdoc .who.1nl/publ1cl\.ons/200Si
duce the nsk of coatraeting cholera by good personal hy- 924 tS93180.pdr (acxeJStd 07i04/10l ma, under Thrombotic Mieroangiopathies. p.1185. In the
giene, avoiding possibly contaminated foodstuffs, and by S. Roy SK. r.r al. Zinc supp1cmcn&11ion 1n children "'uh cholera in absence of oonclusive evidence, most e.'tperts do not rec-
Bangladuh: rsndomoscd ton1rolltd uial. BMJ 2008. 336: ommend the use of empirical antibacterial treatment s.6
boil ing or otherwise disinfecting drinking water. Methods 2~.
of preventing or containing chol.ei:a epidemics ~nc~udc en- 6. Larson CP. e1 al. Zinc 1rc&trncnt 10 undcr-(1ve children: 1pplica· Oral preparations of Vero cytotoxin-binding resins are un-
tions lO impl'OVC Child survival tnd rOdUCC burd~n O( dii>C1$C. J der investigation.
suring n safe water supply, prov1dmg good san1ta11on, and Heulrh Pop11/ Nlllr 2008; 16: 356 6S.
promoting safe handling and preparation offoods. Routine 7. Abromowici M, ed. The chotee or111nubac1cri1I dru;s. Jn: Hand· I. Mead PS, (loiffin PM. Escherichia co li 0 157:H7. lunc<1 1998;
1rc:umen1 of a community with mass chemoprophylax,is. boolr of ontimicrobinl thtrnp)'· 18th •d. New Rochell< NY: The 352: 1207-12.
Mcdi<:ol Lener, 2008: 71. 2. Subcommiuoc or1hc PHl,S AdvisoiyCornmittce onGastroinlet·
parenteral vaccination, and !ravel and 1rade restrictions arc 8. Khan WA~ et al. Randomiaed con&rolled comparison of sinalc:· linal lnfeccions. Ouicklincs for tht controlofinf«CH>n wilh Vero
not effective. Oral cholera vaccines containing either live d - cipronoxac1n and doxycyoline for cllnlcra caused by v;. cy1oioxin producins Eschcrichhi coli (VTEC). Comm1m D11
altcnuated or inactivated strains are available in some brio dlolenc 01 or 0139 U•>e<I 1996, :UI: 2%-300 P11 bll< JI.a/th 2000; 3: 14-2]. Al•o available It: hup:J/
9. Roy SK. e10L /\ n11domiit:d chnM:•l ln1l 10 comperc lhe cffi· www.hp1.ora.ukftdph/issuesiCDPHvol3/Nol/"cc.pdr (••·
countries. Mass vaccination campaigns using the oral C¥:Y of crythromJC'"· amp1c,H1ft .,d tctneychne for the lrttl· u1S<d 111/0Mll)
killed whole-cell Y. choluoe 01 with purified rccom- mentor ci>olcn m choklml. Tro•t AS« 1>op Mid H>t 1998; 3. lulCSOn M,., of Haemorrlu:i< a>liris tpidcmic in Afn.:.. u ...
bUlant B-subunit of cholera toxoid (WC/rBS) vaccine tl: 46G-2. «11993; 341: 961.
ba\'e been conducted in erncigency SCtllng.1 IO protect at- 10. Khan V.'A• ., oL Compu.- or··~ ""'"'''""l'Cl" and
12-dosc. 3-day ctYlhromy<:•• for cl1tldhood cholera. a rao-
' · hqutl C. ., ol Aet>olos;y or lucmanhagjc cobtos <1>>tl•mte m
A1hca. Lo«ot t99l: 342: 17S.
risk populations from potential choleni outbreaks.3 Use of clomised, doal>k-bfind ., .... 1.-.. 2002; 36t: ltll-7 S. Casburn-'-' AC. fanhins MJ. M1n1$<fM!>t of w~ d,_
oral cholera vaccines in such seuings should not replace II. BhauKholya MIC. d ol A"dvoml"'" 10th& trat..... ofchol- ~ G1112004: 53: 296-105.
cn in children. Aelo P--200.; tl: 67~ 6. DuP°"' HL. Clmical ~ Bactcriol clianbta. N £,,,/JU#
control mea5IRS such as improved water supplies, ade- 12. Saha 0. et oL Slftlfo.<losc azWlromy<:oo for 1loc lrtaun<OI or 2009; 361: IS6G-9.
qtiate sanitation, and health educallon.u Vaceinatioa is not chokn .in aduhs. H Enz! J Nod 2006; 354· ?4S:-6l 7. SafdatN.'1ol lllsl:or11<1no1y1i<:urcmicsyndrome1herat01b+-
recommended once a cholera outbreak has surtcd, be- 13. Saha D• ., oJ. Sing!e-doao etprofloucon......,. 12-dolc uytlvo- obc: 1rcatmcAl or Eachcrichia coli 01S7:Hi cntcritis: a mt.tt·
mycila for childhood cholcn a randomised con1rotlt4 trial.
cause of its 2-dose regimen and the time required 10 reach LAncel 200S; 366: 108s-9l. 1Mt)'l11. JA""4 2002 0 288: 996-1001.
protective efficacy.1 Oral choler.a vaccines are suilllble for 14. Anonvmous. EmCtJCftCCof1 unaquc. mu1o-«ua rni111nc Miiin a. F•11.1'1tn& M. el ltl. The ma.nageme.nt ot' infec:liY~ pstrocnlcritil tn
or Vibrio cbolenoe 01 in B•n•lad<ih Hrohh otod ~ 8,,t/,_ 1d-.ilts: 1 COnKn~1statc:menlby1n eA:pert paMI con\"Ulcd by the
use by travellers. For further informalion on Cholera Vf/IC- Ii• 2005; 3: JCOOR,9 Avaobbl• II. hnpJ/ccnu<.icddtb.Oflll Brililh Socitl)I for 1he Study of lnfttlion. J lnftrt> 1996; 33:
cincs see, p.2413. imag..ih>b32 Eng-cmcrs•nc• pc1r(o«t11Cd OMWIO) 143-S2.
Most cases of vibrio gastro-cntcritis are mild 10 modaatc IS. Anonymous. Shuck - oysttrl wllh tall. Lonttt 1990: 336:
21S-l6. Necrotising enterocofrtis. Necrotising enlerocolitis is
and gcncnlly require no therapy other than fluid and elec- 16. Doyle MP. foodbomt ill•- polhost11ic Exh<tichia col~ characterised by diffilse or focal necrosis of the ileum or
trolyte replacement with an appropnate oral rehydration Ycrsinia cn&erocofilica. :1.nd V1bt1n pltlhleMl)1tC\IS,. Ltttttt1 colon (or both) and is one of the most common pstroin-
1990; 336: 1111-IS.
solution (sec Diarrhoea, p. l 842). PaticnlS with seven: ps- 17. fr<neh GL. n al. Anbmicrobtal 1utctp<11Mhtoca ofholopuht ..;. tes1ina.l emergencies in newborn infants. ll mainly affects
tro-encailis, dehydration, and shock should receive vigor- lrios.JAnriaeiaohO.-lwr 1919;14: 10-94 those bclrn before 36 weeks' gesutional age, with the ma-
ous fluid replacement, prcfenibly with intravenous isoton- 18 f.-:11 GL. Ano'biotJca f0< "'"'"' vi'brtOt U-1 1990; 336: jority of cases occwring in very low birth- weigtlt infanlS
S6S-9.
ic solutions such as Ringer's lactate.'.2" Supplementary (less than I 500 &). Although the pathogenesis of necrolis-
zinc has been shown to be effecuve in reduang duration of Esdteridlia coli enteritis. Eschtrichio co/1 is a normal ing cntcrocoUtis is poorly understood, lhcre i~ evidence 10
diarrhoea 3Jld successive diatthoe31 episodes in children intestinal commcnsal and member of the anaerobic Gram- suggest that multiple, interacting mechanisms arc m-
up to S years of age.lJ-' Antibacterials can be &"'en in se- negative family of bacteria lhe EnlCrObacteriaceae. How- volvcd, mcluding immarurity of the gastrointestinal tract,
vere cholera 10 d.ucasc I.he durdtion and vulurnc of diar- ever, some strains have acquired geacs lha1 enable thtm to intestinal ischacmia, rcperfusion injury with activation of
moea, reduce the volume of rehydration Ou ids needed, and cause intestinal infection. When inacsted, the following proinflAmmatory cellular casca~, ente~I f~ing, ~nd
shorten the duration of vibrio excretion. 1 WHO recom- strains can cause diarrhoea: the presence of pathogenic bactenal flora m the m1es1mc.
mends a single dose of doxycycl ine (300 mg) for adults or • entcropathogenic E. coli (EPEC): may cnusc hospital Bacteria implicated in the disease include Pseudomonas,
a 3-day (12-dosc) course of tctracyclinc or a 3-day (6- nursery outbreak but is most often found in developing Escherichia coll, Klebsiello , Solmoncllo spp., and
dosc) course of co-1rimoxazolc for adults and children; countries and mainly causes watery diarrhoea in infants Clos1ridiw11 spp.
furazolidone or crythromycin are considered suitable alter- and children Onsc1ofillnessisusually3 to 10 &ys (bul may range from
nutivcs.• Recommendations from the USA for adult.~ spec- • cnteroinvasive E. coli (ElEC): produces an invasive I 10 90 days) after birth. Necrotising enterocolitis may
ify a tcttacyclinc as the first choice with oo-lrimox,azole or type of diarrhoea resembling that of Shigellt1 dysentery present as a benign illness with mild inflammation of the
a fluoroquinolonesuch asciproOoxacin asallcm11ivcs.7 In • cnterotoxigenic E. coll (ETEC): is an important cause of intestioal wall and mainly gastrointestinal symptoms, or as
the UK. tetracyclines or ciprofloxacin are usually used. !raveller.;' diarrhoea and diarrhoea in infants and chil- 1 caiastrophic illness characterised by full-thickness intes-
One study has suggested that si11&1c-dosc ciprofloxacin dren (see Gaslro-cnteritis, above). It is widespread in ar- tinal nocrosis with pcrforatJon, rcspiialOT}' and cardiovas-
might be preferred IO doxyc:ycline, panicularly an areas of eas with pooc sanitation and is a common contaminant cular collapse, metabolic acidosis, disseminated intravas-
tetracycline resistancc.1 and in Bangladesh, ampialhn has offood and water sourocs. The incubation period is l 10 cular eotgulopathy, grossly bloody stools, multi-system
been found to be as effective as either Cf)llhromycin or 3days; the infection is usually self-limiting and lasts for orpn flu lure, and tn some cases death. Early signs arc non-
ldraC)'CJme' and may be a useful 1hcmallve m children.
°'
Sl\ldies1 1? in Bangladesh and India found s1nglo-dosc
less lhao 5 days spcClfie and sepsis rather than nccrotising cnterocolitis
• cnterobaemorrllagic E. O)/i (EHEC); also known as Sh- may tnilially be suspected.
azlthrornycin to be effective in children and adullS. In chil-
iga-toxin producing E. coll oc STEC: is associa!Cd with Tiie seventy of I.he disease is usually staged acconlmg to
dren a single dose of ciprofloX1cin was also reported 10 be
haemorrhagic colitis, haemolytic-uraemic syndrome, modified Bell's criteria and recommendations for man-
effective in lClms of clinical cure, but was less ctfecuvc
and thrombotic tluomboc)10pcnic purpura. Most out- •gement of necrotising enlerocolitis a!C based on l!J~
than a 3-day ( 12-dosc) course ofcrythromycin in cradiait-
breaks have been linked 10 0 l 57:H7 strains; the incuba- eri1cria.1·J Depending on the stage of disease, nccroc1sm~
ing Y. choleroe from stool. 11 tion period is I to 5 days and the illness usually lllSIS for enterocohus can be treated medically and/or swgically.
Widespread antibacterial resistance in Y. choltroe ~as 4 lo 10 days.. Children and the elderly arc 11 greater risk When nccrotising enterocolitis is suspected treatment iJr
very uncommon befcxc 1977, but repons of resistance 10 of severe disease,1 bot the illness is 11S1181Jy self-limit- volves stopping oral feeds (bowel rest), starting total
some an1ibac1eri1ls (including tetracychne, ampicillin, ing,l Cases have generally been linked with the con- parenteral nutrition, and ghing parenter.al anti~erials lo
kanamycin, streptomycin, sulphonamides, trimethoprirn, sumptioo offoods dcri\'ed fTom Clinic, especially under- limit bectcrial invasion and mmsloca11on.1 Anublcicnals
and gcntamicin) have appeared from several cholcra-en- cooked beef and unpasteurised milk, although there should cover aerobic and anaerobic coterie bacteria. Amp-
demic countrics.1 FluoroquinolOllQ-rcsislant SITlins have have been outbreaks associated with the consumplioo of· icillin (or s1mibr penicillin dcri"lllivcs) oc vancomycin
also bcea reported from lndia1 and a mutt.idrua resistant fresh vegeiablcs and unpasicuriscd juices, probably as a may be used for Gram-positi"e aerobic rover and an
strain of Y. choleot 0 I (resistant 10 oo-1nmoxazolc, tetra- result offaecal contamination. Person-to-person SJXCad aminoglycosidc (such IS gentamicin) oc a third-generation
cychnc, furazolidone, and crythromycin) has been report- is also common, and direct spread from infected animals cephal0$porin (such as cefotaximc) may be used a~inst
ed fi'Om Bangladesh.14 Y. cho/erae 0139 stnltns arc also may occur. E. coli 0157 has also been reported as a Oram-neptivc acrobes. Mctroni~lc or ~lindamyci~ ~e
rcsisiant to oo-trimoxaz.olc, chlornmphenieol, and low lev- cause of epidemic haemorrhagic colitis in Africa. where given for anae111bic cover.1 If the d1a~os1s of necrot1smg
els of streptomycin.' Y. cllo/eroe 0 1 and0139 show spa- ii may be difficult to distinguish from shigcllosis3•4 enicrocolitis (Bells sta&c 11 or above) IS confinned then an-
tial and temporal fluctuations, with pc1iods of resistnnce • Enteroadherent E.coli (EAEC): is a cause of chronic di- tibacterials are continued for 7 to l4 days. •
23
fluctuating with periods of sensitivity. ' an11oca in young children A systemntic review has concluded that prophylactic o~al
Marine or halopbilic Vibrio spp. known 10 cause guSIIO· As with any fonn of diarrhoea (p.l 842), fluid and electro- antibacterials miSht well reduce the mc1dence o~necrot1s­
enteritis include V. porohoemolyti,,,s which is res~nsible lyte replacement is key 10 treacrnenl. '!be use of antibacte- ing cnterocolitis in low birth-weight or pre1enn mfants m
for food poisonin/i from raw or undercooked sea Ood, es- rials is controversial. Those with mild symptoms or who a high-risk environment,• but there arc concerns abou t ad-
pecially in Japan. ·16 Another halophilic sp., V V11lnfjlc11s, are improving do not need antibacterial treatment. Treat- verse outcomes, and prophylactic use (particularly of van-
is incrca.singly associated with wound infection and septi- ment is ad,ised for those with prolonged symptom.~. 1hose comycin) ls not generally recommended because of lhe
caemia. IS On the basis of in-vitro sensitivity testina 17 and who relapse, QI" those considered lo be high-risk; antibac- risk ofinducmg resistance. II has been suggestJlhat oral
anecdotal clioical experience, empirical therapy with terials may also be used for outbreaks of EPEC diarrhoea immunoaJobulins may prevent necrotising cn~i~s in
aminoglycosidcs, ceftazidime, imipcncm, oc ciprofloxaci11 in nurscries. 5 Severe EIEC iafection "'ith cvidcnccofsys- low-birth-wei&hl mf1nts, however, a systemallC rcvie"'.'
should au be etrectivc..11 tcmic involvement can be treated with antibacterials rec- concluded that the IVlilable evidence did not support this
l. Sade DA.. a ol. O>olcn. ' - 2004, 3'3: 22}-)) ommended f<ll" shigellosis (sec below).u Treatment of cbim. There is, howc-..cr, good evidence that supplemen·
2. WHO ,....,,...., ond - orchol... -1....b. WllO poli-
EHEC is generally support.1ve, including coneaing and talion w11h cntcral probiotics reduces !he risk of severe
cy and rccommmdorions (issued 2S1~ No•t.,.b<r 2001)
A•ailablr at ; liillp://www.v.ho.int/cholera/lechnical/ maintaining lhc fluid and elcCtrolytc balance.2 There is lDl- necrotising entcrocolitis and death in prcmawre .infants
WHOPohcyNowmbtr200&4>df (ac«SKd 0711M/t0) certainty as to whether aro'bacterials influence the course born we1&hing less than I 500 g.1•10 but there were msuffi-
3 WHO. O.Oltn: P>bol surnill•- "'""~· 2001. ltll) E/H· of enterohaemonhagic E. coli infection and the develop- cient data 10 determine their value in infants weighing less
, .., Ru 2009; 1 4: 309-24. Al•o aY11l1blo 11 hnp1f
www.who.i••"erl2006/•.-ct81JI pd((ICC<Utd 07/0•llO) ment of haemolytic-uraemic syndrorne7 or thrombotic than 1000 ii 11 birth.1 Supplemcn1:11ion with arginine has
All cross-references refer 10 entries in Volume A
 Antibacterials 185
also been investigated,9 bur there is insufficient evidence including DT 104, have further limited the treatment op- hygiene and sanitation. Onset typically occurs 12 to 96
to detern1ine its value. tions."' ' Empirical treatment with oral ciprofloucin, oral hours after e.'ql()Sure, and ti1e illness may range from mild,
Necrotising enteritis in older children and adults, known as azithromycin. or intravenous ceftriaxone is recommended selr-Jimiling, watery diarrhoea to severe colitis and dysen-
pigbd, has been attributed to toxins produced by Clostrid- although there is also i1iereasing resisuincc to these an- tery wilh blood and mucous in the stools. Severity depends
ium peifringens. Both sporadic and epidemic forms arc tibacterials (especially ciprofloxacin). 1·4 Nalidixic acid re- both on the infecting organism and patient-specific factors
mainly seen in the highlands of Papua New Guinea, but sistance has been reported and hos been shown to predict including age and degtee of malnutrition.
sporadic cases have been reported elsewhere. Treatment i~ lack of response Jo fluoroquinoloncs.1 Resistance to cc- As wid1 any form of diarrhoea (p.1842), rehydration is the
supportive with surgical intervention where necessary. A phalosporins has also been rccognisc<1_'- 11 •11 For patients key to trcatment.2 Although most milder infections, partic-
vaccine is available for prophylaxis. with a recent uavel history, azithromycin may therefore l>e ularly those due to S. sonnei, will resolve without treat-
I. Hall N, Pit."JTO A. NccrolWng Cl'lttrocolilis. Ho~p Med?<KM; 65: the preferred first line option.1 Carbapcnems such as imi- ment within 4 to 7 days, all cases of bloody diarrhoea
220-S. penem, meropcnem, and ertapenem may be useful for should be treated promptly with an antibacterial that is ef-
2. Lin PW. S1oll UJ. Nect01d1.ng cntCTOOoti1is. Lom:n 2006; 368: mullid1ug resistant infecrions.4
1:?71-33. fective against Shigella. The aim ofantibacterial therapy is
3. Thompson AM, Bizz.arro MJ. NccrotWn& cnterocolitis in new- Treatment is usually given for 3 to 7 days•.?.. and is often to speed recovery, reduce the seriousness of the disease,
borns· pa1ho,enc!iiiS, prevention and man.a-'emcnt Drugs 200S; extended to 14 days in immwiocompromised palients.2 ln and decrease the length of time that patients are infective.
68: 1227-38. HIV-infected adults, the CDC recommends ciprofloxacin
4. D"'Y R~ Tudehope D. Enlcr~J amibtot.ics for preventing nec.ro-
1l1e choice of antibacterial has changed over time as resist-
1iiinf en1crocolitis in low birthwciJ;ht or prttcrm infants. Avail- for 7 to 14 days in tl1osc with a CD4+ T lymphocyte couht ance to various antibacterials developed; different pancrns
•blc m The Cochrane Database of Sysct,mat.ic Reviews; Js.sue I. of 200 ceUs/microlitrc or more with mild gastroenteritis of resistance have been reported around tI1e world. As
Chichwcr: John Wtl•y: 2001(accessed16/0SIOS). (with or "\l.ithout bacteraemia); 2 to 6 weeks treatment is widespread resistance has developed lo traditional first-
5. Eibl MM, ~t al. Prevention of nccrotiz.ing cntcrocoli1is in low-
birth-wcight inr.nu by lgA-lgG f<eding. N &ngl J Mw 1988; recommended for those with a CD4+ T lymphocyte count line drugs including ampicillin, co-trimoxazolc, and nalid-
319: 1-7. of less than 200 cells/microlitre.' 4 Relapses in infection ixic acid, WHO' currently considers ciprofloxacin to be
6. Foste< J, Cole M. 0,.1 immunoglobulin for prcvtt1tin1 nccroriz- have been wcll-docu1nented in HfV-infcctcd patients and tl1e drug ofchoice for empirical treatment in patients of all
ing cn1erocolilis in pr~enn and low birlh·wciaht nt0natcs. recurrent Salmonella might require chronic suppressive
Anih1ble in The Cochrane Dmbasc- of Systematic Rc-vic¥i.'S; Is- age groups; in adolescents and children, for whom qui-
••• t. Chichester: Jolm Wiley: 2004 (occuscd 1MlSi05). therapy." noloncs arc not routinely recommended (see Precautions,
8. Alfalch K, Bassler D. Probiolics for prevention of necrotizing Empirical treatment for patients with bacteraemia should under Ciprofloxacin, p.267). the benefit is thought to out-
cnterocolills in prctenn infimlS.. AV1iilable in The Cochrane Oa- weigh tl1e risk. Fluoroquinolone resistanee has been re-
t:n.basc of Systematic Reviews: Issue I. (;h;chestcr: John Wiley; be with both a fluoroquinolonc and a third-generation ce-
200S(a<CUS<d 22/04110). phalosporin to account for multidrug resistant organisms.2 ported in some F.'tsof the world (particulariy the Indian
9. Shah P~ Shah V. A~inine iupplcmcn11tion for preven1ion of Monotherapy should be given once sensitivities arc subcontinent),2• and where local strains of Siligella are
necrocisingmterocohtiJ in preterm inltnts. Avaifoblc in The Co- known to be resistanl, second-line antibacterials recom-
chrane Oat.abase of Systema1ic Reviews; ls.sue 3. Chichester:
known;2 third-generation cephalosporins may be used and
John Wiley. 2007 (1«<sscd OS/08/08). ceftriaxone is considered appropriate for treatment of mended by WHO include oral pivmecillinam, and
IO.Deshj>.andc G.., ol Updated mel.ll-analysis ofprob'°4.1cs for pn=- meningitis.5-' Bactcracmia usual!)' needs a 7- to 14-day parenteral ceftriaxonc. Oral azithromyein is also recom-
vcnting nccrocizing cntero-.""Olitis in pretenn ncon1tes. Pttliotrics course of antibacterial treatment,2.6 and longer courses mended for second-line use in adults by WHO, and as an
2010: 125: 921-30.
may be needed in those with immunosuppression.6 Those allemativc for children by the American Aca&my ofPedi-
Salmonella enteritis. Sa/mo11ello spp. are Gram-nega- with meningitis may need 4 weeks of treatment6 and 6 atrics,6 although there have been concerns regarding rapid
tive bacteria belonging to the Enterobactcriaceae family. weeks of treatmeni has been suggested for those with development of resistance; Shigella spp. resistant to azi-
Tiiey can be divided into: endovascular infections.2 thromycin have already bten reported in Ewopc1 and re-
• those causing enteric fever, namely S. l)phi and S. paro- Chronic carriage can be treated with amoxicillin ( 1 g three sistance to azilhromycin and ceftriaxone in die Indian sub-
typhi, where infection is syslemic although affecting d1e times daily for 3 months). co-trimoxazole (960 mg twice conlinent.3 A systematic revie11<9 of 16 studies (1748
gastrointestinal tract (see under TYPhoid and Paraty- daily for 3 montl1s), or ciprofloxacin (750 mg twice daily subjects} to evaluate the safety and efficacy of antibacteri-
phoid Fever, p.214) for l month).2 als in the treatment of Siligella dyscnte1y foimd limited ev-
• non-typhoid Salmonella (NTS), including S. e11teritidis J. Darby J. Sheorcy H. Searching for Salmonella.""'' Fam Pliy- idence that most of the commonly used antibacterials
and S. typhimuri11m, which cause acute gastto-mteritis sl<lon 2001; 37: 806-10. (ampictlhn, co-trimoxazolc, nalidixic acid, fluoroquinolo-
2. Crun\.Ctannonc NF. Salmonc:llosis and the: &astrointcstinal nes, pivmecillinam, ccflriaxonc, and azilhromycin) re-
invasive infections with bacteracmia, and localised in- ttac1: more than jast peanut buncr. Curr Gastnwaterol Rep
fections, which are discussed here 2008; I 0: 424-3 L duced dianiloea and the durdtion of fever compared with
3. Sirin3Nin S. Garner P. Antibiotics for treating salruondla ~ot i~ no antibacterial treatment, but insufficient evidence to rec-
NTS infection is usually transmitted drrough ingestion of (cctions. A\·ailahlc in l1'C Cochrtn.c Database ofSysccmabc Rt· ommend any specific antibacterial. To accommodate tem-
contaminated food of animal origin, especially, beef, poul- views; Issue I. Chichclltr: John Wiley; t 999 (acc:eued
16105/05). poral and geographical shills and antibacterial resistance
try and eggs, and dauy products. Animal-to-human trans-
4. PotT)' CM. ThrcJtlll1 FJ. Amimicrobi1J rcsistancc in lyphoMbl in Shigella strains around the world, it reconunended that
missions can occur particularly after handling amphibians and nontyphoidal safmoncllae. c." (}pin ltifcct D112008; ?J: empirical therapy should be guided by local or rcgiooal an-
and reptiles, and outbreaks of hospital-acquired NTS have s;1-1.
$. Morpeth SC. rt al. t11vasivc non-typhi S4il1tH.H1t'llt1 di:1ca~( in Ar- tibacterial sensitivity paaerns. 9 Effective antibacterial
also been reported. NTS occurs worldwide; in developed
rica. Ctin hifttt Di1 2009~ 49: 606-11 . treab11cn1 should lead to symptomatic improvement within
countries it is usually a mild, self-limiting diarrhoeal dis- 6. Olimahztna Y, et ol. 11le cpid,miology arwl n\in3gcmcnl of non the first 48 hours; where this does not occur, the i:ossibility
ease that resolves in a few days wid1out active treatment typhoicbl salmonella infec1iun5, A"'' Exp >1..-d Biol 20 10; 659:
)~-16. of antibacterial resistance should be considered.
In less developed areas NTS may cause serious invasive
7. ·rhrclfl"ll FJ.~1 oL lncrcasin; spcclruin of rttlstanc~ in multirc- Vitamin A may be a useful adjunct to treatment, especially
disease. Epidemiological data from wme countries in sul>- si1tant Salmonella 1ypl1imum1m. l0tm.-r 1996; 3.n: IOSJ..-4.
Saharan Afiica indicate 1hat it is one of the most common $. Anonymous. Multidru&·Ttsisl311l Salmonc11a sa-otypc typhimu-
in children in de\~loping countries who are at risk formal-
causes ofbacteraemia in adults and children. Invasive dis- num-llnited Sllltu, 1996. JAMA 1996; 277: 1513. nutrition (see Diarrhoea, under Vitamin A, p.2134).6 Sup-
ease is more commo11 and symptoms mosl severe in the
9. Anonymous. Emers.cnce or muhidrug -rcsistant ul.mondll. plemental zinc, wt1ich may reduce the incidence and se-
WH0Drnghifl991; 11:~1 . verity of diarrhoea both in the acute period and in die next
elderly, infants, people with chronic conditions such as di- 10. Threlfall EJ. ti al. Mullircsistant Snlmontl/(' f)'J>Mmot•f1n11 OT
abetes, or those who are immunooompromiscd. 104 and ••lmonello bacter:i<mia. Lonc.t i 99S; 3Sl: 287-8. 2 to 3 months, is Also recommended for children up to 5
11 . Fey PO, ti ed. Cc:Oriaxo11e--ruis\aru salmonclh.1 in recti<1on ao- years of age (see Diarrhoea. under Zinc Sulfate, p.2162).1
Gastroenteritis caused by Salmonella spp. is often clinical- qu•rtd by• child fron• cattle. N E.ogl J Mu 2000; 342: 1242-9.
ly similar to that caused by other bacterial pathogi;ns. 12. Tt.ou\·cldd1 LS. ru ol. Emergence o( tts1stance 10 1hird-gcncra- Or.II shigella vaccines are being studied for JlTOphylaxis.
Many patients are asymptomatic or have a mild disease. 1ton ttphalosporins amc>ngst SahnoncUa typhimurium i.solatcs I WHO. Gui.1cllr.es for 1/ur C<Hltlol of $/lig~llosls. ;,JC/uding tpl·
in Gr««: RPOrt of 1he first 1hrec ca.sH.J Anlimkrob Ch<!moth· tkmkl due 10 shigclla dr:.·C'mcri<ktt I')~ I. Gcn(Ya: WHO. lOOS.
Symptoms usually bc->.,in 24 lo 48 hours (range 8 to 72 ••· 1998: 42: 27J.-S. Available a1 hup:/f,vhqlib<loc.who.int/publications/200S/
hours) a"f\er infection, with fever, headache, abdominal 1l. Dunne EF. n al. Emcrgc1tcc or domestically acquiml ccftri;,1),- 9241592330.p<lf (acec~<ed 02/09/09)
cramps, ~nd dianhoca. 111~ symptoms and possibly also onc-rc5istant S4l•'I01t.tflo infections Jt..soci::i.ted with A.npC p.. 2. !'liyop SK. Slt1gellocis. J Mic1oblol 2005; -0: 133-'13.
lactamosc. JAMA 2000: 234: JISHS. 3. Mensa L." ol Quin{'llonc n:~ist;ince :i:mon~ Shi:tlla spp. isol:al-
nausea, 'Joss of appetite, ~nd vomiting, usually last for 3 to 1-4. CDC. Guideline:' foe prevention ~nd lr~u1menl ofopponunlstic ed frc.nn travellers rcturttif'i fro1n Jndia. Cli11 Microbiol 1'!fittt
7 days. Less than 5% of cases are complicated by Salnt<>- infcctic>ns in HIV-infec1ed 3dults .:ind Gdolescents; rccomnwnd3-o 2003: 14: 279-$1.
nella bacteracmia; complications of this can include cndo- tions f,onl the CDC. the National Jn.o;tirutc~ ~f Health, and lhe-
HIV Mcd;..:inc Aisociouion ofthe lnfce:1ious 01~.;ascJSociayof 4. Sark:ir I(,,.,'''· Cihigclla dytc:nteriae&yrc I wilh redu«dsusetp-
carditis, meningitis, mycotic aneurysms, septic arthritis, Ammc>. MUWR 2009: SS (RR-4): J-207. Also available at: tibility 11> OuoJuquinokmes. La1llC'et 2003: 361: 18S.
$. Sui· l), ttt "'· Muhidrug"1~i:su.nl Shigclla dyscnta'iac type I:
and ostcomyelitis. ~~';;)vw.edc.gov/mmwrlPOF/rr/rrS804.pdf (•eccued
fotcrunni:rs of :1: ltt'w epickmic: strain in C:QSt<:m India? Enwrg /,,.
Uncomplicated NTS enteritis is usually managed by fluid feet f)i.t 20CH; 9: 4()4-5.
and electrolyte replacement (sec Diarrhoea, p.1842). 1.2 Shigellosis. Shigellosis (bacilla1y dysentery) is an entetic 6 Amlrican Ac.idcmy of Pcdi11rics. :l.J09 Red Book: R~p0n ofthe
infection cau~ by Shigella dysenreriae, S. fkrneri. S. CH11•iltee 011 lufi.·•v.:tltJ11s D;Jcon"#. 28th ed. Elk Grove Vill;,c,
Antidiarrhoeal drugs are generally not recommended as Illinois.. USA~ Amc-rican Acadcmyof Pedialrics. 2009. ·
1hey ma):' prolong bacterial cxcrction. •.1 Anlibaclerials bo.1tdii, or S. so,,nei (a lso called groups A, 8, C, and Dre- 1. Boum~·Bour1chai L. ct nl. Maerolidc-taiscant Shise1ll3 son-
have a limited role and are not usually recommended for spectively), Gram-ncgiitive bacteria belonging to the En- nei. Emerr /11{«1 Dis 2008: 14: 1297-9.
uncomplicated cascs. 1 A meta-analysis3 of antimicrobial tcrobactcriaccac family. It is endemic in most ofthe devel- 8. .Rahman M. rt nl Increasing spectrum in a.nhmictobitl resist·
therapy for SC1lmonella enteritis found that antibacterial oping world and is the most impoJ1ant cause of bloody :ince orShigcU1 isof;sh."S in Bangladesh: rcsiso1.1ncc. co 1zichromy-
cin and ceftriaxone :and dccrca$Cd susccptibihtycociproOoxucin.
therapy" produced no clinical benefit in uncomplicated dis- diarrhoea worldwide, resulting in at least 80 million cases JI/Mith Poptll Mllr 2007: 25: 158--67. .
ease and that it may prolong Salmonella detection in and an estimated 700 000 deaths each year, mainly among 9. Otvid KV. et al. Antibiotic th<11py ror Shigcll1 dy><nt<ty. Avail-
stools. Antibacterials may be given to those patients with children under S years ofage. 1 S. so1111ei and S. boydii usu- 1blc in The Cochrane: Database of Sys1co131ic Reviews; Issue I.
Chi<he.ier: John Wiley: 2010 (o<:ccssed 27/04110).
severe gastroenteritis, those who are at a high risk for inva- ally cause relativoly mild disease, whereas a specific sero-
sive disease, or those wilh proven bacteraemia.1.2 l)'JlC of S. dysemeriae, Sdl or Shiga bacillus, is the organ- Yersinia e nterit is. l~rsima enterrx:alitica is a Gram-
Drug resistance has limited lhe usefulness of traditional ism responsible for shigella epidemics and causes the most 1icg;i.tive bacte1ium of the Enterobacteriaceae family and
first-line empirical antibacterial agents sucb as bcnzylpcn- severe, prolonged, and potentially fatal disease. Tue distri- the species most commonly responsible for yersiniosis. Y.
- icillin, ampicillin, co-trimoxazole, chloramphenicol, tctra- bution of different species varies geographically. enreroco/11ica has been isolated in patients worldwide, but
cyc l ine~ sulphonamides, streptomycin, and genta- Shigella are spread through the focal-oral route, and dis- the infection appears 10 occur mainly in cooler climates
micin.2' Multiresistint R-typc strains of S. (vphimurium, ease is commonest where there is overcrowding and poor and in some of these countries it rivals Salmonella and
I 86 Antibacterials
Campylobacrer and exceeds Shigella as a cause of acute than 2 years old. Other invasive conditions include bacter- risk and severity of infections depends upon the duration
bacterial gas~teritis. Pigs are a major reservoir for Y. aemia, oellulitis, epiglottitis, septic arthritis, and pneumo- of compromised immunity, the degree to which immune
enteroco/iliro SO'ains that infect humans and infection is nia and empyema. In developing countries pneumonia is function is compromised, whether cellular or humoral
usually 1r.1nsmined by eating contaminated food, especial· responsible for more deaths than meningitis. Non-encap- functions are affected, and upon breaches in physical bar·
ly raw or undercooked pork produclS, or drinking con tam· sulated strains invade the mucosa! surface causing infec- rier.;, for example due Jo severe mucositis or prolonged
inated unpasteurised milk or untreated water; transmission tions such as otitis media, sinusitis, and conjunctivitis and vascular access. Thus patients with profound neutropenia
througll blood transfusion is rare. infect patients with chronic bronchitis. These strains are a or a history of splenectomy are prone to rapidly progres-
Infection with Y. ente,.ocolitico occ:urs most often in young common cause of community-acqu ired pneumonia in sive and potentially life-threatening infections; those with
children. Symptoms usually develop 3 to 7 days after ex- adults, especially lhose with chronic obstructive airways neutropenia induced by cytotoxic chemotherapy or by
posure and vary depending on the age of the person infect- disease or AlDS. prcparat.ion for transplantation are particularly vulnerable
ed. Common symptoms in children include diarrhoea Choice of trearment. For further delails of these infec- 10 acute infections whereas those in whom immunosup-
(which is often bloody), fever and abdominal pain, which tions and their management, see under the specific disease pression results from viral infections or congen ital defects
last for up to three weeks or longer. Older children and side-headings. Ampicillin and chloramphenicol have been are at lower risk of acute infections. 1 Patients in whom
adults can present with right-sided abdominal pain and fe- the antibacterials of choice against H. injluenzae, but in- neutropenia persists for more than 10 days are not only at
ver that may be confused with appendicitis. Jn some pa· creasing resistance, especially to ampicillin, should be risk of opportunistic becterial infections but also susccpti·
ti en ts, complications such as reactive polya.rthropathy, ery- borne in mind; there have been several reports of multire- ble to viral, fungal, and parasitic infections.
thema nodosum, and life-threatening bacteraemia may sistant strains.'"' J>areoteral cephalosporins such as ceftri. Infectious diseases are a major cause of morbidity and
develop. Increased susceptibility to Yersinia infection has axone or cefotaxirne have been found to be effectiveS and mortality in patients with AIDS (see HIV-associated Iofec-
occumd in patients with iron overload trc3ted with desfer- are currently preferred for serious H. injluenrae type b in- tioos and Complications, p.946). Some are due to common
rioxarnine (see p.I 580). fections.6 There have been treatment failures in H. injl11en- pathogens, but others arc opportunistic and are caused by
As with any fonn of diarrhoea (p.1842), rehydration is the we meningitis with cefuroxime and there is argument over normally avirulent commensals. Children with HIV infec-
key to treatment and most forms of mild uncomplicated its efficacy.s Meropenem is a further altemative.6 tion appear to be at special risk of serious bacterial infec-
enteritis do not require antibacterials. However, systemic For upper respiratory infections and bronchitis caused by tions with common encapsulated bacteria. For further ref-
infection and bacteraemia require antibacterial treatment 1 nontypable strains oral antibacterials may be used. About erence to some bacterial infections associated with AIDS,
Reports of antibacterial susceptibility from different parts 20 to 35% of these strains are resistant to ampicillin and see Gastro-enteritis (p.181), Nontuberculous Mycobacte•
of the world indicate that Y. 1!11terocolirico is susceptible to some experts suggest co-trimoxazole (or trimethoprim in rial Infections (p.194), and Tuberculosis (p.212). Detailed
many antimicrobial agents. 1 Drugs with good intracellular the UK) as the preferred anboacterial; ampicillin, amoxi- guidelines for the prevention and treatment ofopporrunis-
activicy such as trimethopriro, co-trimoxazolc, tetracy- cillin (with or without clavulanic acid), oral second- or tic infections (including some bacterial infections) an10ng
cline, chloramphenicol, or fluoroqiiinoloncs may be pre- third-generation cephalosporins, a tetracycline, a Ouoro- HIV-infected adults, adolescents, and children have been
ferred. 2 Doxrcycline or co-trimoxazole have been quinolone, or the macrolides azilhromycin or clarithromy- developed in the USA.2 .3 Fungal, protozoa!, and viral in-
reconunended for complicated gastrointestinal and focal cin are suggested altematives.6 fections which can affect immunocompromised patients
extra-intestinal infections or doxycycline and an Prophylaxis. lmrnunisation is the most effective way of are discussed in the relevant chapter$ wider Infections in
aminoglyeoside empirically in bacteraemia. Co-trimoxa- preventing Hio in infants and children and vaccination is lmmunocompromised Patients, p.565, p.909, and p.948,
zole as first choioe or alternatively a fluoroquinolone, an included in the infant immunisation schedules in some de- respectively.
ami11oglycoside, or cefotaxime have also been recom- veloping and most developed countries including the UK Reports .from Europe and the USA show that over the past
mended.' A srudyt undertaken in a paediatric hospital in and USA. However, there are no vaccines available for \he few decades there has been a shift in the oo::urrcnee of
the USA to detcm1ine the antibacterial susceptibility pat- prevention of disease caused by nontypable H. injluenzae. bacteracmia in febrile neutropenic patients from Gram-
tern of Y. e11te,.ocolitica reported that susceptibility pat- For further information on haemophilus influenzae vac- negative organisms to Gram-positive organisms.• Factor
terns of the organism had not changed over the 12-year cines see p.2419. influencing this change include changes in clinical prac-
Sludy period. The most active agents in vitro were cefotax· Young children who develop invasive Hib disease have a tice such as the use of central venous catheters, changes in
irne, ceftriaxonc, cefepime, co-trimoxazole, gentamicin, low but significant risk of a second episode of Hib infoc- antibacterial use, and antibacterial resistance; when anti·
tobramycin, imipenem, and ciprofloxacin; all were also tion and are also more likely to become asymptomatic car· bacterial prophylaxis is given, local resistance patterns
considered to be clinically appropriate. Systemic cefotaxi· riers and 1r.1nsmit the organism to others. Household con· have been shown to affect the aetiology of infections.•
me and ceftriaxone were effective for treating bacterae- tacts of inde.'< cases, especially young children and those TRllATMt::-"T. Onset of fever in neutropenic patients is in·
mia. The majority of isolates were resiswit to ampicillin with Wlderlying medical problems such as immunosup· dicative of potentially serious infection that may progress
and first-generation cephalosporins. Similar susceptibility pression and asplenia, are also at increased risk of develop- to septicaemia and death. The severity of infections de-
patterns were reported in a study conducted in Chinas A ing invasive Hib disease. Recommendations for the pre- pends on many factor.; (see above) and it is therefore diffi-
patient with chronic Yersinia infection who responded vention of secondary Hib disease have been made7·' and cult to produce a standanl drug regimen; in addition, the
well to tetracycline or co-trimoxazole, but relapsed on usually include chemoprophylaxis with rifampicin for the choice of empirical therapy must be adapted acconling to
withdrawal, was treated successfully with ciprofloxacin.6 index case and for close contacts of the index case. For prevailing local antibacterial susceptibility paucrns.
I. Abdcl-lfaq N M ,·~, ol. A!llibiohc susceptibili1if'S ofYtninia ('T)o- further information on chemoprophylaxis see Meningitis Guidelines have been produced in many countries, of
1.crocoli1ica recovered rrom children over a 12.year period. Int J
Antlmicrob Agents 2006; 17: 449- S2. Prophylaxis, under U$es and Administration of Rif· which tliose issued by the In fectious Diseases Society of
2. ll()C)gk.lmp·KOr5Llnjc JAA . Anlltiiotics in Yrf'Jin;o ~n/ErocolHi­ ampicin, p.357. Americas for both the initial and subsequent management
cq in(cc1ions. J .Antimicrob Chemother 1987; lO: 12:>-31. I. Sturm AW,« cf. Outbreak Qf muhircsi.s&ant non-c:ncapsulalcd of febrile neutropeoic patients are fairly typical:
; : Cover Tt, Ahn" RC. Jr...1inin enttot'OCIJlltlro. N &11JUtt! 1989; Haemophtlus innucnzae jnfcctions in a pulmonary rchabilita1ion
311: 16-l•. «l'tlte.l.ollttl 1990;335: 214-16.
• empirical antibacterial therapy should be given prompt·
4. Abra1nowicz. M, ed. The choice ofan1lbactuial drvp. In: J-lot1d· 2. Bri&htm1n CAJ. et ol. Family outbrc.:.k o( ch1ut'llmphenicol- ly to all neutropenic patients at the onset offever; afeb-
book ofomi1ttlcroblol 1htrrt1py. ISth ~. Nt"-' RC!Cbellc NY: The a.mpiei11in rctistanl H•cmophil1;1s influcnuc type b dis.ease. Lnn· rile neutropenie patients who show signs and symptoms
Medic.I Ltncr, 200~: 65. a!I t990; 335: 351- 2.
S. Zhmg H. d al Ytrs/11/0 '1nlh't>t0fitka infection in di:irrheil pa·
compatible with infections should also receive empiri-
3. BarcJay K, e1 hi. Multiruiu.an1 Hacmophilus innuenz.ae. LilHttt
Ucnu. Eur JC/in Microbful Jnf«I DiJ 2008; 27: 741- Sl. 1990; 335: 549. cal antibacterial treatment
6. Rud RC. 8tmy RE. Rebpsinc, ycrsinia infec1ion. BMJ 1990: 4, Scott GM, et ol. Outbreaks of mu1lircsis1an1 Hacmophilus inOu· • consideration should be given to whether the patient re-
300: 1694. enuc infection. /..onc~r 1990: JJS: 925. quires vancomycin therapy. If so. treatment should be·
S. P<.,welt M. Chcmothtr.apy ror inftc1ions caoM'd by HaC"11K'philu1
inOucnuc: curmu problc'"' and future prospta.S. J .•nflinfcrob gin with \'8JlComycin plus cefepime, ceftazidime,, or a
Gonorrhoea c11•.,,.,,,,.,. t991: 21: J-1• . carl>apenem, with or without on aminoglycoside,
See under Sexually Transmitted Diseases, p.206. 6. Abni.mowic1 M, ed. The choice o( 1nlibac~rial drugs. In: Hand· • if vancomycin is not indicated, intravenous monothera-
book o/tmtuntt:rohiol therapy. IRth ~d. Ntw Rocticllc NY: The
Medial L<llcr, 2008: 69. py should be given with
Granuloma inguinale 7. l..adha.niS. rtnl. Recommendations for the prc,·cnlion o(scconO. • either a cephalosporin (cefepime, although concerns
ory Haemophilus innucnz>t lype b (Hib) di ....c. J '"ft:<• 2009;
See Wlder Sexually Transmitted Diseases, p.206. 58: 3-14. have been raised about its safcty,6 or cetla7.idime) or
8. Am<rican Academy of Ped111rics. 1()()9 Rttl Book. R<port ofIM a carbapenem (imipenem-eila~tatin or meropcnem)
Comm;ut:e o,, J11fec1lou~ Dis~oHJ. 28th ed. Elk Grove Villas~ for uncomplicated coses
H aemophilus influenzae infections Illinois.. USA: Aincrican Academy of PcdiJtrics, 2009.
Hoemophilus injluenzae is a Gram-negative bacterium • in more compl.icated cases, or where resistance is a
that colonises the upper respiratory tract in the majority of problem, combined treatment should be given with
H elicobactef' pylor i infect ions an aminoglycoside and one ofoefepime, ceftazidimc,
healthy people. Most are carriers of non-encapsulated (or
Anlibaclmal therapy is uS<!d to eradicate Helicobacter py- a carbapenem, or an antipswclomonal penicillin such
nontypeable) strains, but a small proponion carry H. injlu- lori infection in peptic ulcer disease (p.185 I) and MALT
enzae type b (Hib), the most virulent ofthe 6 encapsulated as tican:illin witli clavulanic acid or piperacillin with
lymphoma of the Slomach (p.714). The role of H. pylori tazobactam.
strains. Transmission is by close contact with an infcetcd and the value of its eradication in dyspepsia (p.1844) and
person or by inhalation of respiratory tract droplets. In • low-risk patients may be treated empirically eithCT oral-
gastro-oesophageal reOux disease (p.1844) is Jess clear. ly with ciprofloxacin and arnoxicillin with clavulanic
most developed countries there has been a decrease in the
rate ofnasopharyngeal colonisation by Hib and in the inci- acid, or intravenously as for uncomplicated cases above.
dence of Hib infection since the introduction and wide- Infections in immunocompromised patients Initial treatment with oeal antibacterials alone is, howev-
spread use of Hib conjugate vaccine. However, Hib infec- Patients with a defective immune system are at ina-eascd er, not recommended for childrens
tion still occurs in unimmunised children or those who risk of infection. Primary immune deficiency is rare, The initial regimen usually needs to be given for 3 to 5
have not completed the childhood immunisation schedule; whereas secondary deficiency is more common: immuno- days in order to determine its efficacy. In parients in whom
Hib infections arc uncommon in children more than 6 suppressive therapy, cancer and its treatment, HIV infec- fel'er resolves and in whom a causative organism is identi-
years old. Hib strains cause systemic disease, the most SC· tion, or splcnectomy may cause neuuopcnia and impaired fied, antibacterial treatment should be modified for the
rious being meningitis which mainly affects childn:n Jess humoral and cellular immunity in varying de17ees. The specific organisms and broad-spectrum antibacterials con·
All cross-references refer to enirics in Volume A
 Antibacte1ials 187
tinued for at l~ast 7 days or until culture results are nega· a fluoroquinolone or co-trimoxazole). A systematic re- tibactcrials (usually cephalosporins) were added in the
tive and the patient has clinically recovered.5 In afebrilc view of 101 randomised, controlled, studies in 12 599 firs• 4 clays of the lCU stay to prevent e<irly infections
patients in whom no causative organism is found bm who afcbrile neutropcnic patients (mostly with leukaemia) • selective orophatyngcal decontamination, (SOD) uses
were considered at high risk at the onset of treatment, the found that an tibacterial prophylaxis significantly de- topical oral application of antibacterials or antiseptics,
same amioocterials should be continued intravenously; creased the risk of death from all causes by 34% when such as chlorhexidine gluconate or povidone>iodioe
those considered at low risk initially may be switched to compared will1 no intervention; the most significant reduc- In an initial reports in 1984 SOD reduced the incidence of
oral therapy with ciprofloxacin plus either amoxicillin-cla- tion in mortality was associated with tbe use of Ouoroqui- nosocomial infection from 81 to 16% in a group of multi-
vulanic acid (adults) or cefixime (childrcn).5 oolones.10 ple trauma patients. Since then further studies ha\'C been
Patien1s in whom fever persis1s throughout the first 3 to 5 Although antibacterial prophylaxis is also effective in afe- done to evaluate the efficacy of SOD in ICU patie.ilS.
days but for whom no ac1iology is detamincd may have a brile patients likely to be oeutropenic, the efficacy of cm- 'N11ile results showed that SOD reduced infection-related
non-bacterial infection, a bacterial infection tbat is refrac- pirie11I treatment means that prophylaxis is less widely morbidity, its effect on mortality was not clear. Further-
tory tq. treatment, the emergence of a second infection, or used 11 and the Infectious Diseases Society of Amcrica 5 more other outcomes, such as beneficial effec\S on dura-
drug fever. 5 Such patien\S should be reassessed and then discourages routine use; reasons include toxicity of the an- tion of ventilation, ICU or hospital stay, and cost-efficacy
one of three options followed. If the patient's condition is tibacterial, potential fungal overgrowth, and problems of were also uncenain.6 Selection of antibacterial resistance
clinically stable. the same antibacterial treatment may be bocterial resistance. is considered a serious adverse effect6 and the preventive
continued; if there is still no change in tl1e patient's condi- effects ofSDD have been considerably lower in ICUs with
tion, consideration should be given to stopping vancomy- lmmunocompromiscd patients may benefit &0111 appropri-
ate immunisation against common infections, allhough high endemic levels of antibacterial dn1g rcsistance.7 SOD
cin if it'has been given. Alternatively, if.there is evidence may therefore be an attractive option because the antisep-
of progressive disease or d1ug toxicity, the antibacterials precautions relating to the use of live vaccines in such pa-
tics and antibacterials used have a low potential for induc-
given may be changed; ifvancomycin has not been given, tients should be observed (p.2407).
tion and selection of antibacterial rcsistancc.R A systematic
it may be added to the regimen. TI1e third option is to add The duration and severity of neutropcnia can be reduced review and meta-analysis! of 11 randomised controlled
an antifungal drug (amphotcricin B) with or without a by the: usc granulocyte or gr•nulocyte-macrophage colo- srudies (up until May 2006) suggested that in mechanical-
change to the antibacterinl regimen if the patient is febrile ny-stimulating factors, and this may be a useful adjunct in ly ventilated patients, antiseptic SOD prophylaxis reduced
~~gh d~ 5 to 7 and n:solution of neutropenia is not infection control in selected paticn\S.7 Bone marrow pro- the incidence of ventilator-associated pneumonia; but no
inunroent.- tective agents such as amifostine are also being srudicd. finn conclusions could be made on the effect of antibacte-
Thc optimwu duro1io11 of1/ruapy is governed by the clin- I. Piuo PA. fC"Yer inirnrnunocompromiscd poti~1s. H £111/J Af~d rial SOD. Nei~lct' of the two oral decontamination regi-
ical situatiOil. The most impollant determinant of success- t999; 3~ I: 893-900. mens appeared to atfCCI mortality, duration of mechanical
fully stopping antibac1crials is the neutrophil count:5 2. CDC. Guidelines for 1hc prcvCllLion and trealmcnl ofOppo11v,.- ventilation, or stay in the ICU. A later meta-analysis' of36
• if no infection is identified after day 3, the neutrophil i.1Hc 1nfCC4ions among HIV~3:.po.std and HIV-inltctcd children: randomised controlled studies (published up until March
rccommendacK>ns from CDC. lhe Nalion.al lnstilutcs ofHt-3llh.
count exceeds 500 cclls!mm3 for 2 consecutive days, lhe HIV Medtcinc Associalion or the JnfecliOUI Di1cucs Soci- 2009 and invoh•ing 6914 patients) assessed the effect of
and the patient has been afcbrilc for at least 48 hours, ely ol' An"teric.a, 1hc Pediatric Infectious Discftses Society, and prophylactic antibacterial regimens for UlC prevention of
then antibacterial treatment may be stopped 1ht Amc:ric:m Academy of PedialriC.'$. MMWR 2009~ 58 (RR- respiratory-tract infections and overall mortality in adults
11): 1-166. Also ~v3ilable a1: hnp;//www.cdc.1o'''n'11nwrlPOF/
• if neutropenia persists in the absence of fever, it is rea- rrlrrSRI l.pdftaccc:s.~cd IMOSilO) receiving intensive care. II found that a combination of
sonable to stop antihacterial treatment after 5 to 7 days l . C:OC. G.uidclinc:s for p<cven1ion ;md trcutmcnl of opportunistic topical and systemic prophylactic antibitcterials reduced
in patien\S who were initially considered at low risk and lnftttfon.s in HIV-inf!!ctcd adult~ and ad()k:scen1s: recommcndu- respirato1y- tract infections and overall mo11ality; treat-
1ion1 from CDC. the National Jnstitult$ afHcallh. and the 'HIV ment based on topical prophylaxis alone reduced respira-
who are clin~lly well, though such patients should be Medicine A~iatioo orthe lnfecliO\IS Diseasc.s Socicly o(
closely monitored and intravenous antibacterials re insti- A01crica . •"f,\,(IYR 2009: 53: (RR-4): 1-207.
Al«> avait•M• II tory infections but not mortality. A large, multiceotre
gated immediately on recurrence offever or evidence of hctp://ww¥..cdc .g.o\·/mmwr/pdf/rr/rr$S04 .pdf (lcc<ntd study9 conducted in 13 ICUs using cluster randomisation
infection.5 Jn afebrile patients with profound ncutrope-
101os1101 showed 1hat the use of either SOD or SOD was a.ssociated
nia (less than I00 ccllsJmml). or in those with mucositis 4. Ramphol R. Chqcs in II>< ctiolotY of badortmia in felwilc 'l'iith improved mortality in critically ill adults.
ncutropcruc. J»licnts 3lld the $U$C'tpllbiliucs: orw cumndy iso·
or other risk factors, con1inuous antibacterial treatment lot«! p>tltoJens. Clm Infect Dis~; J9 (suppl I): S25-S3 t. The risk of antibacterial resistance was evaluated in only
should be considered throughout the entire neutropenic S. ~WT,., of. lnfcctio.a OU.UC. So<itty of Amtrica. 2002 one study1•10 This prospective, randomised, controlled
period Guidtlincs for t.M use or amimkroblal agcnu in neutropcnic srudy of 934 patients admitted to a surgical and medical
p1tic.rlls with c•ncct. Clin 111/ttt Dis 2002: J.4: 7.lO-S I. AllO
• in patients with persistent fever and prolonged neutrope· ICU compared a SOD regimen with a control group re-
nia in whom ooematological recovery cannOI be antici-
a"•ilS\blc <'It: h11p:/lwww.Journals.uchiu10.edu/doi/ pdf/
I0.1086133921 s(.c:cess<d 18/0Si'OS) °
ceiving standard treatmem.1 Colonisation with Gram-
negative bacteria resistant to ceftazidimc, ciprofloxacin,
pated, consider.Ilion may be given to stopping antibac- 6. Paul M. ct nl. Empiric.cal antibiotic monothcrapy (or f~brilc neu·
terials after 2 weeks if no infec.tion has been identified 1ropenia: sys1tma1ic rcvic"'' and meta-analysis or randomized imipenem, colistin, or tobramycin occurred in 16% of
..:onirollcd lrittls'. J Antimiaob CIN!motlu:r 2006: 57: 176-89.
and careful observation is possible.5 SOD paiients and in 26% of those in the control group. No
7. Sinith TJ. et of. Amcricao SOC'it:ty or Cfi11ic3I 0 1u:ol0JY· 1006
• clinically well patients with persistent fever may have updntc or r~com m~ n d,;nions f'or the u ~ or while blood cell patient in either group was colonised with MRSA, while
their amibacterials stopped after 4 to 5 days if the ncu- wrow1h (.ictors: :m cv1dcn('C·bas.ed clink1I pr;u.:tice JUidc:tinc. J I% of all patients were colonised with vancomycin-resist-
Clio Onrol 2006: 24; :>IS7-320S. Also 3\'ail:ible flt: hup:!/
trophil coum remains at least 500 cells/mm 3throughout ~vM;3·~:t1•g/(ii/rc:prinl/JC0.2006 . 06.44S Iv2 pdr (nccuscd
ant enterococcus.
tl1is period and there is 110 sign of infection and no re- Although SOD reduces hospital-acquired pneumonia, US
sponse to therapy; such patients should be closely mon- &. Aopro MS. c111/. Europe~n Or1anis.:ih<1n for Rcs~rch And Trc::st- guidelines discourage routine antibaetcriat prophylaxis/.!'
itored for subsequent infections which are usually easily mcnt of Can-ctt(EORTC) Gr.inulocyte Cotony-Stimu'3ting f•c· especially in hospital settings where there are higb levels
treatable, and empirical amphotcricin B should be con- tor tG·CSF) Gui<l<lincs Wotkifl& Pany. EORTC suidclu1u for of antibacterial resistance.' and particularly in relation to
tht uu or s,ranu~lony stimulttina factor 10 rtdu« lhe
sidered despite cessation of antibacterials if fever per· inctdm« o(chemolhenpy·induud ftbtik n.tu1roptnia in adutt prevention of nosocomial pneumonia. 11 CDC guidelines
sists for 5 to 7 days after the start of initial therapy~ peticn\s 'Vl.i lh l)'mphomas and solid 1umoun. £ w J Conttr 2006; do, however, recommend topical oral cblorhe.xidine gluco-
41: 2433-~3.
• patients who remain febrile after recovery from neutro- nate O. I2% during d1e ~tiveperiod only for adults
9. Cl;\ric OAC. et al. Colony SlimulMint ratlOfS ror chtmolhcrapy undergoing cardiac surgery.
penia and despite broad-spectrum antibacterials should iru:tuccd ftbnlt neutropcni:.. Aw1il::1btc in The Cochntne 0111:>-
be reassessed for undiagnosed infeclion which may be b;iic of Syste1n:>tir Reviews: J:m1c 4. Ch1che:s.t~: John Wiley: Another potC11tial source of infection in intensive care is
fungal, mycobacterial, or viral 2000 (occc$$<d 16i0S!05). from die use ofinlravAscular catheters. Cad1etct'-related
The routine use ofcolony-stimulating factors as an adjunct 10. G11ncr·G,·ili A. et al. Antibiotic erophy1axis for bacterial inrec- bloodstream in feet ions occur in 3 to I O"lo of patients with
tions in afcbril~ ncutropcnic p::H1cnU foltowin& chcmorht:rapy.
to antibacterial treatment is not general ly recommendeds A\'oilnble in The Cochrane Datibase orSya1cm11ic Rcview'S; ls- inserted cathete1~ i2.t 3 and are a leading cause of nosocomi-
but m~y be indicated in febrile neutropenic patients at high >ue 4. Chichester: John Wiley: 2005 (accessed 10/05110). al bloodstream infection in ICUs. 13 Most serious catheter-
risk of serious infections or infection-related complica- 11. Kerr KG. The prophyfoxis ofbac1cri:il infections in ncu1ro1>cnic related infections are associa1cd with central venous cath-
po1icnrs.J Amimicrob Cha111011tcr 1999: 44; SS7- 91. eters.14 Conditions that compromise host defences (includ-
tions; exan~>lcs include some patients with malignant
neoplasms7• and those with persistent severe neutropcnia ing severe bums and 111ab1utrition), severe sepsis, or severe
and infections that arc not responsive to amibacteriols Intensive care .and sustained mulliple organ dysfunctions are associated
alone.s A systematic review9 of the use of colony-stimulat- Like immunocompromised patientS (above), those in in- with a higher risk or c;uhcter-rclated bloodstream infec-
ing factors in patients with febrile neutropenia due to can- tensive care units (ICUs) arc often very susceptible to en- tions.1S Colonisation of the catheter tip due to migration of
oe.- chemotherapy concluded t!Jat their use did not affect dogenous infections, especially respiratory and urin2ry- skin Orl!anisms from the in:;ettion site into the cutaneous
overall monality but did reduce rime spent in hospital and tract infoctions, arising from g;istromteslinal colonisation cathet; tract is the most common route of infection for
the neurrophil recovery time. by aerobic Gram-negative bacilli acquired in hospital. The short-tcnn central venous catheters. i 3.1; For long-tem1
PROPHYLAXIS. Most infections in immunocompromised incidence of pneumonia in ICU patients ranges from 7 to catheters (those staying in place more than 15 days), colo-
patients are caused by tnganisms from their own alimenta- more than 40"/o,1and ln0l1ality from ventilator-associated nisation is mainly due to manipulation of the venous line
ry tract and in cancer patients, for example, may follow pneumonia may exceed 30 to 50%.:!.3 For further infom1a- with migration of org11nisms along die internal lumen of
chemo1herapy-induccd mucosa! damage to the tract. Se~­ tion on ''entilator-i1ssociateJ pneumonia sec under Pneu- the cathetcr.1l.U TI1e ability of organisms to adhere to host
eral prophylactic strategics have been used to try to reduce monia, p.201. proteins such as libronectin that commonlr, build up on
the risk of infection during severe neutropenia. such as iso- catheter tips, makes colonisation easier.13· s The organ-
lation of the pa1ient, granulocyte transfusion, active or pas- Selective decontamination regimens aim to reduce this isms imrlie<1tt"d most often arecoagulase-negative staphy-
sive immunisarion, acceleration of granulocyte recovery, risk by eliminating potentially pathogenic organisms from lococci; 3·" 01hcr organisms commonly involved include
and antibacterial prophylaxis. Possible antibacterial pro- the throat and intestines while preserving the indigenous, Staphylo<:occ11s aurcws, Candido spp., E111erococci, and
mo~ly anaerobic, flora4 Gram-negative bacilli.fl
phylactic regimens have included selective decontamina-
tion of the alimentary tract using oral nonabsorbable anti- • selective decontamination of the digestive tract (SOD), Guidelines for the preven tion of infection associated with
bacterials (sec also under Intensive Care, below) or uses non-absorbable antibacterials given ora lly and both peripheral intrava5cular and central venous catheteri-
treatment witl1 absorbable antibacterials (most commonly through a nasogasnic tube; in some studies systemic an- sation have bccl1 devcloped."· 1 ~ 11 Prevention and control
188 Antibacterials
of infection involves several interventions, which should 11. CDC. Gukh:linti for prcvt-nting hcallh·care-associa1c:d pneu- need 3 to 5 days treatment due to its long half-life and tis-
be used in combination,l3·l5,l 9 Intervention measures in- monia, 2003: recommendations of CDC and lhc Healthcare In·
rc:c1ion Conuol Practices Advisory Commiuec. MMWR 2004~ sue retention.1.:
clude: 53 (RR-3): 1-36. Abo 1vailable at: http://wv.-w.cdc.gov/mmwr/ l. Roig J, Rello J. Legionnaires' dtse•sc~ a r1tion1l approach 10
• banier precautions at the time of catheter insertion PDF/rr/rrS303.pdr(accesscd 07/05110) therapy. J Antimicrob C.he1uo1J1er 2003; 51: I J19- 29.
12. Bhultl A, tt ol. Reduction ofblooduream intCctions associated 2. Amsden GW. Treatment of legionn1irt1' ditteue. IH"gs 2005;
• disinfection of the skin at the insertion site with chlo- whh c11hcurs in pacdi11ric intensive care unit s1epwise •P· 6S: 60S-14.
rhcxidine or alternatively povidone-iodinc prooch. BMJ 2007; 334: 361-S. 3. Oied.cren BMW. Le~nelb spp. and U 1ioclna1tts' diSt:uc. J In·
I3. Frasa D. d ul. Prevention of Central venous ca1hc1cr~elarrd in- /«12008; 56: 1-1!.
• the use ofcatheters impregnated with antibacterial (u.su- ftdK>n in lht in1cnsin care uniL Crit <:.an 2010; l.f: 2tl. 4. Abramo"icz M. ed. The d>oicc or• ntiboCleriol ~p. In: Hand-
ally rifampicin or minocycline) or antiseptic agents l.f. O'Gndy NP, ~' ol. Ciu;&lincs for the prcvcnlion o( inttavoscv- boolt ofontimicn>bial 11'1r"P)'. I 8lh ed ll<w Rodlclle NY: The
(commonly chlorhcxidine or silver sulfadiazine) lar ca1heteMela1od inreciions. MMWJI. 2002: Sl (RR-10): 1- 29. Modicol Lct,.r. 2008: 69.
Correct ion . Ibid.; SI: 71 1. Also avail•bl• • I: htlp://
• use ~f good aseptic technique and hand hygiene (see www.«!c.cov/mmm/PDF/rr/rrSI 10.pcff(occessed 12J07/04)
p.1767) when accessing or maintaining the catheter sys- lS. Timsit JF. 01aanosi.s and prevention of cathetn·related infcc- Leprosy
tem 1ions. CurrOpm Crlt Cora2001; 13: 563-71.
Leprosy (Hansen's disease) is a chronic disease caused by
16. DoH. GuicSclinc.s for preventing infections Jssocietcd \\i1h lhc
Antibacterial prophylaxis has not been shown to reduce inseniori :rind maintenance of central venous catheter1. J Jlosp the bacillus, },.fycobocterium /eprae; it has a prolonged in-
the rate of infection when given during catheter inser- lnftct 2001: 47(suppl): S47-S67. Also available al: hllp:// cubation period (years) and slow onset of symptoms. Dis-
tion, IJ,l5 but when antibacterials were given with a central www.dh.1ov.uk/cnfPublicationsandsta1is1ics./Public11ion1/ ease results from bacillary infiltration of the peripheral
Public1tionst>olicy AndGuidance/OH 40054 81 ?ldcScrvicc•
venous catheter in place, risks for calheter colonisation and GET_Fl LE&.dl0-14080&Rcndition~Wcb (•ccesscd 07/05/J 0) nervous system, skin, eyes, respiratory mucosa, bones, and
bloodstream infections were significantly reduced.13 17. NICE. lnfecdon control: prevention ofhealthcare-associa1cd In- testes. It is not highly infectious and transmission requires
However, the use of prophylactic antibacterials is discour- fections in primary 3tld community care (June 2003). Section 5: both prolonged close contact with an infected patient and
aged because of concern over the emergence of resistant central venous calhctcrisation. an inherent immunological ~11sceptibility to the disease in
Available 11: http;//www.nicc.org.uk/nicemedi1/pdf/
organjsms. 18.19 Antibacterial ointments (such as bacitrac- lnfoction_conirOl_fvllguidclinc.pcff (occ:CSK<! 07/0SJI 0) the exposed person. Clinical leprosy may be regarded as a
in, mupirocin, neomycin, and polymyxin B) or antiseptic IS. Bi.shOp L. ~t al. Guidelines on 1hc iRsertion and manasemcnt of consequence of deficient cell-mediated inununity in SUS·
ointments applied to catheter-insertion sites increase the central venous access device-sin adlJlts. /mJ lAl>He1Mrol 2007; ceptible individuals; most individuals are naturally im-
29: 161-7&.
rate of catheter colonisation by fungi, promo!e the emer- mune, and symptoms are suppressed. The clinical mani-
gence of antibacterial.resistant bacteria, and have not been 19. McGee DC, Ga..ld MK. Pmicnting complications ofo•mral rt·
shown to decrease the rate of infections. 13 Studies suggest
"°"' ca1hcteriza1lon. N Engl J Mcd2003; 348: 1123-33. festations depend on the bacillary load and the host's
immune response to the mycobacterium. Patients with lep-
20. Abdtlkefi A• ., ol. R1ndomoz.ed lrial of prevention of cothetcr-
that anticoagulants such as heparin and low-molecular· rclatcd bloodstream Mrection by continuous irifu.sion or low· rosy may be classified as having:
weight heparins are able to decrease fibrin sheath and dose unfnc.lionatcd heparin in pa1ients with hnnatolo;ic al\od
onc:ololi• disease.JC/in Oncol200,S; 23: 7864-70. • MultibaciUary (or lepromatous) leprosy, which occurs
thrombus fonnation around the catheter and in so doing wben cellular immunity is largely deficient, and in-
21. Mcmel LA •.i ol. Clinical practice guidelines for the diainosis
reduce catheter-related infections.1'·20 Routine replace- and m1nogcmcn1 of intrava.scular ~thetcr·rclarcd infec1ion: cludes the sub-groups lepromatous(LL). borderline lep-
ment of short-tenn catheters as 3 means to reduce infection 2009 Updaic by the lnrcctious Disc:asc.s Society or Amt:r;ca, romatous (BL). and midborde'rline leprosy (BB). as well
rates is not recommended. 13·" Clln lflftct Dis 2009; 49: 1~5 . CO<T<c1ion. ibid. 2010; 50 457.
as any other types giving a positive skin smear for acid-
Guidelines for the diagnosis and management ofintravas- faSt bacilli. Generally the lcproniin test (p.2558) is neg-
cular catheter-related infections have been developed by Legionnaires' disease ative.
expert.~ in the USA. 21 Antibacterials for catheter-related Legionella pneumophila is an aerobic, Gram-negative • Paucibacillary (or tuberculoid) leprosy, which results
infections are often given empirically and the choice of bacterium that was first identified in 1977 as the result of when cellular immunity is only partially deficient, and
drug should take into account local antibacterial suscepti- an outbreak of severe pneumonia at a convention of the includes the sub-groups borderline tuber"culoid (BT), tu-
bility data and the severity of disease, and should usually American Legion. Legionnaires' disease is the pncumonic berculoid (Tl), and indeterminate leprosy (!) when the
cover coag11lase-nega1ive staphylococci. Empirical thera- fonn of the infection and is a relatively common cause of skin smear is negative. Generally the lepromin lest is
py with vancomycin is generally recommended where community acquired pneumonia (see p201); non-poeu- positive.
there is a high prevalence of MRSA. Daptomycin may be monic infection (called Pontiac fever) is a mildeT, usually
given as an alternative if isolates have vancomycin MIC For the purpose oftreatment, WHO classifies patients \\ith
self-limiting, flu-like illness. Legionellosis has been sug· more than 5 skin lesions as having multi bacillary leprosy,
values greater than 2 micrograms/mL. Linezolid is not rec- gested as a broad term to cover pneumonic and non-pneu·
ommended for empirical therapy.21 For empirical treat· and those with I to 5 ~kin lesions as having paucibacillary
monic clinical syndromes caused by any Legionella SPP·· leprosy. The use of this clinical classification avoids the
ment of infection thought to be caused by Gram-negative which may include L bozemanii, L micdadei (Pittsburgh
bacilli, a fourth-generation ccphalosporin, crubapenem, or necessity to provide facilities for bacteriological examina-
pneumonia agent), and L wadsworthii. These bacteria are
combinations of a beta lactam and beta-lactamase inhibi· tion of skin smears.
found worldwide in the environment and particularly in
tor, with or without an aminoglycoside is recommended; warm water and wann damp places. Infection is usually Changes in the hosts immune response 10 the mycobacte-
combination antibacterial treatment should be given when transmitted by aerosolisation or aspiration. Serious OUI· ria may result in lepra reactions and unless 11eated these
multidrug-resistant Gram-negntive bacilli (such as Pseu- breaks hav~bcen associated with infected air~onditioning may lead to severe nerve and tis~ue damagc. 1Most reac-
domonas aeruginosa) are suspected in neutropcnic or se- systems or water supplies. Older adults, smokers, and im- tions belong to one of two main types:
verely ill patients with sepsis, or in those known lo be col- munocompromised people are panicularly susceptible to • Type I lepra reactions, or reversal reactions, are caused
onised with such pathogens.21 Lcgionna~s· disease. Symptoms usually begin 2 to 14 by spontaneous increases in T-cell reactivity 10 myco-
Antibac.1erial treatment can be stopped after 1010 14 days days after being exposed to the bacteria and are similar to bactcrial antigens (type JV hypersensitivity) and occur
if a response is seen within 2 to 3 days. A longer treatment ocher forms of pneumonia. The severity of disease ranges in patients with borderline fonus ofleprosy. ThC$C reac-
duration of4 to 6 weeks is recommended for patients with from a mild cough to a rapidly progressive pneumonia 1ions are characterised by erythema and oeden1a of the
persistent fungaemia or bacteraemia after catheter remov- with respiratory failure, shoclc, and multi-organ failure. skin and tenderness of peripheral nerves. Prompt treat·
al, foe patients who are found to have infective endocardi- The mortality rate from Legionnaires' disease is depend- ment with corticosteroids is necessary to prevent pemla-
tis or suppurative thrombophlebitis, and for paediatric pa- ent on the severity of the disease, the appropriateness of nent nerve damagc.2·S Treatment is usually continued
tients with osteomyelitis; 6 to 8 weeks of treatment are initial antibacterial treatment, the setting where infection for 3 to 6 months. Adding ai.athioprioe may permit the
recommended for adults with ostcomycliiis.21 was acquired, and host factors. Jn untreatc<l immunocom· use oflower cumulative doses of corticosteroid.6 Meth-
I. Liberati -A. e1 al. Antibiatic prophyl:.xil to reduce r~iratory promised patients the mortality rate may be 40 to 80%; if otrcxate was found to be elfeclivc in treating a patient
intolerant to corticostcroids,7 while ciclosp<>rin is con-
~~~1~:ie:1~ ri:~~:.~i~a~~b:~'~1S~:~·~;.i~ ~~~i::~~:
0 1 1
treated appropriately this decreases to 5 to 30"/o. For im-
sue 4 . ChicheSlcr: John Wiley: 2009 (accessed 04/05110). munocompetent patients the mortality rate is about JO to sidered to be effective for chronic neuritis.l·s Prophylac-
2. Kollef MH. The prevention orvc1\lil:>1or·associatcd pneumonia. 15%. The usual treatment for mild to moderate Legionel- tic use of.low-dose corticos1eroids during the first 4
.V Engl J Med 1999; 340: 627-34. Comx:iion. ibid.; 341: 294. /a infections is with an oral macrolide, with erythromycin months of standard multidrug treatment for leprosy has
3. Chan EY, el al. Oral dccon11min1-tion for prevention orpoeumo· now increasingly replaced by azithromycin;'l clarithro- also been invest igated, and found to decrease the
~~=:a~;~~~7iOO~t;i~j~ :::.lt1:
systematic review and mycin, roxithromycin, or telithromycin may be further ac- number of reactional episodes by 75%; but the protec-
4. Krueger WA, Uncnl KE. Selective decon1amina1ion or the di- ceptable alternative macrolides. 1.2 Oral lluoroquinolones tive effect was lost by the end of 12 months.9
gestive tract. Curr Opi" Cri1 Core 2002; 8: 139-44. (such as ciprofloxacin, levofloxacin, or moxifloxacin) are • ~ 2 Jepra reactions, also known as erythema nodo-
S.Stoutcnbcek CP. et ol. The effect of sclccth-c d«oatamiMtiOP also increasingly recommended as alternatives to the mac- sum feprosum (!;NL). represent a systemic inflammato-
of the digestive tract on colonisation and infection rate in mul-
tiple tmima poti<111S. lnttnih'C Ctm! M<d 1934; 10: 185-92. rolides. 1"3 Doxycyclineorco-trimoxazole are furtheraher- ry response (type 111 hypersensitivity) to dead bacteria
6. 8on1cn MJM. tt ol. Sc:lecrive dcconuumnalion of lhc di1;$ive natives.1.l.• For se\•cre infections or in irmnunocompro- and arc accompanied by high levels of circulating tu-
inct: all qUCSlions answered'? CMI Core 2003; 7: W-S. mised patients parenteral therapy (if available) with mour necrosis factor alpha (TNfo). This reaction oc-
7. American Thora<ic. Society; lnftcdous Oiscoi:sa Soc~ty of
ailthromycin, clarithromycin, or a fluoroquinolone is rec- curs only in patieolS with borderline lepromatous or lep-
~~~·,~~~~~~(:~!':o:i!i:f.~nc;'~~~t:e~~oc"f:fc~ ommended.1.2 Combination intravenous b'eatment with romatous leprosy. Mild type 2 reactions may be treated
pn.,,rnonia. Am J Raplr Crlt Co1w Mod lOOS; 171: 388-416. erythromycin and rifampicin has also been used for severe with anti-inflammatories but moderate or severe reac-
Also available al: hup://W'l>Jw.thoracic.org/&eetionsfpublication.sl
s1a1c:mcn1s/pagcs/m1pi/guidel-29.h1ml (•cc•sscd 25/0S/06) infe~'tions.2 Rjfampicin has also been given with nuoro- tions should be treated with corticosteroids or thalido-
8. Kocman M. et al. Oral dccontl'lmina1ion wilh chl0<hcxidine r~ quinolones or doxycyclinc, especially in severe or deterio- mide (in males and post menopausal womco).2_. TI1e in-
duccs the incidence of vcntilulOr•HtOCi1tcd pneumonia. Am J rating illness or in immunocomprornised Ratients, al- cidence and severity of ENL has decreased since the
Respir Cri< Core Med 2006; I 7J: 1348-SS. though this may be of little further benefit. 2 Generally inclusion of clofazimine in multidntg regimens, proba-
9. de Smet AMGA, e1 ol. Occon1omina1ion of the digestive tr:ic1
and oropharynx in ICU pa1icn11. N Engl J Med 2009; 360: about 7 to I 0 days of treatment should be given to those bly owing to the drug's anti-inflammatory action.2
20-31. with mild to moderate infections, while those with more Clofa;,Jminedoes not act as rapidly as either corticoster-
10. de Jonge E, ~' o/. EfTcct1 of "lcclive dccon11miM1ion of diges-- severe infections, multisystem disease, or who are inunu- oids or thalidomide, nor is it as effective. 23 Other TNF"
tive 1rae:1 on inonalily and 1equi111ian or resis1anL OOc:tcrja in inhibiting dru~s that have been t ried include
inrensi~e ea.re: a randomised con1roHcd trial. Lonut 2003; 361:
nocompromised should be treated for up to 21 days. 1.l
1011-0. However, patients treated with oral aiithromycin may only pentoxifyllincs.i and infliximab. " Chloroquine has
All cross-refcronccs refer to entriei in Volume A
 Antibacterials 189
also been used wid1 limited effecL 1 Antileprotic drug • PROl'HY~AXIS wiLh urine, blood, or ti~sue of infected animab or a con-
therapy is generally continued during lepra reactions. Leprosy is spread from person to person through respi- taminated environment. Leptospirosis is more common in
Although mea~ure:; to manage the consequences of nerve ratory droplets, so household contacts may become in- tropical and subtropical areas, where the climate and great-
damage and Jepra reactions are an important part of the fected. A systematic review and rneta-analysis~0 has er contact with infected environments increase die likeli-
management of leprosy. curative an!ibacterial therapy is concluded that prophylaxis. usually with dapsone, in hood of infection. Occupational groups most at risk in-
the mainstay of treatment. Dapsone monotherapy, long some household contacts may prevent disease in this clude farmers and agricultural workers, although there
the basis of this, has been replaced since the 1980s with high-risk group. A large randomised placebo-controlled have been outbreaks among participants in water-sports.
multidrug oral regimens designed to overcome the devel- study21 found that a single dose of iifampicin given to TI1e organisms enter the body through broken skin or .in-
opment of resistance. Dapsone, rifampicin, and clofaz- contacts of new patients with leprosy significantly re- tact mucous membranes, can infect any intemal organ, and
imine form the eleme11ts of the standard combinations.5-1 2 duced the incidence of developing leprosy in the first 2 cause damage to the waJls of small blood vessels. Many
Newer altematives include clarithromycin, minocycline, years but no difference was noted beyond 2 years. infected people remain asymptomatic and most patients
and fluoroquinolones such as ofloxacin, moxifloxacin, and \VH03 suggests that contacts of newly diagnosed cases with symptoms have a relatively mild course Qf infection
pefloxacin. These may be used as second-line therapy_for should be examined forevidenceofleprosy.and then ad- witll an acute flu-like illness characterised by fever, myal-
patients unable to tolerate dapsone or clofazimine. Ethion- vised how to watch for early signs of the disease; proph- gia, headache, and conjunctiva! suffusion. A small propor-
a1niae or protionamide have been used in lig)lt-skinned pa- ylaxis with rifampicin or other amileprotics is not rec- tion, however, develop severe leptospirosis (Weil's dis-
tienti to avoid clofazimine's tendency to pigment the skin, ommended in -leprosy control programmes. BCG ease), with haemorrhagic CQmplicatioos, jaundice, and
but are :10 longer recommended because of their ·risk of vaccine appears to be protective. Vaccines specifically renal impairment.
hepafotoxicity. against leprosy are under investig;ition. The routine =
of antibacterials to treat Jertospirosis is
The most widely used multi drug .regjmens are those rec- • ELJMtNATlON controversial as most cases are self-limiting, and there is
ommended by WH03 and in these the choice of drugs and The niultidrug therapy regimens recommended by insufficient evidence to provide clear guidelines for treat-
length of treatment are oosed on the clinical classification WHO have been widely implemented in recent years ment. However, treatment is usually recommended as
outlined above. raising the possibility of eliminating leprosy as a public . soon as the diagnosis of leptospirosis is sus1>ected,'.2 and
• MULTIBACILlARY LEPROSY
heald1 problem: tliat is, reducing the prevalence to less preferably.within 5 days of the onset of S)~nptoms.2 Intra-
than I case per .J0 000 population in endemic areas. venous benzylpenicillin is recommended for severe lept-
Tlie standard regimen recommended by \VHO for Considerable progress towards this target has been ospirosis.2 Intravenous ceftriaxone,3 cefotaxime, or
multibacillary leprosy"4 is r ifarnpicin 600 mg and made, and it was announced in 2001 that the global level doxycycline4 are alternatives. Aminoglycosides such as
clofazimine 300 mg both given once a month, with of leprosy had decreased by over 90%. Full control of streptomycin ~e used in some countries.s Oral.antibacte-
clofazimine 50 mg and dapsone J 00 mg both daily. leprosy, however, has still not been attained in several rials such as amoxicillin, ampicillin, doxycycline, or eryth-
Treatment is continued for 12 months.4 countries and continued efforts are. _necessary. WHO has romycin may be used in milde~ infections.2 Jarisch-Herx-
A ·2,year treatment duration was chosen originally be- since developed a global strategy for the further redli<;- heimer reactions may occur after penicillin treatment (see
cause it is highly effective in the majority of cases and tion of the leprosy bui:den and sustained leprosy con- Adverse Eflect;, under Benzylpeoicillin p.23 J).' Prelimi-
avoids the need to assess response with skin smears. ~~ . nary data have suggested that a.zithromycin may be effec,.
However, such a long treatment duration is an obstacle I. Walker SL. Lock.wood ONJ. Tiu• clinical and immunological tive in mild to moderate leptospirosis; fluoroquinolones
to implementing treatment programmes in areas where fcoturcs of leprosy. Br Med B11ll Z006; 77-78: 103-21. and carbapenems have also shown activity in vitro.;
2. Britton WJ, Lockwood DNJ. Leprosy rc:ictions: current and fu.
healdJCare is inaccessible or the ii;ifrastructure is poor. ~~r~~froochc.c; to management. BoUlien.s Clin Infect Dis 1997; The incidence of leptospirosis in US soldiers in ·Panama
Ongo'ng clinical studies and experience with patients was reduced when they were given prophylaxis with
defaulting from treatment have encouraged WHO to 3. WHO. WHO expert commirtcc on leprosy. WHO Tedi Rep St1·
874 1998. Also available at: hllp:lllibdoc.who.int/trs/ weekly oral doxycycline throughout the period of expo-
now recommend tliat treatment .for 12 months is ade- WHO_TRS 874.pdf (accessed 13/07/07) sure.6 Prophylaxis has been suggested for travellers at in-
quate.• Early hopes that reducing duration of treatment 4. WHO. Guldt to eUmfoote leprosy as a public hea/1h problem. 1st creased risk of infection, beginning 1-2 days before and
ed. Geneva: WHO. 2000. Also av~ilable ::n: hnp://www.who.int/
to as little as one montl1 would be possible have not been lep/rtsourccs/Goidc: Jnl E.pdf (accessed 28/06/07) continuing throughout the periud of exposui:e. 7 Lepl-
supported by a study using daily rifam"picin and 5. Britton WI, Lockwood" DNJ. Leprosy. Lonct1 2004: 363: ospirosis vaccines are available in some countries (see
ofloxicin. 13 · 1209-19.
p.2427).
6. Marlowe SNS, et of. Clinical outcomes in a randomized con1rol-
In patients for whom 1ifampicin is unsuitable because of lcd study comparing azathioprine and prcdnisolone versus prcd~ t . Bluini AR, et nl. Pcru-Uni'cd Slttles Leptospirosis O:msotthnn.
resistance or intolerance, WHO recommends 3 daily nisolonc. alone in the treatment of severe leprosy type I reac- l..c:ptospirosis: ~ zoonotic disense or global in1portance. Ltmcel
treatment with clofaziminc 50 mg, ofloxacin 400 mg,
tions in Nepal. r,..,,_, R See 7i-op Med Hyg 2004: 98: 602-9. !11f<!c·t Dis 2003: 3: 7Si-71.
7. Biosca G. et ol. Metho1rexa1e treatment for type ( (rCversal) lep· 2. WHO, International Lcptospirosis Sociely. Human lcptospiro-
and minocycline I00 mg for the first 6 months; treat- rnsr reactions. Cf;,, Jn/eel Dis 2007; 45: c7-e9. si.t: guidonc<> for diag11osi.1, .wrwlllonee and comroJ. Ge11eva:
8. De Sen<i CBC. et al. Cyclosporine A treatment of leprosy pa- WHO. 2003. Available at: hllp://www.who.inl/csr/don/cn/
ment is then continued for at least a further 18 months tients with chronic neuriti.s is associated with pain comrol and WHO_CDS_CSR_EPH_2002.2;.pdf (occe$Scd I 51 12108)
witl1 clofazimine plus either m.inocycline or ofloxacin. rl.!duction in antibodies against nen:c growth factor. Lcpr Rev .3. P:m;;iphut T. ct ;1/ CcOriaxonc coinpare-d with sodium penicillin
2006: 77: 121-9.
When clofazimine cannot be given ofloxacin 400 mg 9. Smith WCS. et al. Steroid propfwlt1xis for prevention of ncn·c: G for Lrta1mentofsevere leptos.pirosis. Clin hifec-; Dis 2003; 36:
daily or minocycline l 00 mg daily may be substituted in function impairment in leprosy: ~ndomiscd placebo controlled I E0?-13.
triol (TRIPOD ti BM.I 2004; 328: 1459-62. 4. Supurwmongkol Y. et al. An open, randomiud, controlled lri31
the stMdard regimen.14 of penicillin, doxyc)'clinc, and ccfotaximc for palicnts wi1h se-
10. Moreira AL, .:1 ol. Comparison of pcnlox.ifylline. 1halidomidc
Rifampicin 600 mg, ofloxacin 400 mg, and minocy- and prcdnlson"° in the treahl'le-nt of ENL. /111J lepr Othtr Myro· vere leptospil'O!is. Cliu Infect Dis 20().1; l9: 141 7-24.
bnct Dis 1998: 66: 61-S. S. Griffith rvtE, e1 of. Antimicrobial th~r~py of l eptospiros~s. CJirr
cline 100 mg (ROM) given once a month for 24 months I I. Faher WR, ct al. Treutmcnt of n.!cun-cnl erylhema nodosum Jep· Opi11 h~fec1 Dis2006: 19: S33-7.
was found to be as effective as die WHO standard regi- 1'{)1i.Um wilh iofl1ximcib. N £11gl J Med2006~3S5: i39. 6. Taknfuji ET. et al. An efficacy trial ofdox.ycycline cheinopropb--
men given for 24months 15 and has been suggested as an 12. Sans;,rricq H, ed. MultiJrug therapy a'3inst leprosy: develop- ylaxis against ltplospirosis. N Engl J Med 1984; 310: 497-500.
ment aHd implcnient3tion over lhe past 25 years. Geneva:
alternative regimen. 3 WHO, 2004. Av~il able at: h11p://www.who.int/lcplresourcesl
7. Abr31nowicz M, ed. TI1e choice of an t i~c1ci-ial drugs. ln: H<md-
book of amimio'Obial 1herl1py. 18th ed. New Rochelle NY: The
• PAUCIBACIU ..~RV 1..ErROSY MDT_Full.pdf (accessed 28/06/07)
13. Ji B. et ol. High relapse rale among lcpromatous leprosy patients Medical Le lier; 2008, 359.
The_VIHO recommended regimen3•4 for paucibacillary trc3led w ith rifampin plus oflox:acin dnily for 4 weeks. Amlmi·
uob Agents Clt~mo1her 1997; 41: 1953-6.
leprosy is rifampicin 600 mg monthly and dapsone 14. WHO. Chemo1herapy of leprosy. WHO Ttclt Rep Ser 847 1994. Usteriosis
I 0.0 mg daily. Treatment is continued for 6 months. If Also availabh: at hHp:/ilibJoc.who.inlflt1>/WHO_TRS_S47.pdf Listeriosis is an infection caused by Listeria mo11ocy--
there are severe toxic effects with dapsone it should be (accessed 13107/07)
togenes, an an~robic, food-bome, Gram-positive bacteri-
I 5. Vitl:>hermosa L(h et al. Parallel asscssmcm of24 nlonthty do.~s
substiruted with clofazimine.14 of rifampin, 01loxaci1l, and minocycline versus two yeau of um that occurs ubiquitously and is found in soil, water, and
O~ ..the basis of a clinical study 16 showing that a-single World Hc:alth OrgRniz.:itioo multi-drug therapy for mulli-baeil- vegetation. It is able to grow in a wide range of tempera-
l:try leprosy. Am J Trop Med Hyg 2004; 70: 197-.200.
dose eacl1 of rifampicin 600 mg, ofloxacin 400 mg, and 16. Singfe..h;sion Multiccnlrc Trial Group. Efiic<lcy of single-dose tures, including those found under reliigeration.
minocycline I00 mg given together is only slightly less mullidrug therapy for the tteatntent of single-lesion paucib"cil- Although exposure to L. monocytogenes is inevitable, in-
effective than standard multidmg treatment, WHO has lary lt:prosy. Lepr Re1· 1997; 68: 341-9.
17. Lockwood DNJ. Rifampicin/minGCycl ine :ind ofiox:>cin (ROM) fection is relatively rare in humans.'·3 When it occurs, it
suggested that this is a suitable alternative for patients ~~~i3~J~ lesions-wh:ll is the C-\ idence? lepr Rc1~. 1997; 68:
1
follows ingestion of food contaminated with a high_ con-
with single-lesion paucibacillary leprosy.l However, centration ofd1e bacteria; foods at high risk of contamina-
IS. Katoch VM. Is 1hcrc a microbiological rationale fot sinsle-do.se
resei:vations have been expressed about the study, in- trc"unenl of leprosy? lepr Re'' 1998; 69: 2-S. tion include processed and unprocessed dairy products (es-
cliigi11g concerns regarding the short follow-up 1 ' and 19. WHO Leprosy Uni1, Risk of !'Claps..: in kpro.sy. Indian J lcpr pecially.those made with unpasteurised milk), cold meatS,
po~r microbiological rationale. •& 1995: 67: 13-26.
pate, raw vegerables, and salads. The incubation period
20. Smilh CM, Sml1h WCS. Chemoprophyl:ix.is is cffec1ivc in 1he
• RELAP>E prevention oflcprosy in endemic countries: Bsystcm::alic review may range from l or 2 days up to 3 mond1s. Those who are
and mc1a-analysis. J J11fec1 2000; 41: 137-42. immunocompe1ent may have a selt~limiling gastroenteritis
Relapse after a recommended course ofmultidrug ther- 21. Moet FJ. ct ol. COLEP Study Group. Effectiveness or single
apy for multibacillary or paucibacillary leprosy can oc- dose rif:unpicin in ptevt-1Jting leprosy in close con1acts of p;i· after consumption,1.1 and a mild cutaneous infection has
cur-and WHO recommends re-treatment with the initial tients ""ilh n...:wly diagnosed leprosy: cluslet randoinist-d con- occurred in thore who have direclly handled infected prod-
trolled trial. BM.12008: 336: 76 1-4. ucts or animals. 1•2 Occasionally invasive disease (listerio-
regimen.3 ·' Although the relapse rate after standard 22. WHO. Globol J'/ruu~&rfor fimht!r reducing 1'1e lcpr<>.t)' burden
sis) occurs, especially in the irnmunocompromised, the
~~1~~,G~~~:~: $H°C( ~~'."'~:;;~~~~~e~/P~~~:Y:~:.\!i~f,;
multidrug tlierapy for multibacillary leprosy is generaily 1
low, 3·'9 there is insufficient information on the long- lcptrc!'ourccsJGloh<ilStralcgy.pdf (ac.-cesscd 13112f(l6)
young and elderly, and in pregnant women and their fetus-
term efficacy of shorter treatment courses. l3 es and neonates. Listeria! meningitis and bacteraemia are
the most common presentaiions; the latter may lead to en-
• PREGNANCY
Leptospirosis docarditis.1.3 L monocytogenes may also cause menin-
Standard multidrug therapy is safe during pregnancy.•.S Leptospirosis is a zoonotic infection caused by serovarsof goencephalitis, focal CNS infection, and infection of vis-
Leprosy patients who are pregnant or breast feeding spirochaetes from the genus lep1ospira, such as lept- ceral organs, the ey~. bones, and joints, and pleural,
n1ay experience clinical deterioration and, in genernl, ospira intenogans. These are carried by wild, domestic, peritoneal, and pericardia! spaces. 1.2 Liste1iosis is fatal in
antileprotic therapy is continued in such patients. and farm animals, and can be spread to humans by contact up to a third ofcases.'·2·•
190 Antibacterials
Listeria! infection is especially dangerous to the fetus and be given amoxicillin or cefuroxime. 1.l Pregnant women Lymphogranuloma venereum
neonate. Pregnant women are prone to developing listeria! should avoid tetra?'clines but may be given any of the oth- See under Sexually Tnmsmincd Diseases, p.207.
bacteraemja (although CNS involvement is rare). The bac- er oral regimens.'·
teria cross the placenta and infect the fetus; fetal distress, Adults and children presenting with neurological symp-
spontaneous abortion, still-birth, or premature delivery Me lioid osis
10111s, either early or late, should be treated with intrave- Melioidosis (or Whinnore's disease) 1-3 is ca11scd by the
may then oocur. Maternal deaths a.re rare but lhe fetal mor- nous cefiriaxone, cefotax ime, or benzylpeniciIIin for 14 to
tality rate is up to 50%. Jnfection may also occur during Gram-negative aerobic bacterium Burklrolderio pseu-
28 days. Patients allergic 10 ccphalosporins or penicillins domol/ei (Pseudomonas pseudoma//et/, and naturally oc-
delivery, and pcrinalal sepsis or meningitis are corrunon. may be given oral doxycycline 200 10 400 mg daily in 2 cu1Ti11g infeclion is common in tropical and sub-tropical
Late-onset illness may develop up to a month after deliv- divided doses.1.l Early Lyme disease with cardiac compli-
ery.1.2 regions where it is found in soil, mud, and water; it is en-
cations may be tJeated with either an oral or intravenous demic in south~ast Asia and northern Australia.' Its true
The treatment of choice is intravenous ampicillin at high antibacterial for 14 10 21 days. Lyme orlhritis can general- incidence and distributioo may, however, be much wider
doses, l -4 although penicillin is also active. An aminoglt ly be effectively treated with one of the oral regimens giv- than originally thoughl B. pseudomalleihas some features
coside, usually gentamicin, is often added for synergy. ·S en for 28 days. Patients with ongoing or recurrent joint that makes it a candidate for deliberate release as a bio-
TI>0se with a penicillin allergy may be given co-trimoxa- pain after the initial trcannenl course may be re-treated weapon.
zole,1.J.S vancomycin,'-3 leicoplanin,1 or erythromycin.s with either another 4-week cow-se of oral antibacterials or
Reports of the successful use of ocher antibacterials in- with intravenous cefuiaxone for 2 to 4 weeks. Acrodenno- Naturally acquired infection usually occurs by inoculation,
clude listeria! meningitis treated with levofloxacin and tilis chronico otrophicons may be tre:ited with an oral an- or sometimes by inhalation or aspiration. Most cases occur
meropcnem;6 endocardj1is in a patient intolerant of stand- tibacterial for 21 days.1 in people with some underlying medical condition such as
ard therapy IIeatcd with ora.l linewlid;l lis1erial meningitis diabetes. chronic kidney or liver disease, or those who are
A small percentage ofpatients continue 10 have non-spe- inununocompromised {but HIV infeclion does nOl appeal'
and brain abscesses refractory to standard therapy treated cific symptoms after appropriate trcatmem of Lyme dis-
with intravenous linezolid an d meropenem;• and to be a major risk factor); person-to.person spread is c.x-
ease; there is some controversy over whether prolonged trcmely rare. The incubation period ranges ti'om I to 21
rbombencephalitis successfully treated with linez.olid. 7 Ri f- treatment is effective in these patients and studies have
ampicin has also bceo used but resistance has been report- days and is thought 10 depend on the size and route of the
suggested otberwise.H The use of antibacterials in pa- inoculum; latent int~als as long as 62 years have been
ed with n>0notherapy.5 Ccphalosporins,1.S fosfomycin,5 tients with chrooic(more than 6 months) subjective symp-
and nalidixic acid5 are ineffective. Some fluoroquinolones reponed. The expected incubatioo period after deliberate
toms after recommended trcatment is hotly debated9.1° but release of aerosol-based biological weapons is 10 to 14
{such as ciprofloxacin) show decreased susceptibility, the Infectious Diseases Society of Am.:rica (IDSA) does
however, the newer fluoroquinolones such as levofloxacin days. Diagnosis is difficult because of the broad range of
DOI support such therapy.; clinical manifestaiions. Melioidosis ranges from localised
and moxifloxacin have stroog bactericidal activity against Adults and older children ro-infected with A. phagocy-
L. monocytogenes. 5 ihcrapy should continue for 2 weeks infection 10 :icutc pneumonia and fulminant septic infec-
tophilum should be tJealed with doxycycline for 10 days. tion; any organ or part of the body can become chronically
in those with bacteraemia, 3 weeks in meningitis, 4 to 6 In the US, recommended treatment for severely ill children
weeks in endocarditis, and 610 8 weeks ip brain abscess or infected. However, most cases present as a febrile illness
less than 8 years of age is doxycycline for 4 to 5 days fol- with sevcic pneumonia and sepsis. Patients may become
encephalitis. lowed by arnoxicillin or cefuroxime to complete a 14-day overwhelmed by the infection and die from septic shock
1. Swaminalhan B. Gcmtr-Smidt P. 'rhe epidemiology of human course. Patients with mi ld illness and who cannot be given
lis1criosis. Mi<robts Inf.ct 2001; 9: 1236-0. within 48 hours of developing symp(oms. Untreated, the
2. Ramaswamy v. ~ al. Lts1erla-review of epidemiology ind a tetracycline may be given rifampicin 300 mg twice da.ily mortality rate for melioidosis with septicaemia approaches
p;1tho&:cncsis. J Mkrobiol lmnumol Jnfec:1 :!007; 4'0: 4-13. for 7 to 10 days plus amoxicillin orcefuroximc.3 I 00"!., but with optimal treatment this can be reduced: in
3. Muftoz. P, ti ol. First report of List~,·io ~ogttt'1.I c.ndocar- Preventive measures against LynlC disease include the use Thailand melioidosis is associated with a case fatality rate
dilis uatcd v..ilh lineiolid. Int J ..fnt1Mkrob Ag1nr1 2006; 211:
480-1. of tick repellents, physical protccrion,l,tl,tl and prompt re- of about 500/o, 1.l while in Australia, the rate is about 200/o.1
4. Manfredi Ri .:1 al. Listeria monoc_vtog~n~s meningitis and multi· moval of attached ticlcs.l Most guidelinesl.ll do llOI sup- The prognosis of melioidosis is much better in children
pie brain a.bsc-es~s in an immunocompetent host. Favorable tc• port the use ofempirical antibacterial therapy or scrologic than in adults, and relapse is rare. 1
spo.nse to combin1uion linezolid-meropencm r~tmcnl. J CIN111-
01//or 2006; 18: 331-3. testing after tick bites as generally the risk of infection is Melioi.dosis is difficult to treat, and response 10 treatment
S. Afkrberger F, WaY'Cf M. Ustcriosis: a rc.surgcnt foodbornc in- low, •3 particularly if the rick is removed promptly. The risk is often slow despite high-dose parenteral antibacterials
(cc1ion. C/in Mkrobiol lnf«t 2010; 16: 16-23. of infection may, ho~evcr, be greater if the tick has fed 10 being given. B. pseudomollei is also intrinsically resistant
6. Viele P. ti al. Major role of levoOoxtcll'I in the treatmenl of a repletlon. 14 A study 1> has shown that empirical treatment to many antibacterials including some third-generation cc-
cau ofLJ11a.ri4 •onoqtogenes mcnineitiA. Diag11Microbial hl-
f«t Dis 2001; 58: 137-9. with a single dose of doxycycline giveo within 72 hours of phalosporins, penicillins, rifamycins, and amiooglyco-
1. Morosi S, a ol. A cue of rhombcncepha1iris c:tuscd by Lis-rcria a 1ick bite may be warranted in endemic areas where the sides; it shows relative resiSt.ance to fluoroquinoloncs and
monocy1oaencs succeufully treated wi1h linez.o!id. J Jufec1 probability of infection is high. Although routine antibac- macrolidcs.2 Treatment was based on anecdotal regimens
2006; S2: e73- e7S. terial prophylaxis is not recommCllded by the IDSA,; they until, in a study from Thailand,4 intravenous ceflazidime
recommend that a single dose of doxycycline may be giv- halved the mortality ofsevere mclioidosis when compared
Lyme disease en provided that the tick has been attached for 36 hours or with conventional parenteral treatment with high doses of
Lyme disease is a seasonal infectious disease caused by the more; prophylaxis can be started within 72 hours of the chlormnphenicol intTilvenously, doxycycline, and co-bi·
spirochaete Borrelia /Jurgdorferi and transmitted mainly lime of tick removal, and the tick species can be identified moxazolc. As a result ceftazidime came to be considered
by lxodes ticks. I. scapu/oris, one of the species of ticks as /. scopuloris. Lym~ disease vaccioes are available in the trealnlCnl of choice for the intensive phase of rreaL-
that may cause Lyme disease, may also be infected with, some countries. ment.'.2.S Alternatives include the carbapenems such as
and transmit, A110plosmo phogocytophilum an<Vor Bobe- I. Ste<rc AC. Lyme disease. N Engl J .U.d200t; )45: llS-25. imipcnern and meropenem.1.2.s Cefoperazone with sul-
sio micro/I and therefore the bite from this tick may lead 10 2. Loewen PS, « of, Sys1ematic review of the 1rc:urncn1 of early bactam and amoxicillin with clavulanic acid have also
~>me disease. Dnigs 1999;!'7: IS1- i3.
Lyme disease, human granulocytic anaplasmosis (sec Ehr- J. Wonnset GP. 11 al. The clinical assc.ssmU1t. treatmcnl. and pre·
proved efTectivc and the lallcr may be given as empirical
lichiosis, p.177), or oobesiosis (p.907) as a single infection vcntion of Lyme ditease. human gnnvlocytic anaplosmosis. and treatment for septicaemia in areas where mclioidosis is en-
or as a co-infoction. 1Lyme disease was first recognised in babatosis: clinical pt'IClicc auiddincs b)" the Jnfi:c1ious Di.teas- demical. •.2 Resistance 10 ceftazidime and amoxicillin~la­
the 1970s in Lyme, Connecticut, but when the spirochaete es Soci•'l'. o( America, C/ln Infect Dis 2006; 43: 1089-1134. vulanic acid has been reported,6 emphasising the impor-
Also av31l:1ble at: hup:l/www.journals.uchicago.cduldoi./pdfl
responsible was later identified, it was found 10 occur I0. 10861S08667 (1ett....S 1810i!/08) tance ofcareful monitoring for the emergence of resistance
worldwide with regional variations. Lyme disease is a 4. Wormser GP. Early Lyme cfjscuc. N Engl J Med 2006; 35": dwing treatment. Ceftazidime plus co-ttimo~37~1e, both
muhisystem disease characterised by inflammatory reac- 2794-2801. given intravenously, has been advocated by some for se-
S. Klcmpner MS~ et ol. Tv.-o controlled 1rials or anlibiotic:: trcac·
tions that mainly affects the skin, nervous $}'Siem, heart, mcnc 1n patienas wieh pttSi.sltnl symp1oin111nd a history of Lymt vc:rc mclioidosis, especiolly in potients with septicaemia.7
and joints, and can be divided into 3 stages. In the early disease. N Eng/J M•d2001; 345: 85-92. High dose parenteral antibacterial treatment should be giv-
. ~i:~~== ~ ::.di~io~:f~j~~~·~i:i~~a~;.p~ .~t;,:;;,,un;o~3~y;~~
slllgc a characteristic skin lesion (erythema migrans) oc- 6 en for at lea~! 10 to 14 days for systemic infections fol-
cw·s al the site of the tick bite and may be aocompanied by 1 9 1 ~22. lowed by eradicotion-phase (or maintenance treatment)
flu-like or meningitis-like symptoms. This may be fol- with oral antibacterials. Prolonged in1ensive·phase
~Tb'P-t~):~~ ~~d!~~1fe:d!u::~~~~8:~~~1~~~ t~~~:i.
7
lowed weeks or months later by signs of disseminated in· · parenteral therdpy is genually used for deep-seated infec-
ogy 2003; 60: 1923-30.
fection, including neurological and cardiac abnormalities, &. Baker PJ. Pcrspeclivcs on •chronic. Ly1nc disease·•. Am J Med tions such as osteomyclitis, multiple undrained abscesses,
and even years later by chronic arthritis and the late skin 2008; 121: S62-4. or CNS infection. Granulocytc colony-stimulating factor
nianifcsl3tion acrodermatitis chronica atrophicans, both (G·CSF) has beco added 10 intensive phase therapy (usu-
· :~~~:~':~it~~~;;~~~i!::m~h::,~f6u:~;:.~~~~a=
9
signs of persistent infection. C/111 /nft<t Dis 2007; 45: I 0 - 8.
ally mcropencm) to decrease early mortality in patients
Appropriate treatment should prove curative, especially 10. Stricker RB. Countapoint: long·tcnn 1ntibiock therapy im- presenting with severe sepsis.1.l lnlloduction of G-CSF
in the early stages. Recommendations for trenhnent 1... give Y,if;1
&,~;;~.if~~;:~;.associa1ed wi1h lymc disease. C/in therapy at one hospital in Australia was reported to de-
oral tetracyclines (doxycyclinc or lclracyclinc) and the crease the mortality rate from 95 to I 0%. However, a
11 . American Academy of Pediatrics Com.mitt« on lnfce1ious Oi.$---
beta-lactam antibacterials (amoxicillin, phenoxymethyl- uscs. Prevention or Lyme disease. Pediatric$ 2000; J05: study in Thailand, reported no significant effect on mortal-
penicillin, or cefuroximc) as the antibacterials of choice 142-7. (R••ired Oc1ob<r 2003) ity when G-CSF was given to patients with SC\'ere sepsis.9
~.!,~~r~i1~~!d;!:ri!'; fJ~1~fri~~::!~"~:~\;1~)'· 0 rsf•ii'
1
for early Lyme disease in the absence of neurological Oral treatment should only be started when there is clear
symptoms or advanced AV block. Treatment is usually for 12. H1ycs EB. Pies1nan J. How ctn v.ie prcvcnl Lyme disease? A' evidence of clinical improvcmenl. 1 Jn Thailand, a conven-
14 days (r.mge 1010 21 days for doxycycline and 14 Lo 21 Engl J Aftd 2003: 348: 2424-30. tional treatment regimen of chloramphcnicol given for the
days for amoxiciUin or cefuroximc). The macrolides (azi- I). Sh1piro ED, et al. A controlled tr~I ofanlimicrobi.al prophylu- first 8 weeks of Ot'lll tre.im1cn1, with doxycycline and CO·
is (or Lyme disuse after dccr-ti4:k bi1e1. N Engl J .Wal 1992;
thromycin, claritbromycin, erythromycin, and roxi1hro- 327: 1769- 73. trimoxazole given for 20 weeks, has been associated with
mycin) are less effective and should only be used in pa- relapse rates of about I 0%; 1•2 this rate increased 10 nearly
3
14. ~;~~:P~:b~~.SL':~:~~J~i~~;~~9~c~:on from and l~at-
tients allergic to, or who cannot be given, first-line 30"/e if antibacterial treatment "l&S taken for 8 weeks or
drugs.2•3 Young children (usually specified as below 8 15. Nadelman RD. • I al Prophylaxis with single-dose doAycyclinc less. 1 Lower relapse rates have been reported in Australia
for tbc pcevcnhon or
l.yme d;sease af1er an lxodes scapulatis
years of age in the US and below l 2 years in the UK) may tick bite. .Y Eng/J Mtd2001; )45: 79-$4. whcic co-IIimoxazole monotherapy is given for 3 to 6
All cross-references refer to eniries in Volume A
 Antibacterials 191
mouths. 2 A regimen of co-trimoxazole with doxycyclioc fusion, and vomiting, are rarely present in infants. In and 5 years, intravenous ceftriaxone is recommended.
was found to be equivalent lO the COO\'cntional regimen, as genera~ the younger the patient, the more subtle and atYi>' Those older than 5 years of age may be given intravenous
defmed by culrure-confinned 1uurrcnce,10 and treatment ical are the signs and symptoms. Fatality rates can be as ceftriaxone or ampicillin. i; .
for at least 12 to 20 weeks is recommended by some ex- low as 2"/o in infants and children, and as high as 20 to 300.4> Prophylaxi.~. Immunisation is the most effective way of
perts.3 In children and pregnant women high doses of in neonates and adults depending on the causative bacteria preventing bacterial meningitis in children and since the
amoxicillin with clavulanic acid may be givcn. 1.l.11 Some and patient's age. Braio damage. transient or pem1anen1 introduction of effective conjugate vaccines against the
patients with mild infections, including sltin and soft-tis- deafness, or learning disability may occur m up lO one- common meningeal pathogens the epidemiology of bacte-
sue lesions and parolid abscesses, have been successfully third of survi,•ors. A less common t>ut more severe (often rial meningitis has changed. In the developed world where
treated with the oral regimens alone. 12 fatal) form of meningococcal disease is meningococcal these vaccines are routinely given as part ofchildhood im-
Although there is no evidence of the prole<:tive efficacy of septicaemia which is characterised by a widespread hacm- munisation programmes bacterial meningitis has become
postelq>osure antibacterial prophylaxis io preventing ocrhagic rash, acute adrenal insufficiency, and rapid circu- a disease ofadults rather than ofinfants and children.3 Vac-
mclioidosis, on the basis of animul experiments doxycy- latory collapse. (For further information see Meningococ- cination is recommended for trdvcllers to areas affcctro hy
cline ·or co-trimoxazole may be given orally for 7 days to cal Infections, below.) meningococcal outbreaks and is cornpulso1y for pilgrims
those known to have been exposed to heavy contamina- Choice of tre.itment Bacterial meningitis is a medical going to Saudi Arabia. Several vaccines are available to
tion.13 eme,.gency and almost universally requires hospitalisa- prevent bactecial m.'!lingitis.
•• Unconjugatcd polysaccha-
I. WbiceNJ. Mclioidosis.Lo-?003: 361: 11 1s-22. tion. Dcatl1 may occur in a matter of hours if left untreated. ride vaccines against N. meningitidis subtypes A, C, Y,
2. Chmg AC, Cutric BJ. Melioidosis: cpidtmioloi)', pathophysi- Outcome is worse if treannent is delayed and therefore and/ or WI 35, in various combinatioi1s, have been availa-
olog. and mona~ement Clin Mkroblol Rev 2005; 18: 383-416.
3. Peacock SJ. Mehoidosis. C"rrOpln Jnftt1Dis2006: t9: 421 -8. doctors in the UK are advisedu to give emergency treat- ble for many years and are recommended for children old-
4. :~::~!;:.'t~~·;~S~:oit~·;~~o>j ~' scYCR melioidosis by
ment wid1 parenteral benzylpeniciUin in all suspected cas- er than 2 years who are at high risk of infection, such as
es ofmeningitis before transfer to hospital. Alternative an- those with asplcnia and with tenninal complement defi-
S. Samu-el M, Ti TY. Interventions (or treating mclioido.sis. Avail·
able in Tht Coch.rant Database of Systematic Rc:vic"'·s.; Issue 4, tibacterials include a third generation cephalosporin or ciencies, and students living in dormitories. A 1iewer con-
Chlchcster: John Wiley; 2002 (ac«ssed 16/0SiOS). chloramphenicoJ.•.6 Patients with suspected or confirmed ju~tcd tetravalent ACWY meningococcal vaccine pro-
6. D;,ncc DA 0, er nl. Oc-vclopmcnt of resistance 10 cdbztdjmc bacterial meningitis should have blood and/or CSP sam- tects against A, C, WJ35 and Y meningococcal subtypes
and ccrainoxiclav in PuudOmollJ.S pseudomallci. J ..f11ti,;1krolt
Chcmorlicr 1991; Z8: 321...C ples taken for culture and receive empirical therapy until and is now a visa requirement for pilgrims to Saudi Arabia.
1. Soolcprance M, ~r al. Multi~tcr prospca_ivc randorniicd trial the causative organism has been identified and susceptibil- A monovalent conjugate vaccine against N. meningiridis
comparing cenutdimi: plut co-trimoxaz.olc wilh chlOr.'lmphcn- ity patterns have become available.s.7.s Empiiic antibacte- subtype C has recently been licensed in developed coun-
icol plus doxycrctine and co-trimox.azole for trc.atment of ~e­
vcrC melioidoslS. An1imkrob Agent• Ch••olh~•· 1992; 36: nals are given intravenously in relatively high doses, and tries for use in childm-t a.nd adolescents. This conjugate
156~2. as
tream1ent should be Ulrgetcd at Specific organisms sOOn vaccine produces better protection than unconjugated
8. Chcna AC. tt ol, Adjunctive aranulocyte eolooy-st.imu.lating
factor for trcntmcnt of sc:plic shOoCk due to mdioidosi.s. Oin J,,. as the results of blood and/or CSP cultures are known. The polysaccharide vaccine, in children undcr2 years ofage. 1·•
ftt't 'Dis 2004; 38: 32-7. choice of empirical therapy depends on the bacterial path- For funher information on meningococcal vaccines see,
9. Ch<'1g AC. tt of. A r.uidomized controlled trial of aranuloeyte ogens (and their antibacterial susceptibility patterns) tl1a1 p.243 J. lhe newer conjugate Haemophilus vaccines (see
:r:;t~i~~~~ai~ t::ifa°:lO'!.e1:j::,m;~t;ri~{v:;~ 3~i t.ue
1 0
are most likely to have caused meningitis and varies with p.2419) are similarly more immunogenic than the polysac-
10 C"'owaiul W, ct al. Open·lob<I randomitcd trial or oral lri· age and the presence of predisposing factors such as trau- charide vaccine, and universal immunisation of infants
mcahoprim-sulfanlC«iho.utolc. doxycyelint. ind chlorarnphcni- ma or neurosurgery. Guidelines have been published for with tl1csc conjugate vaccines has been associated wid1
col comp:1red with trimc1hoprim-s-ulfamethoxuolc ond do>iycy- die UK5•7.9.21 and the USA,' and cowitiy specific guide-
cline for mainttn:incc thcr:ipy of mclioldosis.. Amimicrob more than 99% reduction in invasive H. injl11e11zae type b
Agcm.s ChcmOlhfr 2005; 49:·4020-5. lines should be consulted where available. diseases in developed countries.2 In 2000, a conjugate vac-
t I. Rnjclumuvona A," al. A prosptttiYc compari.son ofm-2moxt- • In most countries, a third generation cephalosporin cine, directed against the seven most preva lent invasive
clav uod lhc combination orchloramphcniool, doxycycline, and
co·1rimo>.atolc for the oral mtintenancc treatment of melioido- (high-dose ceftriaxone or cefotaxime) is recommended pneumococcal strains in the USA, was approved for rou-
sis. Tro"s JI Sr>< Trop AINJ Hrt I~S ; 89: 546-9. as empirical treatment for bacterial meningitis in adults tine childhood immunisation and since 2009 a 13-valent
I?. G1hncy KO. ct al. Cutaneous mclicidos.is in the tropical top end and children. Tiiese drugs are active against N. meningi- conjugate vaccine has been available in several countries.
or AuS:tr:lli3: 3 prospccth-c stlldy Ind rcYicw of lhc literature.
Cll• lnf«t Oi1 200~; 47: 603-9. ridis, most Sri: pr1eumaniae st111ins, and H. inf/uenzoe, 11!fee doses of the 7-valent vaccine, given at 2, 4, and 6
and penetrate CSF well. months of age, were associated with a reduction of more
~:!~~i~ ~~!~C: ~~~~li ~~~i:ra~=~i:~~~~u~:.~~~;
13 0
· than 90% in invasive pneurnococcal infections, including
2008). A••ilablc at: hctp://Www.hpa.Of1.uklw<l>'HPAwcbFile/ • Where ceftriaxone or cefotaxime are not available or are
HPAwcb_C/1194947412449 (ue«s.scd 22/03110) unaffordable, a combination of ampicillin and chloram- sepsis and meningitis.2 For further infom1atiori on pne1>-
pheniool or chloramphenicol alone may be used as an mococc:al vaccines see, p.2439.
Meningitis °
altemative. 1 For tliose patients allergic to both penicil- • Close contacts of patient, infected with meningoco.ccus
A, C, Y, or WI 35 and nged over 2 years should be of-
Meningitis1..:i refers to infection of the subarachnoid space lins and cephalosporins, a combination of vancomycin
and chloramplicnicol may be given. 5 fered tetravalent meningococcal vaccine.2·U11
:ind meninges, which may be caused by viruses, bactcna,
protozoa, or fungi . The symptoms and signs of meningitis • ln patientS over 55 years ampicillin should be added ro • Those over 3 months and exposed lO serogroup A infec-
result Crom the host inflammatory response to infection. cover Listcrio.1 tion may also be given a tetravalent meningococcal vac-
Whereas viruses cause the majoiity of generally mild cas- • Empirical treatment in neonates may also include amp- cine, while those over 2 months of age and exposed to
es of infectious meningitis, bacterial meningitis is usually icillin to cover Lisreria, and an aminoglycoside to cover serogroup C infection who an: unimmw1ised or incom-
a more serious condition. Meningitis may occasionally be Gram-neg;ative or<>.,anisms.s. 11 pletely immunised may be vaccinated with a meningo-
a manifesllltion of non-infectious (auto-immune or neo- • In the USA and other areas where penicillin and cepha- coccal C vaccine. Those who complcled a course more
plastic) disease. TI1is section discusses bacterial meningitis losporin-resistant pneumococci or meticillin-resistant l)lt)n one year before should be offered a booster.•
and its managemenL F'or reference to fungal meningitis, staphylococci are encountered, vancomycin (with or • All unimmunised index cases under the age of25 years
secp.566. without rifampicin) should be given with a third-gener- should also be of!Cred a meningocoocal C vaccine. Cas-
Tiic bacteria mosi often found in adull or childhood men- ation cephalo~1i.n lO children 01· adults wW1 bacterial es of confirmed scrogioup C disease who have Jl(CVi-
ingitis (from 3 months of age) are Neisscrio mcningitidis meningitis.5•1- ously been immunised with meningococcal C or telrav-
(meningococci) and Slreploccccus pneuma11iae (pneumo- • Vancomycin togeihe1· with ccftazidimc (or/ccfcpiinc or alent vaccines ~hould be offered a meningococcal C
cocci),N. meningitidls A, C, and Wl35 arc the main sub- rneropenem) should be given to patients with meningitis vaccine before discharge from hospital.4
types involved in epidemics in the African meningitis belt, complicating neurosurgery, head trauma, or CSF shunts. Antibacterial treatment does not eliminate nasopharyngeal
whereas B and C subtypes are responsible for outbreaks in Because of concern of suboptimal CSF penetration, ca1Ti3ge ofN. me11i11gitidis and chemoprophylaxls should
Europe and Nonh America. Haemophi/11s inj/uenwe men- vancomycin should noc be used alone in patients with be given to close contacts of the index case(irrespectiveof
ingitis was a common cause of meningitis in infants and meningitis due to rel'istant pneumococci or staphyloco- vaccination status) to reduce the risk of invasive discase.4
young children before the availability of H. inj/11e11zae cci, ~ially when dcxamelhasone is given as well. A systematic review 's found that cefiriaxone, cipro-
type b vaccine, and this pathogen is still found in non-vac- TI1e durotion of antibacterial lre:ttmeol depends on the or- floxacin, and rifrunpicin \Ytte all effective nt eradicating
cinated young children, particu larly in resource-poor ganism isolated. For Srr. p11eu111onlae 10 to 14 days of carriage for up to 2 weeks although resistance to ri-
countries. In neonates, infants, pregnant women, immuno- treatment is re1:ommended and for H. inf/11e11UJe 7 10 14 fampicin may occur after prophylactic treaUnent; penicil-
compromised paticnlS, and the elderly, Lisrerla monocy- days. For N. meningitidis 7 days, treatment is sufficient. In lin was less effective.
rogm'!:S. and Gram-negative bacilli may also be encoun- l. ma11acyrage11es and group B streptocoocnl meningitis, ' Oral rifampicin twice daily for 2 days (or a single oral
tered, aild Sn: agoloctiae may cause meningitis in neonates antibacterials should be given for a minimum of 14 to 21 dose of ciprofloxacin or a single dose of intramuscular
and infants. Meningitis after head 1111uma, neurosurgery, or days while Gram-negative bacilli should be treated for a ceftriaxone) should be staned in the close contacts with-
in the presence ofCSF shunts is not infrequently caused by minimum of3 weeks.s.12 in 24 hour.. or as soon as possible after diagnosis of the
staphylococci (botl1 Staphylococcus aunus and coagula- Chloramphcnicol is effective for the treatment ofepidemic inde.• case.4
se-negative staphylococci) or Gram-negative bacilli. meningococcal meningitis and ccftriaxonc or chloram- • If further cases occur within a group of close contacts
111e bact~ria are transmiued from person to petSOn through phenicol are the drugi; of choice fo1· patients over 2 years within 4 weeks of receiving prophylaxis with ri-
droplets of respiratory or throat secretions. Infection is of age in areas with limited health facilities.l.ll An intra- fan1picin, then repeat prophylaxis should be with either
spread by prolonged close contact (such as kissing, sneez- muscular dose of ceftriaxone ( l 00 mg/kg lo a maximum of ciprofloxacin or ceftriaxone.•
ing and coughing, living in close quaners or dormitories, 4 g) was found !O be as effective as an intramuscular dose • Index cases (except tl1ose whose disease was treated
and sharing eating or chinking utensils). The average incu- ofoily chloramphenicol (I 00 mg/kg to a maximum of3 g) witl1 ceftriaxone) should be given antibacte1ial prophy-
bation period is 4 days, ranging between 2 and l 0 days. for the treatment of meningococcal meningitis during epi- laxis before discharge from hospital.4 Chcmoprophy-
The clinical presentation of acute bacterial meningitis is demics in resource-poor settings.14 For children under 3 laxis is also recommended for healthcare workers
largely dependent on the. patient's age. The classic mani- months, intravenous ampicillin plus cefotaxime or gcn- whose mouth or nost.is directly exposed lo large parti-
festations of meningitis in older children and adults, in- tamicin are n:conunended to cover probable bacteria for cle droplCIS or secretions /Tom the respiratory tract of a
cluding fever, headache, neck stiffness, photophobia, con- d1is age group, while for children aged between 3 months probable or confim1ed index case ofmcningococcal dis-
 192 Antibacterials
case during acute illness and until 24 houtS of systemic 7. Bntish lnfcchon Society. Early M.lr\lfmzmt of suspected bac- Guidelines for prevention and conrrol of meningococcal
terial mcniniiitis 11nd meningococe:al sq>ticacmia in immuno-
· amibacterial ITeatmcm has been completed. 4 competcnt ad'uhs-second cdi1ion (12/04). disease have been developed for the UK6•7·1J and the
Similarly, treatment of H. i11j111enzoe meningitis docs not Av11lablc at: hltp:/fwww..britis.hinfeclionsocicty.org/documons/ USA.11.9
eliminate nasopharyngeal carriage of the organism and ri- McningitisAlgorithmOJ.pdf (accmcd IS/08108)
Choice oftreatment. Mortality is reduced by early recog-
8. Tunkcl AR. a oJ. Jnfccuous Diseases Socittyof America. Pr1c·
fampicin should be given to index cases for 4 days before tice 1uidclitles foe the mana:gtmenl ofbac1cri1I ~njngi111. Clin nition of the disease and prompt treatment with antibacte-
discharge from hospital. Anyone who has been in direct or lnfut D•s 2004; 39: 1267-84. Also a '·ai l•blc at: rials. In the UK doctors are advised that if meoingococcal
prolonged close contact with the infected persons shCluld ht1p:l""'-·wJoumals.uchie110.«luldoitpdfJI 0.1086/425368 (•c- disease is suspected, benzylpenicillin should be given
eased 18/1)8/GS)
also be given rifampicin for 4 days. Un\'aceinatcd children 9. Heydcrman RSi Bri1ish lnrcction Society. E•rl)• managcmtnt or parenterally, preferably intravenously, before transfer to
should be immunised. suspected bac1tri.1I meninai111 •nd mcnlngococcal seplic:acrrua hospilal. 1•5•1 Alternative antibacterials include a third-gen-
Olemoprophylaxis is not norma lly indicated for close in immunocompcten1 a:duJts-.sccond edition.) lttfect 200S; SO: cration cephalosporin or chlorarnphenicoJ.'-6 Both initial
373~.
contacts of rineumococcal and other types of bacterial 10. Praud K, ~al. Third gcneTation Ct'Phalosporins versus conven~
empirical and later treatment may be "ith benzylpcnicil-
meningitis. s. , tional antibiotics for trcuing 1cu1c bxccri:al meninQl1i1. Availa~ lin, ampicillin, chloramphenicol, or third-generation ce-
The WHO recommendation for outbfeak control is mass blc in The. Cochronc Database ofS)'S4em11ic Reviews: Issue 4. phalosporins such as cefotaxime or cefuiaxonc.-.s.7.io.u
Cbichcst<r: John Wiley; 2007 (a-..cd 20/06/08). However, there arc concerns about calcium chelation
\'accination of persons residing in district~ in the epidemic IJ. Heath PT, #fol. Neon.al.al meningitis. Ai·ch Dis Child Fdol N~
phase as well as surrounding dislTicts in an alert phase. It onutol Ed 2003; 88: Ft7J..F178. when ceflriaxone is given with parenteral calcium-con-
is estimated that a mass immunisation campaign, promptly taining products and therefore some experts advise ccfo-
12. ::u!a~~:c~i/r:;tot~~8~nt)~~;~~tftl ofblctuiaf mcnin· taximc as the drug of choicc.~·11 In infants less than 3
implemented, can avoid 70% of cases. 1
13. MCdccins Sans Frontihcs. Clinkol guidrlin11: dlog11o.sis and months of age ampicillin (or amoxicillin) should be added
Adjunctive treatment Mortality and morbidity, i~clud­
ing deafness in children, remain high in meningitis despite
tr«Jlmtnl mof/uOIfor 1:ur01/w rogr-omflte~ in ho1pi1of1 ondtlis-
~:i°rics : g11/do..afor -<rlblnt- 10/0<ditlon. Paris: MSF,
to provide covei against listeria! infection.7 Oily chloram-
effective antibacterial therapy. Endotoxins and other mi- phenicol or ccftriaxone arc used during epidemics in Afi'i·
crobial products, released from bacteria after antibacterial 14. N1thtn N. et al. Ccf\riaxone as cfTecli\-c as: aon,-.c1ing chlo· ca and in areas with limited health facilitic.~.• Unoompli-
treatment, are able to dicit a severe in nammatory re- r~~~=~~f~n:::~i~~rs: ~:=~'=~'1;f:i~;·,:~~~ eated meningococcal disease usually requires 7 days of
antibacterial treatment For further details of the treatment
sponse, suggesting that anti-inflammatory drugs may be of Ll>nttt 2005; 366: 3011-13.
benefit A systematic review 16ofadjunclivc corticosteroid JS. Frucr A, et al. Antibiotics for preventing mcningo-coccoa1 inftt:- of meningococcal meningitis, including the treatment of
1ions. Avail~bte in The Cochrane Database of Systcnutic Rc- close contacts, see Meningitis, above. Immunisation is the
therapy concluded that corticosteroids reduce monality, v.iews; Issue 4. Chichester: John Wile)': 2006 (acccnc:d
neurological sequelae, and especially the risk of severe 29/07/08).
most effective way ofpreventing mcningococcal meningi-
hearing loss in both children and adults. This systematic 16. van de Beck D. d al. Corticoslcroids foracu11: bactcrfol menin.. tis and several vaccines are available (see Meningococcal
review concludes that corticosteroids should be given be- g:i1is.. Avai11bJc in The Cochnu\C 01tabasc of Svs1ematie: Re· Vaccines, p.243 1).
views: Juue I. Ch iGltctter: John Wiley~ 2067 (accessed I. Welch SB, 'Nat'Jcl $. Treatment of mtningococcaJ infection.
fore, or with the first dose of antibacterial in adults; the 20/08/07). Arch Dis Childl003; 88: 60&-14.
same recommendations apply to chi ldren li\'ing in high- 17. Scarborough M, ttoL Cortic:osacroids for bacterial men•.ngi1is in 2. Singh J, AtT;Cll AC. M.ln;igemenl of meningococctmia.. /ndi<m
incomc countries. However, results from a study in sul>- tdulls in sub ..Stharan Africa. N Engl J Med 2007; 357: J Prdiolr 2004; 7l: 909-1 3.
2441- 50. 3. Sttphcm DS. ~t ol. Epidemic mcn1n¥ifis. mcningococcacmia,
Saharan Africa 11 did not supp011 the routine use ofadjunc-
tive corticosteroids in the ITeatmenl ofadults with bacterial
meningitis in resource-poor countries where Strep. pneu-
m
18. Nr.uycn niM, «tol. Oexamctha$0l1c in V'te\nl~c1dolctct"nlS
.~J~ with bactcri;if mcnlngills. .>I Engl J Met! 2007; 357:
and Ncisscria mcningitidis. IJ;mttl 2007; 369: 2196-221 O.
4. WHO. Mcningococ:cal meningitis. FMt 3h~et No. NJ 2010.
Available a1; http://,.•ww.who.int/mcdjacenlrelfael5hc:cts/
moniae is the main pathogen and where a large number of 19. Assjri AM, er al. Corticosteroid 2d:minis.1ra1ion and outcome of fs 141/cn (ooccsscd 24/03/10) ·
adolcsccn1s and adulcs with acul.: bacleri11I meningitis: a met•· S. Mcning.;1is Rcse:arch Foundation. Mcnin;.ococcal mcrungili~
patients are also likely to have advanced HIV disease. An-
other study IS of dexamethasone in Vietnamese patients
analysis. Moyo Clin Proc 2009; 84: 403-9.
!~,:r;:~~~~-~~hi~~~~~!t:e°!~ and tr~a•mtnt in
20. Maeonochic IK. a al. Fluid 1herapy ror ac-ulf: bxterfa.I menin·
htrp:l/www.meningitis.oralusclJ/x/50631(occu<ed24/0JllG)
over 14 years of age with suspected bacterial meningitis g.itis. Availablt in The CochDne Oallbast: of Sy-Jlc1n3tic; Re·
6 Health Ptotcctfon Age~. Guidance for public hcahh manag,c-
reported !hat dexamethasone did not improve survival in views; Issue l . Chkhutcr: John Wiley: 2008 (accessed
24/03/lG). 1nent of meningococcal disease in the UK(issued August 2006).
all patients; significant benefit was only seen in patients Available 11: http1/w-ww.hpa.org.uk.JweblHPAwebfilcl
21. Yoiev R. Guzman.C01trill J. Bx~eria l meningitis in children.: HPAwcb_C/1194~7S&9261(occe•scd 28/0 1/0I)
with proven bacterial meningitis, including those given crit1c•I rcviewofct.ll'ftn( conc~plJ, Dr11g12005; 65: 1097-112. 7. ScoHish J:ntercollcJiale Guidelines Net\\-or:k. Managcm~nl of
prior trea tment with antibacteria ls. This finding was 22. NICE. Bxu-ritl meningitis :\nd meninQ.OC'oCCll sepcteaemia; in\t-Hi¥C mcnin.aococcal disease in children and you n~ people:
thought to be due to patients with tuberculosis meningitis maMJtmC'nt of ba:ctcri;.f meningitis and mcningocoec:al scpti- a national clinical auidcline (issued M1y 2008). Ava1hsb1c at:
cacmr.a in children and young people younJOi 1han 16 ye111 in hllp://www.sign.ac.ul</pdOsign I 02.pdf tocccsscd 24/03/10)
in the treatment group. The results of a later systematic re-
ri,~fiw ,~w~~f~Z~~.~·.:~n~=Jr!'i1;.0~1%t2'~~;~~.~;
1 8. CDC. Recommendations of the Ad\·isory Committee on Jmmu-
view and rnela-analysis,19 which included these 2 studies,
suggested that in patient popula1ions similar to those seen 49339.pdr ( acccncd 252I0&/10) ~:a:!r:i:~~~~~7Jrst;:n(;;.;~ l~l~~~!:i~tr;
at: http:l/wv."fll'.cdc.govlmmwr/POF/rr/rr$407.pdr (acces~ed
in high-income countries and in populations with a low 20/03/06)
prevalence of HIV, adjunctive trenunent with corticoster- Meningococcal infections 9. ·"mcriun Actidemy of Pediatrics Commirtcc on Infectious Dis-
oids improved survival and neurologic recovery in adults Meningococcal disease1'3 refers to systemic infection with eases.. Preven1ion and ccmtrol of mcflingOCO<"cal disease: rcc.om-
and adolcscenis. mcndation$ for use of mc:ftin:ococcal ,·accines in pcdi.atric pa·
Nei.sscria meningilidis and may present clinically either as tients. Ptdintrlts 2005; 116 : 496-505. Full version:
Careful management oftluid and electrolyte balance may meningitis or scpricacmia, or both. Less common forms of htlp://pcdiuriCJ &IJ>PUblications.orglcailrcprin11116fl1496.pdf
be important in the treatment of meningitis and nuid re- (accessed
metastatic mcningococcal infection include polyanhritis, l 0. Me:r1ingjtis20/0J/06)
R~atch Found~tiott. Etrl,r .ma:iag.cmcnt or menin·
striction to prevent cerebral oedema has been widely advo- pericarditis, pneumonitis, ond genito-urinary-tract infec- gococta.I dlst-ase in children-sixth cd111on 08/06. Availahtc at:
cated and used in children.20J • This practice was based on tions. N. meningitidis is a Gram-negiirivc bacterium, oc- hup:/lwww.mcningi1is.ofl/1sscL<lxllOISO (accused 18/08/08)
reports of hyponatraemia which were attributed to inap- curring worldwide, and is classified into several ser0types. 11. Briti'h Infcc.lion Socic1y. Early management of 5uspteted bac·
propriately increased concentrations of antidiurelic hor- Serotypcs A, C, and WJ35 are responsible for epidemic ~~~!c%~~i:f~~~'!=i~ifo~~~'t:~1ic11emia in immuno·
mone. However, subsequent studies have suggested that meningitis in sub-Saharan Africa, while scrotypcs Band C Avallable ac: hup:Jiwww.britishinfcc1ionsociety.Ofsfdocumcnis/
McningitiJAlaorithmOJ.pdf(1ccened 18/0&/0&)
the raised concentration of antidiuretic hom>0ne may be an are the cause of outbreaks in Europe and North America. I2. Cathie K. '' ol. Drug use in acute mcningococ:cal disease. Arch
appropriate host response to hypovolaemia, and that more The number of eases of meningococcal disease due to se- Dis Child Educ p,..<I Ed 2008; '3: 151-8.
liberal use of parenteral nuids may be beneficial. 2 A sys- rotype Chas decreased significantly after the introduction 13. NICE. Bacterial meningitis and mtningocoecal septicaemia:
tematic review20 concluded that there is some evidence to of vaccination in developed countries. management or bac1crial mcnin&his and meningococ:cal sepli·
cacmia in childrc:n and young people young.er tha.n 16 yars in
support the use of intravenous fluids, in preference to re- Infections are more common in young children under 5 primary and scconcbry care (issued June 2010).. A"lifAble at:
stricted nuid intake; particular!)' in the first 48 hours in set- http ://www.nice.ora.uk/n i ccmediallivcl1 3027/49.) 39/
years of age and in adolescents. N. mc11fngiridi.s only in- 49339.pdf(acccsscd lS2/08/IO) .
tings with high mortality rates. However, where children fects humans and about 10 to 25% of the population may
present early and mortality rates arc lower, there is proba- be carriers of the organism. The bacteria are carried in the
bly little benefit and insufficient evidence to guide prac- pharynx and may sometimes penetrate the mucosa and Mouth infections
tice; it has been suggested that fluids should not be restrict- spread through the bloodstream causing sy~temic <liscase Infections of the mouth include those of dental origin such
ed in children. 12 The British Infection Society working that may rapidly progress to shock and death. Patients with as dental caries, abscesses, gingivi1is, and periodontal in-
party5.7 recommends that adult patients with meningitis meningococcal disease and asymptomatic nasopharyngeal foctions, and those without a dental origin. Infections aris-
should not be nuid restricted in an attempt lo reduce cere- carriers may spread meningococcal infection via respirato- ing in the nasal cavity, middle car, oropharyru<, and para-
bral oedema. ry droplets or throat secretions. Close and prolonged con- nasal sinuses can also affect the Ordl cavity. Emphasis 1
has
I. WHO. Mcni11iococcal rnening.ili$.. Fact 1hctt No. 141 2010.
Available at: hup:llwww.who.1ntlm.:dfoccntrdfac1s-hee1s/
tact such as kissing, sneezing and coughing, living in close shifted from treatment to prevention oforal diseases. This
fsl4l/cn (accessed 241!13/tO) quarters, and sharin.£ eating or drinking utensils are estab- discussion deals mainly with infecrions of dental origin.
2. SA c~-Ll()rens X. McCracken Gii . Bnc1cri:il nlcnin;nis in chil- lished risk factors. 1 • Symptoms and signs during the ear- The organisms most often found in oral infections arc viri-
dren. /..,,:mer/ 2003; 361: 2139-:IS. ly stage of meningococcal disease are non··specific and in- dans streptococci, a variety of anaerobes, and facullative
3. Nudelm~ Y. Tunkcl AR. Bacterial ineni.ngiliJ: cpidcmJo•ogy.
pa1h0&cncsis and manugement update. Drugi 2009: 69: chide fever, vomiting, malaise, and lethargy. Most patients streptococci.
2577-96. with meningococcal septicaemia develop a vasculitic rash Dental ca ries2 is a chronic d·isease caused by the erosion
4, H"l1h Protection A1cncy. G"idancc ror public heallh manasc- (petcchiaeorpurpura) which is often scant or absent in pa- of tooth enamel due to acid produced by bacteria (usually
ment ol'meningocoecal d1sca1t in the UK (is.MJed Aug-..m 2006).
A\•ailablc <11: hup://~ww.hp a . org. uk /wch/HPAwcbFilc/ tients with meningitis. Purpuric rash, dro"''Siness or im· Streptococcus mutans) in plaque. This process is affected
HPAweb C/119494738926 1 (accessed ?&/07/0S) paired consciousness, and shock arc late presentations and by salivaTY now and composition, exposure 10 nuoride, di-
S. Begg N, It ol. British Infection Soc-icty "'ort•n& Parry. Cnn~cn­ associated with high mortality rates, which may be up to e1ary sugar content, and preventative measures such as
$US sta1mxna M dfag.nosis, hwt>lip1ion, trc~11mcnt and prcvcn·
lion ohcutt bnctcriol meninsiti• in immu:noco1npctcnt i1duhs.J 50% in severe forms. Meningococcal meningitis usually tooth brushing and flossing. Fluoride in various fonns is
hf«l 1999; )9: 1- 15. presents with headache, neck stiffness, photophobia, and used in dental caries prophy taxis, where it may promote
6. Sudarsanem T, •r of. Prc-admisston an t i bioli~ (or suspected drowsiness. Mortality from meningococcal meningitis is remincralisation or reduce acid production by plaque bac-
cases of mcningococc:al disc:isc. Available in The Cochnne 0>
less than in septicaemia and may be below 5% with leria.13 For further information on the use of nuoridc for
~a~(a~~di;~ ~~.cws: lnue L ('hK:ht'sltr. Jahn Wiley~
7 prompt tteatment. '..2.S dental caries prophylaxis see under Uses and Administra-
All cross-references refer to entries m Volume A
 Antibacterials i 93
tion of Sodium Fluo1ide, p.2124. Sugar-free chewing gum often hand (12%), legs, and knee joints. The term Madura • benzylpenicillin and clindamyc.in plus a tluoroquinolo-
can also help prcvcm ca1ies by stimulating the production foot is used for mycetoma affecting the foot. Mycetomas ne or an aminoglycoside4 ·
of sal iva.3A For fu11her references sec Dental Caries under may be caused by various organisms; those caused by fun- • benzylpenicillin and gentamicin plus metronidazole or
Xyli1ol, p.2254. Dental caries vaccines have been investi- gi such as Madurella myc£toma1is are called eumycetomas clindmnycin 1
o.aied. and are discussed on p.566. TI1ose caused by the filamen- • ampicillin-sulbactam and clindaruycin plus
TI1e term periodontal disease5 refers to conditions affect- tous bacteria, actinomycctes, are called actinomyceto- ciprofloxacin~
ing the supporting snuctures around the teeth (periodon- mas: Nocarrlia brasiliensis is die commonest actinomyc- • patients known to be hypersensitive to penicillins may
tium), including the gingiva. peridontal ligamen~ cemen- ete responsible; others includeAcrinomadura 111adurae, A. be given clindamycin or metronidazole with an
tum, and alveolar bone. Pathogenic bacteria in the plaque, pelletieri, and Streptomyces somalie11sis. For detai ls of aminoglycoside or fluoroquinolone1
genetic factors. tobacco and alcohol use, diabetes, immu- systemic infections caused by Nacardia spp., see under
Nocardiosis, p.194. If gro up A Strepracoccus or Clostridium is the liki:ly
nosuppreision, and the use ofsome dmgs can contribute to
cause. a combination of clindamycin anll benzylpenicil!in
such d ise!ISe. Gingivitis (or gum disease) is an inflamma- Combined drug treatment is preferred for actinomyceto- should be used.~
tion Ot the gums SUITOUnding the teeth in response to bac- mas so as to avoid resistance and eradicate residual infec-
teria) biof1hn or plaque that accumulates between the gin- Unti l meticillin-resistant staphylococcal i11fectio11 has
tion; cures are usually achieved after treatment for 4 to 24
giva and the teeth; irritation fi:om plaque causes pockets to months.•.:? The most common regimen is streptomycin and been ruled out, treatment re!limens should also include
develop where the gingiva separates from the tooth. Gin- vancomycin, daptomycin, linezol id, or quinuptistin!dalfo-
dapsone; co-trimoxazole may replace dapsone in patients pristin.•s
givitis may or may not develop into periodontitis, but per- who have not responded to initial treatment after a few
iodontitis is always preceded by gingivitis. Per iodontitis months and in those who cannot tolerate dapsone. Suc- Hyperbaric oxygen therapy has also been beneficial al-
is an infection of tl1e periodontium causing inflammation cessful treatment has been reported witlJ amikacin, either though prospective controlled studies ~re .lacking.1·3.i. In-
of tl1e peiiodontal ligament, gingiva, cementum, '<Ind alve- as monotherapy or witl1 co-trimoxazole. 1 !Ufampicin, sul- travenous nom12I immunoglobulins have.also been tried in
olar bone. Witl1 ongoing inflammation the periodontal fonamides, or pyrimethamine with sulfadoxine, have been patients with staphylococcal or streptococca l necrotising
coniiecti~e tissue breaks down a11d destruction of the local trie<l in resistant infections and are considered suitable for fasciitis but funher study is considered warranted.Z-1
alveolar bone occurs. Periodontal infections arc usually second-line tl1erapy;1 amoxicillin with clavulanic acid has I. Hishain S, t!I al. Necrotising fascii1is. BMJ 2005; 330: 831>-3.
Correction. ibid., 1143. ·
mixed infections6•7 and are associated with an increase in also been used successfully.' A two-step regimen4 has also 2. Stc,-cns OL. e1 al. Infectious Ojseases So:::iety of America. Prac·
the number of Gram-negative and anaerobic bacteria.M been used: intensive therapy with benzylpenicillin, gen- tice guidelines for lhe diagnosis ftnd man::igcmcnt of skin and
Most.g ingivitis and periodonLiLis can be prevented and tamicin. and co-trimoxazole for 5 to 7 weeks is followed soft-tissue inftctions. Clin Infect Di.t 200.5; 41: 1373-1406. Co,...
rections. ibid.; JS30 and ibiJ. 2006; 42: 1219. {dose error] Also
treated by adequate oral hygiene and plaque removal using by maintenance tlierapy with amoxicillin and co-trimoxa- :ivoii lable al: hnp:l/www.j<'1urn3ls.uchic2go.edu/doi/pdf/
mechanical means such as tootl1brushing. Mechanical re- zole for 2 to S months after clinical remission. More re- 10.1086/497l43(ac<:esscd 15112/08)
moval of calculus is necessary where the build up is signif- cently, a modified two-step regimens has been tried, omit- 3. Kih i c~k GG. et al. Nccr<'ltizing fascii1is: a deadly infcajon. J
Eur Ar-ad Der11>010/ J~nercol 2006; 20: 365-9.
icant: :<\.ntiseptics may also help to reduce plaque accumu- ting benzylpenicillin and giving gentam icin and co- 4. Anaya DA, Dt llingcr SP. N~c rotizing soft.tissue infection: diag,
lation and several, but most notably chlorhexidine, have trimoxazole for 4 weeks followed by maintenance therapy nos is ~nd m~nag·emenl. Clbi h:fer1 Dis 2007: 44: 705- 10.
been used.M Oral antibacterials may be used as an adjunct with doxycycline and co-trimoxa?_ole for 5 to 6 months af- S. S<mmi O. et al. Necru1i2ing. fasciiti.s: turrcnt concepts and review
of the litcnturc.J Am Coll Surg 2009: 208: 279-88.
to scaling root planing, or drainage in patients with refrac- ter remission. 6. faJl:ili N. el al. Hyr-erbaric oJ.:ysen as adjuvant therapy in 1hc
tmy disease, who are immunocompromised, or have signs Surge1y is indicated for patients with infections resistant to mam1gemen1 nr necro1 i1.ing fascii1i11:. Am .I Smg 2005; 189:
·of systemic illness. 5•7 Antibacterials commonly used in- drug therapy, deep or extensive infections, or infections 462-6.
clude tetracyclines, metronidazole, amoxicill in (with or with bone involvement that wi ll not respond to long-tem1
without clavulanic acid), ciprofloxacin, and clindamycin.6 conventional therapy; amputation may be required in Neo natal co njunct ivitis
Combin2tion therapy with metronidazole and either some cases. 1·? Conjunctivitis ofd1e newbom, also known as ophthalmia
amoxicillin orciprofloxacin, or amoxicillin with clavulan- I. fahal Afi. Myc.etoma: a thorn in tfo: ilc~h. Tran.t R Snc Tro11.Hl!d neonatorum, is defined as any conjunctivitis with dis-
ic acid followed by doxycycl ine has also been used.6 Den- Hyg 2004; 98: 3-11. charge occurring drning the first 28 days of life.1 That d ue
toalveolar abscesses originating from the periodontal tis- J. Lichon V. Khacheinount:- A. Myeetomo: a review. Am J Clin Dl1'- to Neisseria go1101rhoeae is the most serious; it usually ap-
sue (usually caused by anaerobic bacteria) may be treated mowl 2006; 7: 315-21.
3. Bnnira7. A. et u/. Treatmcnl nf actinniny<:ctnm3 due to Noc:irdia pears by the thir:l day after birth and can rapidly result in
with metronidazole: clindamycin is an altemative. 7 Those $pp. wiih 3moxicil lin·duvolanah::. Br J Dtrm(Jft>I 2007; 1S6: blindness; systemic infections, especially severe septicae-
originating from periapical tissues (usually caused by 308- l I. mia, ma)' occur. Chlamydia lrachomatis is another major
mixed infections) can be treated with amoxicillin, metron- .i. Ratnam M, et of. A two-slep schedule for the trc-atmem of xtin.. cause of neonatal conjuncti vitis (inclusion conjunctivitis);
idazole, c•r clindamycin.7 Antibacterial treatment may be Om)'COtic mycetomas.. Acta Derm Vcuei·eol 2000; 80: 31g...so.
5. Ramam M, ~'<ii. l\ modified two.step 1re:umen1 for ac-tinomyc· it characteristical ly occurs 5 to 14 days after birth and is
stopped once tl1e systemic sigiis of the infection have re- less threatening to sight than gonococcal infection, but
etoma. iudlon J Dtrmarol i-e11ereo! lepro/ 2007; 73: 235-9.
solved (usually after2 to 3 days oftreatment).7 In the UK, may also infect ihe nasopharynx and can cause pneumo-
the BNF 59 advises against the routine use of clindamycin nia. Ch lamydia! conjunctivitis is more common than
in oral infections. but notes tl1at it can be used for the treai- Necrotising enterocolitos gonococcal conjunctivitis in developed countries. Borh or-
ment of dentoal~·eolar abscess that has not responded to See p.184. ganisms are sexually transmitted and the infants of moth-
penicillin or metronidazole. ers with such genital-tract infections are infected during
Pn!FOlella inlermedia, fusifonn bacteria, and spirochaetes tl1eir passage through the birth canal. Other less serious
Necrotising fasciit is
have also been linked with acute necrotising ulcerative bacterial causes of neonatal co1tjunctivitis include Srap/1y-
Necrotising fasciitis 1•5 is an uncommon but severe soft-tis-
gingivitis (ANUG; also called Vincent's infection or lococcus aureus, S!repfococc11s pneumaniae, Haemophil-
sue inf~-ction resulting in necrosis of the subcutaneous tis-
trench mouth}. ANUG may result in accelerated destruc- sue a11d adjacent fascia, together with severe systemic ill- 11s spp., andPseudomanas spp.; they are often hospital-ac-
tion of affected tissues. as well as local or systemic spread ness, and is associated with high morbidity and mortality quired. 1
of infection. Treatment i1wolves deb1idement and an oral The managemem of gonococcal and chlamydia! neonatal
rates. Type I infections are caused by a mixture of aerobic
penicillin with metronidazole; clindamycin monotherapy conjunctivitis varies from country to counlly depending on
and anaerobic organisms. whereas type II are monomicro-
is an alternative. Antibactctials and antiseptics delivered the prevalence o:gonoo-hoea and C. rroehamatis infection
bial infections due to group A streptococci or staphyloco-
locally to the periodontal pocket may be of value.~ cci and may be associated with a toxic shock syndrome and on bacterial resistance.
I. WHO. Recent ad\'anccs in oral l1c~hh: rcporl of a WHO c:xpe(l
C(lm1ni11ee. WHO T«lt R~p S~r 826 l992. Available .-,1: (p.21 I ). Some definitions recognise type Ill infections due • PROPHYLAXIS
hnp'Jnib:i-0<:. who.imf1tslWHO_TRS_826.pdf(ace<.'Ssed 18i0Si08) to Vibrio vulnificus, mainly occuning in patients witl1 liver The ideal mert1od of prophylaxis is to treat the infected
2. St h~ilz RH. ti ul. Dental carits. ltm(·r1 2007: 369: 51-9. disease and often rapidly progressive and fatal. Necrotis- mother during pregnancy, bu\ this is not always possi-
3. i;di;:ir \\'M. Sugar substitutes., chewing gum ::ind dcnl:i.I caties- ing fasciitis can affect any part of the body but is most
3 rc\'icw Br ~111 J 1998: JS4: 29-32.
ble. Where the risk ofgonocacc'11 i11fec1io11 is high, oc-
4. V:rn lovNcn C. Sugar alcohols: wha1 is the C\'idcnce for caries. common on the exlremities, the perineum, ond the trunk. ular prophylaxis at birth is panicularly important be-
pre-.:enfrtc and c-a1ieS·lhcrapeu1ic errec1s"? Ct1rit!S Res 2004: 38: (The tcnn Foumier's gangrene has been used to describe cause of the rapid onset of conjunctiv itis and its
286-93. rapidly progressive necrotising fasciitis of the perineum potential seriousness and is preferable to early diagnosis
5. f>ihlstrom Bl... "' nl. P(ri t>dont~\I disl!as..:s:. ltnK'C!I :!00~; 366:
IS09-20. and genitals.) Necrotising fasciitis usually follows trauma, and treatmem of the neonate. 2 Cleansing of the ne-
6. Greenwdl H. Bissada NF. Emt.rging C(lnccp1s in periodontal and most patients have pre-existing conditions that predis- onate's eyes immediately after birth followed by the
therapy. Drug> 2002: 62: 258 1-7. pose to infection, such as diabetes mellitus, chronic renal topical application of either tetracycline 1% eye oint-
7. Ellis'on SJ. The: role of pbcno.xyniethylpcnicillin, ::imoxit·illin.
mctroniciazoli! and d inclamycin in the m:m:igcmc1ll of acu1c den·
failure. peripheral vascular disease, or parc:nteral drug ment,3'' erythmmycin 0.5% eye ointment,3 or silver ni-
h.1ah·c.-ular al,scesses-a review. 8,. Dem J 2009; 206: 357-62. abuse. trate I% eye drops is advised 4 and is sometimes re-
S. Ek )' BN. Antibx1erial :i!cnt.s in lhc control or surra~ingival Complete debridement of the infected tissue is considered quired by law.; Silver nitrate 1 is active against all strains
plaqoc-:i. revic\V. 81· ~111 J 1999: 186: 286-96. of N gonorrhoeae regardless of their susceptibility to
essential for treatment; repeated debridements are neces-
sary until infection is controlled. Intravenous antibacterial amibacterials; it is inexpensive and widely a\'3ilable, but
Mycetoma therapy is given as an adjunct and should be continued un- may cause chemical co1tjuncti vitis and has been ineffec-
Myc~toma ·2 is a localised infection found worldwide, but til no further debridements are needed. 1·5 Antibacterial
1
tive in preventing chlamydia! conjunctivitis (see below).
most conunonly in the tropics and sublropics. Infection tn:atmen1 regimens should cover Gram-positive. Gram- Tetracycline has been repo1ted to be as effective as sil-
mainly results fi'om trauma to tl1e skin, and may spread lo- negative, and anaerobic organisms. The possibility of in- ver nin·ate in protecting against gonococcal conjunct'.vi-
cally through the lymphatic system to surrounding tissues, fection with group A Streprococcus or Closrridium ~-pecies tis caused by multiresistant strains5 and \l./H O now hsts
progressively destroying connective tissue (fascia) and should also be considered. Possible treatment regimens for both drugs as :he drugs of choicc.4
bone. It is characterised by painle!:S soft-tissue swelling, mixed infections include monotherapy with ertapenem, The value of prophylaxis against chlamydia/ neonatal
draining sinus tracts, and discharge of grains composed of imipenem, meropenem, piperacillin-tazobactam, or tige- ccmjunctiviris is less certain. Tetracycline ointment has
large aggregates of til3ments (fungal or actinomycete). cycline.' Multidrug regimens for mixed infections in- been reported to be less effective in preventing chlamy-
The foot is most often affected (70 to 80% of cases), Jess clude: dia! infection than gonococcal infection1 and erythro-
194 Antibacterials
mycin ointment has also been unreliable.6 Silver niO"ate be the best choice for initial therapy when parenteral anti- The treatment depends on the site and nantre of the infec-
is generally con~idcred ineffective,1 despite an unex- bacterials are rcquired. 16- 17 Other su1U?Csted alternatives tion and whether immunodeficiency is presenL Both HN-
pected reduction in the incidence of chlamydia! con- include mcrooenem,' 5•16 cefuroxime,16-cefotaximc., ' 6 and negative and HIV-positive patients may be affected and
junctivitis in one sl\ldy.5 The CDC3 does not recom- ceftriaxone;IS,l6 due to their relatively low toxicity and ex- the possibility ofdrug interactions should be borne in mind
mend prophylactic antibacterial ucatment for infants cellent CSF penetration, these antibacterials may be panic- in patients receiving antil'CIJoviral therapy. For further i1l-
bom Lo mothers with untreated cblamydial infection. ularly useful in cerebral nocardiosis. 16 Treaunent ofnocar- formation on drug interactions with antiretrovirals see Ta-
Screening and treatment of prewiant women for C. tra- diosis needs to be prolonged and may continue fC»' at least ble l, p. l 014, and Table 2, p. l 044, in Antivirals.
chomatis infection may be a more effective method of 6 to 12 months, depending on tbe site of infection and lhc • MYCOBACllJUIJM AVIUM COMrLEX (Mt.Cl.
control than ocular prophylaxis.5.7 This approach also immune status of the patient5-' 6 US guidclincs1.2 produced by the CDC, National Insti-
tackles the more serious problem of pneumonia.1 I. Abdi EA. el ol. Nocardja in(cction in splcnectomrzcd patients: tutes of Health, HIV Medi~ine Associatioo, and lnfec-
Neonatal conjunctivitis continues to cause blindness, es- case rcpo:tS ind I review or the literature. Post8f"Hl J,kdJ 1987:
63: 455-41. tiOus Diseases Society of America recommend that the
pecially in developing countries. Povidone-iodine is less 2. Smego RA. et cl. Treat.men( of systemic noc.ardH>slJ. lo,,c~t treatment of HIV-positive patients with MAC should
expensive and perhaps more readily available in such 1987; i: 456. consist of at least 2 antirnycobacterial drugs. Clarithro-
countries lhan silver nitrate or Cl)'lhromycin. rn a study 3. Filice GA. Tr..1mcn1 ofnocardiosis. IAnc:n t987; i: 126t-2.
4. ~r;hcse GK. et al. Nocardia bruilicn.sis meningi1is. P011grad
mycin is the preferred first drug (with azithromycin as
in Kenya involving more than 3000 infants9 a 2.5% oph- U<dJ 1992; 68: 986. an alternative) and is given with ethambutol. Use of a
thalmic solution of povidone-iodine appeared to be a
more effective prophylactic than either a 1% ophthalmic s. :1;~i~~!·nd :;:~~~::: rt!::c~~~:~d~~c~i;bo~~~ third, and possibly, fourth, drug should be considered in
patients with advanced immunosuppression (CD4+ T
199- 202. .
solution of silver nitrate or erythromycin 0.5% eye oint- 6. Bcnnen JS, JtMin.gs AE. factors influencin& SU~tiDiHty of lymphocyte count less than 50 cells/microlilre), high
ment Jn particular, there were fe~cr cases of chlamy- Noc.erdio specje:s \o 1timethoprim~s"lfamc1hoxnolc. An1im;. mycobactcrial loads, or if the patient is not taking effec-
dia! conjunctivitis with povidone-iodine. crobAg<ms C/,.•tOIMr 1978; 13: 624-7. tive HAART. RifabuLin is often used as the U1ird drug,
•TREATMENT 7. ~=n~~--:.!f.0~r~!:,:f~%~i~~crc~;d;;:cr~g;~~ °ls~ while a fluoroquinolone (ciprofloxacin, levofloxacin, or
All casei of neonatal conjunctivitis should be treated for 819-24. moxilloxacin) or aminoglycoside (amikacin or strepto-
both N. gonorrhoeoe and C. trachomatis because of the &. Golds,cin FW. et al. Amikecin--containing regimens fc.'lr treat· mycin) can be considered when a fourth drug is needed
IJ'ICnt of nocardiosis In immunocompromizcd patients. E1tr J
possibility ·of mixed infection.• Gonococcal neonatal Oin Microb;ot t981; 6: 1911-200. or rifabutio cannot be used. In disseminated disease, pa-
conj1111Ctivitis must be treated systemically. WH.04 rec- 9. Meier 8, #fol. Sue<;essfU1 trealmcnt of 1 pancreatic Nocardi.a 1ients who are not tal:ing HAART should generally de-
ommends ccfuiaxone 50 mg.'kg by intramuscular injec- asieroidcs abscc-.ss with amik.ac:in ind 1uraic.11drainagc.Antitrtl· lay starting antiretroviral treatment until after at least 2
crobAgtmlJ Chcmother 1986; 29: lS0-1.
tion as a single dose (to a maximum of 125 mg) or, if JO. Moy~U EH, ~t al. Clinical aperienct with llnciolid for the weeks oftreatment for MAC has been completed, in or-
ceftria.xonc is not available, spectinomycin 25 mg.'kg (to trea1ment of Nocardi1 infection. Clfn In/tel Dis 2003: 36: der to reduce the risk of significant drug interactions or
a maximum of 75 mg) or kanamycin 25 mg/kg (to a 3J3-t8. complications due 10 immune recons1itution syndrome.
I I. Jodfowski Tl. et al. Line:iolid for the 1rcatmcn1 of'Noc1rdi1 spp.
maximum of75 mg) by intramuscular injection as a sin· infection•. Ann P"°""""orhtr 2007; 4t: 1694-9. Those already on HAART should continue this treat-
gle dose. 12. ~i~~-c~A~ f ~;~;o~~i~2. trcauncnt o(pulmon1ry nocar· ment if possible.
In the USA, CDC3 recommends a single intravenous or 9 Earlier UK guidelines from the British Thoracic Society
13. Naka W. et al. Unusually loc1ccd lymphocut•ncous nocardiosir
in1ramuscular injection of ccftriaxone 25 to 50 mg/kg cause:d by N0t:ardia bratilie:nsis. Br J DermaJo/ J99S~ 132: (1999, not subsequenlly updatedf for treatment of HI v.
(up to 125 mg) when there is no evidence ofdisseminat- 609-13. positive patients with MAC broadly concur with the US
ed infection. 14, 8tlh PMW, tt ol. Tre;1tmcnt or mt.1h1ple subcutaneous Nocardia recommendations. Rifampicin or rifabutin, ethambutol,
asceroidtt abscc»es with ciproflo.uatt and do:<ycycline. Post·
Soc also under Gonorrhoea (p.206) for the treatment of trod M«I J 1989; 65: 190-1. and clarithromycin or 37.ithromycin were recommend-
infants exposed to gonorrhoea at bi11h or with estal>- JS. Abnmowicz. M, ed. The choice or 1n1lbaeterial dl'U&S. ·Jn: Hand- ed. A fluoroquioolone such as ciprofloxacin, or even
book of0111/mkrohlo/ tMropy. I S1h ed. New l{ochcllc NY: The amikacin, might be added for patients who were intoler-
lished gonococcal infection at any site. Medical Leucr, 2008: 72.
For nongonococcal n~natal conjunctivitis WHO' and 16. Corti ME, Villafaf'.c Fi0ti MF. NO(ardiosis-: a rcview. /nl J ln/«r ant of first-line drugs or who failed to respond. UK
CDC) recommend Cl)'1hromycin 50 m~g daily in 4 di- Dis 1003; 7: 243-SO. guidelines recommended lifelong treatment; the US
17. ~~:;c~~:·!fr!c':~~~i:iko~!:;~!)~:rJ!:-~:,!!
vided doses orally for 14 days; WHO recommend co- considen that treatment may be stopped in selected pa-
trimoxazole 240 mg twice daily for 14 days as an aller- 10120 t O; 62: 23~6. tients (see Oiernoprophylaxis, below). In disse111i11ated
native. There is no indication that topical therapy is of disease, the same treatment should be given and cont in·
additional beoefit.l·• ued indefinitely.
Nontuberculous myco bacterial infections A prospective, randomised study' undertaken to com-
I. WHO. ConjNnctfvi1i.J oftht ntwbor11: prn·tntion ond rrtotmtnt
oJ tM prirnory A.a/th can leWJl. Geneva: \VHO. 1986:.
Environmental mycobactcria are widespread, and many pare 3 regimens (clarithromycin and ethambutol, clari-
2. Lap M, ••of. Epidemiology and control or gonoccccal oph1h1(, species other than those responsible for leprosy (p.188) thromycin and rifabutin, and:an 3 drugs) for the treat-
mia neonalOf\lm. 8,./1W/fO1989; 67: 47t-8. and tuberculosis (p.212) arc facultative parasites capable
l . CDC. Sexually transmitted diseases lmltmenl guidc:lines 2006. ment of disseminated MAC in patients with AIDS
MMWR 2006: SS (RR· ll): 1-94. Also available 11: h11p:// of producing disease in man.These organisms, which have found that all regimens appeared to provide effective
www.cdc.~ovlmmwr/PDF/rrlrTSSt I .pelf (accessed 23/06/01) been referred to as atypical, nonl\lbcrculous (NTM), tuber· treatment and the differences were not stat.istieally sig-
4. WHO. Guideline.-t for the m1n.agc:mcnt of sexually tranynlutd culoid, opportuniSlic, or MOTT (mycobacteria other than nificant However, patients taking the 3-drug regimen
lnfec1ions. Gcncv1: WHO, 2003. Aho available:: at: l\lberculous), are rarely, if ever, transmitted from person to
h11p:l/whqlibdoc.who.int/publico1io1u/2003/92 41 546263.pdf had greater overall clinical efficacy, a lower relapse rate,
(ocoemd 22/06/04) person but are acquired !Tom the environment. Sympto· and a lo'vcr risk of death.
5. t.aa• M. ti ol. Prophylaxis of gonococul and chlamydiaI opli- malic infections are usually associated with focal or gener-
The 1999 B"ritish Thoracic Society guidelines3 slate thal
lhalmi1 ncona.tonin1: a ccmparison of silver nitraac ind lctracy- alised dcfectS in the host's immune sySlem. The diseases
clinc. N Engl J Med 1988; 3t8: 653-7. produced include localised skin and soft tissue lesions, treatment for HIV-negative patients with MAC puf.
6. BlacJc-Plync C. ct cl, Failure of eryfhro1nycin ointrnc'!'lt for posl monary disease should consist of rifampicin and ctham-
nalal ocular prophylaxis or chlamydiaJ conjunchvilis. P~diotr pulmonary infections, lymphadenitis, and disseminated
hl/w Dis J 1989; 8: 491 -5. infections. butol for 24 monUJS, with or without isoniazid. In ex-
7. Hammc:rtehlag MR, ct al. Effieacyofnccn>i.al ocul>r prophylax· trapulmonary disease affecting lymph nodes, surgical
is for che prevention or chlamydial and gonococcal conjunelivi- cutaneous disease may follow tr-.umatic inoculation with excision of the nodes should be uni!ertakcn; chemother-
lis. N Engl J Med 1989; 320: 769-72. Mycobaderium marim1111 ('swimming pool' or 'fish-13nk' apy wiU1 rifumpicin, ethambutol, and clarithromycin for
S. Schachter J. Why we ncc:d I proa.ratn for the eon.trol of Chfamy- granuloma), M. ulcerans (Buruli ulcer), M chelo11oe (M.
d1a lrochomoli•. N £,.g/ J Aftd 1989; 320: 802~. up to 2 yeais should be considered if disease recurred or
9. lsenbtr& SJ, rt al. A controlled trial of povid<>ne-iodine as pro~
chelonei), M abscessus (fom1crly M. chelonae subspe- where excision was incomplete or impossible. In sites
ylaxls aaains1 oph1halmia ncona1orum. N Engl J Med 1995: 332: cies), or Mfortuirum. Ulccrat.ed lesions due to M. haemo· other than lymph nocles, chemotherapy should he given
562-6. phi/um have Deen described mainly in immunocompro- for 18 to 24 months. US guidclinesS from 1he American
mised paticnts. Thoracic Society and the Infectious Diseases Society of
Nocardiosis Pulmonary disease may be clinically indistinguishable America suggest U1at for mild nodular or bronchiectatic
Nocardia spp. are Gram-positive aerobic branching bacte- from pulmonary tuberculosis, and has most frequently pulmonary disease, an intenniltent regimlln ofclariLhro-
ria that cause systemic or localised infection. The principal been annl>uted 10 the M avium complex (MAC), wbieh mycin (or azithromycin), rifampicin, and ethamblllol
pathogenic species in man is N. asteraides; others include includes M avium and M. avium·introcellulnre, or to M. three times weekly is usually suflicient; therapy should
N. brasiliensis, N. pseudobraslliensis. and N. caviae. Lo- kansasii, and to a lesser extent M. xenopi; less common be continued until spul\lm cultures have been negative
calised chronic infection nr actinomyceloma is described causes include M abscessus, M asiaticwn. M celatum, for J 2 months. For severe pulmonary disease or in pre·
under Myeetoma (p.193). Syslemic nocardiosis is mainly M. chelo11ae, M. fo1111i111111, M. molmoe11se, M scrofu· viously trea1ed patients, a daily regimen should be used;
a lung infection and often involves abscess foml3lion; it laceum, M. simiae, and M szulgai. addition of intermittent amikacin or streptomycin for t.hc
occurs especially in irnmunocompromised patients and Lymphadenitis, which is usually self-limiting and occurs first few months of therapy can also be considered.
may be disseminated with abscesses in the brain and sul>- particularly in children under 5 years of age, may be Prophylactic treatment is used to reduce the incidence
cutaneous tissues. caused by many species but the great majority ofcases are of disseminated MAC disease in patients with HIV in-
The treatment of choice has been a sulfonamide such as due to M avium complex, M genavense, M malmoense. fection. There appears to be a tendency to delay starting
sulfadiazine or co-trimoxazolc,1·5 although a sl\ldy in vifl'O and M. scrofiilaceum (sometimes collectively known as prophylaxis until later in the disease process; US
indicated that the fixed ratio oftrimcthoprim:sulfamcthox- the MAIS complex). guidelines2.5 recommend starting prophylaxis in adults
:u.ole in co-trimoxazole might contain too little trimetho- Dissemination of opportunistic mycobacterial infections and adolescents at a CD4+ T lymphocyte count of less
prim for optimal activity.6 Sulfafurazolc7 has been used may occur rapidly in immunocompromised patients. The than 50 eclls/microlitre with either azithromycin or clar-
successfully. There have been reports of the effective treat- majority of cases have been attributed to the M avium i1hromycio. Ifthese dmgs cannot be tolerated then rifab-
ment ofnocardiosis with amikacin,8•9 Jinczolid,'0. 11 mino- complex; other species implicated include .IJ. abscessus, utin may be given as an alternative. Combination thera-
cycline,'2·13 or ciproOoxacin with doxycycline.' 4 Jmipen- M celatum, M. chelonae. M. ge11avense, M. /Jaemophilum, py with one of the macrolides and rifabulin is not
cm may also be used, 15 and is most active when combined M. kansasii, M. malmoense, M scrcfulaceum, and M sim- recommended. US guideline$ state 1hat prophylaxis
with amikacin; the combination is considered by some to iae. need not be lifelong in patients responding to l IAART;
All cros+-references refer lo entries in Volume A
 Antibacte1ials 195
specifically, primary prophylaxis may be stopped in t ibacterial regimens have been used for M. scrofu- 10. Aubcy A. a ol Si.:uy-rhr~e cas~s o( Mycobacttrium murinum
inJ~ction : clinial features. treatment, and anubfodc tuS«ptibil-
adults and adolescents whose CD4+ T lymphocyte laceum infections. 3 Symptomatic improvemcot was ity orcouRhvc isolJlC$.. An:lt /111,·rn Mcd2002o 161: l/4~52 .
count has increased to more than 100 cells/microlitre for achieved in an AIDS patient with M, ce/0111111 infection 11. Oon11 Sr. r1 ol. Thenpy of Mycobactcrium m:winu1n infec-
3 months or more, but should be rcsta11ed if the CD4+ with a regimen of isoniazid, rifampicin, and ethambu- tiuns: u~c uf tetrac:ycfot:es vs rifampill. ,frrh lm~m MN 1936;
count falls to below 50 to 100 cellslmicrolitre again. tol.9 146: 902-4.
12, l.aing RBS, el al. Antimicrobial lttalmtnl of fish tank gn.nulo.-
Observational data from a large cohort of patients in the For cutaneous infections due to M marinum (swim- mt. J Hond S11rg (8rJ t991; 22 B: llS-7.
USA found no evidence or increased risk of MAC in ming-pool granuloma or fish-tank granuloma) many an- 14. TJ. Gray SF, er a/. f ish iank Sfanuloma. BM.I 1990; JOO: 1069-iO.
patients who had stopped primary prophylaxis in ac- bing R.BS. 11 nl. New ant~microbials agiitUt Mycobac1c.rium
tibacterial regimens have been used, 1° including rif- marinuni infccciou. Br J Dc.rn1a1ol 1994; 131: 914.
cordance with these guidclincs.6 ampicin with elhambuto!11 or isonia?id, rifabotin with IS. Siuirc V, ~'al. Mycob.itctcrium uk:crus infection: control, di·
US guidelincslJ also state that it may be possible to stop ciprofloxacin, 12 minocycline with co-trimoxazole, 13 agnosis.. and trca1ment. Lonee/ lnf«J Dis 2006t 6: 288-96.
16. Etuaful S. ti ol. EffiC'ilicy of lhc comb1nation rt f1mpin-s1rep10-
secondary prophylaxis (chronic maintena11ce therapy) clarithromycin with rifabutin14 or ciprofloxacin 12 or mycin in preventing growth of Mycobacterium ukcrans in ear1y
in HIV-infected adults and adolescents who have com- ethambutol. 1 ~ Monotherapy with clarithromycin, mino- lesions or Bundi uker in homans. AnrindC'f'Ob.4g~ntt Ch~w1/l­
plctcll al least 12 months of trcatmcnl for MAC, who cyclinc, doxycyclinc, or co-trimoxazole have each been cr 200S; 49: 3182~.
17. WHO. l'ro•#k1uol guidmrc~ un 1hu ,,,,, ofl~jic anlibioHC3
remain asymptomatic with respect 10 MAC, and who tried, mainly in small series of patients. US guidelines5 l11 lilt' mon~I ofAfyc.oboct6rlwn t1l«rons disease (Bur11/i
ha,·e a sustained response to liAAITT (CD4+ T lym- suggest that for treatment or M. marinw n infection, the ulcer). Geneva; WHO, 20CM.
phocyte count greater than I00 cells/micro litre for more use of 2 active antimycobacterials until I to 2 months Avai ta ble 11: ht1p:l/whql ;bdoc, who.intlhqll004/
WHO_CDS_CPE_GBUT_2004.tO.pdf(acccsS<d 1311:1/06)
rhan 6 months). Secondary prophylaxis should be re- after symptoms of infection have resolved may be area- I&. Johnson PO, ~' of. Con~us rcccmmendations (or the diapo-.
started if CD4+ T lymphocyte count falls. below I00 sonable approach. sis.. treatmcna and control of Mycobac1crium uJccnms infection
ccllslmicrolitre. In children, CD4+ T lymphocyte count (Bairnsdile or Ouruli ulcer) in VtelOria, Aus1talia. Mctl J .4usr
Buruli ulcer, due to M ulcerans, is ditfjcu!t to treat and 2007; t86! 64-8.
thresholds for starting, stopping, or resuming prophy- usually requires surgery; responses to antimycobacterial 19. rhillips R. err nl. PilOt randomii.od double~blind trial of treal•
laxis vary depending on the age of the child.1 monotherapies have been generally disappointing. ment or Mycobac-terium ulcenans discasie (Buruli uJc:er) with.
topical nhrocai O>;idcs. Autimicrob ~ntl CllD'lotlt~r 2004;
In the UK, however, the earlier British Thoracic Society However, recent evidence suggests that combination 48: 2866-70.
guidelines noted there was no iiencml agreement about antibac1e1iat therapy may reduce tl1e heating time and 20. Adjei 0, « ol. Ph~myloin in the: 1rc:1\!"nen1 of Buruli ulcer. Trous
when prophylaxis should be used. If prophylaxis were recurrence rates of ulcers, and minimise or avoid the 2 l. R Soc 7l'op MtdHn 1998; 92: 108- 9.
Eluyed S, Re.d R. Mycobacccrium hacmophilum cntcomyeli-
to be given to patients wilh a C04+ T lymphocyte count need for surgery. 15 Treatment of nodules and plaques of tis: case report and review or 1hc literature. BMC ln/«1 DiJ
below 50 cellslmicrolitrc the first drug of choice would early Buruti uloctS with rifampicin and streptomY.:in for 2006; 6: 10. Available 11: hup://www.biomedc.entral.com/
be azithromycin; clarithromycin was an alternative and up 10 12 weeks, showed inhibition of growth 4 wccl<s 22. contenllpdf71471·23J4-6-70.pdf (accessed t3/J 2"'.16)
Kyle SO. Porter WM. Mycobacterium dlclonae inf'ection sue:-
azitl1rom)'Cin wilh rifabutin would be a third choice.) after starting treatment. 16 Furthermore, no lesions en- cusfuUy trc.:ited with oral clarithromycin and linczolid. Br J
These guidelines, partly based on srudics "11ich predate lmged during the treatment period. WHO therefore rec- l>mn<Jtol 2004; ISi : 1101.
the wide USC ofHAART, recom.mcndcd that prophylax- ommends the use of rifampicin and streptomycin or
is be continued indefinitely.3 amikacin for 8 weeks. 17 Consensus recommendations · Obstetric disorders
• MYCOBACTER.IUM KANSASll tNFEC'llON. issued by practitioners in .Victoria, Australia" consider See under: Endomeaitis (the prophylaxis and treatment of
UK guidelines slated that infections with M ltamasii surgery to be the best treatment for Buruli ulcer, with postpartum endometritis), p.179; Prcmarure Labour.
might be treated with rifampicin (or ri fabutin) and antibacterial tbetapy being indicated for more extensive p.202; and Urinaty-Trict Infections in Pregnancy, p.216.
ethambutol.; Pulmonary disease in HIV-negative pa- disease. Use of antibacterials may also possibly allow See also Neonatal Conjunctivitis, p. 193, and Perinatal
tients was usually treated for 9 months whereas HIV- more conservative resection and reduce the risk of re- Streptococcal Infections, p. I 98. ·
positive patients should receive therapy for 2 years or lapse. The rccorruncnded oral regimens were: at least 3
until the spun1111 has been negative for 12 months. For montl1s of rifampicin given with clarid1J0mycin. cipro-
disseminated infection in HIV-positive patients, clari- floxacin, or moxifloxacin. For more severe or extensive Osteomye litis
thromyein should be added and possibly also isoniazicl. disease patients may also require intravenous amikacin See under Bone and Joint Infections, p.173.
TI1e place of macrolides and fluoroquinolones in pul- for 4 to 8 weeks in addition to oral therapy. Reports of
monary or disseminated M. kansasll infection remained other therapies include a beneficial response with topi- Otit:is extema
to be established. In extrapu!monary disease in H!V- cal nitrogen oxides in a ~mall pilot swdy of37 patients Otitis extema is a general term used to describe inflanuna-
negativc patients, chemotherapy with rifampicin and with Buruli ulcer,19 and healing after local application of tion of the skin of tbc external audito1y canal that may be
ethambutol might be used before excision of an infected phenytoin.20 due to infection witl1 bacteria, viruses, or fungi or second-
lymph node. fn orherextrapulmonary disease ~lc guide- Cutaneous disease due to M. hnemophi/11111 infection has ary to skin disorders such as eczema. Otitis extema ls as-
lines stated that the data were insufficient to make rec- been treated with an initial treatment course ofrifabotin, sociated with high humidity, wanner temperatures, swim-
ommendations, but considered that rifampicin and ciprofloxacin, and clarithromycin, followed by c!ari- ming. loca l trauma, or obstruction of the car canal.
cthambutol for 9 months appeared sensible, with the ad- thromycin for 2 years.2 1 M chelo11ae was successfully Sub1ypcs include acute localised Otitis cxtcma, acute dif-
dition of protionamide and sfi·eptomycin and/or a mac- treated with claritJ1romycin and 1i111:Zolid for one month, fuse otitis extcma (swimmer's car), chronic otitis extema,
rolide ifthe condition is not responding.> US guidclincs5 followed bv a further S months of trcamient with clari- nod necrotising (111alig11ant) Olitis extcrna. Acuie diffuse
sugg.est the use ofrifiunpicin, cthambutol, and isoniazid thromycin.!l disease is characterised by crythcrna, itching, pain, puru-
for M. ka11sasii pulmona1y infection; treatment should I. CDC. Gutdeli:oes for the ptc:V¢nti'1n 11od 1rcauneol of opporcun· lent discharge, oedema, fullness, and deafness. If left un-
be continued until sputum cultures have been negative is1ic infcction5 amon.g HIV-exposed :md HlV-infected children:
recommendations from CDC. tl\e Nalinnal ln"Litutcs of Heahh, treated or iflrcaled inadequately it may progress to chronic
for 12 months. for disseminated disease in immuno- 1he HIV Medicine A&sociatioit of the Infec tious Oi5eaK':S S4Jci· otitis extema. Chronic otitis extema may also result from
compromised patients, indefinite treatment may be re- cty of A1rn~rica. ahc l'td•atric lnfc~tiou.s Diseases Society. 1nd allergic contact dermatitis or other underlying skin coodi-
lb• American Acodemy of Pedialric•. MMWll. 2009; 58 (RR-
quired until sufficient recovery of immune status oc- 11 ): l 166. Also 1v1il:t.blc :tt: http://www.cdc.aov/mmwr/PDF/
tions, such a.~ ec7.ema. Malignant otitis extema is rare and
cu~ rTlrTSS 11.r.ir(occcssed OSJOZltO) occurs mainly in ilrurumocompromised persons and in <li-
• OTHER Of'!'ORTUNlS'rlC MYCOBACTEIUA. 2. CDC. Guidelines for prcvcntK>n and trc;atmt-nt or opportunist;.: abetics and can be life-threatening if temporal bone infec-
infections in HlV-infcctcd adults and adotcsccn11: tccomnlenda- tions occur.
fn M malmomse and M. xe11opl pulmonary disease, tions from CDC. the Nation#ll lnstituta o<Huhh. and the HIV
UK guidelines ha'<e recommended that rifampicin and Mrd1c.ine Association of the lnfcctious Oisa1cs Society of The tre2tment of both acute and chronic otitis extema in-
America. AIMWR 2009; 58: (RR-4): 1-207. Also ava;t.blc ut: cludes thorough cleansing :ind the use ofappropriate acid-
ethambutol should be given for2 years in HIV-negative http;l/\Yww.cdc.gov/ininwr/pdf/rr/rrS804 .pd( (accused
patients. EXtrapulmonary M. malmoense infections OS/02110) ifying and/or antibacterial ear drops, with or witho11t a cor-
should. be ti:eated in the same manner as eitrdpulmooary J. Subcommittee: of the Joini Tuberculosis Commiuce oftk Bri1- ticosteroid, even though some have doubled the value of
MAC or M knnsnsll infections. M malmoense infection i~1(c~!i::1~i~;.~~~::i~C~~~~i~:~~j~~~.::r.°~mn: topical aoribactcrials. A systematic re••iew1 d1at examined
rarely occurs in AIDS patients, but if necessary, treat- rox 2000; 55: 210-IS. the eftects of car cleaning, topical treatments (generally
acetic acid, antibacterials, corticosteroids, or combinations
ment with rifampicin, ethambutol, and clarithromycin,
and possibly isoniazid should be used. For M xe11opi in
~:;~i~:~~~~fn}~,~~r~·:~~;~~~~~~!~-o~:ck~::~~~~~ of these), and oral antibacterials on d1e resolution of acute
GuideTrnes/OppMy<:o.p<ff(a«<S1ed t8/08108)
HIV-positive patients the guidelines stated that there .a. 8cns4n CA. •I al. A praspcctiw, randomiud triAI c~an;ining uncomplicated otitis cxtcma found that topical therapy
was effective, but there was lillle evidence that one lleat-
~';t,.~~:c2 rif:b~~j~~~r ~o~~ar/!'~r,~~m~:, ~~;~~~1~ in~~
was no evidence on which to base recommendations; 0 0 1

treatment as for pulmonary or disseminated MAC infec- Mycob:tcterlum avium complex d1SC3S.C in J)C'rsons with ac· ment was better than another in short-tenu management.
tion was suggested.> quirrd immunodefteicncy syndrome. Clin lnf~ct Di.I 2003: 37: Ear drops contain ing aminoglycosides, such as gen-
12;t-43. iamicin, neomycin, or framycctin, or polymyxins should
For pulmonary disease due to rapidly growing bacteria S. American Thoracic Society. An ofricjal ATSllOSA st.atemcnt:
(M. aqcessus, M. chelonae, M fortuilum, and M. gor- di3gno$is. trc.amwn1. and prevention o( nontubcrcuJow myco- not be used when d1e ear drum is pcrforattd because oflhe
donoe) and other species (M ge11ave11se, M hue1rl<)phil- baclcrial diseases.. A'" J Rt:spir Cn'1 Ca~ Mn/ 2007; 175: risk of ototoxicity.
367-< 16. CO<Tecl1on. ibid. ; 744-S. [do.c] Also available ai: The management of the vario11s s11blypes of otitis extema
um, M. simiae, M. szulgai, and M. 11/ce1·a11s) smgCI')' http://ujrccnut$journals.or:fcgi/rcprint/l 7S/4/36 7 (Kees.sc:d
shoufd be used if possible. Drug therapy should proba- 051il2110) has been dcscribed.2•5
' · ~;::;c~~ri'u~; ~~=~::~~r:rc:1"~~~i~fe~t:f~~
bly include rifampicin, ethambutol, ond clarithromycin. Acule localisedorilis ex1erna is an infection of the hair fol-
Arnikacin, cefoxitin, imipenem, qui11oloncs, and sulfon- sons receiving a ~ti rc:?-rovi~I therapy; obstrvations from a large licle (furunculosis), commonly due to Slaphy/ococcus ou-
ainidcs might have a place in treatment. For extrapul- n•llON.I cohort 10 the Un,tcd St.tees. 1992-2002. Clin ltrfttt 1Y111s. It may cause severe pain, which may be treated with
monary disease due to these organisms, there had been O.s 2«JC»; 41: 549-53. an analgesic such as parac:ctamol or ibuprofen. If the fu-
7. Bartilai A.~ al. Succr-ss(ul tre:.rmcnt o( disscminalcd My~·o·
several anecdotal reports outlining treatment but there bActerium simin il'lfcction in AIDS ~tienu. ScaJHI J lu/dct D/1 runcle is not pointing (ready to rupture spontaneously), lo-
was no evidence from controlled clinical studies.> Suc· 199S:JO: 10~. cal beat application and systemic treatment with a penicil-
cessful treatment of M. simiae infection in patients with 8. Oailcy WC. Trc.alnK"nt orotypical mycobattcri1I d1se...e. Chtst linase--resistant penicillin such as flucloxacillio or a first-
1983; 84: 625-1.
AIDS was reported with clarithromycin, ethanlbutol, 9. Pic:rsimon1 C, tt ol l>issc1nin:ned inrcctic>n due to Mycobacte- gcneration cephalosporin such as cefalcxio may be used.2
and ciprol1oxacin.7 Surgical treatment and intensive an- rium cch1tu1n in pa1icnt with AIDS. lo11ctt 1994; 344: 332. Others have suggested application of topical ~tibacterials
l 96 Antibacterials
using wicks which are left in the car canal for 3 to 5 days.• analgesic,1 although the need for routine antibacterial mended as routine treatment.?4.?S A meta-analysis28 on the
Pointed furuncles require incision and drainage followed treatment is questionable. :i-5 Systemic antibacterial treat- use of antibacterials for the treatment of OME failed to
by a course of topical and/or oral antibacterials.::.• ment aims to speed resolution and prevent complications. find any benefit and their use cannot be justified.24.2.I
Jn acute diffuse olitis l!Xlerno, Staphylococcus aureus, S. However, meta-analyses and reviews have shown only Treatment ofchronic suppurotive 01ilis media aims 10 stop
epidermidis, and Pseudomonas spp. arc often prescnL modest benefits from routine use of antibacterials6-1 and the discharge, eradicate the infection, heal the ear drum,
Treatment includes thorough cleansing of the car canal and experience from srudies where antibacterials were not giv- and to prevent serious complications. Treannent options
instillation of ear drops including acidifying agents (2% en rou1inely for AOM has suggested that there is no con- for uncomplicated cases include aural toilet (thorough
acetic acid) and antibacterials such as aminoglycosidcs, sequent increase in complicatioos.•·S.9 Another mcta- cleansing and mopping of the ear), systemic antibacterials,
fluoroquinoloncs (ciprofloxacin and ofloxacin), chloram- analysis10 to estimate the natural history of AOM fouod and topical treaunents with either an antiseptic or antibac-
phenicol, or polymyxin B, with or without corticosteroids that about 60"/o of children not initially treated with an an- terial, sometimes also "'ith a conicosteroid. Surgery may
such as dexamethasone.2•4 Anlifungals may sometimes be tibacterial showed symptomatic improvement within 24 be needed ifcomplications develop.'.29 There is cootrover-
required. A wick may be used if instillation proves diffi- hows, and that symptoms resolved within 3 days in about sy over the use of ear drops containing aminoglyoosides or
c:ult.2 Systemic antibacterials may be necessary in severe 80% of these children. Suppurative complications oc- polymyx.ins in the pTtSence of a puforoted ear drum, as
cases of otitis externa.2,• curred in about 0.12% of children not immediately treated they are potentially ototoxic. However, it is considered that
Chronic otitis externo is treated similarly, although the top- -,yith antibacterials and in 0.24% of those given immediate deafhess is more likely to result from untreated disease
ical antibacterials and corticosteroids used should not be treatment. A systematic review9 reponed that clinical signs than from a short course of these ear drops. A systematic
the same as those used previously for the treatment of and symptoms resolved within 4 to 7 days in 78% of chil- review29 found thal treatment with topical fluoroquinolone
acute disease.2 dren noc initially treated with an antibacterial. However, ear drops w~ more effective at drying the ear than no drug
Necrolising (malignant) 01iris extema. due to fulminating some clinicians have argued that although the benefit is . treatment or topical an!i$tptics; effects of topical non-fluo-
infection, especially with Pseudamonos, is uncommon but modest, it is significant and therefore the routine useofao- roquinolone antibacterials when compared with no drug
can occur in susceptible patients. Topical antibacterials are tibacterials is clinically justifiable. 6 A later systematic trca1111ent or topical antiseptics were less clear. Another
not effective and systemic treatment with antipseudomon- review" concluded that antibacterials do provide a small systematic reviCwJO found that ear drops containing fluor-
al drugs such as gentamicin, ceflazidime, a carbapenem, or benefit in very young ch ildren and a funher meta- oquinolones were also more effective than systemic anti-
a fluoroquinolone is needed for about 4 to 8 weeks.2 •4 analysis12 repor1Cd that most benefit was seen in ch.ildren bacterials at drying the ear. EffectS of topical non-fluoro-
However, resistance to ciprofloxacin has been reported.6 under 2 y~ of age with bilateral AOM, and io children quinolone antibacterials or antiseptics were less clear and
Combination treatment with an aminoglycoside and an- with both AOM and discharge. Another suggested ap- no additional benefit was noted by adding a systemic anti-
other antipseudomonal drug or a penicillin (such as azlo- proach has been to delay the start of antibacterials for 72 bacterial to topical antibacterial trcabneot.
ci!lin, piperacillin, or ticarcillin) may also be used.2.• hours and to then only give them if the patient remains un- PRJSV E~TION
well.8·ll.14 No one antibacterial has been found to be supe-
rior to another io the treatment of AOM.9 Adjunctive treat- Long-term antibacterial prophylaxis.has been tried in chil-
I. Kaushik V. er ol, ln1crvcnlion.s for acute otilis cxterna. Av1il1ble
in The Cochnne Database of Systematic Reviews; Issue I.
Chichester. John Wiley: 2010 (acc<S<ed 17/03/10). ment with topical and systemic decongestants and dren at his!h risk including those with recurrent acute otilis
2. Brook I. Ttca1mcnt of 01i1is cxlcma in chiktren. Ptmllotr Drugi antihislamines has not been found to be beneficial15 and media,>•J'l but the 33
evidcoce for its benefit is inconsistcnL
1999: I: 283-9.
) . H~hes E. LeeJH. Otitisutcrna. P•d;orrR~ 2001: 22: 191-7. there is insufficient infonnation to conclude whether there A meta-analysis on the use of antibacterials to prevent
4. On& YI<. Chee G. ln(ectiOfls or the external ar. Ann Acod Med is any benefit from the use of topical analgesics (including recurrent AOM concluded !hat they appeared to have lim-
Slnf'1P<H'< 2005; 34: 330-34. corticosteroids, local anaesthetics, and NSAJDs). 16 ited benefit and that 9 children would need to be treated to
S. Ossuthorpe JO. Nielsen OR. Otilia extuna: rtvicw and clinical show an improved outcome in one. A later mcla-analysis3'
upcbte. Am Fam Pl•J~lcion 2006; 74 : IS 10-16. The American Academy of Pedia11ics has produced concluded that antibacterials reduced the probability of
6. Cooper MA. 41 al. CiproOoxac1n resisltncc devc1opini du:rin& guidelines 17 for the diagposis and management of uncom- disease recurring during the treatment period, but that the
t.rca1mc:n1 of 1nali1nant otitis c~tcm1 . J At11imicroh CM..othcr plicated AOM in children from 2 months to 12 years of long-term benefits of treatment were unclear and that 5
1993: 32: 163-4.
age. They suggest that in a select group of children an ob- children would need to be treated ro show an improved
servation period may be recommended depending on the outcome in one.
Otitis media patient's age, the diagnostic certainty, and the severity of
Otitis media is a general term used to describe inflamma- illness. These children should be given symptomatic treat- The use of xylitol, which 3inhibits the growth of St1: pneu-
tion ofthe middle ear that usually results from dysfunction ment and observed for 48 to 72 hows; if the illness wors- moniae, as 7che1ving gum S.J6 or as syrup for very young
of the Eustachian tube after a viral infection of the na- ens during the observation period or there is no impro\'e- childrcn36.3 has been reponed6 to reduoe the incidence of
sopharynx. It isoneofthemost frequent childhood illness- ment then systemic antibacterials should be considered. AOM. Randomised studies3S.3 with xylitol chewing gum
es seen in general practice. Subtypes of otitis media may Pain management is important, and appropriate analgesics reported a 40% reduction in the incidence of AOM in chil-
be classified ~ follows: should be offered. Ifantibacterial treatment is given high- dren with recurrent AOM. However, xylitol was found to
• acute otitis media (AOM) is seen especially in young dose amoxicillin (80 to 90 mg/kg daily) is recommended be ineffective when it3was used only during an acute respi-
ratory-traet infection 8 and the need for use 5 limes daily
children and is often due to bacterial and/or viral infec- for most children. In children with severe illness or those
may make this treatment impracticaJ.35.36
tion and is sometimes associated with upper respiratory- noc responding to amoxicillin and thought to be infected
tract infection. It is characterised by rapid onse1, ear dis- withH. inf/uenzae or M catarrhalis high-dose amoxicillin Vaccination against AOM with pneumococcal vaccines
comfort, and pain. Common bacterial pathogens include with clavulanic acid should be given. Alternatives in pen- has also been tried but unconjugated multivalent polysac-
Streptococcus pneumoniae, Haemophilus inj/uenzae, icillin-allergic children include cephalosporins, azithro- charide \'accines do not prevent AOM in children under 2
23
and Moraxella catarrha/iy (Branhamella cararrlralis) mycin, or clarilhromycin. Similar recommendations have years of age J9 and U1eir benefit in older children is min-
been made for the treatment of AOM in the UK. 13 imal.39 A meia-analysis39 found that Slartiog immunisation
• rec11mm1 acute otitis media refers lo fiequerit episodes
with the 7-valent pneumococcal conjug;ite vaccine during
of AOM (3 or more episodes within 6 months or 4 epi· Duration of therapy for AOM has varied from 5 to JO or
infancy has marginal beneficial effects in tenns of reduc-
sodes within 12 months) and may be due to relapse or more days. A systema1ic review 19 of published clinical
ing the incidence of recurrent AOM. Giving 7-valent
re-infection studies suggests tha1a 5-day treatment course may be giv-
pncumococcal conjug;ite vaccine. followed by 23-valent
• otitis media with effesion (OMEJ or serous otitis media, en to children with uncomplicated AOM. The American
pneumococcal polysaccharide vaccine, to older children
commonly known as 'glue ear', is defined as the accu- Academy of Pediatrics recommends treatment with anti- wilh recurrent infections appears to have no benefit in pre-
mulation of fluid in the middle ear without local or sys- bacterials for lOdays in younger children (up to 6y~ of
venting funlier episodes.
temic illness. It may be associated with recunent upper age) and for children with severe disease; those aged 6
respi ratory-tract infection and is characterised by denf- years or older with mild to moderate disease may be given Vaccinati!)D may also have a role in reducing the incidence
ness although some episodes may be asymptomatic IJ'eatment for 5 ro 7 days. 11 and in preventing the development of antibacterial
resistanCe2l bul use ofconjugated pneumococcal vaccines
• clrro11ic mppurative otitis media (CSOM) is often pre- Penicillin-resistant strains of Sir. pneumoniae have been was found to cause a shift in the pathogens responsible for
ceded by one or more episodes of AOM and is associ~t­ reported in children with otitis media and ore reported to AOM from vaccine-type pneumococci to nonvaccine-type
eil with perfordlion of the ear drum, and continued in· be increasingly prevalent.20 About one-quarter of Str. strains and to H. inj/uenzae." .
fection and inflammation in the midd le ear causing pneumoniae isolales, one third of H. inj/uenzoe isolates,
I. WintenMycr SM. Nahata MC. Chronic suppunli"e: otitis n'H:-
persistent or recurrent discharge and deafuess. The con- and nearly all M cata1rha/is isolates are resistant to peni- di1. Am1Phon,J11co11rcr1994; 28: 1089-99.
dition has been divided into inactive or active. Inactive cillin and amoxicillin. 2 However, resistance rates vary be- 2. Hend ley JO. Otitis media. N E>1t/ J Mcd2002; 347: 1169-74.
t.lisease-(tubo-tympa.nic disease) is typically character- tween countries21 and many penicillin-resistant strains re- J . ?m~~&: ~~S~ildhood 01al1i1: acute otilis media I. BMJ
ised by perforation of the car drum, deafness, and a pro- main sensitive in ·.,;.,o to high-dose amoxicillin.20.22) 3
4. Majeed A, Ilerris T. Acute mili.s media in children. B,\U 1991;
fuse mucoid discharge associated with upper respirato- Optimal treatment of otitis media with effw;ion is contro- 315: 32 1- 2.
ry-tract infection. Jn active disease (attico-antral ver;ial and the majority of cases will resolve spontaneous- S. Damoiscaux RAMJ, "oJ. Primary care base.ct l"i\ndomised., dou-
disease) there may be cholesteatoma with bone involve- ble blind 1rial of amoxictlfin vcrSus placebo for acute otitis: me-
ly within 3 months. Guidelines have been developed in the di• in ohildren ag«I undtr 2 years. BMJ 2000; 320: 3S~.
ment. The commonest infecting organisms are Pseu- USA 24 forthe dia~is and management of uncomplicat- 6. Rosenfeld RM, rt 11/. Cllnic:ll c ffic11cy oran1imkroba1I dnlgs for
domonos aeruginosa and anaerobes. Other common in- ed disease in children &om 2 months to 12 years of age. acute otilis media: me:taannlysis of 5400 children from 1hiny-
fecting aerobic organis ms are diphtheroids, lhrec randomiz.ed •ri•li. J Pt tliW 1994; l24: JS~7.
They suggest careful assessment and observation for at 7. Del Mar C, c/ al. Are an1ibiotics lndtcucd as initial trc:HnlCnl
Stophylocaccus a11reus, and Klebsiel/a. 1 least 3 months before considering surgery. Those at in- for children with acute otitis med11? A mtia·omaly&is. BMJ
T R£ATMENT creased risk of developmental difficulties such as children 1997: J 14: t ~26-9.
1Teatment ofacute oritis media aims to relieve symptoms, with cleft palate or Down's syndrome should be referred to 8. Froon1 J, 11 al. Anlimicrobials (or mcu1e 01i1is media? A review
rrom lhc lntcmational Primary C:&re. Network. B.\'11997; 315:
avoid complications, and pre~ent relapse, recurrence, and a specialist Similar recornmcndations have been made for 98-t02.
progression to the chronic state. Sometimes an analgesic the treatment ofOME in the UK.25 Antihistamines. decon· 9. T~ka13 GS, tt 11/ E'idencc 1sscssmen1of mana,cmcnt of ac\ltc
such as paracetamol may be all lhat is required as long as gestants, and mucolytics are ineffective.2•·26 Oral or topi- 01i1is media: 1-- The role of amibiotics in tre11mtn1 of\lncom·
plica1cd scutt ot11iJ mccha. Pedia11·i<s 2001 ; 108: 239-47.
frequent inspection is possible. However, it is common cal intranasal conicosteroids alone or with an antibacterial 10. M.oscnreld RM. Kay r.>. Nat\lral his1ory ofuntre11ed 01i1is media.
practice to prescnbe a systemic antibacterial as well as an have only short-term bcnefit27 and their use is not recom- L<>rvn.eoscoP"2003; 113: 164S- S7.

All cross-references refer to entries in Volume A

 Antibacterials 197
11. (jJasziou PP. el IJI Antibiotia for acute othiJ. media in children. nidazole, or a third gener2tion cephalosporin plus metron- though recommendations may need to be locali~ be-
Awtl~lc in Tht Coc:hr.:me Oatabuc of Systematic Reviews: Is·
SU< I Chichester: John WHcy: 20Gt (K«SS<d 22/0S/07). idazolc; vancomycin is a reasonable choice for Gram- causeof differences in pattenis of infection and drug resist-
il. Ro'1Cf'S MM. ti ul. Antibio11c1 for 1c.utc oe:itis media: a meta. positive bacteria.> ance:
tnalysis with individu.;i l pa1icnt d11:1. La.,c.tt 2006: 368: • WHO
1n~;s.
There has been considerable interest in d1e early preven-
13. Liu le P. ~10/. Pr.t;tnali4: rvndomised control~ ll'lll of two pre- tion of infected necrosis with antibacterials; cepha- • inpo1le111<:
$cribins str~tg.jcs for childhood t:1C.l1te 01i1is mcd11. BMJ 2001: losporins. carbapeoems, and fluoroquinolones have been LntrantU!.CtJ.lar ceftrfaxonc 250 mg dail)',p/us
Jll: 336-42. studied as they are considered to have the best penetration
1'4. McCormick OP. #I al, 'Non$Cvtte acute Oli1is medlJ: a clinical oral or intravenous doxycycUnc 100 mg twice daily (or
lrial comparing outcomes or ~tchfut ~iting versus immediate into the pancreas.' There is, however, uncertainty about oral lctracyclinc SOO nig four tin1es daily).p/1u
antibiotic trcitmcnl. Ptdiorrics 200.S: 115: 14SS...OS. their value in acute necrotising pancreatitis due to con- oral or intravenous metronidazolc 400 to soo me twice
IS. Chonm1itrce T. ~' ul. A randomi~ed. plac:cbo--controlled trial of cerns about promoting antibacterial resistance and oppor- daily or chloramphenicol 500 mg four times daily
the effecl or intihistami'nc or cortieostttOid treatment in acute
olilis medi.1 J Pediorr 2003; 143: l77-IS. runistic fungal infcctions,S and conflicting results from intravenoos chnclamycin 900 mg cvel}' 8 hours, plus
16. Foxk:e R, ~I al. Topical analxcsi1 ror 1cutc otitis media. A\'til- studies. A systematic review4 of 5 srudies in patients with intravenous gentan1icin 1.5 mg/Ilg CVCI}' 8 hours
able on The CoclonM: D•11balie or Systcmo.tic Reviews: luue 3. proven pancreatic necrosis found that, despite variations in
Chichester. John Wiley; 2006 (•ceesscd 22/0Wi). or.ii ciproOoxacin 500 mg twice daily or inuamusculAr
drugs used (cefuroximc, imipenem, or metrooidazole with spcctinomycin I g four ~mes daily,p/11.r
t7. :i~ng~~e~~ ~nC:~~::.;::;:;o~?~u;~i~:~~ ':dli~ J~:!r;:~ ciprofloxacin or ofloxacin) and in the quality and method- oral or innvcnous doxycyclinc 100 mg twice daily (or
2004: 113: 14Sl-6S. oral tctnc:yclinc 500 nig four limes daily).pl11t
Also available al: hup:l/aappolicy.aappublications.org..lcgi/ ology of studies conducted, intravenous antibacteria l
r<prinllpcdiatrics:l 13/S/14Sl.pdf (xcCSS<d 22/0S/07) prophylaxis appeared to reduce d1e risk of death in patientS oral or intr.tvenous melronidazole 400 to SOO mg twice
IS. UK National Library for Health. Clinical Know&ed~e Summa- with pancreatic necrosis, but with ooly a trend towards a daily or chlcnmphenicol SOO mg four times daily
ries. 01itis media-acute (issued Jan 2007; updated 2009). TI1erapy should be continued for al Jcasl 48 hours af-
Avtiibblc 1t; hllp://cks.library.nhs.ukloti1is_media_acutc/ reduced rate of infected pancreatic necrosis. A subsequent
view_"hol< topie(aec:cssed 30/04110) meia-analysis4 of 7 studies, including the 5 studies in the ter clinical improvement, and 1he11 followed by doxy-
· 19. Koz.yrskY.f' Al.. n al. Short course anribiolic:s for acute otitis me· previous systematic review, found no reduction in the risk cycline or tetracycline orally for 14 days.
die. Avai able in The Coc.hrane O:uaba.se o( Sytttm11ic Re· • ou1p01ie111s:
views: Issue 2. Cbic·h uter: John Wiley: 2000 (accessed of infected pancreatic necrosis or death, and suggested that
22/0S/07). routine prophylactic antibacterials may not he useful. • a sioJle-dose trc:a1me111 for uncomplicated gononhoca
20. Klugman KP. Epidcmioloay. control and trcatmenl of muhifc- Guidelines therefore vary in their recommendations. >vc:lt as a single intramuscular dose of ccfiriaxone 125 mg
•iSlanl pneumococci. Dr•iv 1996; S2 (suppl 2): 42-6. is recommended (s<c Gonormoea, p.206)pl14
21. RovC<S MM. •I ol. Otitis medil. lanc<l 2004: 363: 46S-73. Cor· Those developed in the USA 3 do not recommend antibac-
r<aion. ibid.; I080. terial prophylaxis in patients with necrotisiog pancreatitis; orol metronidazolc 400 to 500 mg twice daily mid oral
22. Pelton SI. New conccpu; in the pathophysiolol)' and managc- doxycyciine 100 mg rwicc daily (or oral tetracycline
mcnl of middlt c~r disease in childhood. l>Ntp 1996; Sl (suppl however, if signs of sepsis are present. antibacterials may soo mg foortime.s &1ly) ro.. 14 days.
2): 62-7. be given while the source of infection is investigated.
23. Jacobs MR.. Prevention or olilis media: roJe ofpoaunococcal Treatment should be stopped if no source of infection is UK:
~~~~~:a~;~~i~~ :~~~~f-~3~idcncc and ~ntibiotic rCJisl· found. UK guidelines2 do not make a recommendation as • inpa1ients:
2•· :rc>:!i:~~:!~~~:H !:a=: J!r~~:;~;¢.~~~c~ia~~C:
0 1 there is no consensus on !he issue, but state that if antibac-
terial prophylaxis is used. it should be given for a t113Xi-
with the regimens below intravenous therapy is con-
tinued until 24 hours after clinical improvement, and
my"' Pcdialrie:s Subcommmee on 01itis Media Wi1h Effusion. the oral regimen is then substituted until therapy has
Oti1isrnedia with effusion. Pttimrics2004; 113: 1412-29.Also mum of 14 days.
nailablc ~t: h11p://pedi11rics.aippublica1ions.ofl/csi/rcpri11lf I Frou;i.rd J·L. ~t al. Aculc pancrcatitis. ltmccl 2001: 371: been given for at least 14 days.
113/S/1412 (ICC<'-'«126/0 1/07) IO- S2. intravenous ccfoxitin 2 g •hrcc tin'lCS daily plus intre\'C-
2S. UK National LibnU]. for He<1hh. ClinK:al Kfto..'kdgc Summa- 2. Wort.ing Party ot'the Ari1ish Society ofG:l$&.roen1crology. Asso- nous (or oral if tolerated) do.'ycyclinc IOO mg twice daily,
ries. Oti1is mcd1t w11h effusion (issued M:ateh 2007). Av:.ilablc cR.tion of Su«gcons or Orc:al Brl1ain and In: land. P1ncrcA1ic So· until clinical improvement, lht:n
at: hnp://eks.hbrary.nhs.uk/otitis media with effusion' ciet)' ofGreat Britain ind lrellmd. UK gu.~linca for lhe manage•
view whole_topic (ocu5"d 18/08/0~ - - mcnt of acule ~ntreatitis , Gut 200S: 54 (suppl IU); iii J-iii9. oral doxycyclinc 100 mg twice daily,pl1.r oo-~I mc1ronida-
26. Gtirf.'n OH. ct ol. Anlihi.siamints a_nd!or decongestsnts for 01iti1 Also available ar: hup://www.bsg.or£;.uk/pdf_word_doc$/ 20le400mg1wicedaily
nledia wilh effusion (O~E) in chlldrcn. Availabfe in The Co- pancrcl\tic.pdf (acc:ostd 2l/l 2i08) in1ravcn-clindan1yci11 900 mg three: tunes daily p/11s in-
chninc Dau1basc of SyM.ematic R¢Vicws; ts..~uc 4. Chichcs:tc1: 3. 83nks PA. Free1na" ML Pr~cticc Pan:imetcrs Commincc of'th<:
John WH<y: 2006 (oc«1$ed 18/01/07). travenous genumicin (2 1ng/kg as a loading do$e, rhc11
American C:(lllegt of Gastrocnterofogy. Prt1c.1icc guidelines in I .S mglka three times daily 01· a single daily do.~ of
27. Thom.as CL. et of. Oral or 1opical NS3J Steroids for hearini, to" acute pancr<a1i1is. Am J Gam0<n11,.ol 2006; 101: 2379-2400.
associ1ted wich otitis media with ct'f'u.sion in c.hildrtn. Available Also a'l'aileblc at: http://\\iv.'W.KS.1i.org/physiei&ns/goidc1incJI 7 ma/kg) until clinical improvcrncn~ 1Mn
in The Cochrane Da1abasc:. of S)'slcmatic Rc11icwsj Issue 3. Acu&cP•nc:~atit is . pdr (acce.sscd 2)/ lll08) oral C·lindamycin 4SO mg four limes daily or oral doxycy-
Cliicll<Stcr: John Wiley; 2006 (•c=scd 13101/07). cline I 00 mg twice daily plus oral metronida:wle 400 mg
28. Canlckin El. McGuire TW. Antibiotics art not efTtc1ive for ot:i- Bai Y, ~ ol. Prophyh1ctic Rnlibtot1cs camot reduce inrectcd p:1n-
1is media wi1h tffinion,: reanalysis af mctA·anatyses. OiorM- cre.11ic necrosis and monallty in acu1e n~iiin& pancrernhis: twice daily
evidence from a mcUL·ant.llysis of randomized cornroUcd trials. alternative regimens, given for a total of 14 days, are:
29. ~~:z:~:~ ~~ !'»J:~~!:l~~iibio1ics without steroids ror Am J Gosrronitm>l 2008: 103: 104-10.
S. Ki.,g<north A. O"R<illy 0 . Acute poncr<llllis. BMJ 2006: 332: intravenous olloxacin 400 mg twice daily plus
chronically discharging t:af$ with undctlying tardrwn J>"f'for>o
tio11s. Available in The Cochrarw Database of SySlematic Rc- 1072~. intravcnrus n1ell'Onidawle 500 mg three: umes daily
vicw1; lssui: 4. Chichester: Johl\ Wi ley; 2005 (accused 6. Villa1oro I!, vol. Autt"biotic lhtrdpy for prophylaxis against in- intravenous ciprolloxaein ZOO mg twice daily p/14
IMll/07). or
fection pincre111ic. necrosis in ac ...\C p.incre.:ilitis. :\vailablt in
int.-.venous nictronidazolc 500 mg three limes dajly.plus
30. Maic:f.c!ym CA 1 e1 ol. SystcmiC' 1n11biotia versus topical trail· The Co:h.r1nc O;i1ahase C>( Sysatm.a1tc Reviews; Is.sue- 4. Chlc:h-
mtnts (or chronically di&charsin& cars with undcrl)'inJ cMdrurn <>tcr. loon Wiley; 2006 (ucc<.,.ed 23112/03). imravenous or oral doxycycline 100 mg twiu dajly
pC'rrt'W'Jtions.. Avajlablc i1' TI1c Cochrane Daiabut afS)'slcmatic Metronidazole may be stopped in women with mild
Revio,.s; Js.su~ l. Chichutu: John Wiley. 2006 (1cccs:sed
18/01/07). Pelvic inflammatory disease or m~ratc disease who tolerate it poorly, but 01e im-
J I. Roark R. Berman S Continoous cwicr. d"ily or ouce dttilyamox- proved coverage of anaerobic infection that it pro-
icillin prophyl•xis eotnparcd witJI place.bo (UC' children with re- Pelvic inflammatory disease (PIO) is a broad term for in-
current ocutc ocitis media. PC"diotr llifcct Dli J 1991; 16: fectious disorders of the upper genital Inlet in women and vides is more import.:1n1 in women with severe dis-
316-81. may include endometritis, salpingilis, lubo-ov-Mian ab- ease.
32. Teele DW. rt ul. Antimicrobial prophytaxis for infant~ :..t risk for
recurrent 3CUlc otitis medi:i. Votdne 200 I; 19 (suppl I): scess, and pelvic peritonitis. h is generally due to ascend- • ou1pUlie11ts:
Sl~O-SIO. ing infce1ion through the cervix and uterus to the.fallopian a single mlnunuscular dose of c:cfi.riaxone 2SO ms or c:e-
33. Williams RL, ~' al. Use or
an1ibio1ks in pt'eYMting rccurrcnl tubes, resulting in salpingitis, and from there may extend foxitin 2 g with or.ii probenc<id I g, 1hc11
aicut~ O\itis media and in 1ru1ins otitis media with effusion: :.
to the ovaries and perironeum. Long-ienn complications ool doxycyclinc 100 mg twice daily plus Or:JI metronida-
1net1·:in.:1l)1ic ancmpl to resolve 1he brouhaha. JAMA 1993:
270: 134+.SI. Corr«<1on. Ibid. J994; 271: 430. include infenility and ectopic pregnancy. The use ofintra- 20lc 400 mg twice doily for 14 days. or
34. Le,3Ch AJ. Morris PS. Antibiotics f« tht prevent~ ohcutc 3.1'l6 uterine contraceptive devices might increase the likelihood oral oOo.ucin 400 mg plus cnl 1n<UOnidazole 400 m11
chronic suppunniYe olitis medi.J in children. AvaH1blc in The boch lwtcc daily for 14 dnys
Cochrane O;itabuc ofSystc.matic ReviC''lt; Issue 4, Chich~cr-: of PIO althougli the risk may have been overstated;' it ap-
John Wiley: 2006 (1ocuS<d 18/01/07). pe3rs to be greatest during the first 20 days after insenion • USA:
;s. ~~~ci:o~bi~ ~r~~':!,~~~~ii~~,:,i. fA~~;;~~'f[;~~~s~~i~
0 • parenteral treatment:
of the device.2
36. Uhari M. tt ol. A novel use of xylitul IU!ar in preventing 2cu1t The majority of these infections are probably sexually (regimen A): inuavenousceroxitin 2 gevery 6 hoursorc.e·
otios mcdi,.. P~dicm'ics t998: JO?: 879-8~ . fotetan 2 gcvcry t2 houisplu<
37. Uh1ti M, ~ ol. Xytitol in prcvcnlins tcutc otiti.s media. l~ra:lmt
transmitted and at one time were mainly due to Nr:issttrio
or.ii or intravenous doxycyclinc lOO mg every 12 hours
21Kll: 19: Sl44-Sl47. gonorrltoeoe, but Chlamydia 1roclromo1is is increasingly
{ttginien 8): inlr..venous clindamycin 900 mg every 8
38. 'kl
r~rc~~~~~ ~jr~:~~!~~·!~::1::f,~~d:~r~.d~~~i';:;!;.
2002; I tl9: 302.
responsible and may be the commonest cause of PlD iu
some al'CllS. Other organisms that have been isolated in-
l10Ul$ /J/1,.
parentCfll gcntamicin 2 m~ as a loading dose 1he11
Full vcrsioo: http://pcdilurics.aa.ppublica1ions.or~csilcon1cnu clude Mycop/osmo hominis; Ureoplosmo 11reolyticu111; I .S ffiS/l<g a-cry 8 hours
full/10912/el9 (oeoo:ued 22JOSAl7) ana.:robes such as Boc1eroides, Pep1ococc1tS, and Pep10-
39. J;m.scn AGSC. "' 111, Pneumococc:1I conjugate \'xcines for prc- In each case parenteral treatment is continued for 24
ven1;n.g otitis nH:diat. Available in 'The Coctinnc Database of srrep1ococcus ~-pp.; Gram-negative enleric aerobes such as hours after substantial clinical improvement has oc-
Systonat~ Reviews: ls.sue 2. Chichesta: John Wiley: 2009 (4C· Escheric/1io coli; and Gram-positive aerobes such as curred and then followed by oral therapy to complete
ccssed ;OI04J10~ group B streptococci. Some of these organisn.is occur in a toial of 14 days of treatment.
the abnonnal vaginal flora associaled with bacterial • in regimen A, CQ<llinuation is usually wilh oral doi.-yey-
Pancreatitls vaginosis (p.172). Thus, the aetiology of PIO appears to be cline 100 mg !Wice daily; in patients with tul»o•arian ab-
The overall management of pancreatitis is discussed on polymicrobial; some think that prirnary infection with N. scesses oral clin<l3mycin ()r or.ii meuonidazole may be
p.2592. Pancreatic necrosis is the most serious local com- gonorrhoeoe or C. troclromo1is, or both, allows opDOrtun- added 10 doxycycline
plication of acute pancreatitis. When necrosis is sterile, istic infection with aerobic and anaerobic bacteria.I in rci;imcn 8, continu:nion may be with oral clincbmycin
monality is low and trco1me111 is conservative. 1 Morbidity 'n-ealment regimens are of necessiry broad speGlrom and 450 mg four times daily IN' doxycycline; oral clindamycin
and mortality increase if the initially sterile pancreatic empirical and should include antibacterials active against is preferred in patients with tuba-ovarian abscesses
necrosis becomes infected by bacteria from the gut. 1•1 the major pathogens. Many consider lhat treatment should Another parenteral regimen which has been tried is:
When i11fection is proven and cultures reveal !he presence be started in h05piia l so 1hat dnrgs can be given parenteral- • ampicillinlsulh3c11m ) g every 6 hourspl11s
of Gram-negative bacteria, choice~ for antibacterial treat- ly. Guidelines produced by WH0,3 by an e.'<pert group in onl N intravenous ·doxyc:ycline 100 ms CVCI}' 12 hours.
menl include a carbapenem, a fluoroquinolone plus metre>- the UK,~ and by the CDC in the USA 5 are as follows, al- • oral treatment:
198 Antibacterials
• • >i"!llc in1111111uscular dose of ufoxitin 2g plus 01111 2. Ohlsson A, Shih VS. ln1rapar1um antibiotics (or ~:nown malemal ic patients presenting with acute upper gastrointestinal
prubenccid I g. ur a single intmnuscular dose of ceftria· Group 8 SlrcplOC:()ccal coloniution. .4\·ailable in 11tc Cochrane haemorrbage.2 Although most srudies have involved the
xone 250 mg (ur equh•alent third·&eneration cepha· Oacabase of Sys1cm1ulc Rnicws; Issue 3. Chichu.1cr: John Wi·
Icy; 2009(ecusscd 1erov 10 ~ use of a fluoroquinolonc, other drugs including third·gen-
losporin),ph« 3. Sirnp<0<1 AJA, Heard SR. Group 8 Strtptococeus. 1.a...., 1995; eration cephalosporins, carbapencms, and amoxicillin-cla-
oral doxycycline 100 mg iv.ice daily, wilh or witllOUt oral 346: 700. vulanic acid have also been tried.13
mctronidawle 500 ma twice daily, for 14 days 4. Jakobi P. ti ol. New COC guidelines for pn:;venlM>n of perinatal
Pregnant women who have suspected PIO disease should grollp B 1trepuxoeeal dis•..• · Lancot 2003; 361: 3S J. Secondary peritonitis. Secondary peritonitis is associated
be hospitalised and treated with a parenteral regjmen.s 5. Sie¥,t:l JD. Cushion NS. PTC\'C:ntion or early.onset group 0 Slrcp- with perforation of the gastrointestinal tract, conditions
Sexual
treated.
rnners of patients with PJD should be lCSled and
lOCOC.C:lll di.seuc: another look u sinslt·+dosc: ~nicillin at birth.
Ol>sm Gynrco/ 1996; 37: 692-8.
6. \Vondgatt PO.~' al. lntramusculu penicillin for the preven1ion
such as appendicitis and diverticulitis, and contamination
at surgery. lnfec1ions are generally mixed and originate
or o riy onsel s,roup B strcptococaaJ infccliOf'I in nc:whom fo:.. from 01e gastrointestinal tracL Bacteria responsible in·
Women co-infected with HIV appear to be more likely to fanls. A\'ailablc in The Cochrane Oaubase of SyS1cm11ic Re· elude£. coli and other Enterobacleriaceae, anaerobes (es·
develop rubo-Qvarian abscesses but respond similarly to views; l$sue 2. Chichester: John Wiley; 2004 (aCC-eS$<d pecially Bacteroidesfragilis), enterococci, and sometimes
treatment compared with women who are HIV-negative.s 18/02110).
Pseudomonas aervgi11osa. Timely control of the source of
I. Pearce JM . Pch·ic Mfla.mmatory disease. BMJ 1990: JOO:
109()-1.
infection, where possible, is critical for successful treat·
l . Farley TMM. et al. lnuauterinc devic..-cs and pelvlc inllamma1ory Pe r itonitis ment, but antibacterial therapy is an important adjuncl
discose; an international pcnpcc1ivc. lanctl 1992; 339: 7~. Infective peritonitis, a type ofintta-abdominal inrection, is Broad-speclnlm antibacterial therapy is usually given, at
3. WHO. Guidelines for the mana;tment of st).'llally lnnsmitttd an inflammation of the peritoneum resulting from contam· least until the infecting orynisms are known, and should
infect ions. Ctnev&: \VUO, 200). Also a\·ailable 01 :
h11p://whqh bdoc.who.int/publio01ions/200)/924 I 54626).pdf ination of the peritoneal cavity with bacteria or fungi (for generally include, at minimum, an1ibacterials effective
( • - 23/03/07) infonnation on fungal peritonitis, see under Choice of An· against enteric Gram-ne&l!tive aerobic and facultative ba·
4. Clinical Efftclivcnc-s.s Group (British Assod~uion for Sc.xu1I tifungal, p.566). It may be primary or secondary or may be cilli, and entericGram-posilive streptococci. Coverage for
Hea.llh and HIV). United Kin_gd.(lm National Guideline for the a complication ofperitoneal dialysis (PD). Peritonitis may
managcincn1 of pelvic inflammatory dise:uc (issued J4th fcbrv· obligate anaerobic bacilli should also be included for in-
ary, 2005). Av1i11blc at: hup:J/w\vw.bashh,orJ!documcnu/ be complicated by inuaperitoneal abscesses, and absoesses fections derived from distal small-bowel, appendix, and
118/1 18.pdf(ICC<SS<d JBIOS/08) of the intra-abdominal viscera such as those of the liver colon, as well as for more proximal perforations in the
S. CDC. Sexually uan.smitltd diseases trealu~nt g1.1idcliocs 2006. (see under Abscess, Liver, p.170), pancreas, and spleen. presence of obstruction or paralytic ileus. 14 In addition,
MMWR 2006; 55 (RR-11): 1- 94. Also available at: htlp://
www.cdc.gov/mmwr/POF/rr/rrSS 11.pdf (accused 23/03/07) Primary peritonitis. In primary or spontmeous bacterial choice ofregimen should-take into accounl patient-specif·
Upd11td reccmmendcd treatment r~mcns for ionocoocal in .. ·peritonitis there is no specific focus of infection and it oc- ic risk factors for more resistant infection. For patients
fcctions and :sssociatcd conditions-United Statc.s. April 2007. with a history of antibacterial exposure or prolooged hos-
Available at : http:/lwww.cdc.10\'/Std/ trcatment/2006/ curs most often as a complication of ascites, particularly in
GooUpdortAp<il2007.pdf(ac«SS<d 12/04/07) advanced liver disease. Infecting bacteria include Es- pitalisation, a regimen with anlipseudomonal activity
cherichia coli, other Enterobacteriaceae, and streptococci should be considered. IS Si milarly, coverage for MRSA
or entcrooocci; anaerobic bacteria are very rarely encoun- should be added for healthcare-associated infections in pa-
Peptic ulcer disease tients known to be colonised wid1 MRSA, or who are at
tered. Infection is most often due to a single organism.
The Gram-ne811tive bacterium Helicobocter pylori is in- risk due to previous treatment failure and significant anti·
volved in the aetiology of gastritis and pepcic ulceration, Because ascitic fluid culture$ are often negative in p1imary
peritonitis, initial antibacterial treatment is generally em- bacterial exposure. 14 Coverage ror enterococci has also
and ITCatment regimens to er:ldicate the orga.nism are rec· been advocated in severely ill patients witp a history of
ommended in pe11tic uleer disease (p.I 851 ). pirical and targeted towards the most likely pathogens.
Historically, multidrugrcgimens such as ampicillin plus an prolonged cephalosporin use or recurrent intra-abdominal
aminoglycoside have been used, and mor<: recently, other infection, active immunosuppression, and in those with
Pe rinatal st reptococcal infections alternatives have included broad-spect?Um penicillins, car- prosthetic heart valves. 16 Empirical antifungal treatment
Group B streptococci are a major cause of perinatal infec- bapenems, fluoroquinolones, and combinations of penicil· might also be considered in cases of g;isrointestinal perfo·
tions, often leading to neonatal pneumonia or septicaemia, lins with beta·lactamase inhibitors.1-4 Third-generation ce· ration, anastomotic leak, or severe necrotising paocrcati·
sometimes with meningitis, although the incidence varies phalosporins such as cefotaxime are considered by some tis.1S For healthcare-associated infections, inslitution-spe·
in different parts of the world. Infections arc acquired to be the treatment of choice.1.U Current e\•idence, how- cific resis lance patterns are also an important
through matttnal genital caniage during pregnancy. It has ever, does not appear to show a significant advantage for consideration in the choice of therapy.
been suggested that prevention of group B sb'Cptococcal the ccphalosporins over other antibacterials in terms of No empirical antibacterial regimen has been shown to be
infection in infants may be achie,·ed by giving appropriate resolution of infection or palient survival.4 consistently superior or better 1olerated than compara-
antibacterials lo the mother during labour,1 but a S}'Slemat· Intravenous antibaclerials are generally preferred, howev- 1ors,11 and various single- and multi drug regimens have
ic review found a lack ofhigh-qualily clinical evidence to er, oral antibac1erials such as amoxicillin-clav-ulanic acid, been suggested by the lnfec.tious Diseases Society of
support this practice.2 Ideally maternal carriers ofgroup B cefiximc, and some nuoroquinolones' have been tried and America (lDSA) depending on infection severity and
streptococci would be identified during pregnancy, bul this may be as effective in patients with uncon1plicated infec· whether it is considered eonununity-aequired or health-
may not be practical. Factors thot increase the risk of ac- tion. The optimal duration or therapy is unclear. Intervals care-associated.14
quiring neonatal infeclion include premarure labour, pro· of 10to14 daysha"e been used, but, in one sludy,6 a 5-day For mild-10-modera1e romm1111it)Mcquired infection, the
longed ruprure or membranes, maternal fever, a previous regimen was noted to be as effective as a I0-day course. In rDSA recommends the following regimens:
child with neonatal group B streptococcal infection, and most srudies, however. length of treatment has heen dictat· • monotherapy with 1icarcillin-cla"ulanatc, ccfoxitin, er-
mulriple pregnancy and they will intluence the decision of ed by the resolution of signs and symptoms of disease, tapcnem, moll'.ifloxacin, or tigccycline
whether or not to give intrapartum antibacterial prophylax- rather d1an completion ofa predetermined course of thera-
is to the mother. A penicillin is the preforred drug. • combination therapy with metronidazole and either ce-
py.• fazolin, cefuroxime, ceftriaxone, cefotaxime, levo-
Guidelines from the USA 1 recommend prophylaxis based
Given the very high ralc of recurrence in patients surviving noxacin, or cipronoxacin
on universal prenatal screening. Where required, they rec-
an initial episode of primary peritonitis, long-term second- For high-severity communil)>-acquired infection a regimen
ommend bcnzylpenicillin or, alternatively, ampicillin, giv·
ary prophylaxis has been advocated. h1 some srudies, dai- with an expanded spectrum of activity ar.inst Gram-neg-
en intravenously during labour. In women allergic to pen-
icillin but who are not considered to be al high risk of
ly oral doses of norlloxaein have been associated with ative bacteria is suggested by the IDSA,1 and suitable reg-
lower rales of subsequent peritonitis; in one, the probabil· imens include:
anapbylaxis, intravenous oefazolin is recommended as an
ity of recurrent infection at I year was reduced from 68 to • monothenpy with meropenem, imipenem-cilastati n,
alternative; those considered to be at high risk of anaphy-
20%. 7 Cipronoxacin8 and co-trimoxazole9 are also report- doripenern, or pipcracillin-tazobactam
laxis should be given clindam}'Cin or crythromycin intra- edly effective.
venously or, where there is resistance lo clindamycin and • combination therapy with metronidazole and either cip-
c1)•tl1romycin or susceplibility is unknown, intravenous In addition, long-term prophylaxis against first episodes of rofloxacin, levofloxacin, ceftazidimc, or cefepime
vancomycin. infection has also been suggested for some high-risk pa· (however, see below regarding E.coli resistance to qui·
Jn other parts of the world, including Europe, the incidcnoe tient groups. Patients at highest risk appear 10 be those with nolones)
of neonatal streptococcal infections is much lower and the low serum sodium or ascitic fluid protein concentration, as
well as those with acute iastroinlestinal bleeding. or very • combination therapy with metronidazolc, 11.1reonam,
US model for prophylaxis may not be appropriate.3•4 and another antibacterial effective against Gram-posi-
advanced liver disease.4•1 A meta-analysis' examining ef·
Another strategy suggested for areas wi01 a high incidence ficacy of antibacterial prophylaxis in cirrhotic patients tive cocci
of neonatal group B streptococcal disease (above 1.5 per with advanced liver dysfunction or low ascitic nuid pro- For healthcare-associated i11fectio11, empirical antibacteri-
1000 live births) is to give a single intramuscular dose of tein concentrations reported a 28% relative risk reduction al regimens should be informed by hospital-specific
penicillin to all neonates al birth.5 However, despite posi- for first-time incidence of primary peritonilis, but a trend microbiological and resistance data and may require drugs
tive results in some uncontrolled, retrospective, and non· towards survival benefit failed to reach statistical signifi· active against a wide spectrum of Gram-negative organ-
randomised studies, a systematic review4 found that rou- cance. It has been suggested that short courses of antibac· isms. Multidrug regimens are suggested, and the JDSA
tine use of intr<1muscular penicillin in neonates did not re- terials may be of benefit in cirrhotic patients with aSA:ites recommends using metronidazole combined with either
duce the incidence of early-onset group B streptococcal
disease, or mortality.
withour gastroi111es1inal bleeding, but the bodr
ofevidence meropenem, imipenem-cilastatin, doripenem, piperacil-
lin·tazobactam, ccftazidirne, or cefepime; useofeolistin or
in support of this practice has been criticised. t Use of pri·
As mentioned under Premature Labour, p.202, the elimi- mary prophylaxis in such patients remains an area of con- an aminoglycoside may be required. 1•
nation of bacteria su<:h as group B streptococci in pregnant troversy and is currently not routinely recommended.2,;.to Because B. fragilis has shown substantial acquired resist·
women might also reduce the risk of premarure labour. Jn contrast, short courses of antibacterials have been asso- ancc to clindamycin, cefotetan, eefoxilin, and the fluoro-
Streptoooccus group B vaccines are under investigation ciated with significantly reduced rates ofsubsequent infec- quinolones, these drugs should not be used alone as initial
for use in pregnant women to prevent neonatal infeclion. tion, including peritonitis, and redu<:lions in overall mor- thcrapy. 14 Given the high rate offluoroquinolone-n:sistant
L CUC. Prevention of pcrinaLal c_roup 8 strep1ococcal disasc: re· tality, in cirrhotic patients wilh acu1e gasrrointestinal E.coli in some communities, Ouoroquinolones shou ld not
vised guidtlinc1 from CDC. J.IMWR 2002; SI (RR-11): t-22.
Also available 11: hnp:/!www.cdc:.gov/mmwr/PDF/rr/rr5 1I l .pdf bleeds; ii.n as a result, routine antibocterial treatment for a be used empirically unless hospital microbiological sur·
(•<«sscd 20/US/OJ) minimum of7 days has been recommended for all cirrhot· veys indicate> 90% susceptibility to fluoroquinolones. 14
All cross-rercrmces rcrer to entries in Volume A
 Antibacterials 199
For patients with only mild or moderate community· aseptic wom1d care and on minimising contact of the PD • oral clarithromycin 500 mg twice daily for 7 days; in-
acquired infeclion. drugs with !he broadest spccln11n of system with domestic water.21 fonts and children may be given oral clarid1romycin
Gram-nel!l'live and Gram-positive coverage (such as cr- 1.5 mg/kg twice daily for 7 days
iapenem and tigecycline) have no advantage and may co11- I. ~~~ll~~~i~;i;;~~',~·,~::J~~~s~~:~~.°C~C:}~f!c~YD~~l~i§1~~:; • oral erythromycin 500 mg four times daily for 14 days;
1035-17.
trib1.1tc to the emergence of more res1s1J1nt organisms. Sim- 2. R11nob A. t'I al Oia2nosls. UC'~rne:nt and pfophyloxis of spon· infants and children may be given oral erylhromycin 40
ilarly, aminoglycosides are not routinely recommended taMOUS bactcri:it pc.rltoni1is: a COllUftJUJ docu1nent. J Hf'ptuol to 50 mg/kg daily in 3 lo 4 divided doses for 7 to 14
due to their potential toxicity, although empirical use may 2000: Jl: 142-53.
l . Koul:iiouzidi$ A, er ol. Sponuancous bacterial pcrltonili$. Wm·ld days, or 60 mg/kg daily in 3 divided doses for 14 days
be warranted in patienlS witl1 healthcare-associated infec· J Gosfr'Ot'l110"012009; t ~: 1042-9. Oral co-trimoxazole for 7 lo 14 days may be given as an
1ion or intolerance to bcta-lactam or Ouoroquinolone- -1. Cha\:c:i-Tapia NC. tt.I '''· Anlibiolic5 for sponlanW!il bac1crial alternative trcatmenl for patients unable to tolerate mac-
bascd regimens. 14 peritoni1is in ,;rrho1ic palienu. Avaih1ble in The Coehrone Da.-
taba~ ofSyJtC1na1ic Meviews.; Issue I. ChiC'beslcr. John Wiley; rolides. Oxytellacycline or chloramphenicol are not rec-
The inir-ilvenous route is generally prefcn-ed, and therapy
2009 (1C<CS>Cd IS/04109). ommended because of their potemial ad-sc effects.
>. Gilbcn JA. 1Um:nh PS. Spontaneous bac1eri~I pmtoni1is: an
should be wi lorcd to culture and susceptibility report.~ updale, M(l)<> Clm 1'1-oc 1995: 70: 365-70. Mact·olidc antibacterials, given in the same doses as for
when available. Treatment is generally continued until 6. Runyon DA. ~' al Shon.""CC>Urse versus lon;·coursc antibiotic treauncnl and within 3 weeks of onset of cough in the in-
tre11mcnt <lf ,;ponl3llCOUS bacterial periton1lis: a randomit.C'd dex patients, may also be given prophylactic.ally to close
clinical signs of infection and gastrointestinal function controlled study of 100 ~limu. G"111wfltdrology 1991; 100:
have returned to nonnal; where source control has been 1737-42. contacts. 2 However, protection is limited and a systematic
adequate, aboot 5 to 7 days has been suggested.11 7. Ginb P. e1 al. NorOClxacin pttWnlS spomant'Ous bictcrial f)t'ri·
1onitis rtturre:nce in cin1tosit: rnulrs or a. double-blind. pltcc'~
reviewl concluded there was insufficient evidence to de-
b<KonlrOll<d 1r;e1. Htpo1olu1.• 1990; 12: 716-24.
termine the benefit of prophylactic treatment of healthy
For reference to the prevention ofpostoperative infection, 8. Saab S. n oi. Oral antibiotic prophylaxis reduc-es spont1nwus pcrlllSSis coniacts.
see under Surgical Infection. p.2 11. bacterial pcrnonitis occummcc and improves short-tum 1un•iv- I. CrO\\-aofl NS~ Pcbody RC. RC"tenl dtvdopmcnis in pertussis.
;.1J in cint.os.s: 1 mcta·•n:.fysis. Am J GastrMnt~rol 2009; 104: Loircc< 2006: 367: 1926-36.
PD peritonitis. Peritonitis is lhe main complication of 993-1001 . 2. CDC. h-wmmcnd(d an1imicrobial a,enu rur lhe treatrnen1 and
peritoneal dialysis(PD). Like primary, and, unlike se<:ond- 9. Sin"h N. N ttl. Tnme1hoprim-sulfamctbo>.11zote rorthc preven- postuposu.~ prophylixis of pcrtu.ssi1: 2005 CDC Guidelines.
tion of spont:iJ\tous bacteri1l p4:'ritonitis in cirrhosis: :a r:and- MMWR JOOS: S4 (RR· l 4) : 1-16. Aho avoilable ai:
ary perilonitis, above, a single infecting organism is often Clomi1.cd trial. Ann /nfUIJ Mtd 199S: 122: 59!'i....S. h11p:l/wY11•'.cdc.gov/mmwt'/PDFlrrlrrS414 .pd( (acctsscd
responsible. The most commun infoctions have usually 10. Frnue LA, et al. Lon;-lcrm pn;1ph)"laxis of sponta~ ba.ctt- 18/08/0S)
been due to Gram-positive organisms, especially siaphylo- ~~f.:);1~9g~~:~. pa1icnts wilh cirrhosis. Amt Pharmocot/w_,. 3. Ahunt1iji S. ei nl. Antibioocs for whooping coug.\ (pertussis).
cocci, but infections wilh Gram-nega1ive bacteria (typical- I I Cohen MJ. t:I al. Antibiolic ptophylnis for spontaneous bacte-. Avail3ble in The Cachrar"C Oaub11.s.c of Sysltmatic Rcvi~ ls.-
ri:il peritoniris in cirrhotic p:iticnts wirh :iscitcs, withoul sas1ro- SU< 3. ChicheSier: John Wiley: 2007 (accessed 27/06/08).
ly Enterobaclcriaceae) arc becoming more common, and
intestinal bleedi111. Av:ilablc in The C"och~nc Darab:ue of Sys.
fun~ are an incr:casingly important cause of peritonitis in 1enuric Reviews~ Jssuc 2, Chichester: John Wiley~ 2009 (ac-
PD. The origin of infeciion is often conlllmination of the t.....S l311l4.110). Pharyngitis
dialysis catheter or the exit site. 12. Berna.rd B. tt ol An1ibio1ic prophyla..'<is for Lhc prtvcntion of Pharyngitis and tonsillitis arc upperrcspirnlory-tract infec-
bxtcrial infcction.s in cirrho tic patients With aastroinlcstinal
bleeding: 1 mct1-anatysls. H~pntol<>c)' 1999, 29: 16.S.S-61. tions with similar causes and occur especially in children.
Th e ln1erna1ional Society for Peritoneal Dialysis I 3. Soarca-Wcistt K. tt ol. Antibiotic prophr.laxis for cirrhotic pa- Acute pharyngitis is an inflammalory syndrome of the
recommends 18 that the choice of antibacterial for empiri-
cal treatment be based on the history of sensitivities of ~1~~!t:~~~~,;!~i~";~~l!~si:n~$~:21.1C~!fc~"tt":: ~::~~~ oropharynx that may include the tonsils whereas tonsillitis
Icy: 2002 (a«=>ed l 5104!09). is, strictly speaking, a more localised infection. The com-
orgnnisms causing peritonitis in the particular hospital or or
14. Soloml:.in JS. et al Oi:ignos1s :ind mu.nagtment compltca~J monest causes are viral and a sore throat is often a symp-
centre involved, and be active agiiinst both Gram-positive infra-abdominal infect.on in ldiuhA an.d children: guidelines b_y tom of the common cold as well as influenza and infec-
and Gram-negative organisms. In many case.s, first-gener- I~ Su~ical Infection Soctay and th~ Infectious Disease$ Soa-
<IY of Am<r;co. C/111 /iiftc1 Du 2010: 50: 133-<14. Also pub- tious mononucleosis. For further details of these viral
ation cepbalosporins such as ccfazolin or cefalolin provide li"1cd ;nsu1-g llifcct 1La,.tho11) 2010: II: ~~109. infections, see under Choice of Antiviral, p.938.
adequate Gram-posi1ive coverage, but in centres wid1 high Also available At: hUp:l/www.id&ocicty.oralWorkAreet
The most impo1tant bacterial cause of acute pharyngitis
rates of meticillin-resistanl infection empirical va11comy-
cin may be needed. Drugs for Gram-negative coverage
IS. ~-=·~~:::~~i~~~:!t~~~fi:l~l~~::~~~~~%~~)l and tonsilli1is is lhe group A beta-haemolytic streptococ-
j~ t::2S~ic•1cd inlr:l·:'lbdomin:il infe:C'lions. Drugs 2005; 65: cus, Struplococcus pyoge11es. An erythrogenic loxin-pro-
should possess activity against Ps. aerugilroso and may in-
clude the aminoglycosidcs, ceftazidime, cefepime, a =· 16. Harbtnh S. Uckay I. A rc there p:aticnls with perrtonitis ,,.ho
re-.
quire empiric lherap~· for c.nterococcu1? £11,. J Clin Microliiol
ducmg str.iin causes pharyngitis and tonsillitis in scarlet fe·
ver.
bapenem, or aztreonam. Fluoroquinolones are onl)' appro- /11ftc1 Dis 2004: ?;: tl-7.
priate for Gram-negath·e coverage iflocal susceptibility is 17. Wong PF. Cl nl. Antibiotic re1imcns for s«ondary pcrilonilis of In view of the prevalence ofa viral cause, opinions have
shown. gasrrointcstinal ori;.in m ldulU. Availoblt in The Cochrane: 0.. differed over whether and when 10 treat pharyngitis wilh
'"base of Sy$1co11hc RnltWS; luuc 2. Chichester. John Wiley; antimicrobial drugs. Some have advocated waiting until a
1005 (accessed I S/0~:'09).
lntraperitoneal dosage. by mixing the antibactc1ials with t8. Pir::1ino 9. er al. rc,;1onc:a1 dfal)"5is-refated. infections t'"°'1l• definite diagnosis of Sir. pyogenes infection is made, but
the dialysatc, has been shoM1 lo be more effective than in- mend:lliM~: 200S update Pnit Diof Im 2005; 2S: I07-31 . od1ers treat immediately ifstreptococcal pharyngitis is sus-
travenous IJS(.'. For many antibacterials, once-daily inter- Also a\aif:ible 01: hnp:/fwww. ispd.oralgu idcline.sl pected because of the risk of longer tenn complications
03Piraioo42371SP0%20with%20walerm.1rk.pdf (~cces.sed
mittent dosing regimens (in a single dialysate exchangel 27/0Ml6) such as rheumatic fever and the need to emdicate Sir. p~
are appropriate and as effective as continuous regimens.' 19. WtfJins KJ. d al. Treatment for pt:ri1oncal d1alysis·associatc:d ge11es &om the 1hroa1. 1-3 The incidei1ee of rheumatic fever
lnlenn ittent doses ofvancomycin are generally given once p...,·nonnis.. Awilabl~ in Tilt Cochr.)nc Oat.aNte or System3tic has been low for many years in developed countries, but
Re,·itws; 1ssue I. Chichcsler; John Wiley: 200S (;i,cccssed
every 5 10 7 days. 18 Once tl1e infecting organism is identi- I S/04/09). there \\·as evidence of a resurgence in par!S of the USA in
fied, an appropriate narrow-spec1nm1 anlibac1crial can be 20. Strippoli GF. ~al. Antimicrol'linl agents rot
preventing pcruo- the mid-l 980s. Thus, in nddi1ion to shortening the illness
nilis 1n 1>critonal dial)sis patients. Av<1ilablc in The Cochr~ne
substituted. Treatment is generally continued for 14 days Database ofSy5lcmalic Rt,icw$; Jnuc 4. Chichcs.tcr. John Wi- and inte1rupting transmission, the antibacterial treatment
in patients who have a clinical response. Treannenl should ley; lllll4 (a<e<SS<d I SI04/09). of streptococcal pharyngitis also serves as primary preven-
be e.~tended to 2 1 days in patients Y<ith severe infections 21. Ludlam H, 11 nl. P'~\cnt ion or peritonitis ir- continuous ambu· 1ion of rheumatic fever(sce below). However, in coun!Ties
l.:ltocy peritoneal dialysis. L.an«t 1990: JJS: 116 1.
(such as Stoplr. aul'eus, Gram-negative, or enlerococcal in which lhe incidence of ri1eumatic fever remains low !he
periLOnilis). routine use of antibacterials for the managemenl of sore
Pertussis throalS is discouraged.•.s
Exil·site infections can be treated with an oral penicilli- Pertussis or whooping cough 1 is caused by infection with Penicillin is the standard treatment for streptococcal phar-
nase-resistanl penicillin, a firs1-genera1ion cephalosporin the respiratory pathogen Bortl111ella pe,.tussis, a Gram- yngitis or tonsillitis.6-8 generally as phcnoxymethylpeali·
such as ccfalexin, or co-trimoxozole for Gram-positive in- ncgative aerobic bacterium. 'Ilic rcl3ted species B. parap·
fections. Vancomycin should be avoided for routine use cillin orally for 10 days or a single intramuscular injection
erlussis causes a similar b111 generally mi Idec illness. Per- ofbenzalhine bcnzylpenicillin. Both options are advooiled
bul may be needed if lhete is meticillin resistance. Rif·
ampicin may be added m severe Staph. a11reus infections.
n1ssis is very infectious and occurs m_ost frequently in chil- by WH07 and the American Heart Associalion8 for the
dren, but may be more common in adults than once primary prevention of rheumatic fever (see under Rheu-
An oral lluoroquinolonc such as ciprofloxacin may be thought. The incidence of pertussis has been greatly re- matic Fever, p.204), the latter particularly where compli·
used for Gram-negative infections. 18 l111raperi1011eal duced by the active immunisation of i11fo111s (see under ance with a JO-day course of oral penicillin is unlikely.
celi.azidime may be ndded in cases of pscudomona I infee- Pe1111ssis Vaccines, p.2438) and effective prevention by Oral amoxicillin is also e(fec1ivc7•9 and a further treatment
lion where resolution of infection is slow or where there is the adequate uptake of vaccine remains the ultimate objec- option for confim1ed strcplococcal pharyngilis;8 however,
recunence. 1ive. some suggest dial empirical use of aminopenicillins (in-
Long-Lenn antibacterial prophylaxis is not generally ef- Erythtomycin has been the Anllbactcrial of choice, but the cluding amoxicillin and ampicillin) should probably be
fective, bu1 intenninent use has been advocated in situa- newer macrolidc-s, clarithromycin and azilhromycin, have avoided because of the risk of maculopapular rash if the
tions associated with higher risk of infection. Pcriopcrative similar efficacy and are also recommended for the treat- patient proves 10 have infectious mononuclcosis. 10 E;ryth-
intravenous antibacterial prophylaxis during PD catheter ment of pcr1ussis. 1·J Once infection has occurred antibac- romycin or another niacrolide may be gi»cn to penicillin-
insertion is recommended." and has been shown to signif- terial therapy is thought 10 render the patient non-infec. allergic patients, except where there is evidence of signifi·
icantly reduce the risk of peri1oni1is in the firs1 month after tious by eliminating nasopharyngcal carriage of B. cant resistanee,7.s as in some parts of Europe,' die USA, 11
surgery.io Staph. aureus nasal carriage is associated with perrussis. Such treatment is unlikely to affect the clinical Japan, 12 and Finland;13 it may also be a bellcrehoiee lhan
increased risk of exit-site infections and intl'llnasal or exit· course of pertl.1ssis because diagnosis is diflicult until the penicilli n if there is a likelihood of infeclion wilh~ano­
site mupirocin (cream, as ointment may damage the cath- paroxysmal s~~gc, by v.i1ich time the bacteria have already fx1c/eri11111 lraemo~11icum (Co1:vnebac1erium /raemolyli·
eler) or e~it-site gentamicin cream have been used to re- damaged the respiratmy ITllCt and released !heir toxins. Ef- cum). but should be avoided if there is risk of infection
duce them." llle results of a systematic review suggest fective regimens include:lJ with Fusobactel'ium neci'OphoMlm (see below). Clindamy-
Llm u-eaiing carriers with in1111nasal mupirocin significant- • oral azithromycin 500 mg daily on the first day of treat· cin may also be used.s Oral ~alosporins nre another al-
ly decreases o'·crall ralo:s of exit-site infections. although mem tl1en 250 mg daily for 4 days; infanlS and children ternative, and a meta-analysis 4 has shown that the likeli-
there d.xs not appear lo be an associated reduction in risk ma)'-bc giwnoral aiithrumycin 10 mg.lkgdaily for 3 to hood oftreatmcm failure with oral cephalosporins may be
of perironitis.~ Dramatic reductions in pcri1onitis rates 5 days, or 10 mg/kg daily on the first day of treatment abont half tha1 with penicillin; first-generation ccpha-
have been achieved with programmes based on suiogent then 5 mg/kg daily for 4 days losporins appear no less effective than later gcncraiions.' 4
200 Antibacterials
and are generally freferred due to tlleir narrower antibac- algesics, or ifthey are safe for use in pharyngitis not requir- lS. Brook 1. Treatment of p,aticnts ~ith acutt tceum:n1 1onsilli1i$
terial spectrum.'' ing antibacterial therapy. due to 1roup A D·h.aemolyaic weptococcl: 1 prospecch•c ramJ..
omized stud7iwcomp1ring penicillin and amoxycillin/chtvulanate
Despite the general efficacy ofpenicillin a trend of increas- I. Anooymous. llacte,;11 ~haryn4i 1is. Lanat 19117; i: 1241-2. pota.sium. lf»l/Mf<rob ci..-thu 1989; 24: 227-33.
2. Marco.ntch H. Sore throa1>. 1frch Dis Child 1990; <>5: 249-50 36. Dykhuiz..cn RS. ti ol. rhenoxymt:thyl penicillin vi::CJus or
ing numbers of relapses and recurrent infections has been l . Lan.& SDR 1 Singh K. The sore throat: when to invcslipte •nd omo.xiclav in the lrc.llmt'nt of :tCUIC SlrtplOCOCCal p}wyftiiUS.
noted.is Some treatment failures have been attributed to when to prescribe. or..g1 1990: 40: 854-62. and the ro~ of J-lactama.st ac1ivi1y in ~a liva. J An1it11icrob
poor patient compliance with a 10-<lay COW'Se of penicillin 4. Liu.le P, et a l. Rca1tcndance ind complications in a randomMd Chemother 1996:J7: lll-8.
and attempts to overcome this have included giving fewer ~r~~~~~~~ir~~i;g5:!t'~!:t~~8:i1 9~j~i1~3~~icatislni 37. Foote PA. Brook J. Penicillin and clindanwcin lhcr:1pvin recur·
rent lonsillitis: effect. of microbiol nor1 A;,.lt OIOID.T):,,gol Heotl
daily doses or shortening the length of treatment Meta- S. Del Mar CB. ~1 al. Antibiocics for sore lhr04L AvaHablc in The Neck S>1ri l9S9; 115: 856-9.
analysis of studies suppons the use of twicc-<laily dosIDg Cochrane 01t.1baseofSystcmat·ic Reviews; lssuc .J. Chichester: 38. Rot R, ~t ol. OindQ.mycin in the trutmcn' o{ an outbreak of
of phenoxymethylpenicillin which appears to be as effec- Joh n Wiley; 2006 (accessed 18108108).
6. Bisno AL. Aeutepharyngiti•. N Eng/J Mtd2001; 344: 20$-11. ~':cf~i:!~::.:~;.~1~h:;,t~~i:;:0~~ 11g2~~·1actamasc
tive as doses three or four times daily, 16 but a single daily 7. WHO. Rheumatic. fever and rhcuma1ic hart disc:asc. WHO T1i1~h 39. Tam RR. et ol Pcnic:Jllin plo$ rifampin eradicates pharyngeal
dose is less effective. Cow-scs of phenoxymethylr.:1icillin Rep Ser 91J 2004. Also Available at: http://~ww.who.int/ camagc or iroup A strcp1ocoui.J Pedia1r I98S; 106: 876-80.
cardiovascubr_ disc.aseslre:soorce~enlcvd_trs923.pdf (accu.~d
shorter than I 0 days have not proved effective.' ·" There 02/03/10) •o. ~~a;eR~/~r~~PC~~~~J~:,~c;: f~~~~if1~~T;~L'
is some evidence that shorter courses may be possible with S. Gat>er MA, ~t ol. Prcvcn1ion o( rheum:atic. fe11t:r nnd di:agnosis 41. Gray G~ el cl. Hypcrcndtmic Streptococcus pyogencs infec-
other anubacterials. 19 Courses of S days or less of crythro- and ttcatmenl of acute slrcpl:oc:occal pharyngitis: a scientific tion despi1c prophylaxis with penicillin G benz.athinc. .Y Engl J
sutcmcnt from the American Hc:an As.soci11ion Rhcumitic Fe.. Mui 1991; 325: 92-7.
mycin,20 amoxicillin with clavulanic acid,2 1 azithromy- vu. Endoc~rd itis, and Kawas:aki Disuse Commiuec or the
;:;~~.~~d~~:;~:~t~~89'.~Fsf~:.:t"°""'n"
42
cin,1?.D cla:rithromycin,24 josamycin,2S tclithromycin,u or
~~~=~'t:u~i~:nFu!:tta.:!afG:!:i\~~ :~i.~~~-=li~:
.
ccphalosporins21 have been given as alternatives to a l O- 43. Gruyston IT, ~t ol. A acw respiratory traC'I pathoicn: Chlamydia
day course of phcnoxymethylpeniciJJin. Ho111ever, defini- ology, and the Interdisciplinary Council on Quality ofC.rc and pncumoniae strain TWAR. J ln/¢ct Di.s J990; J'I: 618-2S.
tive studies have not been done, and the broader rtrum
Oul<."Omes Rcscarch: endorsed by the AmcriCll'I Academy of a.
44. Hayward n al. Corticosteroid.-. for pain rehtf in sore 1hroat:
Pedia1rics. C;rc11/otion 2009; 119: 1541-.SI. Also av1ilabte at; sys,cmat.ic rC\'1tw and mcla·tlnalysis. Abridgod version; BMJ
and higher cost of these regimens are drawbacks. http://circ ..1h1journals.org/cgilrcprintll l9/l 1/JS41 (accc.s.scd 2009; 339: 418-90. Full vmion: http://www.bmj.co1n/cgil
02/0S/JO) reprint/3391aua()6_2/b2976 (aoccssal 02/03110)
Penicillin resistance in Sir. pyogenes remains rare. In ilddi- 9. Lennon DR. ttl al. Oncc·drtily 1JnO.Xicillin versus twicc--daily
tion to poor compliance, treatment failures with penicillin, penicillin Vin group A P-·haemoly&ic s1rq>1ococcat pbaryngitl.\,
ArdrDis Child2008; 93: 474-8. Pinta
leading to recurrent infection, might be explained by the 10. Scouish Jntcreol le~iatc Guidelines Network.. Management or
presence ofbela-lactamase-producing oropharyngeal bac- sore lhroat and indications for tonsilltclomy: a national clinical Sec Syphilis, p.207.
teria that arc able to protect Sir. pyogencs against penicil- auideline (issued January 1999). Av•ilable at: hllp://
lin,:>& although this theol)' was not supported by a study in www.sifn.•c.uk/pdflsigr>J•.pdf(occascd 02/03110)
11. Manin M, ct al. Erythromycin-resiatanl aroup A streptococci Plague
462 chitdren. 29 Antibacterials less susceptible to beta in 0<:hoolchildrcn in Pittsburgh. N Engl J Mtd 2002; :U6: Plague l,2 is caused by the Gram-negative bacillus Yersinia
lactamase have been effective, sometimes more so than 1200-6.
peslis (Yersinio pse11do111berculasis subsp. peslis) and is
phenoxymethylpenicillin. They include the oral ccpha- 12. Maruyama S, ~1 al. Scnsi1iviry of grouC A strep'OC«ci 10 anti·
~~t~~;J;;'~~~J: ~~;.ce lo cryt romycin in Japan. Anr J usually transmitted to man via rodentS and their infected
losporins ccfaclor,lO ccfuroxime axetil,'' cefiximc,l2 ccf- fleas. It has occurred as worldwide pandemics, for exam-
prozil,31 and cefadroxil..., and tltc combined preparation 13. Sc:ppll$ H, el oL Rcs\stante to Crythromycin in group A SUCP" ple, the Black Death in Europe in the Middle Ages. In the
oococci. N Eng/J M<d 1992; 326: 292-7.
amoxicillin with clavulanic acid3S.l6 (however, see above 14. Casey JR. Piehieh<ro ME. Mel•·•nalysisof<q>holospo,;nsver- l 980s the largest numbers of cases reported were in Tan-
regarding the risk of rash with aminopenicillins). Clin- s:us penicillin for ttcatmcn1 of poup A strcpcococcal tonsillo- zania, Vietnam, Brazil, Peru and more recently in Mada·
damycin has eradicated Str. pyogenes and beta-lactamase- pharyngitis in adults. Cli>1 Jnf«r D/12()().1: 38: I S26-34.
IS. Diiion HC. Strcptococeal ph31)'nlitis in the 1980.. P<diotr ,,..
gascar. Plague may take several fonns of which bubonic
producing bacteria in children aged I 2 years and under /«• 1);1J 1987; 6 : 123-30. plague is the most common; others include pncwnonic,
with recurrent tonsillitis, but might be less effective in old- 16. Lin AJ, ttol. The impact of dosing Crtquencyon lhecfficacy of septicaemic, and meningitic plague. Streptomycin, tetra-
er patients,;7 It was also effective where penicillin and 10-<l:i:y penicillin or 3moxicillin therapy for strcpcocoe:cal 1onsil- cycline, and chloramphenicol have traditionally been used
crythromycin had failed in an outbreak of streptococcal loph:aryngi1is: 1 met.a.analysts.. Abstract: Pedlotrlct 2000; IOS:
414. Full vcnion: ht1p:J/pcdiatrics.aappublication1.orafc1i/ in the treatment of plague; with streptomycin being the
pharyngitis.13 contcnLlfull/IOS/21<19 (accessed 20/0S/04) treatment of choice, although the possibility of a Jarisch-
17. Gerber MA. ~t ol. fiw: vs ten days of penicillin V thenpy for HeIXheimer reaction resulting from the bactericidal effect
Pharyngeal carriage ofSir. pyogenes is common, especial- 1trep1ocoeeal pharyngitis. A•• J Dis Child 1987; 141: 224--7.
ly in primary~ool children and tl1us its presence docs of streptomycin must be borne in mind; it is also contr'd·
not necessarily reflect acute infection. Eradication is gen- lS. ~1~;~1·:S~n~~~;:i~i~fs~~n~!romU:::!1~!1f~~i:. indicated in pregnancy. Success has also been reponed
erally uMcccssary7.8 but may be beneficial in selected cas-
es and has been achieved by a single intramuscular injec-
111/«J °"
ical tt•al with phenoxymethylpenicillin and c.cfadro:-:il. $cand J
1988; 20: 37-46.
19. Aftamuni S, •I ol Short vcrsuss~ncbrd dunrion anlibiotic ther..
with aminoglycosides such as gcntamicin and kanamycin.
Although there is no clinical experience with fluoroqui-
tion of bcnzathine benzylpenicillin together with a 4-day apy (or xutc srreptococcal pharyngitis in children. Available in nolones, i11-vi110 susceptibilities and animal studies sug-
cowsi of oral rifampicin;'9 a JO-day course of ora l clin- The Cochrane Database o(S)'Slcmatic Rcvie~'S: Issue I. Chich- gest that they would be effective.;
C>l<r. John Wiley; 2009 (acccucd O;IOS/JO).
damxcin has also boeo effective."° lo order to ensure that 20. Acbm D, cl nl. Five days: of tr)"lhromycin estolate versus Im In the UK, the recomrne!lded treatmenl for adults is gen-
outbreaks of Str. pyogcr1es arc prevented in closely con-
fined populations, some have rcc:ommcnded prophylactic ~~;:;1~!;.ca~~~~tis~n1 ~h~=-~n;~;';':f;~,:b~1:JcJ':;::, tamicin (first choice in pregnancy); ciprofloxacin ordoxy-
cycline may be used if aminoglycosidcs are unsuiltlble and
1996: 15: 712rl7. •
antibacterials for all members of these populations. with- ma)• also be used for first-line therapy in children, but dox-
· ~~~o~~~~~=!?:i~i~r~:·1:?cdr::¥i~c J.~'!h;,::1~1~nr~
21 0
out exception.' 1 ycycline is only suitahle for children over 8 years of age. If
ror 1en days io acute group A strep1ococcal consilloph.aryngitis.
Other bacterial Cll11ses ofpharyngitis includeArcanoboc- Ptdiotr lnf«I Dis J 2004; 13: 8S1~5. plague meningitis is suspected chlomnphenicol should be
Jerium hnemolylicum (Corynebocterium haemolyticum), 22. O'Dohcny 8, ~t al. Ari1hromycin vcrsu.s penicillin V in the used as it crosses the blood-brain barrier.3 Similar informa-
Ch/amydophila pneumaniae (Chlamydia pneumoniae). 1rc:itmen1 o(pacd.i:iuic p3ticntt with aculc SUt:pcococc2I ph.aryn- tioo is provided by WHO,' with sulfonamides bcing men-
:iriJ/1on'<ilht1s. Eur J Cli11 Microbiol llf/ttt Dlt I996; 1S:
Corynebacterium diphlheriae (sec under Diphtheria, 718-24. tioned as alternatives. European g11idelincs5 consider ei-
p.177), Pusoboc1ei·i11m necrophorum, Neisseria gonor- 23. Hooaon TM. /\ comp:iri.sonof u:ithromyci.n oind penicillin V for ther streptomycin or gentamicin 10 be appropriate for first-
rhoeae (sec under Gonorrhoea, p.206), groups C and G lhc trcacmcnr or strc_pcococal pharyngi1i.i;. Am J Mid 1991; 91 line treatment of plague in both adults and children, and
(suppl 3A): 23S-26S.
beta-haemolytic streptooocci, and anaerobic bacteria. 24 Portier H, et al. Five d:ay e:l;rithromycin modified release vusus suggest that ofloxacin and lcvofloxacin may be appropri-
ate alternatives to ciprofloxacin for second-line treatment
A. haemolyticum is thought to be an important cause of ~ou~?'crn~ri:.i1~~~.. 1~bef,~~d~~ri~~~o~::;~ ~h~'!,~!i:;!~b in adults.
pharyngitis in adolescents and young adults; there is often C/1cmv1hv 2002; 4': 337-44.
an accompanying scarlatiniform rash. It has been reported 2S. Ponicr H, ~1 al Groupe d'ftude de pathologic inftcti~ pCd1· In UK guidclines3 ciprofloxacin is considered to be the
to respond 10 a single injection of benzathine benzylpcni- atriquc. Tnilemcnt des angint"S algufs ii •Ucptocoqu~ beta-hi· drug of choice for prophylaxis in adults and children con-
molytiqvc du 17oupe. A chcz l'cn(3nt pat la jos.am)'Cine pcnd3nt sidered to be at risk af\er close contact with cases of pneu-
cillin or a 10-day COUISC of oral crythromycin, but not to cinqjours. A~ll l'tdiotr 2001; 8: 700-6.
phenoxymcthylpenicillin.6 26. Notlt>y SR. 11 al. Evaluation of S-day therapy with tcliohromy· mooic disease or after a deliberate release of Y. pestis; rlox-
cin, • no,·e.l kc1olidc ::intibacleri1l. for lhc treatment of tonsilfo· ycyclinc may be used as an o.ltemntive in those 01·er I 2
F necrophon1m is also common in adolescents and young . pharyngitis. Cli• Microbial fn/ect 2004; I 0: 61 S-23.
years of age. European guidelines! offer similar advice,
adults, and is thought to cause about I O"/o ofacute pharyn- 27. Pichiehcro M. Casey J. Comparison of Euror>ean ond U.S. r°'
but consider levofloxacin and ofloxacin as possible op-
suits for ccphalosporin ver5vs penicillin trcatmenl of a.roup A
gitis within this age group.'2 Of particular concern is its l:trt'ptococcal tonsillophaf")'nlil1s. £11r .I CHn Microbiol J,;/«.1 tions for prophyla.~is in adults. Other suggested antibacte-
association with Lemierrc syndrome, a life-threatening Dis 2006: 25: 3S~4.
28. Drook l. '111< role of p.tacum1sc-producin~ oococria in w per· rials include co-trimoxawlc,3· 5 chloramphenicol,3..S and
condition cha.racteriscd by bacteraemia, metastatic infec- sulfadiazine.5
tions, and suppurative thrombophlebilis of the internal jug- ais1cnce or strtptococeal tonsillar inf~cuon . Rev lnfe~t Dis
1984; 6: 601-7. Commenting on the plague epidemic that occurred in In-
ula:r vein. Although susceptible to penicillins and cepha- 29. Gerber MA. et ol. PolcntiJl mcc;hani.Mns (or failure to eradicate
losporins, F. necropharum docs not respond to treatment group A llrcp<ococci from the pharynx. P~t1;01ria 1999~ 104: dia in 1994, workers from the US CDC6 considered that
with macrolidcs; it has therefore been suggested that em- 911- 17. prophylaxis should be given lo those who have had f'ace-
30. Stillerman M. Comparison of oral ccphalos:porins wtlh penicil- to-face contact or who have occupied a closed space witl1
pirical use of macrolide$ be avoided in adolescents and lin thtnpy for poup A streplococcal phary~lis. P1dia1r /nf«I
young adults with acute pharyngitis.42 Dis 19&6; 5: 649-$4. someone who has pneumonic plague. For prophylaxis, tet-
31. Gooch WM, ct ttl. Efficacy of ccfuroximc a.xctil $\Jspcnsion racycline could be given to adults and older children or
For pharyngitis associated with C p11eumoniae infection, compared with thtl or penic1Hin v sus::pension in children with sulfonamides to children of8 years or less; chlorampheni-
tetracycline or erythromycin are effective antibacterials. 0 poup A strepccx:occal phlr')'ft&itis. Antimicrob Agents Chem·
co! was a.lso effective.6
01htr 1993; 37: 15~3.
Systemic conicosteroids have been tried for the sympto- 32 Kianl R, c t a l. Compantive, muhiccnter 11udies of~cfh:imc and Infection \\~th a strain of Y. pestis resistant to all the drugs
matic relief of acute pharyngitis and in a meta-analysis,.. Amoxicillin in Lhe uutment of rcsp111i1ory 1nic1 infections. Am J usually effective against plague identified in a patient from
M•d 1988; 85 (suppl 3A)< 6-13.
patients with severe or cxudative sore throat who took cor- 33. Milatovic O. et al. Cefprozil versu-1 penicillin V in trealmt-nt of Madagascar7 responded to treatment with co-trimoxazole
ticosteroids in addition to antibacterials were 3 times more strcplucoc~t lonsillopharyngitis. Allllmic1'0b Agen11 c:Mmolh· and streptomycin.
likely to have complete resolution of pain at 24 hours than <r t993; 37: 1620-3.
34. Milatovic 0, Kniucr J. Ccrodroxil versus penicillin in lhe 1rc:at- A ,;accinc is available for active imnnmisation.
those who did not However, it remains unclear whether nlenl of Slrcptoaw:cal t0t1~illopha ryngi1is. Eur J Cli11 Mic1'0hlol I. Prentice MB. Rahalison L. Pl•guc Usn<'CI 2007; 369:
corticosteroids offer additional benefits over simple on- Infect Dis 1989; 8 : 282-8. 1196-1207.
All cross-refcrenus refer to entries in Volume A
 Antibacterials 20 l
~-Buller T. Plq~ mlo ~ ll • c.c-ntury Clm lnf«I Du 2009; -49: ogeo is oflen unknown, mitial antibac1crial therapy is usu- • Ps. oe111g1nosa: preferred treatment. intravenous
736-42.
ally empirical. Guidelines for the treaoncnt of ~monia ccftazidime plus either gentamicin or tobnmycin; alter-
Hutth PtOlttUCH1 ACCll\t)' G111c!di.Mt fot ac•1on 1n tht event or
1 dchbcrll• rtl<»• plopc (tSSll<d April 2007). Av11l1ble a: ~ been issued by bodies in many countries s.i1-1s Al- natives, intravenous ciprofloxacin or piperacillin plus
IUI;> /;._., . hp1.or;.ukl 'Wcb!ll'A""cbf1lcl t-IPAwcb_CI though common principles can be identified, recommen- either gcnwnicio or tobnmycin
11 ~~ 1J9607l (occt-.1 IS/IWOI) dations must be localised because of differences in pit· • Staph aweitS (noo-meticillin-rcsistant): prefcned treat-
• WHO l'ktJw ,,,,,,,_I •f"d'"'""''i>· ~'""""-· •-illo1.u 1cms of infection and drug l'CSISlance, variations in the ment, intravenous Oueloxaeillin with or without oral or
ottd t:011irol Au1lablc 11 hl1pJ,,,._..,..,,. • ho.tn\fcsr!ruourcH/
.,.1i1--p1opc.-w11o _cos_csR_EOC_99_2_eww <ac· availability ofantibaclerials and local policies for their use, intraVCOO<IS rifampicm; alternatives, intravenous~
cat<d2 7~) and differences in medical prectlce. COWltries also vary m mycin, lmczolid, or tcicoplanin with or witl1out oral or
S Bou1 P. " "' Tail. f O<U
Tim:a\$ of Ille~
°"
B'°lotical and C'Nnocal 11~1
c.....,........
BICHAT .......... for
the degree to which such guidelines are aca:ptcd in pr4C· intravenous nfampicin
&he d1n1ca1 m.a.na;c-MCM of pbi&ae •nd b1otenonsraootclatcd 1ice. Thcscguidelinesgcnetllllygiveadviceford1ffcrcnces • Staph. auttll$ (mcticillin-resistaot): preferred trealJlJCnt.,
pla;" c. Ettr S•n-.111 ~004 : t: 1-6 Also 1u.1lablc 1t· associated with age, the severity of the infccuon, and the intravenous vancomycin, lioezolid, or teicoplarun with
hnpJlwww turOJUr"lttl&arta ori -' 1rn11nidynan1te1~ 121 presenceorabsenccofunderlyingorco-cx1stentdisordcrs.
09 12·230 pclf(occessed OWl.110) or without oral or intravaious rifampicin
C1.,pbcll GL. Hushes JM. l'lalu< • Ind•• 1 new...,,,,.. from In the UK, guidelines for the management of CAP have In the USA, guidelines for the management of CAP in
MIOld,_,.su Annl"t""/>kdl99S, 122• ISl· l been produced by the British Thoracic Society (BTS).1 For adu ltS have been jointly produced by the Infectious Dis-
7. Gakmud M_ a 111 Mulctdnlt t•ti\MU 1n Ycnan11 pcstis: med•· initial empirical treatnWll in tlle comm1111ity oral amox1-
a1rdb) 1 innsfcrabl• pl••nud. A L't'J Altd 1997.337: 677-80. eases Society of America (IDSA) and by the American
cillin is usually preferred. Aliematives in penicillin-aller- Thoracic Society (ATS). 11 For previously healthy outpa-
gic paticms include doxycyclioe and the macrolides clari- tients with no risk factors for drug-resistant Srr. pneumom-
Pneumonia thromycin and crythromycio; claritluomycin is acnerally ae (DRSP) infection they recommend a macrolide (such as
Pneumonia' is a ~iratory disease characterised by in- preferred to eiythromycin due to better toler1lllCC and more ery1hromycin, azithromycin, or clarithromycin); doxycy-
flammation of the lun¥ parcnchyma with congestion.his convenient dosin11- The approach to treatment Is similar cline may be given as an alternative. In those with co-ex-
mostly due to bacterial or viral infection, but may be for patients hospitalised with /ow-revei·iry CAP, many of i~ting cardiopulmonary disease and/or otl>er complicating
caused by l\mgi in immunocompromised pntientsor by the whom are admitted to hospital for non-clinical reasons factors (such as renal disease, diabetes mcllitus, alcohol-
aspiratJon of chemical irritants. Pneumonia is a common such as old age, family preference, inadequate horne care, ism, malignancies, or asplenia). taking immunosuppres-
illness occurring in all age grou))) and throughout the or adverse social circwnsiances; when oral therapy cannot sivc drugs, those who hove received antibacterial therapy
world; it is a major cause of dea1h among the elderly and be used in these patients, intravenous amoxicillin, bcn· 'Nilhin the previous 3 months, or those with other risks for
those who are chronically and/ortenninally ill. Symptoms zylpenicillin, or claritluomycin are suitable altcrnotivcs. ORSP infection a 'respiratory fluoroquinolonc' (gemi-
and signs of pneumonia include cl1ills, cough, dyspnoea, In those patients lrospitaliS'ttd with madtrately-scvere Ooxacin, levoflox1cin, or moxilloxacin) is recommended.
fever, headache, myalgia, plcunt1c chest pain, and spu1um CAP there is an increased likelihood of infection with Alternatively a beta-lactam (high-doseamoxicillin witll or
production. Treatment of pneumonia relies on prompt use atypical pathogens, or with legiOlll!lla spp.; consequently, without clavulanic acid, or ccftriaxooe, cefpodoxime, or
of anlibactcrials and identification of the infecting organ- combined empirical treatment orally with amoxicillin plus ccfuroxime) plus a macrolide (or doxycycline) may be
isms and their sensitivity to antibacterials. Cases of pneu- either erythtom)'Cin or clarithromycin is prcferrcd.1 When given.
monia are usually classi6cd as community-acquired or oral therapy is inapp-opriate, intravenous ampicillin or In llospilaliSLd patients who are not in intensive care the
hospital-acquired (nosocormal) pneumonia. Cases ofcom- benzylpen;cillin is given. with intravenous clarithromycin. preferred treatment is a bet2 lac1am (cefotaxime, ceftna't-
munity-acquired pneumoma can also be funher S1Jb-divid- For those intolerant of bcu lactams and macrolides, oral one, 3mpicillin, or ettapeoem) plus a maaolide (or doxy-
ed into tl!0$1C who can be treated in an ambulatory (outpe- doxycycline, levoOoxacin, or moxiOoxacin can be consid- cycline). Jn penicillin-allergic patients a respiratOI) tluor-
tient) setting and those ~lilt need hospi!alisatioo. Pattents ered; intravenous altemati\leS include either monothcnpy oquinolone is recommended. Jn hospitalised patients who
who need hospitalisation are generally infected with unu- with lcvofloxacin, or the combination of • second- or are in intensive care the preferred treatment is a beta
sual pathogen$ and/or hove more~ disease Pneumo- third-gcncralion ccphalosporin (such as cefuroxlme, cefo- laetam (cefowime, ceftriaxone, or ampic1llin/sulbectsn)
nia occumna 1n long-term-care facilities can be treated as 13Xime, or ceftria.wne) with clarit.'vomycin ' plus athcr azithromycin or a respiratory tluoroquinolone.
either comrm.wnl)'-.cqutred or hospital·11Cq11ired pneumo- In pc111ci111n-allergic patientS a respiratory Ouoroquioolone
Patients liospiJalised with Sevt!re CAP should receive
nia. Cases of holpital«q111red pneumonia are generally and azD'eonam are recommended. For Pseudomcnos in-
parenteral empirical treatment rcprdless of their ability to
classified according to the time of onset after hospital ad- fecuon, an antipneumococcal, antipseudomonal beta
take oral medi<:3tion. Since CAP caused by Lt!gl()nel/a
m1ss1on These categones also provide a rough gwde as to laciam (such as piperacillin/tazobacwn, ccfepime, imi-
spp. is more lilcely to result in severe disease, lhe initial
the hkely pathogen and seventy of the disease. penem, or meropcncm) plus either ciprofloxac:in or lcvo-
empirical regimen should mclude appropriate therapy.
Other iypcs of pneumoma include aspiration pneumonia Current reconunendations' are for combined innvcnous Ooxacin are recommended. Alternative regimens include
and the various fonns of in~tial pneumonia or pneu- treatment with a broad-spectrum beta-l:ictamase-Stable an- an antipneumococ:cal, anllpseudomonal beta lactam plus
monitis (sec also Aspiration Syndromes, p.1841, and In- tibacterial such as amoxicilhn with clavulanic acid or a an aminoglycosidc and azi!hromycin, or an antipoeumo-
terstitial Lu11g Disc~ p.1644). lntcrslitial pncumonitis is sccood- or third-generation oepbalosporin such os cefuro- coccal, anupscudomonal beia lactam plus an am~
a oommon comphanion in cancer pauenlS and has also :ilme, cefotaxime, or cefuiaxone, iogethcr with o mac- side and an antipneumococcal fluoroquinolonc. Jn pecicil-
been associated with cettain drugs, for e.'t:tmple amiodar- rolide (preferably claiitluomycin). r<or hf&-threatcning in- lin-allergic patients aztreonan1 should be used in place of
one, bleom)cin, and nitrotiirantoin. fection where Legionella is suspected, the further addition the be11 l1ctam. For community-acquired meticillin-resist-
Comm unlry-acquired pneumonlu. In community-ac- of levoOoxacin should be considered. As an alternative to ant Staph. mnl!us (MRSA) infection, ~1111comycin or line-
quired pneumonia (CAP°f·' Uie commonest pathogen in the above regimens, benzylpenicillin with either levo- zolid should be added.
previously healthy subJectS is Sneptococcus p11eumon1~ floxacin or ciproOoxacin can also be used.1 In children pneumonia is caused by a wider spectrum of
(pn1:mnococcus). Other cammon rathogens include Hae- The following treatments are recommended in the UK,• organisms than in adults. Viruses, especially RSV, are very
mophilus mj/1111nzt11 and atypical pathog~n s such as along with local microbiological advice, for the minority conunon pathogens in infants and children up to 4 years of
Chlamydopl11/a pna11mo11iac (Chlamydia pnaumaniae), ofpatients wiU1 CAP in whom the causnli•c orga11it1n has ai;e and, as In adults, pneumococci are very common bac-
Mycoplosma p1111u111011foc, and ~oncllo pneumophila been identified, usually in hospi1al: terial pathoi;ens. Guidelines for the management of CAP
<= Legionna1m' Disease, p.188). Less common caus-
• Srr. JNieumoniae: preferred treatment, ora1amox icilli n or
in children have been produced by tl1e BTS. 11 Amoxicillin
es include Slapl'l)loeoct:us aureus, which usually occurs as 15 considered the antibacterial of first choice for empirical
a seconda1y bectcnal infection afier influenza and is asso- intravenous benzylpcnicillin; alternatives, aral clari - oral therapy in children under 5 years of age because it is
ciated with high nlOl'taliry; Moroxefla ca1arrllolis (Bro- thromycin, or intravenous cef\Lroxime, cefotaxime, or effective against the majority of causative organisms. Al-
nhamella cutarrhalis) occws especially in patients with ceftriaxone ternatives are amoxicillin with clavulanic acid, ccfaclor,
dvonic lung disease; Gram-ncginive entcric bacilli; Pse1t- • M. p11e111110111oe or C. pnt!Umonlae: preferred treatment, erythromycin, clarithromycin, or azithromycin. Mac-
damal/4S oerugiriosa; Clllomydophila psi/loci (Chlamvdta oral or intravenous clarithromycin; alternatives, oral rolides should be &iven as first-line empirical thernpy in
psutaci) (see PsitulCOSiS, p.203); and Coxial/a burnetii (see doxycycline or an 0!1.I or inlnlvenous OU01oqu1nolone children over S )Ul'S since M p11e11monioe pneumonia is
Q Fever, p.203). Gram-negative becilli rarely cause~ • C. ps111oci or C. bumetli: preferred treatment, oral dox- more prevalent in older children. Macrolidcs should also
monia in the community, especially 1n previously healthy ycyclinc; alternatives, oral or intravenous clarithromy- be used in children of any age if either M pneumonioe or
patierltS, although the frequency of such infections is in- cin C pneumonioe are suspected. Amoxicillin should be used
creasing.1 Anaerobic bacteria are assocu11ed with aspira- as first-line treatment at any age if Sir. pneumamoe 1s
tion pneumonia. V'uuses are 1he commonest pathogens in • Ugionella spp.: prefem.-d ucatment, an oral or intrave-
nous Ouoroquinolone; altcmatiw:s, oral or intravenous thou£ht to be the likely pathogen. IfStaph. a111~s is sus-
youn11 children. pected then a macrolide or a combination offlucloxacillin
darithromycin (or azithromycin, 1fnccessaiy)
Pneumococcal pneumon11 usually develops over several with amo'ticilhn is appropriate. Intravenous therapy
days and i11 elderly patients onset m~y be insidious. Sir. • H. i;ifluetroe (noo-bcta-lactamase-producma)· pre. should be given in severe infection or when the child is
pneurnomae has usually been considered to be sensitive to ferred treatment, oral or intravenous amoxicillin, alter- unable to absorb onl antibacterials, for example due to
penicillms (benzylpemcilhn, amox1cilhn, or ampieiUin), natives, inn\'CllOUS a:furoxime, cefotaxime, or ceftri- \'Omiting. appropriate intravenous drugs for severe pneu-
cephalosporins, erythromycin, or co-trimoxazole, but axone, or an oral or intravcnous fluoroquinolone monia include amoxicillin with clavulanic acid, cefuroxi-
there 1s increasing prevalence of &Jobal resistance al- • II. injlue11zoe (bela-lacumase·producinll): preferred me, or cefotaxinie. If the causative organism is known to
though there are marked aeoaraphical dilTerences.9•10 treatment, oral or innvenous amoxicillln with clavu- be Str. p11e11mo11iae a penicillin may be used alone.
However, in clinical practice pnewnococc:al pneumonia lanic acid; alternatives, intravenous cefuroxime, ccfo- Chlam)'dia llYJchomalis is another common cause ill in-
frequently responds to hi11h doses ofpemcillins or cepha- taxime, oc cefiriaxone, or 3n oral or intravenous Ouoro· fants up to 3 monU1s of age for which erythromycin may
losporins and the routine use of penicillin for CAP may quinolone be used or, allcmatively, sulfafurazole.
still be reasonable in many c:ounoies. • Gram-negative enteric bacilli: preferred treatment, in- Pneumonia in neonates is usually due to organisms ac-
The trcabnent of CAP is complicated by the increasing travenousccfuroxime, cefotaxime, orcef\riaxone; alter- quired from the mother:s genital tracl. especially group B
spectrum of causative orgllllisms and prevalence of anti- native~, intravenous fluoroquinolone, 1mipenem, or streptococci, Escherichia coli, and Klebslel/a pneumoni-
bacterial resisiance. Furthermore, since the causative path- meropenem ae; initial treatment with gentamicin and bcnzylpenicillin
202 Antibacterials
or ampicillin has been suggested. For prophylaxis against Broad specwm antibacterial therapy is essential for treat- 10. Felminst\.lm 0, Cl of. Increasing J)R'Vllcnc:e or antimicrobial re..
s.istan« amon.a isolates ofSU'Cpioco<:cU$ pncumoniac rrom the
group B sueptococci in neonates. see under Perinatal ment ofH."'P and HCAP, and most initial therapy is empir- PROTEKT surveillance Jtudy. and comparative in vhro 1e1iv1tv
Streptococcal Infections, p.198. ical. As in the treatment of CAP, selection ofantibactcrials of the ketolide, tc1ilhromyc:in.J An1imlcrob Chcmolher 2002; sO
must be localised. For initial empirical treatment of carly- (suppl SI): 25-37.
Similar guidelines for the empirical management of CAP 11. Bri1lsh Thoracic Soci-c1y 8TS GuKfelincs for the ~men t
in children have been developed in South Afiica.•s Addi- onset HAP or YAP in patients with no known risk factors or community <1cquircd pMumonia in childhood. Thonu ?002;
tional recommendations have been made to tal<e into ac- for multidrug-resistant palhogens, and any disease severi- S7 (>uppl I): il-i24.
count the high prevalence of HIV infection. The drug of ty, ATS reconuucmls21 the following drugs: ocftriaxone;
levofloxacin, moxifloxacin, or ciprofloxacin; ampicil-
~~:,:1:/0:~~~n~~~1~~0~!~~~~,~~~i~~!~·~~~i~~i~~fi~~c~j
choice is amoxicillin; althougJi standard doses of amoxi- paedialticcap.pdf (accQ.<;<d 18108/08)
cillin will treat most cases of pneumococcal pneumonia lin/sulbactam; or crtapenem. Where there is late-onset in- 12. Mandell LAf c1 ol. lnfCchous Oistasu Soc:tt.ty of Ameri-
fection or risk factors for multidrug resistance (including ca/AmtrtCln Thoracic Society consensus iuidclines on the
the use of high-dose amoxicillin (30 mg/kg given 3 times man.1gt"mCflt of communily-acquircd pneumonia in adults. Clin
daily) is recommended in order to overcome and limit the possible HCAP) the following are recommended: an an- /llfecr f);s 2007; 44 (suppl 2): S27-S72. Also available at:
emergence of resiSWJt pneumococci, and to successfully tipseudomonal ocphalosporin (cefepime orceftazidime) or http://,.ww,joum•l<.uchicago cdu/doilpdf/10.1086/S 111 S9 (K·
an antipscudomonal carbapenem (imipenem or meropen- ccssed 22/01/08)
treat those few children with high-level pneumococcal re- 13. Woodhead M,., ul European RCJpiratO<)' Society, European
sistance the following additional factors should be consid- cm) or piperacillin-ta1.0bactam together with an antipscu- Socict,r or Clinical Mictob1ology and Infectious Disuses.
ered: domonal fluoroquinolone (ciprofloxacin or levofloxacin) Gu.ideJmes ror tht m.anagcmcni or adult lower respiri1oty tnia
or an aminoglycoside (amikacin, gentamicin, or tobramy- infectio.n:s. Eur Resp1r J 200S; 26: I I 38-80. Also available al:
• children younger than 2 months have more Gram-nega- cin); if MRSA is likely then linezolid or vancomycin
'/Wo'fmd)°''joornals.cornlcJilr<prinVl6/6; 1138.pdf (acc::.s<d
tive infections and therefore need an intravenous should also be used. Intravenous therapy should be given 14. Brink A.~ al. Soll1h African Thoracic Society (SATS). Guide-
aminoglycosidc or an intravenous cephalosporin, while to all patients initially, and changed lO 'the oral or enteral ~~!. ~~;e.u:,nj~~~~~6:~~~~lio1 infccuons in Souch Af·
children older than S years have more infections caused route as soon as possible. Efforts should be made to short- Also available: at: hup:llwww.pulmon<>IOl)'.co.ulsuidelincs/
by M pneumonioe and C pneumonioe and need a mac- en the duration of therapy from the tnditional 14 to 21 ~~~}ial%20infcc&ions%20guidc:line.pdf (acc.esscd
rolide (erythromycin, clarithromycin, or azithromycin) days to as little as 7 days provided Ps. oeruginoso is absent IS. Zar HJ, u ol. Workina Croups ofth• Paediatric Assembly of lhc
• HIV-infected children requiring hospitalisation and and that the patient shows a good clinical response. Guide-
=;:,,~~:~~:c~~~n!,~~ ~~·~~o~-"Su:u31te~;,i~!
those with a higJi risk of being HIV-infected or who
have symptomatic HIV disease or who are severely
lines for the managemenl ofllAP, YAP, and HCAP have
also been issued in the UK,21 and emphasise the need to ThorocicSocicry Guidelines. S Afr M«I J 200S; 95: 977-81,
984-90. AL'>o available at: hnp:/lblue:s.sabinet.co.:u/WcbZI
malnourished should be given an aminoglycoside plus choose initial antibacterial therapy based on patient-spc- Authori>c'l<ccsionid=O-.autho-;>llbm<el:P'SSword "'Puhmed2~
their empirical anlibacterial regimen; alternatively they cific factors (such as previous ant.ibacterial use, length of AdvancedQucry?&form•t•F&ne>.l•lmages/c:jour/m samj/
may be given a regimen that provides effective treat- m umj_v9S nl2_•2 1.pdf(occesscd05/0SI08) -
hospital stay, and comorbidities) as well as local microbi- I 6. ln1cctiouJ Diiusa Socir:ry of Taiwan, Taiwan Socid)' of Pul-
ment against Gram-negative bacteria ology and resistance patterns. F'or intensive care patients monary a11d Critical Medicine. and Medical Fou11da1ion in
requiring mechanical \"entilation for 48 hours or more, se- Memory of Or. Deh-Un Chcn,g. Guidelines on antimierobial
• if pneumocystis pneumonia is suspe;:ted. co-trimoxa- lherapy of pneumonia in ~dults in Taiwi.n. revlsed 2006. J
zole should be added. All hospi talised HIV-exposed lective decontamination of the digestive tract (sec unciCr ,\licrobiol l•urnnol lnf«:t 2007; 40: 279-83. Also available at:
children less rhan 6 months of age should be treated em- Intensive Care, p.187) is recommended lo reduce the risk http://w\11.-w.jmii.org/content/pd(/v40n3p279.pd( (occcued
ofVAP. OSJ03/08)
pirically with co-Dimoxazole, unless HIV infection sta- 17. Miyashita N. el nl. Ji~nesc Respirata<y Society. The JRS
tus is negative and the child is not being breast-fed. Em- fmmunocompromised patien ts. lmmunosuppresscd pa· ,u'4elincs for 1hc m:m11gcment or community-acquired pncu·
pirical treatment with co-Dimoxazole plus amoxicillin tients are at increased risk of pneumonia. In addition to the monia in 1dul1s: an update and 1\CW rttomnlCndations,. llflem
Mttl 2 006 ; 4.S : 419-28. Also avai lab le at: http://
and an aminoglycoside should also be given to older bacteria mentioned above they are suscepliblc to oppor- www.jstage.js,t.go.jpia.rticleiintemalmcd icinc/4 sn/419/_pdf
HIV-infected children with fearures of AIDS who are tunistic infections with Myccbaclerium tuberculosis (see (accessed OS/03108)
not on co-Dimoxozole prophylaxis Tuberculosis, p.212): viruses such os CMV a.nd fungi, in 18. Maxwell OJ. fl-I 111. Empiric man11gi:1ncnl of communi1y...ac·
quired pnoumonia in Ausiralian emergency dC'part~IJ. ~dJ
• when Stoph. aurcus is suspected, cloxacillin is the drug particular Pneumocystis jirovecii (see p.566), are also A11SI 2005; I SJ: Sl0-1.
ofchoice. In l·I IV-infected children, about 60"/e of com- causes of pneumonia in these patients. 19. ~::::.~~!~.wm~c;~~~~:~t-accinotl0f1 in adults:
munity-acquired Staph. 011re1rs may be resistant lo Aspiration pneumonia. Aspiration of organisms present 20. Jackson ML. ct al. l nnuen1.a vaccination and risk or comm\1ni·
cloxacillin and vancomycin should be given in the upper respiratory llllcl into the lungs, often as a result ly-acquircd pneumonia in immunocompc1cnt elderly go:oplc: 1
~~a~~~n--based. nc.sted casc-..conuol study. Lonc~12 08; 312:
F'or the prevention of CAP, pneumococcal (p.2439) and of loss of consciousness or di fficulty in swallowing. can
influen?.a (p.2424) vaccines are generally recommended cause aspir.ition pneumonia.23 When community acquired 21. American Thoracic Socitty; Jn(eaious Diseases Society of
the organisms responsible are mainly anaerobes, but in America. Cuideline:s for 1he mal\lecmc-nt of adults y.;th hosp;_
for active immunisation of individuals considered to be at tal·acquircd. venlilator·llsoc:iated. and hcillhcarc· a$SOC"iated
high risk of pneumonia-related complications.'- 12 Howev- hospital-acquired aspiration pneumonia Gram-negative pneumoni1. Am J Rupir Crir Ca~ M<d 200S; 171 : 388-416.
er, a meta-analysis 19 of pneumococcal vaccination in bacilli and Staph. oureus are also found. Confusion has Also ov1ila hJc al : hup:!/www.1horacic.org/nctions/
arisen over the term 'aspiration pneumonia ' because it has publica1ions/t1a1cments1pagcs!mtpi/guicJe I·29.hunl (aC«ssetl
adults (with unconjugated vaccine) has suggested that the 2S/05i06)
practice may not effectively prevent pneumonia, even in also been applied more generally to aspiration, for exam- 22. Mute.no" RQ ~ ol Gu1dctiner for the man>gC'mtnt ofhospit1l-
high-risk populations. The role of influenza vaccination in ple, of gastric acid (Mendel~o1fs syndrome), resulting in acquired pncumon11 in &he UK: report of the working pan~ un
chemical pneunionitis and not associated wid1 bacterial in- hospitaJ.aequircd pncUmonia of the Brilish Society (Of Anhnli-
mlucing lhe risk ofCAP in elderly, imrnunocompetent pa- crobial Chc-mot~erapy. J Antlmiuob Clt~m01h~r 2008; 61:
tients has also been questioned. 20 fection. Ltmg obscess gencmlly characterises late-stage as- S-34. Also available 1u: h11p:/ljac.oxfordjournats.org/cgi/
piration pneumonia involving anaerobic bacteria. l11e ae- reprint/6211/S (ac:«ssed 24/02110)
Hospital-acquired and healthcare-associated pneumo· 23. Mank. PE. Aspiration pntumonit111nd asp1ra1ion pneumonia. N
tiology is rarely established, but specific anaerobic
nia. Pneumonia occurring at least 48 hours after hospital £f111/J M<d2001: 344: 66S-71.
bacteria involved include Peptostreptococcus, Prevotello
admission that was not incubating at initial presentation is
meloninogenico (Bocteroides meloninogc11icus), and Fu-
termed nosocomial or hospital-acquired pneumonia Pregna ncy and t he neonate
(HAP). Ventilator-associated pneumonia (VAP) is a spe- sobocteri11m m1cleatu111. Nearly all patients with anaerobic
pulmonary in fcctions are treated empirically. Some23 For infections associated specifically with pregnancy, see
cific sub!YPe of HAP defined as pneumonia occnrring at Endomctritis (p.179). Perinatal Streptococcal Infections
workers have expressed the view that penicillin and clin-
least 48 hours after endolt8Cheal intubation and/or me- (p.198), and Premature Labour (below).
damycin are inadequate and that antibacterials with activ-
chanical ventilation, usually resulting from aspiration of
ity against Gran>-ncgotivc organisms, such as third-gener-
pathogenic material that colonises the oropharynx. While
ation ocphalosporins, nuoroquinolones, and piperacillin Premature labour
early-onset HAP (occurring wi~1in the first 4 days of hos.
arc usually required even in community-acquired aspira- Prelcrm birth, with or wilhout rupture of membranes,
pita) admission) is usually caused by typical community
tion pncwnooia. Most patients wilh lung abscess receive causes sigJJificant perinatal morbidity and mortality. There
organisms, late-onset infection can be caused by a wide
parenteral therapy unti l they become afobrilc Md show is evidence that infection appears to have an import:aut role
spectrum of possible pathogens, many of which may be
clinical improvement; oral therapy may then continue for in the cause or as a consequence of ruptured membranes'~
resistant to multiple antibacterials; these CllJl include op-
weeks or months if necessary. and as many os 50% of spontaneous preterm binhs are due
portuniscic Gram-negative bacilli such as Ps. oemginoso,
AcincLobacter spp., Ste1101rophomonos maltophilio, Bur· z.
I. Hoare Lim WS. Pneumonia: t1pda1c oo diagnosis and 1nan· to infection, with /olycoplosma spp. being the most com·
•&•men•. BMJ 2006: 332: ton-9 monly isolated ~nisms from the amniotic cavity.3 Olher
klrolderio cepacio, and the Enterobactcriaceae, as well as 2. File TM. Cominunity..acquiM:l pncu1noni.a. Loncr1 2003: J62:
Staph. oureus. More recenlly, au increased incidence of 1991--200 1. bacteria that have been implicated include group B strep-
these potentially drug-resistant bacteria among patients tococci, Chlomydia trachom(J(is, and those associated with
3. ~~~a[~i~c~A~,a;0;~:;~}!T,;~~(M[~irs~~~ in infants bactaial vagjnosis. The role of antibacterial treatment has
with early-onset pneumonia, thought to be a consequence
ofprevious hospital stays or antibacterial use, hos led to the 4. Epitcin BJ. Gums JG Optimal ph~n" ac.ologica.1 lherapy for been evaluated. However, it is possible that roatemal anti-
community..cquircd pneumonia: 1hc role or dual antibacte-risl
concept of healthcare-associated pneumonia (HCAP). 1herllpy. i>-.,,2oos: 6S: 1949- 71. bacterial treatment may suppress the stimulation oflabour
This is pneumonia occurring in any patient who has been 5. l utfi)')'I MN. ti af. Diagnosis and treacmeni of co1nmunity--ac. without effectively treating fetal infection2 and concerns
hospitalised for at least 2 days in the previous 3 months, quired pneumonia. At" Fom Physic.inn 2006~ 73: 442-50. have been expressed that delaying delivery in the presence
lives in a long-tenn care or nursing facility, has received 6. Nicdernui.n MS. Rcccrll ad\'anccs in community·0icqulrcd p1icu· of a subclinical infection may not produce the best out-
mooio: Ulpatient ond ou1~tient. Chm 2001; J31 : llOS-1 S. come for the neonate.•
intravenous antibacterials, chemotherapy, or wound care 7. G1rau J, Calbo E. Comnutnity·ac:quireO pncumQni1. lonctJ
in the previous month, or attends a hospital or haemodial- 2008; 37t: 455-8. A meta-analysisS and a systematic review' ofstudies ofthe
ysis clinic.21 .21 The speclnun of bacteria causing HCAP is 8. Lim WS, <!f al. Pneumonia Gu•de11ncs Committee of the British routine use ofantibacterials as adjuncts in the management
similar to late-onset HAP, and patients are considered to be Thurul.!ic Society Standwds ofC11c Conunince. OTS guidelines of premature labour in women with inroct mcmbrones
for the m:inag.cmcnt of community :icquircd pneumonia in
at high risk of multidrug-resistant infection. Other risk fac- adults: upda1c 2009. Tnorox 2009; 64 (suppl 3): iiil-iiiSS. have failed to show an overall improvement in neonatal
IOl"S for multidrug-rcsistant pneumonia include immuno- morbidity; indeed, an increase in neonatal mortality was
suppressivc disease ortherapy, and high frequency ofanti- ~~~~1:1~~~~T:l~1~lo~~~~~~~i:,;;~~~~-~~~i:~~i~~fi~uc~~ actually noted.5 Furthermore,.a loog-tcnn follow-up
CAPVuid<lint·Ml.pdf (a<«sscd 24102110)
bacterial resistance within the community or speci fic 9. G:\rau J. Trauntnt or dru,-rdistan1 pneumoeocal pncunlonia. study' indicated an increased rate of functional impair-
hospital unit. lane<I Infect Du 2002. l: 404-15. ment among 7-year-olds whose mothers had received
All cross-references refer to cnlrics in Volume A
 Antibacterials 203
erythromycin for sponwncous preterm labour; an in- actcristic symptom.? Te1racyclines are the tremmenl of 6. R;1oult D. ~' ul. Treatment nt' 0 f( \'t'r cndocardhis: C<'ntpnrison
creased incidence of ce11:bral palsy was also noted among choice•.3 a11d early therapy may be life-saving; a 21-day ('If 1 regimens con111ininz doxycyclinc and <'lno~acin or hydroxy·
c hloroquine. An:h lutc!iW ,\/qd 1999: 159: 167-73.
children exposed to eid1er e11ithromycin or amoxicillin course has been su~csted since relapses have occurred af- 7. C~lz.a L. r:r ':I, Dosycyclinc and chloroquine os tre;i1mec11 for
with claHilanic acid. ter shorter periods. although 14-day courses are also chronic Q fever endoc~rdids. J '11/t:cl 2001; 45: 127-C>.
In women with preterm premature mpTUre ofmcmbra11cs, widely recommended.? An altemativc is chlorampheni- S. Ciarcopinn X. n al Manacm.i: O fever d\1rinv prci;n:mcy: the
col.3 El)'lhromycin or a similar macrolidc have also been benefits of lon£·tcrm colri1nox:itt'IC thc:r.tpy. CUn l1tfi•c1 Di:r
meia-analyscs7~ and a systematic revi~ have shown that 2007: 45: S-1&-55.
antibacterials could delay dcli\'ery, and reduce both mater- used successfully.•..1
nal morbidity (chorioamnionitis and postparrum infec- I. Macrartan< JT. Mocr><: AD. Psi1ucosis. Br Aird 8111/ 19SJ: 39:
tions) and some aspects of neonatal morbidity (sepsis. 163-1 Relapsing fever
l . Si.w..,..i.oo AJ. Gnry><'" Ml.. Psi1 ~is. /n/ca Dis Clrn llonh Relapsing fever is caused by spirochaetes of the Borrelia
pneumonia, and intravcnlricul:ir haemonhage). No effedS ,,., 20t0: 1~ : 7- 2S.
on neonatal mortality (If g.:stational age-related morbidity genus that are transmitted to humans by body lice or Omi-
3. Atnmo\\·ta M. t'd. The choice of :mtib:ldc-ri:il druJS. ln: Hond~
were noted,u and a long-tenn follow-up stu~ found no booll ofonlfmi<ro/,;o/ 1/t,,rtrpJ' IS:h ed. New Ro;:hellc l\V: The thodoros ticks. 8. recwrenlis causes louse-borne relapsing
evidence of negative health effects on the child. However, Mtdteal Lener. 2008: 73. fever(LBRF). Global distribution and incidenceofLBRF
an increased incidence of neonatal neerotising enterocoli- 4. MOITiSOn WM. ttl al. An ou1bre.lk of 1>5i1tac~is. J lnf«:I J991: have reduced substantially due to improvements in sanita-
22: 71- S. tion and hygiene; however, it is endemic in some areas
tis has been found after maternal use of amoxicillin with S. Chan& KP, Vcilch PC. F..!vt:r. h~maluria, pn>teinuri3, and 1 par·
clavulanic acid specifically and it is considered best avoid- rot. lonecl 1997: 350: 1674. such as.northeastern Africa, nnd can occur elsewhere in
ed in women at risk of p1-emature delivery; erythromycin populations affected by war or natura l disasters. Many
may be the antibacterial of choice.2 A systematic review species of Borrl!lio may cause tick-borne relapsing fever
and mcta-analysis3 evaluated the effect ofantibacterials on Qfever (TBRF), which has a global distribution, but is highly en-
the rate ofpretcnn births when given in the second trimes- Q fevcr 1.l (or que1y fever) is a rickensial infection (p.204) demic in sub-Saharan Arrica.
ter of pregnancy to women at risk ofpreterm births. Gi\•ing caused by Coxie/la bumetii. It is a zoonosis occurring Clinical manifestations of LBRF and TBRF are similar.
macrolides or clindamycin was associated with a lower worldwide and is transmitted to humans from domestic TI1e onset is typically sudden, with high fever (son1etimes
rate of prcterm delivery, whereas giving merronidazole animals such as caule and sheep, mainly by inhalation of with delirium), headache, chills, sweating, myalgia, ar·
alone in the second trimester was associated with a greater infected dust. Q fever is asympiomatic in about 50 to 60"/o thralgia, and gastrointestinal disl\llbances. Complications
risk ofpreterm delivery in a high-risk population. of infected persons. Symptomatic acute infection general- include epiStaxis, and gastrointCS1inal and CNS haemor-
ly presents as a febrile flu-like illness and many patients rhage. Without treatment, symptoms intensify, resulting in
Clinical infections of the gcnito-urinary tract during preg- may also have hepatitis or pneumonia that can progress to
nancy are a cause of significant morbidity in the neonate a crisis. This comp1iscs two phases: a d1ill phase clwac-
acute respiratory distress syndrome. Endocarditis is the terised by rigors, increasing temperature, and hypcnnctab-
and antimicrobial treatmcn! is necessary (see Bacterial most frequent fonn of chronic infection and the most seri-
Vaginosis, p.172, Chlamydia! Infections, p.175, and Peri- olism, and a flush phase of decreasing temperature, dia-
ous form ofQ fever; infection may be difficult to eradicate phorcsis, and hypotcnsion, which may be fatal. Death due
natal Streptococcal Infections, p.198). and prolonged treatment is generally needed. There is also
I. King J, Flcnady V. Prophylactic antibiotics ror inhibiting ptt· to TBRF is rare. However, w1treated LBRF has a high fa-
term lat>o..ir wnh in1ocl 1n-cmbnnes:. Available in The Cochrane evidence oflong-tenn scquelae including lethargy and fa- tality rate, especially in malnourished populations.
Dauibasc of Systcinatic Re\'itwt; Issue 4. Chichester: John Wi- tigue in patients who have not had cardiac involvement.
ley: 2002 (accessed 16/0S/05). T11e treatment ofchoice for relapsing fever is a tetracycline
Suhclinical acute infections should be treated if recog- such as doxycycline; l>enzylpenicillin or erythromycin are
1. Kenyon S, rtl "'· An1lbioctc1 for ~..retcnn rupture of membr:rncs.
Avaifablc in TllC Cochrftll( o.itoba~ of Systematic Reviews; IS· nised and if possible treatment should be started within 3 alternatives; treatment is given orally where possibleu
sue'.?. 01ichesrc:r: John Wiley: 2003 (aeccsscd.1 6105:'05). days of the onset of symptoms. A Jetracyclinc such as dox- T11erapy with single oral doses of telnlcycline, erythromy-
; . Morenq• AM, Oujold E. The cFf«:l o f sccond-trimeste: oniibiot- ycyclinc for 14 days is the treaonent of choice for acute Q cin, or chloramphenicol has been effective for LBRF,
k thtnpy on the r.uc or prct<nn bir1h. J Obf1~1 Gynuttol Con fever. The role of macrolides in acute infection is unclear
2007: 29: 35-44. whereas treatment for 7 to l 0 days is usually given for tick-
J. Br<><kl<hurJI P. lnre<:1io<l 1nd pmcrn1 <kli-"1)'. BM/ 19'9; 318: and clinical data on the use offluoroquinolones are limit- boroe disease,2 because of the higher rate of treatment fail-
548-9. ed.1~ Co-trimoxazole is recommended for children young- ure and relapses in these patients. Antibacterial treatment
~. EiwtcrC, #'I ~ AdJuncll\'-C an1ibioliC' 1rc~tmcn1 in rrctcnn labor er than 8 years of age. 1 Q fever endOCllrditis is more dif- often causes a Jarisch-Heixheirne'r reaction within 4 hours
and neo~tal morbidit)·: a mc:u-o-nalysis. Obs1e1 GJnccol 1996:
88: 303-9.
ficult 10 treat l!lld surgery may be required in ~ddition to ofthe first dose, and associated with a release of~10kines,
6. Kenyon s. ,, o/ C1uldhood OUlCM'lt:S after pttscTiptiC!O or IOU· antibacterial treatmcnt. 2 MonoU1erapy with tetracycline the symptoms of which resemble the crisis phase of un-
biotics lo prc1nant "'OfTK'n with spont.ancous ptttcnn laboc.tt:. 7. decreases S)mptoms but fails to eradicate C..: bumetii and treated patiems;2 th is reaction tends to be more severe in
year follow-up of 1he ORACLE 11 uial. Ltmcet 2008; 372: combination antibacterial therapy has been evaluated.
1319-27. LBRf. Attempts to prevent this reaction include use of pa-
7. Mcfc<r BM. Arhcan Kl... Antimicrob'31 1hcrapy in cxpcctanl
Long-term treatment with doxycycline plus rifampicin or racetamol, NSA lDS, and corticosteroids, to little elfect.2
managtmtnl or prctc:rnl prcmalurt rupture of the: mcinb1111c.s.. with ciprofloxacin alone3 has been successful in individual Antibodies against tumour necrosis factor o. have also
lnnc<1199S: 346: 1271-9. Correclion. ibid. 1996; 347: 410. patients with endocarditis, whereas pcfloxaci11 alone• was been triecl.3
8. Egarccr C. c1 "'· Anlibiutic lrentmc:nt in prcterm premature ru1>· not. A retrospective comparison of doxycycline alone or
turc o( 1nen1brnncs 11nd neori:ual morbidity: a meta.analysis. Am J I. Abramowicz. M. ed. The choic~ ol'nntibtlc:lcrial drugs. In: lfo11d·
Ob>t<t G1·11t1.-ol 1996: t74: 589-97. with rifampicin, fluoroquinolones (ofloxacin or pe- l>oak ofantimltrvbiol thcw1py. I 8ch t:d. New Rochell\! N'\': Thi:
9. Kenyon $. ,, "'· ChildhClod OUlCOnl(.S after ptc.!Kription or nnti· floxacin). or co·tiimoxazolc, recommended tre<1tmcnt for Medical Lcuer. 2008: 7~ .
b ioliCS lo pr<"an1nt v.•01n~ 1\ with f)(°~l~fl'H rtlpture or the n~n,. at least 3 years with cloxycycline plus wfluoroquinolone;5 2. Roscoe C. Epperly T. Tick·bornc relapsing JCver. Am Foni Phy-.
branu: 7•)C!lr roHow-up M 1ht ORACLE I !rial. LnttC.~I 20'og: sici<m 2005; 12: 2039--'4.
doxycycline plus 1ifa01picin also app.:ared effective, but in 3. F..!kadc 0, e1 <11. Prcvcn1ion or Jorish·l lcn:hcimc:r rcaclions by
372: 1311)..18.
mostcasesrifampicin had been stoppedaftcra fewmonlhs trr:itmenl wilhan1ibochcs a;..ainJt lumor necrosis. foctora..N Engl
because of interactions with anticoagulants often pre- J M•d 1996: JJS: 311- 15.
t"roctltis scribed at the same time. Patients given doxycycline plus
t>roctitis is inflammation of the rectum that may be caused hydroxychloroquine needed a shorter treatment course
by sexually transmitted pathogens, most commonly ·"'eis- and had fewer relapses than those treated with doxycycline
Respiratory-tract infections
Principal community-acquired bacterial pathogens in the
seria go110n·hO«H!, C/1/amydia rraclwmalis, Trt!poncma plus ufloxacin; mortality r-dtC for botl1 groups was 5%.6
rcspiratOry tract arc Srrt!ptocaccus p11cr1111011iae and Hae-
pa/lid11111, or herpes simplex virus. .. Successful treatment with doxycycline and chloroquine
mophilus i11jlue11=oe, although Maraxella rotarrlrnlis
For empirical tru tment of sexually tran5111itted proctitis for 2 years has been reported in a patient with a biological
(Bra11hamella catarrlralis) is increasingly important in
1
the CDC in the USA recommends a single intramuscular prosthetic aortic val\IC and aortic homograft. 7 The combi-
some areas. Other respiratory pathogens include Cltlcmry-
dose of ceftriaxone 125 mg, plus oral doxycyclinc 100 mg nation of doxycyclinc JOO mg twice daily "nd hydroxy-
dophi/a pneumoniae (Chlamydia p11eim1oniae), u:gio11el-
twice daily for 7 days. chloroquine 200 mg tlu·ee times daily, both given orally for
la pneumophi/a, ond Myccplasma p11e11111011iae. Strr!plo·
The specific trc.itmenl of rcc1al infections caused by C. at least 18 months, is considered to be the treatment of
coccus pycgenes is the predominant cause of pharyngitis.
trachomatis and N. gonorrhoea<: is discussed under choice forQ feverendocarditis.1•2 An alternative regimen
Swpi(1•lococc11s <11fl'cus and aerobic Gram-negative bacilli
ChlamydiaI !11fcctions(1). f 75) and Gonorrhoea (p.206) re- for patients unable to toleratt hydroxychloroquine is dox-
such as Pseudo111011C1s oel'llginosn and Klebsiella spp. may
spectively. Patients wi01 herpes proctitis should be treated ycycline plus a fluoroquinolonc for Al least 3 to 4 years.?
be resp()nsiblc for hospital-acquired (nosocomial) infec-
in the same way as those with gerutal herpes (p.942). Q fever during pregnancy may resu lt in obstetric compli- tions.
I. CDC. SeiU01.lly •~nsm itlcd discasC'$ ttolmcnt guidelinn 2006. Clllions, such as spon111ncous abortion. inl!'B·utcrine gro"1h Non-specific, conununiry-acquired rcspiratory-lrnet infec-
MAlll'R 2006; SS (RR· ll): 1-94. Also .-ailabl< 11: hllp:// retardation, intra-uterine fetal death, and premature deliv- tions arc vcty conunon and usually viral in origin. Because
"""''"·cdc.11<1v/mmW</Pl>F/rrfrrSS 11.pdf (acctssod 23103/0' I ery.' TIC3tment with co-trimoxawlc for at least 5 weeks thc:sc infections arc generally self-limiting, US1 and UK2
during pregnancy was reported to protect agninst maternal guidelines suggest that antibacterials should not be rou-
Prostatltis chronic Q fever. placClltal infection. and obstetric compli- tinely givc11, although they may be appropriate fur some
Sec under Urinary-rract lnfeciions, p.215. cations (in particular intra-uterine fetal dcath).8 patients based on severity of illness or risk factors for seri-
A vaccine is a\.11ilable in some countries for prophylaxis ous complications.:?..l
in occupational groups who regularly handle potentially For details on infections of the upper respiratory tract, sec
Psittacosis infected animal tissues.
The couSlltive organism of psittacosis1.l (omithosis) is under Epiglottitis (p.181 ), Pharyngitis (p. J99), and Sinusi-
Chlamydoplrila psillaci (Chlamydia psi11ac1). It is usually I. ror~cr NR. er ol. O fever. lu,,~12006; 367: 6 79-$8. tis (p.208); sec also Otitis Media (p. 196). for infections of
1. Hanzell JO. e1 al. Q re~ct: cpideinioloi.y, dlaanosis, a1xl treat·
transmit1ed to hwnans by direct or indirect contact with in· ment. Muro C/i,, Pnx: 2008: SJ: S74- 9.
the lower respira101y n11cl, see under Bronchitis (p.174),
fccted birds and the primary site of infection is the lung. ' or
l . Ycbra M.' t:1 ul. Ciproflo.ucin io a C'O)C Q fevtr endoc3rditis. Cystic Fibrosis (p. l 76), and Pneumonia (p.201); those
The clinical presentation of psittacosis can vary widely N £,,g/J Med 1990:323: 6 14. with a specific cause include Legionnaires' Disease
from a mild ' flu-like' illness to a fulminating toxic state 4 . Cccou~ P,ct al Q-revcr «ndocu.rdi1is ind trt•llment with lhc fluQ· (p.188), Nocardiosis (p.194), Pcrtussis(p.199), and Tubcr-
with multiple organ involvement 1Most patients 1vill have roquinolonts.Art:h Jm,rnM~ 1991 : lSt: 816. 818. cu105is (p.212). For discussion on the eradication of nasa~
Lt'vy rv. €'/ al. Comp:ari.sou of dirTtten1 1ntibioric rcsimtns for
a cough, althoug)l this is not always prominent 1·3 Howev- lh~rapy or n CUC$ or Q '"'Cf cndourditis. A111imkrob AgenlJ
staphylococci carriage, see Staphylococca I Infections,
er, severe headache similar to that of meningitis is a char- Cit<'"°'"'' t991:35: 5B- 7. p.210.
204 Ant1bacte na ls
For details on the symp1omatic managemen1 of rcspira10- Howeva, it is unclear whether anti-inflammatory treat· 10. Colling A, ., al Minimum ontc>lll'll ofpmic:illin Pn>ph7laxis ~
ment has any influence on such long-tcnn scquelae. 12Car-
quued to conuol Stttpcococcu.s pyoe:cnes epidemic t.n cbcd
ry-1raet infection, sec under Cough (p.l 686) and Fever and comn>uno<y BM/ l 982; 2$5: 9~-
Hyperthenn1a (p.10). bamazepine or valproate may be given for severe and dis. 11 Gray GC. " ol. H),,.mtdcm;c Streptocoa:u• pyott:na infcv
Snow v. ,, al Amcrtcan Cotlcac of Phys.cians_ Ameor:aa Sod· tressing chorea.1 Secondary pm1m1ion is then continued 'Mo!/i°:f.'~JfS,P';r:;•is ,.;thpenicillin Gbenr.11hi"" NE~ J
ety o( lnlem1I Mcd1<1ne, Amtncan A<odemy or Faintly l'lly1>- with prolonged antibacterial prophylaxis because of the
ci1ns. Cc.f\let'I (ot OdCau ConlrOl Pnncipk:s of approprialc an- 12- Clfhen AM 9 ct al. Anti-intlammatcry trealmtnt for card1ti1 tn
db1otic use for uulmc.nt of nonspecific upper respiratory tract high risk of recurrent attacks of rheumatic fever after sub- ac:utc rhtuMalte fever. Avaitable in The Codr.tnc Da:tabt:.c o(
sequent sucptococcal upptt respiratory-tract infections. Systcnuhc Re~iews.~ Issue 2. Chichester. John Wiley; 200) (a<·
it"fcc:hons 1n adults A11n lnl#fn Mttf 2001. 13"1 ~ •li- 9. Atso ......, 06/0l/OSJ.
1v11lable 8'; hlt,p:J/www 1nn.1ls Qra/c1j/repr1nlll ;4/6!487 (ac· Ag;iin, penicillin is the prcfCITCd antibactenal, the usual 13 . Ayoub E."4. ProphyJuis in patients v.-ilh rhcum;t1ic fcffr; c,·cry
ccsscd 0$IO&IOC) reconuncndation being an intramuscular injection of bcn- lhrc• « cvay (our •Vtt'i!.s? J P•diarr 1989; 115: 89-91.
NICE. Rup11111'!';i..in1ct 1nroc1lo- 1ndblotic plU<f11>ioi; p«- I• L.ut H..C. tr ol Lone-term outcome of p!timts with rhrwnallc
scribina of •nhbt011C:S (Of ICJ(·htn1lint Mptfltory I.rid Jnfec> zathinc bcnzylpcnicillin every 4 weeks, although mjcc-
reve:r rcccivan1 bcnnlhinc prn:icillin G prophylaxis e\Cty lhtee
lion$ In ldulll 1n4 clolldrcn on pflmary cwc (inoed July 2008). ti-Ons every 3 weeks may be ~arranted where the risk of """' """sc.ery fOL1rwcek$.J PrdN>rr t994; 125: lll-16.
Avai lable at hup ://www.nicc or1.•k/ n1ccmcdia/ pdf/ rccurrcnce is higti." This advice has been influenced by IS Koplan EL. et ol. l'humxotioelies ofhennthine ~n.lcil!•• G:
CC69FullG•odehnc.pd( (occeued OllOlllO) WNm knls duriJ\IC, lhc 28 ~aft.et tnU11muKUJar tnjcc:\K)n of
reportS of high rtlCUm:nce rat.cs with the monthly ref men
PcttrKn I, " ol Prottct1\'C c:ffttl of enubioztcs apm~• serious t.200,000uo11s.JPMio1r 19a9; 115: 1•6-SO.
comphtations or ~mmOft rap.irator)' &rlC'f infecttOPI: rctrOSptt- in such siruations.13 A 12-year study in Taiwan' con- 16 Mora ZMA, ., ol. E\..luMioa of secon<lary pnll'h)1•<1lc
u.... <0hor111udy ,.,,h die UK Gent.ral Pratuce R.tscarch 0111- fumed lhat prophylaxis with ben7.alhinc benzylpcnicillin K~ baud on bentalhinc penicillin G. fOf rhcunmic fever
bue. Abridst4 vmlon BAU 2007. 335: 912-4. Foll
hup bmJ
/lw,.., com/ca ilrcpnn11)lSn6271982 (1cceucd
•et1••" injectioos every 3 weeks is more effective than iajccuons 1n children. J Ptdiolr 199}; 123: 156-8.
17. lntcrnat1onaJ Rheumaric Fe'v Srudy Oroep. Allergic rttetK>ns
0)/0)110) every 4 wedcs and it was recommended that the 3-wcelt \0 aona·icm1bcnuthmc pcn_i,ciJli;n proph)lnis for rbeutnatic (e-
regimen should be used in adults and ch11dren with a recen1 ""'·""""' l99t;J)7: 1308-10.
episode ofmeumatic fever, especially in devclopini coun-
Rheum atic fever tries where exposure to streptococci is still intense. In ad-
Acute rheumatic fever' OCCUI$ especially in ciuldrcn aged Rkkettsial infections
dition, phannacolcinetic studies ha~e indicaled relallvcly Bacteria of the Riclc.ettsiaceae ramify !hat infect man in-
6 to I 5 years as a consequence of upper rcspiratory-trael low serum concentrations of penicillin in the fourth wcdt clude Rickelts1a spp. (sec under Spotted Fcven, p.210 and
infeclions, such as plllll)'Tliitis Of tonsillitis, with meuma· after an intramuscular injection ofbcnzathine benzylpcni-
togenic strains of the group A beta-haemolytic Sb'Cptococ- 'fyphus, p.215) and Coxiel/a bumetii (see under Q fever,
cillin, 1s.16 despite the successful use of monthly injections p.203). Ehrlichia spp. (see under Ehrlichiosis, p. l n) and
cus, StreptocOCC11s P>'°8""s. The pathogenesis ~f rheu- in most patients. However, Australian and New Zealand
matic fev~ is unknown, but an immune mechamsm may Bartone/la quintana (Rochalimaeo quintana) (see under
guidelines consider the 4-wcek regimen suitable in most Trench Fever, p.212) are no longer classified as a ricken-
be involved. There 111ay be• latent period of I to 5 weeks patients.a Alternatively, oral prophylaxis with phc-
after the initial infection, before clinical manifcStations of $ia The treatment of choice for ricktasial infections is
noxymethylpenicillin or sulfadiazine may be iivcn, al- doxycycline; chloramphenicolora fluoroquinoloneareal-
meumatic fever appear. The major ones arc arthritis, cardi- thougji, over the long time scale involved, compliance is
tis, chorea, erythema margjnarum, and subcutanc0us nod- ternativcs. 1
likely lo be a problem;5•7" a macrolidc is suucsted for the I Abramow1c2 M. ed. TM choi« ofanriba<1erial druis- In: Han&.
ules. Those atrcctini the heart oie the most serious and aie rare patient who is allergic to penicillm and sulfonamides.6 6oo.t of on1i1rtlcro~ial 1/.,,.opy. l 811> ed. New Rochelle NY: Tiie
a major cause of cardiovascular death in children and Sulfonamides should no/ be used for primary prevention Mcdic:•I Lcuc:r, 2003: 7•.
young adults in developing counmcs. Rheumatic fever has because they do nol aadicate die streptococci.'-' The du-
been associated with poverty and ovm:rowding and has ration of secondary prophylaxis depends on the individual Salmone lla ente ritis
declined dnunatically in developed countries, but is still a patient, but in those who have not had rheumatic cardilis ii
major problem in the dcvelopini world. Howcv~. in the Sec p.185.
should generally continue for a minimum of 5 yean af\cr
1980s there was evidence of a resurgence in the USA with the last attack of rheumatic fever, or oolil ear~ adulthood
outbreaks of rhcumallc fever reported in middle.class (18 to 21 years of age}, whichever is longer." Those who Salpingit is
children: and mihlllry recruit$. 3 Increased pathogcnicity of have bad rheumatic carditis bul withoul residual valvular Sec under Pelvic lnOammatory Disease, p.197.
Str. pyogenes serotypcs might have contribuled to 1his re- disease should perhaps receive prophylaxis at least until
surgence.' A high incidence is also seen amon1 indige- the age of21 6 or 25 yc:ars,1 or for 10 years after the last Septicaem ia
nous populations in Australia and New Zealand. attack,6 whicheva is long~. For those with card1tis and Traditionally, transient bacteraemia (the presenceofbaac-
Guidelines for the management and prevention of rheu- pcrsistcot valwlar disease. prophylaxis should continue at ria in the blood) has been regarded as a fairly oommon
matic fcvtf have been published by sources including the least until the age of 40 years, or sometimes for lifc." 7 oond1tion which does DO! usually cause complications,
American Heart .A$sociation,6 WHO,' and expert groups Fears of serious allergic reactions associated with long· whereas uncontrolled bacteraemia leads to septicaemia
from Au$11"31ia and New Zealand' as well as lndia.9 Rheu- tenn bcni;athine bcnzylpenicillin prophylaxis appear to be with serious symptoms such as feva and shock. This dis-
matic fever can usually be prevented by primary prophy- unfoundcd. 17 - tinct ion has nou!ways been adhered to in published sourc-
laris, that is, by the prompt uearmcnt of strcptoooocal up- e¥ and the terms have sometimes been used interchangea-
Household oontacts ofrheumatic feva patients who lhcm-
per respiratory-lrllct infection with cnldicallon of group A bly. Added to this, the identification of the cascade of
sch'CS have positive streptococc.al cultures should be treat•
streptococci (GAS) from the throet Penicdhn is the drug cd_6 inflammatory mediators involved and the real.isation that
of choice, either as a sinile intramuscular injection ofbcn- what had been called 'sepsis' oould arise in the absence of
zathine benzylpcnicillin or as an oral C:OUl'$C of phe- Some patients with rhewnatic valvular heart disease as a 111fcction have prompted reassessment of the ienninology
noxymethylpcnicillin (or alternatively, amoxicillin) for 10 result of rheumatic fever arc at risk ofdeveloping infective used both in the UK and in the USA.1 Jn the UK. some
days.'1 An injection containing bcnzathinc bcnzylpcnicil- endocarditis and those at highest risk may need add1t1onal authonllcs2 considered that the tenn 'septica=ia' should
lin and procaine benzylpenic111in, which is less painful appropriate short-term antibacterial prophylaxis when un· no Ionia be used since it does not distinguish between
than bcnzathinc bcnzylpcnicillin alone:, is a suitable 1ltcr- dergoing dental and some sw-gical procedures (sec Endo- mild and severe disease. The term 'sepsis syndrome' was
nalive for use in children.' For poticnts who are intolerant carditis, p.178). preferred for policnts with a gCOC131iscd systemic response
of penicillin, a nanow·spcctrum oral ceph:llosporin such 1. Carape1G JR.. rt al. Acute rhaJm11ic rtvcr Louc11 2005; J6': toaethcr with evidence of organ dysfunction and .'septic
as cefadroxil or cefalcxin may be considered in those who ISS-68. shoclc' to describe patients who also have hypotenston nol
do not ha'-e type I penicillin hypersc11sitivi1y. Further tn:at- 2. Veasy LG, H ol. R~ of aaott rbtumallc (ever io die on· due to hypovolaemia or cardiac causes. The American
ment options include oral clindamycin, and the macrolides 1crmom10in ara o(d>e United Su1cs N E.,i J Htd 1917;) 16:
421-7. College of Chest Physicians and Socicl)' of Critical Care
erythtomycin, elarilhromycin, and azithromycin; howev- Medicine proposed the following series of definitions to
3. WaUacc MR. d al. The return of xutc rheumatic (cvct in youn5
er, because macrolide-resistant GAS arc oommon in some acMts.. JAMA 1989; 261: 2557-61. cov~ the spectrum of syndromes resulting from !his in-
areas of the world, there may be a higher risk of treatment flammatory response; l.J
failure when these drugs are used.6 For further delails on '· ~~i;~r!.!:t~ ~~~ i~:~~J~~~1i"/,~1r•pto- • sys1emic Inflammatory response syndrome (SIRS),
the treatment of streptococcal sore throat, sec under Phar- s. Cllhcr-$ AM. Rheumatic fen., and it.J man1gcmc.nt BM.11006~
the systemic inflammatory response to infection or var-
yngiti.s, p.199. Failure to cr:ldicate GAS is more oommon JJJ: 1153-6.
ious other severe clinical insults including pancreatitis,
aft~ oral antibacterials and in the USA many of these pa- 6 Oubc:r MA, rt al. Prcvcn1jon of rhcumabc fc'\IC:t and diapoad
and 1rtatmeot of awlc $ltep.oc.occal pllaryna.His: a scitol1fic ischacm13., trauma, and haemorrhagic shock
tients arc asymptomatic, clvonic streptococcal carriers;' statemcn1 from lhc American Hurt AJ.soc:iloon R.1'1aunatlc Fe-
rc-trca1ment of these patients is usuallyuMeccssary,6.7 and • sepsis, !he SIRS caused specifically by infection
ver. Endoc:orditis. ar.d Ka'""Ul:.ki Ducne Comminct of 1hc
should only be considered in those with a personal or fam- Council on Cardio~alar Oisu.se 1n the Yaun&. the. lntctd1i.c1· • se,ere sepsis, sepsis associated with organ dysfunaion,
plinary Council on func1ion1l Genomits anJ Tran,l11tiorwl Bl· perfusion abnormalities (such as lactic acidosis, oligu-
ily history of rheummic fcvcr.6 Symptomatic individuals ology, ~ud the Jnterdisci.plinary Council on Quality of Care and
can be ic-treated either with the same, or au alternative an- Outcomes Researc:h: endorsed by the Ammcan Acodcmy of na. or an acute alteration in mental status), or bypo1en-
ulladerial regimen; where initial treatment with penicillin Pcdiotrics. Circvlotio• 2009; 119: 1541- SI . Al$0 aY11lable 11· sion
hup://circ.ahajoumals or;fccilreprint/119/ l l/IS4 I (tcccue:d • septic shock, sepsis wi1h hypolension, despite adequ~e
has failed, a narrow-spectrum oephalosporin, clindamycin, 26/02/10)
amoxicillin with clavulnnic acid, or penicillin with rif- 7. WHO. Rhcun,.oic: (cvtt and mc.ima1oc: hcort disease. WHO Tech
fluid resuscitauon, togeth~ with perl\lsion abnonnah-
ampicin are all reasonable ahemativcs.6 Broad-based pri- 11.#.p S~r 91J 2004. Abo anllable al: hUp ;/~""'w·"'ho . in\/ ties
mary prophylaxis in communities rather than individuals c:ordiovucular ducu:s/rcsourccs/c:nlcvd lrS923.pdr (...,<Sled • multiple organ dysfunction syndrome (MODS), the
OSIOSIOS) - -
has been tried 10·11 but a study in mihllry recruits showed prcsencc of altered organ function in an acutely ill pa-
&. lteart Fou:odation or Aw.u-a1ia, Cardiac Soctecy of Au-51rah1 al\d
that Sir. pyogenes infection could not be prevented in .:~ Zulan-d. Dilgnosis .and managvntnl of acute rhnimah<
tierit such that homoeostasis cannot be maintained with-
closely oonfmed oornmunities unless all individuals in the fner and rheumatic Kan disease in A'3tralia .. an c\-·idcnct· out intervention; it may be a cause as well as a conse-
population received prophylax.is. 11 based re,·iew (issYcd June 2006). Avail•blc at: hnp :I/ quence of SIRS.
www.heartfoundalioa.org.auldocumcnll'NHFIPP·S90_Dia,a
Ifacute rheumatic fevaoccurs. a full thcrapcuticoowseof os1s-M1n11cmcnt_ARF-llHO_Evidcnc•-Bucd%20Rcview_ Septicaemia can be ceused by many bacteria.• Communi-
penicillin should be given initially, as for primary pre,·en- Stp06Upd>tc_F1NALpdf(acccucd OSJOSI08) ty-acquired primary septicaemia is often associated with
tioo, to eradicate GAS.'-' Treaunent then comprises bed 9. Saxena A, ~'cl. Working Group on ' ediallic Acu.tc RM-umauic a specific infectious disease, such as mcningococcal scpu-
Fcve< •od Cardiology 0..pler ofln4100 A~cmy of Pcd11ltlC$
rest and anti-inflammatory drugs, usually corticosteroids Consensus gu11klinu on pcchatric aane rhcvm•Oc fever ind cacmia with mcningoc:occal meningitis (p.191) or strepl<>-
or salicylates, in an aucmpt to prevent valvular scarring. o!tcumllic: hart di-1<. lrtdion Prdiolr 2008: 45: S6S-7J. coccal scpllcaemia with pneumonia (p.201), Strep1ococ-
All aoss-refere~ refer to entries in Volume A
 l\mbacterials 205
matory, and pro-tibnnolytic propcrttCS. Its benefits, how- IS. Bcm~rd GR. f'I .J. Efficacy and $1.kty o( recombinant human
cus pneumonlot and HMJ>iop/1i/11s inj/11cnute are oommon
IC.11\':Mc:d P'O'"" C (Ot 1iewr~ sepsi~ "1.' EittJ J '1ktl 2001~3.a.t:
causes of primary sepucacnua in children (although this ever, appear to \Jc limited to those at high nsk of death and b99-709
pattern is changiug in countries where immunisation a systematic rcv1ew16 found there was msuffic1ent evi- I~. Martl-C1r1;apl AJ. n ol. H"1'1'1an r«ombtn&l'W activated rrcnein
agamst H inj/uemot l)'pe b is rouhne); Gram-negative dence to support the use of activated protein C in ldults ( ror1<-c-Anilatlle inTh<CnchroncO.W.....<>fS,..._
tcmllic Revi~ Issue I. Cbtehcittr . .JMn W1ky; 200B (ac·
rods and group B sncp1ocooc1 are commonest in neonates. and children with severe sepsis. Funhcnnore, it was asso- CCSSC<1 1-1/0.lltO)
Hospltal-11cquired septicaemia 1s often iatrogenic and ciated with an increased risl. of internal bleeding A 1- 17. St<U•I CL no/. Hydrocon-thenpy for p<!!i<:nts , . , . . _
t>< shod. .IV ERtlJ >*d21JOS. 351: 111-14.
may occur as a complication of surgery or indwelling tbough deficiency of adrenal cortiCOStcroid production has ti w..... BL.no/. Ho...->Michrombin Win..,......,.. a
cathc1ers5a-maybe1SSOCia1ed w11h neulr'Opellia in immu· been &scribed in severe sepsis. high-dose corticosteroid r:>adonu~d concrolled lnll. JAMA ?001; U6: 1869-7&. Cor·
nocompromised pauents (sec under Infections in lmmuno- treatment was found to be of no benefit, but improved out- rca-161d :002; 111: 192.
19, Abnh>m E. n ol Eflkacr aochafesyoflifxogin <-ombo-•
compromised Patients, p.186). Hospital-acquired scpti· comes have been reported with the use of lower doses of ou.>e factor p1chway i:.h1bitor) iii K'Y'Cf~ sc:pk$; 1 random1ud
caemia is often associated with acute respiratory distress
syndrome (p.1636).
Wha.ievcr the cause. septicaemia requires prompt empiri-
cal ~trnent. 64 Choice of antibacterial depends on the
conicos1m>ids..' lntemationa.I guidelines dt'<elopcd by the
Surviving Sepsis Campaign' consider that low-dose intra·
venous hydroconisone may be given to adults with septic
shock who remain bypolensivc despit~ adequate Ouid re-
20 Croft AP,
pr<trml -cs.
....,,.,........... J,4/,(,12003; 290: 23"47.
n ol V..ocomycin for prophyb1is o;aiast S<pSlS in
AY>il•bl< in Th< C.a..- 0.11- of Sys·
1e11tahe R.- ,..."' Issue I. Chi<hc:ot<r.
ct~<od l&IOSIUS).
Jo~• Wiley; 2000 (ac·

probable source of infection. Fa- example, urinary-tract suscitation and vasopressor tbenpy: the addition of oral
infection is likely to be associated with Gram-negative fludrocortisonc is optional but dcxamclhasone is llOI rec- Sexually transmitted diseases
septicaemia due 10 E.scheric/110 coli; abdominal sepsis ommended. The addition of daily oral fludrocortisone 1s The sexually transmitted diseases, formerly tcnned YCne-
with Gram-ncgauve septicaemia due to mixed infection suggested if an alternative oorticosteroid is used that lacks rcal diseases, arc defined as a group of communicable dis-
with £. coll, cntcrococci, and anaerobic bac1eria; and skin significant mincraloconicoid activity.9 However, since eases that are transferred mainly by sexual co11t.act Many
sepsis, bactcnal 111hntis, acute osteomyelitis, Ind cardio- these guidelines wel'e published a multiccntrc, ran- pathogens arc known to be transmitted sexually including:
vasculor shunts with Gram-positive septicaemia doc to sta- domised, doublo-blind, placebo-controlled SIUdy 17 of 499
patients with septic shock reported that low-dose hydro- • bectena:
phylococci. TI1e antibacterials used should also reflect cur- • C/llomJ'd"' ll'ot:f>0mnlis {see Lynlphognmuloma Venereum,
rent patterns of bacterial resistance in the commwiity or cortisone did not significantly affect ¥urvival rate at 28 p.207 and Chlamydia! lnfcc1io1~" p.17S)
hospital. lmemational guidelines' hove recommended days or the rate of l'C\oersal of shock either overall or in • Hoemoploiha d11crtyi (see Chancroid, p.205)
starting intravenous antibacterial therapy as early as possi· patients who did not have a response to conicotropin, but • Klabsl•lla grotmlot1101b (see Granuloma lnguioal<, p.206)
blc,and within the first hour of recognition of septic shock; a decrease in time to reversal was noted in those patients in • Nelssodo 1:0,,,,,.,.,_ (scc Gonorrhoea, p.206)
the initial choice of therapy should be broad enough to whom shock was reversed. Studies with other physiologi- • Treponema pollidwn (sec SYPftilis, p.207)
cover all likcly pathogens, ond 1t should be reassessed dai- cal anticoagulants such as antithrombin fll 11 and tissue • l..ireap/DJ11w urtolyllc111rt
ly to optimise activir:y and prevent the development of re- factor pathway inhibitor (tifacogin)19 have not been suc-
• protozoa:
sistance:. De-escalation of combination therapy to the most cessful.
• Tr~l>omontu mgi110/il {sec Trichomcniuis. p.912).
appropriate single thcnpy should be carried out as roori as Neonatal Kpticaemia play be divided into tarly...,nsct, • viruses.:
susceptibilir:y of the infection is known. The typical dura- which is acquired from the mother's genital tract and man· · hu1nan immunodeticie.ncy virus (see HIV Infection and
tion of therapy will be 7 to 10 days. Empirical treotmort ifests itself during the first few days after bl11h. Ind late- AIDS. p.944)
has often begun with a penicillin ind an aminoglycoside. onset which may be nosoc:omially acquired. Bacteria • hepatitis YVUSCS (scc Hepori1is. p.939)
metronidazole being adckd if anaerobic infection is sus- commonly causing early-onset sepsis include entcrococci, • h<fPC"'iJUSCS (sec Hcrpo:svinlS lnfeclions, p.941)
pected. Jn the UK, the BNF 59 recommends that initial E. coli, ff. injluem«, LurwKJ monix:yfogenes. and stttp- Clinical syndromes associated with sexually transmitted
emp1ncal treatment for communtty«:q11ired sepucaemia tocooci. Some of these orpnisms may also prodooe men- diseases, and which are discussed in this section, include
is with either a brold·spectrum C1tipscudomonal penicil- ingitis in theneonate(p 191). Empirical treaoncnt for both urethritis (p.21 S) and epidid)mitis (p.180) in men; ccrvici-
lin (such as p1pcn1C1lhn with taz.obactam) or a broed-spec- early-and lato-ooset sepsis is based on surular principles to tis (p.175), pelvic inflannnatary disease (p.197), and bac-
trum ccphalosporin (such as cefuroximc), for hospiial-ac- those in ocher patients, giving COllSICknbOll to local pat- leNI lfaginosis (p.172) in women; and proctitis (p.203)-
quircd scpllCIClllll a broad-spectrum ant1pseudomonal terns of infccuon and resistance and to the su1tabili1y of PCS'!Nltal transmission of sexually tnnsmitted pathogens
beia-laclaln antiblclerial (such as ceflazid1mc, piperac:illin individual lll'lliboicterials for this age group. However, car- from the mother can result in neonatal conjunctivitis
with tazobactam, 1mipcnem, or mcropcnem) is recom· ly--OllSCl sepsis is usually best controlled by prenatal tr'C8t- (p.193) a-pneumonia (p.201).
mended. In both cases, an ammoglycoside should be add- ment of the mother or by pcM3lal prophylaxlS. Prophylax- General guidelines for the managancn~ of sexually trans·
ed 1f Puudomonos is suspeded or if sepsis is severe, met- is for group B sueptococal infc:t.1iuns is discussed under mittcd diseases have been published'"' althougb recom-
ror11daiole if anaerobic organisms arc suspected. and Perinatal Streptocoocal Infections, p.198. V..1ule va/IQOmy- mendations may need to be loca1ised becau.<e of d11f.erenc-
\'811C01Dycin if meticillin-resistant staphylococci are sus- cin bas been shown to prevent infections with coagul~ es in patterns of infection and drug resistance. Early
pected. US guidelines 10 recommend a lhtrd-or fourth-gen- ~ve staphylococci and to reduce the incidcnoe of nc- detection and trcaunent are required to prevent long-term
eration cephalosporin (ccfotaxime, ceftriaxone, ceft.azi- onalal sepsis. wide5f1"tad prophylaclie use of this drug is comphcations, including infertilir:y, still-births and neona-
dime, or cefep1me). or pipcracillin-tuobactam, or not rccommcndcd.2 lnrravcnous na-mal immunoglobulin ial infections, genital cancers. and an increased risk of ac-
imipcncm, or meropenem, in each case with vancomycin (sec Neonatal Infection, p.2436) and filgrasllm (sec Neu· quLnng and transmitting HIV.
and sometimes also an aminoglycos1de (geniamicin, tropenia,p.11g1)havc been tried for the prevenuon of sep- The suggestion that spcnnicidal contraceptives may pro-
tobmmycin. or arnikacin) for the initifll treatment of life· ticaemia in pretenn neonates with variable results. vide some protection against sexually transmitted diseases
threatening sepsis in 1dults. When there is some inform•· is discussed under Nonoxinols, p.2234.
.. Bone RC. Why M" dcfin1hun1 or M:p11is and orpn f't1IUft ·~
tion on which to base chotce of ll'Catmcnt, but before the nttded. Am J Alff 1993; fS; 348 SO. I. ('UC s~xually transm1ned di.seas.ct trcatmc.-nt g.u1dtlina 2006.
infecting organisms are definitely known, the following l. Lyno WA, Cuh<n J. Mmoiemcntor«ptic shock. J Jefttt t99S; MMWR 2006, SS (RR·ll). 1-94. Also av1ilabh: al' hup://
U"tallncnt is suggested: 30; 207-12. www.cdc.'°•/mm\\rll'Dfhr/n-55 I I .pdf (sccesS<ld 23/03Al7)
3. Amcricon Coll<&e or Ch«t PhysicianSISo<iecy or Crhlcal Ca~ 2. WI 10 . Gu1dt1incs for 1he m:an:i.~cmcnt of so.u:-lly transm1ned
• suspected bocterinl endocarditis-«flriaxone with van- fn(ccclo ns. Gene,· 1: WHO, 2003 . Al so &\'eileblc :at:
comycin, po55ibly with gcntamicin as well
• suspected mcticillin-resistant staphylococci-vanco·
&q!!StS and Of¥tan f;ulO«" and gu1dtltna '°'
Mcdie:lnc Con.!e1\Su~ Confcrcnu Commiucc. Oc:Onilion1 for
lhc Utt' Of innov~tin
lhcnpic> in S<J>$i1. Cri1 Ca"' M<d 1992, 10: 1164-74.
hltp;//whql ibdoc.~110. inllpublic.cions/2003/924 I S46263.pdf
(occcs~d ~3/0l/07)
Chnical Effcctivcnt:s.s Group (Bn\i.sh Associ<'lion for Se:x."'I
mycln. 1lone or with gL'ntamicin ondlor rifampicin 4 Eykyn SJ.~ of. The f;~Unlhe Ofltlt•snH or upt1eae:mi11 and Hcaltb and HIV). United Kinadom national tuideline oo 1hc
1herr epidcmiolosy- J Amimicl'Ob Cl•~•IOl/ta' t990: l5 (suppl NM.scmcnt o( sc.~uaUy tran.Stniut.id infCC'licns and related <on·
Once the infecting organisms have been identified. choice C); 41-SS. di,ions ie chikfrtn and youns J)e')Pk (2009). Avaif11blc tt ;
oftreatmeot will again depend on their sensitivity and cur- ~. McrmtJ LA.~ of ChniC111I prac1lct ,u1de1tncs (or che dta.&M!IS hnp:l/www boshh.oo'J/doc\lmen1r/227S (acttS1ed OS/03' I0)
rent pauems of rcsistancc in the communir:y or hospital. Md m:J;n•gcmc:nt or inlr1,·ascul~ r nthcltr•nlatcd infttlion
For comments on the consequences of c1ncrgmg mulu- 2009 UpchHe by 1?te lnftttM)UJ Ois~a.r.cs Socte:ty o( Alltef'tc:a Chancr-oid. Oiancroid is a sexually lmlSmittcd disease
Cli• /oif•cl Dl1 2009: 49: 1-45 Al&o available 11: caused by the Gram-negative bacterium Hocmophilus
drug-resistant strains ofentcrococci and siaphylococci, sec http:!/www,joumal>.u<lhe>JO <duldcWpdf/I 0 t ~
. • 99~76 (1<-
Enterococcal Infections, p.180, aod Slaphylococcal lnfec- cesscd 1111>5/IO) comc1- ;w 2010; ~: •S7 ducn:yi. It occurs \\ oridwidc. but is endemic in p!lflS ofAf.
0

uons. p.210 6- Mact.=ie I, Lr•tt A.

'129-32.
M..,......,,. or"'"'" BMJ 2007: »S: rica aod South East Asia, wh= it is a frequent cause of
pamful aenital ulcers and a risk factor in the transmissiou
In addition to anti microbial therapy, patlC11ts with sepsis or
~pllc shock require rigorous supponive measures 1 . ._., 'MKkcnD<: l. Sq>st1. c1cr"'"""'·
cpodcr•oolo&r. 111d do· of HIV.
......... BM/ 2007; 33S: &79- &J Specific treatment guidelines have been provided by
(p.1304). Spec1ficsupportivc trealmcntairnedat inhibiting 8. O'Brien JM. a o/, Sepsis. A•J Mt.11001; llt: 1012-22.
endogenous mcd11tOB released 1n response to sepsis has
WH0, 1 bv expcn groups m the Ul<.2 and by the CDC in
9. O.llincer RP. tt o/ Surv'""I $cps•1 C - t p ••tenacoo.,11 the USA.j Tl'C3tmcnt failure lllllY be more common m pa·
been tried v.ilh llhlc clinical success. and includes adjunc-
tive therapy with cndou»tin Wltibodies. anticytoluncs such ~~It: ~':.."':F=: l~llr ..... Mp&>< shock tients also infected with HIV1 (scebelov.), but in othcrpe·
as anakinra and tumour necrosis factor antibodies, soluble uents sinaJc-dose trea~11C11t regimens might be preferable
10. AnonymC>UL Th<~of1nobo<'l<n1ldrup lo.H-1ilovl•f
lllmOllr necrosis flelor receplor, badencidal pennc3bilir:y ,,..,,.,;crobio/
1,,.,,,,,,_ lllh ed. New Y0<k: 'the Mecl•cal Len•. if compliance is a problem. Guideline regimens are as fol-
ina-cas111g protein, nitric oxide synthase inh1bit<MS, guan- 2008: O-S7. lows:
)'btc cyclase inhibitors such as mclhylthioninium chlo- 11. S...m;aMerl·D, Calondra T. Treatment oh<!"'> past ..... r•. •WHO:
turc l\tnocs. Drngs 1999: 57: t27 ·32. soo ror
ride, and platelet-activating factor antagomsts. 11 ' 13 A sys- • 0<al copmfloxacin n-c iwice daily 3 days. ...
tematic review" of the use of intra,'Cllous polyclonal 11. :,r:c:~·~~~~:ih.':~.:,'6,°tJ~7~"PY orae•<upsos J • oral erythro:nycm 500 mg four llnX'S daily for 1 days. or
immunoglobulin concluded that it hod a promising role as • a single orol dose ofazilhrom)'an I g
13. ~I SM. Ya RL. Antiendoto~m Jtratt&H'S for 1he preve:nhon
adjuvant therapy m sepsis and septic shoclc. Specific mon- and creatmcnt nf &ep4fc shock· new approKhcs and future dircc- an alternative regimen is:
oclonal immunoglobulins were not elfecuvc. 14 Reduced uons. Drlll;S 1998. SS; 497- SOS. • a sinaJe in1romuscular mjec:rion of<rilna><one 250 ma
mortalir:y has been reponed 11 after the treatment ofpatients 14. A5cjandn11 MM.~' ol lrm1.vtnoos immunoaJotM.hn tor trtat1ng • UK:
sepsis ar.d scphc shock Av1ilablc: in TilC Codnnc O.ti.baK tff
witl1 severe St'J>SIS with recombinant activated protein C SySlemAtic: Rtvo<ws; Issue I. Chiche>lc:r: Jolin '\\'oley: 2002 (ac· • 1siniitcun1ldoscofazithromycin I g.cr
(drotrccogin alfo) "hich has antithrombotic. ami-inflam- ccsscd 16/0SIOS). • a &in,le 1mrsmuscular dose of cefiriou:one 2SO n>g. or
206 Antibacterials
• 0<al cipronoxacin 500 mg cwice daily for 3 days nr as a single • •single inlramuscular dose of cefota>imc 500 ms Treatment should be extended to JO to 14 days if
oral dose. or • a single intramuscular dose of cefoxitin 2 g plus ornl meningitis is present.
• oral erythromycin soo lnJl four times daily for 7 ooys prnbcnccid I g Treatment for children with uncomplicated gonococcal
further alternatives arc: •USA: infoctions, most commonly due to sexual abuse in pre-
• single oral doses ofocher nuoroquinoloncs such as neroxaein · a single oral do"' of cefixime 400 mg. or adolcsccnts, is as for adults in those weighing 45 kg or
400 mg or norfloxaein 800 mg • a sin&)c intramuscular dose of ceftriaxonc I 25 mg more. For those weighing Jess than 4.S kg a single intra-
• a single intramu.<cular injection of spectinomycin 2 g Other single dose cephalosporins may be substituted. muscular dose of ceftriaxone I25 mg or spcclinomycin
·USA: A single intramuscular dose of spectinomycin 2 g is 40 mg/kg (maximum 2 g) is recommended. For dissem-
• a single oral close ofuilhromycm I & or an alternative in patients who cannot tolerate ccpha· inated infection in all children an intramuscular or intra-
• a single incramuscular close of ceftnaxone 250 mg. or losporins. venous dose of ceftriaxone 50 mg/kg once daily for 7
• oral ciprofloxacin 500 m& rw;ce daily for 3 days • PllARY:'ICEAL ll'-'1'ECTIONS. days, up to a maximum dose of I g in those weighing
a further alternative is: • UK : less than 45 kg is recommended.
• oral erythromycin soo ma chrce times daily for 7 days • •single oral dose ofciprofloxacin 500 mg. or The Jl£even1ion and treabncnt of neonatal gonOCQCCal eon·
Sexual partners of patients wilh chancroid should also be • a single oral dose of oOoxacin 400 ing. or jurictivitis is discussed under Nconatlll Conjunctivitis,
tested and treated.2·) • • single intnimuscular dose of ceftriaxonc 250 ms p.193 .
Patients co-infected with HIV have ulcers that heal more ·USA: Sexual partners of patients wi th gonococcal infection
slowly and may need to be treated for longer to prevent • asinglc inlramuscular dose of ceftriaxone 125 ms should be tested and created. 1
treatment failure;3 trcatmenl failure is common with sin- • GONOCOCCAL INFECTIONS IN PREGNANT WOMEN. Patients co-infected with HJV should receive !he same
gle-dose regimens.1 •WHO: treatment as those who arc HJV-negative.1
I. WHO. Guidelines for lhe manticme.nt of .sexually tr::in.smiucd
infections. Geneva: WHO. 2001. Al'o l\'lilablc at: • a sin&le oral dose of ccfixime 400 mg, or I. CDC. Sexually Lransmiued disnses lreatmcnt guidelines 2006.
http:/!whq libdoc. who.inllpubHcatiot1s/1003/924 I 546263.pdf • a sin&le int12muscular dose of ceftriaxonc 125 mg, or MMWR 2006; SS (RR·ll): I 9C. Al•o 1vail1ble at: http://
(accessed 23JOJ/07) ww... cdc.gov/mmwr/POF/rT/rrSS 11.pdf (aceeased 23i03/07)
• a single inlramuscular dose of spcciinomyci n 2 g Updated recommended 11ea1mcnt rq1mc111 for 1onococ:e1I in-
2. Clinical Effcctinn"s Group (8ri1ish Auociuion tor Suual
Hcollh and HIV). 2007 ll1110MI guid<Jine for the management · UK : fections and usociated con.di1ioM>--Uniicd States, April 2007.
of chancroid. Available al: h1tp:J!Y."WW.bashh.orsfdocumentsl • a sin&k tmramuscular dose of cefiriaxone 250 mg. or Av~it:ablc a.1: hnp://www.cdc.aov/s1d/1ru.1mcnt12006/
8S.~.pd( (occ<SS<d OSJOlJIO) GooUpd>t<April2007.pdftacce.,.d t2JOCI07)
• a s;ngle tnttamU'lCUlar doscofspec1inomycin 2 g. or 2. Health Prou:aion Agtncy. GRASP The GO<IO<OCCll Rcsi.,.ncc
3. CDC. Scxu1Uy trMS:mittcd disa&e'1 tru1men1 guidelines 2006.
MMWR 2006: 55 (RR· JI): J-9C. Also ava;Jable at: http:// • •single O<al dose of ceftxime 400 mg. or to Antimic.robiab Survcillsncc Ptopammc: 1nnual repon. year
www.cdc.gov/mmwr/POFirT/roS 11.pdf (1cc:e.sed 23103/07) • uinglcoral doscofamoxi<inin3 g(orampidllin2or3 g) 2006. Available at: hnp://www.hpa org.ul</Webc/llPAw<bFile/
plus probcnccid I g HPAweb_C/119494739310 (acccs«d 18108/08)
Gonorrhoea.. Gonorrhoea is a sexually transmitted dis- • USA: j, CDC. Sext>ally transmitted di>cUe surveillance 1007 supple·
ease caused by infection of mucosa with Neisscria gonor- mcnt: Cionoeocc.al Isolate Surveillance Project (GISP) annual rc-
• a ceplialosporio or spectinomycin pon-2007. Avail•ble ot: hllp://www.cdc.,ov/stdtGISP2007/
rhoeae (gonococcus), a Gr.im·neg;itive bacterium. lt oc- GISPSutVSupp2007'1lon.pdf (acoc.md OS/03/ I0)
• GONOCOCCAL EYE Jlll'ECTIONS JN ADULTS.
curs mainly in the lower genital tract as urelluilis (p.2J 5) 4. WHO. Guidelines for the 111a11a8c1nent or sexually trans.nilled
in men and cervicitis (p.175) in women, but also as phar- • WHO: frequent inigation of the infected eye wilh sa- infections. Gencv3: WH O, 2003. Also ava ilable at :
yngitis, proctitis (p.203), or conjunclivilis. Infection may line togelher wilh: http:l/whq l ibdoc. who.inllpublic• t ;ons/200319241 S ~ 6263. pdf
• a sini:Je intramuscular dose of ccflriuonc 125 mg. or (acce<scd 20/06/0?)
sometimes ascend to the upper genital tract to cause com- 5. Clinical EITecti,·cness Group (British Associ11ion for Sexual
plkations such as pelvic inflammatory disease (p.197) in • a single inlr3muscular dose of speainomycin 2 g. ,,,. Hcohh and HIV}. ~ atM>n31 guideline on •he diagnosis ~n<l trcat·
women and cpididymitis (p.180) in men. In the USA1rou- · a single oral dose of ciprotloxacin 500 mg me111 of gonorrhoea in adulL( 2005. Avai11blc at: http:/I
wv,ow.bashh.org/documents/116/116,p<if (llCC<:...,d t&I0&/08)
tine screening is recommended for all sexually active a further alternative is:
women with an increased risk of infection. Disseminated • a sinalc intramuscular dose ofkanamycin 2 g Granuloma inguina le . Gmnuloma inguinalc or dono-
gonococcal infection TC$Ulting from gonococcal bacterae- • USA: irrigation of the infected eye with saline togeth- vanosis is caused by the Gram·ncgativc bacterium Kleb-
mia is rare and may lead to septic anhritis, an anhritis-der- er with: su!lla gra11ulomatis (fonnerly known as Colymmatobacte-
rnatitis syndrome (not to be confused with Reiter's disease · a single intramuscular dose ofceliria.~onc I g rium gra1111/oma1is) and occurs most commonly in the
which has been associated wilh non-gonococcal or non- • DISSEMINATED GONOCOCCAL INFECTlONS Ill ADULTS. tropics and subtropics, especially Papua New Guinea and
specific urethritis), and more rarely to conditions such as • WHO: India. It is characterised by genital ulcers and is generally
endocarditis or meningitis. Gonorrhoea in pregnant wom- • pc11en1cral ceftriaxonc I g once daily for 7 days. or considered to be a sexually transmitted disease.
en may cause neonatal gonococcal conjunctivitis (ophthal- • intramuscular speclinomycin 2 s twice daily for 7 days Guidelines produced by WHO, t by an expert group in the
mia neonatorom). Anolher third-general ion cephalosporin may be s11b- UK,2 and by the CDC in the USA3 for the treatment of
An\ibacterial drug resistance is a problem in the manage- stitu1ed if neither of these drugs is available. Treat· graouloma inguinale are as folluws:
ment of gonococcal infection. Penicillins were once the ment for endocarditis should continue for 28 days. •WHO:
treatment of choice for N. go11on11oeae but are no longer · USA: • oral uilhromycin I g on lhc lirs1 day then SOO mg once daily,
recommended. High-level plasmid-mediated and chromo- • porenteral ceftriaxo.~ I g °'""Y 24 hours or
somally mediated resistances have also bccu reponed with alternatives an:: • oral doxycycline 100mg1wicc daily
tc1t2cycline, and clvomosomally mediated resistance to · intravenous ccf\iwxime 1g e'"ery 8 hours alccmatives include:
other antibacterials may occur. Gonococcal resistance is • ccf<>W<i~ IS tYCry 8 hours • oral erythromycin SOO mg four 1imcsdoily
now monitored in England and Wales via the Gonococcal • intramuscularspcctinom)On2gevcry 12 hours • oral tcttacycline 500 mg four times daily
Resistance to Antimicrobials Surveillance Programme Once improvement has been established for 24 to 48 • oral co-uirno.xazole 960 mg twice daily
(GRASP)2 and in the USA by the Gonococcal Isolate Sur- hours, oral therapy with cefiximc 400 mg twice daily,
veillance Project (G ISP).3 Of concern are the increasing Treatment is Q)lltinued w1til all lesions ha'-e completely
or cefpodox.ime 400 mg twice daily may be substirut· resolved. The addition of parenter.il gentan1icin should
number of reports worldwide of resistance to lluoroqui- cd until at least a I-week treatment period is com-
nolones, which has resulted in revision of ueatmcnt guide- be considered for HIV-infected patients. Streptomycin
plete. Provided antimicrobial susccptibi liry is docu- is no longer recommended because of its toxicity and
lines. In the UK lluoroquinolones arc no longer recom- mented fluoroquinolones may be given as an
mended as first-line drugs, while in the USA they are no the ueed to reserve it for tuberculosis.
alternative trealmenl. •UK:
longer recommended for gonococcal infections.
For gonococcal mcningi1iS"and endocarditis, inlrtlve- oral azithromycin I g unce weekly or 500 mg daily, or
Jnfecti0n with Chlamydia 1roc/1omulis (sec under Chlamy- nous ccfuiaxonc l to 2 g every 12 hours is rccom·
dia I Infections, p. 175) ofien occurs along wilh gonorrhoea parcnceral ceJlriaxone I s once daily, or
mended; trClllmcnt for meningitis should conlinuc for oral CO·lrimoxo;;ole 960 mg twice doily, or
and should be tested for or treated presumptively. I 0 to I4 days and for cndocarditis for at lcas14 weeks.
Guidelines produced by WHO,• by an expert group in the orJI doxycyclinc 100 mg lwice doily, or
• GONOCOCCAL INFECOONS IN NEONATES AND CHILDREN. OrJl.crylhromycin 500 ms fourlimesdaily, or
UK,5 and by the CDC in the USA 1 for the treatment of
gonorrhoea are as follows, although recommendations Neonates born to mothers with gonorrhoea arc al high oral norlloxacin 400 mg twice daily
may need to be localised because of differences in patterns risk of infection and require prophylaxi.r: Duration of trel!Jment should be until lesions have
of infection and drug resistance: ·WHO: healed; the addition of parenteral gentamicin 1 mg/kg
• 1.Jl<COMPUC>.TEO ANOGDllTAL OC»<OCOCC>.L INfECTIOl<'S • a single intramuscular injecrioo of cdiriaxonc 50 msJl<i every 8 hours should be considered if lesions do not re.-
(maxtmwn 125 mg) spond during the first few days oftrcatmenl
NAOOLTS.
alternatives arc: •USA:
•WHO:
• a single maamuscular dose of spec1inomycin 2S m!llkg • oral doxycyclinc JOO mg twice daily for• minimum of 3
· a single oral dose ofciproOo•acin 500 mg, or (ma>.imum 75 m&)
· a single oral dose of ccfixime 400 mg. or weeks
• a sin&fc imr-.imuscular dose ofkanamycin 25 mg/leg (max-
• a single intramuscular dose of ceftriaxonc 125 mg. or imum 75 m~) alternatives are:
• a single inll'llmuseular dose of spcelinomycin 2 g USA: • oral ciprolloxacin 750 ms lwice daily, ()r
• UK: • a sin11Je parcmeral dose of ceftriaxonc 25 10 50 msJl<i • oral erythromycin 500 mg four times daily, or
a single intramuscular dose of ccl\riaxone 250 mg, or ( maximum 125 mg) · oral azithromyd n I g once weekly, nr
• a single intramuscular dose of spectinomycin 2 g. or For those neonates with disseminated go11ococcal infac· • oral co-lrimoxo;;olc 960 ms 1w ice daily
• a single oral dose of cefiximc 400 mg tion (sepsis, arthritis, meningitis), US recommendations In each case treatment is for at least 3 weeks, and until
alternative regimens arc: -arc: all lesions have completely healed. The addition of an
• a single oral doseofciproOoxacin SOO mg paren1tral ccftriaxonc 25 to 50 mg,lcg once daily for 7 aminoglycoside may be considered if lesions do not re-
• a single oral dose or ofloxocin 400 mg days, or spond during the first few days·oftreabnent, in pregnant
• asingleoralcloseofampicillin2or3 gpl1<tp<obcnecid I g para>l<ral ccfOlaximc 25 mg/kg every 12 hours for 7 days women, and in those co-infected with HIV.
All cr0$S-rcferenccs refer to entries in Volume A
 Antibacterials 207
Sexual partners of pe1icnts wilh granuloma inguinale been applied to late-stage symptomatic neurological altematives for non-pregna11t penicillin-allergic pa-
should be tested aiid trealed. ?.l disease, although it is recognised that CNS invasion by tients are:
Paticnls co-infected with HIV should receive the same T. pallidwn is common in early syphilis 3nd that CNS • oral doxycycline 200 mg twice doily fOI' 30 days
treaiment as I.hose who arc HJV-oegative.l involvement may occur at any stage. - oral tetracycline 500 nia four 1in1es doily for 30 day$
1. WHO. Guidthnes for the manq.cmcnl nf sc-xually transmirtcd • Conge11i10/ s>philis may result from transplacenral in· •UK:
infections. Geneva: WHO, 2003. Also available at: fection et any stage of pregnancy and any stage of 1113· - inliamuscular bcnulhine !x.nzylpenicillin 1.8 p
hu p:l/" hqlibdoc. who. iniip11blica1ion"'2003/924 I 546263 .pdr
(•«es.«d 2310311);) temal syphilis. (2.4 million units) weclly fur 3 doses, or
l. Clinical Ef'fccti\-C'MU Group (Association for GcnitOUTin1ry The incidence of syphilis fell dramatically after the inu-o- - intramuscular ~inc benzylpcnicillin 600 mg ·
Medicine and &he McdKll Soc:;cty for the Study orVtncrat 01•,. duction of penicillin and T. pallidum remains sensitive to (600 000 units) doily for l 7 days
eases - now Britis.h Associ=>tion for Sexual Heolth and HIV).
2001 National auidclin~ for 1ke management or dono\•anosb it. There has, however, been a resurgence of syphilis, allematives for patients allergic to penicillin and
(granuloma inaulnnfc). A\'ailable at: hup:.//www.buhh.or:f linked in part with HIV infection. In HIV-infected patients lhose d«lining parenteral therapy are:
docu<n<nts/39/39.pdf (ac<:ascd I S/08/08) syphilis appears more virulent and neurosypbilis occurs oral doxycyclinc I00 mg lwice daily f0< 28 days, DI'
3. CDC. Sexually transmiucd di:sc:.3sff tttllnMnt a,uldclincs 2006. more quickly. Like other diseases causing genital ulcers,
MMWR 2006; SS ( RR-11 ): 1-9•. Also 1v1iloble at: hnp:// - if penicillin can be tolerated, oral amo.\ici.llin 2~ 1lucc
......w.cdc.gov/mmwr!PDFirT/rrSS 11.pdf(accessed 23/0:;/07) syphilis is a risk factor for HN infection. limes daily pl11s oral probcnceid 500 mg four times daily,
The treatment of choice for both early and la<c syphilis is bo1h for 28 days
Lymphogranulo m a venere u m. Lymphogranuloma still penicillin and long-acting injections arc generally For those with 11e111wyphllis recommendations arc:
vcnereum or chlamydial lympbogranuloma is an invasive, used. Treatment for late syphilis is less well-established - intramuscular procaine bcnzylpenicillin 1.8102.4 g(l.810
systemic infection caused by certain serotypes of Chlamy· than that for early disease and is usually given for longer. 2.4 million 11nits) once daily p11u oral probcnccid SOO mg
dia 1rachoma1is and is endemic in tropical and sublt'opical A Jarisch-Hetxbeimer reaction may occur after the first four limes daily for 17 days, or
areas, but may also occur in the developed world. It is a dose of antibacterial, especially in patients with early • inlnlvcnous bcnzylpenicillin 1.8 to 2.4 g (3 to
sexually transmitted disease and in the early phase may syphilis, and corticosteroid cover may be beneficial, espe- 4 million units) every 4 hours fur 17 days
cause genital ulceration although the commonest clinical cially in patients with cardiovascular or neurological in- alternatives are:
manifestation is unilateral inguinal ond/or femoral lym- volvement. • oral doxi'Cyciine 200 lfli twice daily for 28 days
phadcnopathy. Multisystem involvement occurs, and late • oral amaxicillin 2 & thn:e limes daily plus o~I probcnccid
complicarions, including those related to fibrosis and ab- Guidelines produced by WH0,1 by an expert group in the
UK.1 and by the CDC in dic USA3 for the treatment of 500 mg four limes daily, both for 28 days
norm3l lympbatic drainage, may require surgery. · inlr3muscular or intravenous ccfttl3XOnc 2 g d:uly for I0 to
acquired and congenital syphilis arc as follows:
Guidelines produced by WH0, 1by an expen group in the 14 days (in the absence ofanaphyl2Xis 10 pcnieilhn)
• F.'RLY SYPHILIS
UK} and by the CDC in Ute USAl for the treatment of ·USA:
lymphogranuloma vcncreum arc as follows: •WHO:
- in1r.1mUJCular bcnz:tlhinc bcnzylpenicillin 1.8 g
• WHO: treatment for 2 weeks with: • imramuscular bertZalhine bcnzylpenicillin 1.8 g (2.4 million units) weekly for 3 CCNCcu1ive weeks
(2.4 million units) usually given as 2 mjectlons at separate
- or.ti doxycyclinc 100 mg twice daily, or sites in a single sessjon, or alternatives in penicillin-allergic patients are:
· 0<al erythromycin 500 mg foor 1imcs daily • in1ranmscular procaine bcnzylpc!lieillin 1.2 g • onl doltycyclinc 100 mg 1wiccd1ily f0<28 days. or
an alternative is: (1.2 million units) daily for 10 duys · oral 1etraeydinc 500 mg four 1imes daily f0< 28 days
• onl tetracycline 500 mg four limes daily allcmati vcs for non-pregnant penicillin-allergic pa- For those with neurosyphilis:
• UK and USA: treatment for 3 weeks with: tients are: - illlravcnous benzylpcnicillin 1.8 to 2.4 g (3 10
• <nl doxycyclinc t 00 m11 iwicc daily. or - oral doxycyclinc 100 mg rwic.: daily for 14 days, or 4 million unil5) c:vay4 hours for I Oto 14 day$(0<1hc10lal
- oral ldne)'Clint 2 g daily, or • 0111J letracyclinc SOO mg four times daily fur 14 days daily dose may be given by continuous infusion). or
- orol minocyclinc 300 ins as a loading dose 1/Jm 200 mg twice Pregnant women allergic to penicillin may be given: • if outpatient compliance can be ensured. then intmmuscu-
br proc»ine bcnzylpenieillin 2.4 &(2.4 million unirs) daily
dail)',OI' • cnlCf)1hromycin 500 mg four times daily fOI' 14 days(but pl11soral probenecid 500 llll! IUur tintcs daily, both for 10
• oral c1ythromycin 500 mg !bur 1imcs daily sec Syphilis in Pregriancy, btlow)
10 14 days
Sexual partners of patients with lympbogranuloma ve- •UK: Since the duration of treaUnent for neurosypbilis is
nercum should be treated with: • in1T01nuSOJlar bcmndiine bc"Z)1pcnicillin 1.8 g shorter than tha.1 for late syphilis in the absence of
- a single oral dose ohzilhromycin I g or (2.4 million units) as a single dose, or
neurosyphilis, some clinicians give intramuscular
• onl doxycycline 100 mg rv..ict daily fOI' 7 days • intramuscular procaine bcnzylpenic.illin 600 mg
(600000 unil5) daily for 10 days bcnzathine benzylpenicillin 1.8 g (2.4 million units)
Patients co-infected with HfV should receive the same
An additional alternative if parenteral therapy is re- once weekly for up to 3 weeks after completion of
treatment as those who arc HIV-negative, although longer
fused is: neurosyphilis trealJtleflt to provide a comparable total
therapy may be required.3 duration of treatmeoL
• 0<al amoxicillin 500 mg plus oral probcnecid 500 mg,
I. WHO. Outdcl1ncs for the cnanagcmcnt of sc-xually tr:tn1mi:ted • SYPlllUS IN PREGNANCY
in(tc•ions . Geneva: WHO. 2003 . Aho a\•ail1blt at: both four limes daily for 14 days
hnp:/I" hqlibdoe.\\'ho.inilpublic•lions/!003/9241546263 .pdr alternatives for penicillin-allergic patients are: All guidelines recommend penicillin as uodcrcarly and
(acccs!Cd !JIOJ/07) · oral doxycycline I 00 mg twice d:uly for 14 doys late syphilis, together with close survctllancc. In the
2. Clinical EtT«th-cncss Group (Oritis.h As.wciation for Sexual USA, CDC3 nO(es that some recommend a second dose
Hl'.:thh and HIV). 2006 Nttional guideline for the mana;emcnt · oral Cl)1hromycin 500 ma four 1imcsdaily for 14 day$
or lympho:ronulom• Wf'lcttu1n (LGV). AV3ilable at: http:// • oral az:ilhromycin 2 a as a single dose of bcnzatbine bcnzylpcnicillin a wed< after tlic initial
......w.baihh.orgldocumenu/92192.pdf (accessed 18/0SIOS) • oral azi1hromycui SOO mg daily for 10 day$ dose forpaticiits with early syphilis. In the UK1 it is rec-
3. CDC. S-rxu:ally 1ransmittcd diKDscs ttcatmcnt guidclinc1 2006. • ir.cramusculor ccllriuonc SOO mg daily for JO days (in the ommended that when the first dose is given in the third
MMWR 2006: SS (RR·ll): 1-94. Also available al: hup·/I trimester a second dose should be given one week later.
www.cdc.aov/mmwr/PDF/rr;,.,sst l.pdf(aecascd 23103/07) oooe11cc of anophyloxis lo penicillin)
·USA: According to CDC,3 pregnant patients who are alleigic
Syphilis. Syphilis is a sexually transmitted disease caused • 1 sinsJc inlramuscular dose ofbcnzalhine ben:eylpenicitlin to penicillin should be given penicillin, after desensitisa-
by the spiroch:icte Treponema pa/lidum and occurs world· 1.8 g (2.4 million units) tion if necessary, since 1he alternatives, tclr.!cyclines, are
wide. Non-venereal trcponematoses include endemic alternatives for penicillin-allergic patients are: contra-indicated during pregnancy and erythromycin
syphilis or bejel, also caused by T. pallidum; pinta, caused • oral doltycyclinc I00 me twice daily for 14 days cannot be relied upon to cure an infected fetus. WH0,2
by T. carateum; and yaws, caused by T. pertenue. • oral tetracycline 500 mg four lime$ daily for 14 days on die other hand, advises against desensitisation in a
Syphilis may be classified as acquired or congenital and in Preliminary data suggest that azi1hromycin 2 g orally primary care setting and suggest that erythromycin, al-
cacti case has early and late stages. Syphilis may be do- as a single dose may also be effective, or parenteral though inferior, should be given in lhese circumstances;
scribed as latent, when serological tests arc positive but the consideration should probably be given to use ofa lhird·
ccftriaxone I gdaily for 8 to 10 days may also be con·
patient is :isymptoma.tic. gcncratioo cephalosporin in the absence ofanaphylaxis.
sidered.
• In acquired sexually transmitted disease the eal'/y stage Afier 1tealment, the mother should be re-treated if01ere
• LATESYPHILIS is serological evidence of re-infection or relapse, and the
includes primary and secondary syphilis and early latent •WHO:
infectron;early latent in fection is defined in the UK 1and infant rreated.2 UK.guidelines' list altemative antib3ctl}-
• imramusc.ular benzathine bcnzytpenicillin 1.8 g rials that may be given as: amoxici llin , ceftriuone.
by WH~ as of not more than 2 years in duration or of (2.4 million units) once wecl<ly for 3 consecurivc weeks,
lcs~ than I year in duration by 01e qx: in the USA. 3 erythromycin or azitltromycin. they also state that de·
• Lale stage disease includes la!e latent infection and all
sensitisation should be considered in 1hose allergic to
• intta1nllSQJtar procaine bcn2ylpc!licillin 1.2 g penicillin. ·
late clinical stages. The late clinical SUtges fall broadly (1.2 million units) daily for 20 consecutive days
into three types: 11eurosyphilis manifesting as neurolog- altematives for non-pregnant penicillin-allergic pa· • COh'GENITAL SYPHILIS
ical symptoms, commonly including dorsal column loss tients arc: ·WHO:
(tabes dorsolis), dementia, or meningovascular involve- • ornl doxyeycline 100 mg twice daily for 30 days. er for early congenital syphilis, infants up to 2 years of
ment; cardiavascular syphilis, characterised by aortitis • oral 1e1racycline 500 mg four times daily for 30 days age and having abnormal CSF may be given:
wbicll may manifest as aortic regurgitation, aortic aneu· Pregnant women allergic to penicillin may be given: • intravenous bcnzylpcnicillin 30 mg/kg (50 000 units/leg)
rysm, or angina; and gum111a1a, 10flammatory fibrous • or:il •'}~hromycin 500 mg four times daily for 30 days 1wice daily for the lirst 7 duys of life and 1hen lhrcc times
nodules or plaques which may be locally destructive d•ily ror a 1otal of 10 days. or
For those with ncurosyphilis:
and which commonly affect the bo1te and skin but may - iiuramuscular prccainc bcnzylpenicillin SO nl&lka
• intr3YCOOUS ben:eylpcnicillin t.2 10 2.4 g (2 lo (50000 unirsllcg) once daily for tOdays
occur in any organ. Some !enn all these late clinical 4 nullioo uni1s) every 4 hours for 14 days, oi·
stages tertiary syphilis whereas others use tertiary for • if oulpltitnl compliance can be ensun:d, 1nmomuscular For infants with nonnal CSF (although some treat all
benign gummatous syphilis and quatemary for the more procaine benzylpenicillin 1.2 s (1.2 million units) daily infants as if the CSF were abnonnal):
serious complications of cardiovascular syphilis and p/11.• oral probenecid 500 mg !bur 1imcs daily each for 10 - 1 sinJI< inlr.lmuscular dose of bcn?llhinc bcnzylpcnicillin
neurosyphilis. The term neurosyphilis has generally lo 14 days 37.S mg/kg(50 000 unitslkg}
208 Antibacterials
Children older than 2 years may be given: small.2 Io the UK, guidance issued by N1CE1 suggestS that ocr update. J All~rt.YClin hnmuno/200S; 116 (suppl): Sl3-S47.
Also available at : hnp;//www.uui.or2/pro(cuiona lc/
• parenteral benzylpcnicillin 30 mglkg (50 000 units/kg) antibacterial preSO'ibing should be avoided or delayed, un- ....,.,,cesipdl7sinusitis200S.pdf(•cccssed OS/0$(10)
r:vcry 4 to 6 houn for I 0 10 14 days less the patieot is systemically very unwell or has signs or S. Young J, ~' ol. Antibiotics (OJ adults with clinically diagnosed
For penicillin-allergic infants aged over l month: symptoms of, or is at high risk of developing, serious com- acute rhinosinusi1is: 1 mN·mafysis of individual pi.timt dJ\a
Lance/ 20-08; 371: 9011-14.
• onl c:rythromycin 7.5 10 12.S mg/leg four times daily for plications. US guidelines' su&gest that appropriate criteria 6. American Academy of Pediatrics: Subcommittee on Manage·
30days for use of antibacterials include symptoms of sinusitis for mcnl or Sinusitis and Comrniucc on Quality Improvement.
• UK: recommended doses are as for infants up to 2 I0 IO 14 days or severe symptoms (including fever with Clinical practice guidtlint-: mana1cmcn1 of sinusitis. Pediatrics
2001; 108: 798-4!08. Comctions. ibid. IOI (S): >.24 and ibid.
years with abnormal CSF in WHO guidelines, above. purulent nasal discharge, facial pain or tenderness, and 2002; I 09 (S): A40.
• USA: periorbital swelling). However, a meta-analysis concluded Afso av11l1ble. 11: http://pcdiatdcs.1appvbhca1iun:..org/cgi/
that for immunocompctent adults with acute sinusitis, an- reprint/IOl/Jf798 (•cccsscd 19/0t/08)
Neonates(up t04 weeks of age) and having proven or 7. Sc.adding GK, ~r of. Brili.sh Society fot Allergy and Clinic.al Im·
probable disease: tibaclerials could not be justified, even in patients who re- munok>zy. 8SACI guidelines for the mana.gcrrM::nl of rhinosi-
intravcoous bcnzytpenicillin 30 mg/kg (50 000 units/kg) ported sympeoms for longer than 7 or I 0 days, and that the nusiti• and nual polypOlis. Oin Exp AU<'fY 2008; 38: 260-7S.
twice daily for the fir$t 7 days oflifc and lhtn three times only reason for antibacterial treatment was the presence of ~J'i:'C:~~i;;~\•Ji~ 3'j;!g7™f,:i{;:=~s7~~/i·g}mtcsi·bin/
daily for a total of I0 days, or signs suggestive of serious complications. 5 Guidelines 8. Fal•gas ME, er ol. Elfceli•cneu and $8fcty of shon vs. Jons du·
intramuscular procaine bcnzylpenicillin SO mg/kg from the American Academy of Pediatrics for the manage- or
n lion antibiotic thttapy for acute bacterial sinus iiis: a mcta-
ment of sinusitis in children6 recommend that antibacteri- a.naly1is or randomlzcd 1riats. Ir J Clm Pllormocol 2009; 67:
(50000 units/kg) once daily for 10 days 161-71.
Neonates who have a normal physical and a non- als be given to children clinically diagnosed with persist- 9. Hwang PH. A Sl-ycar.oJd woinln with acute CM'lsct of facia~
treponemal serum titre the same as or less than 4 ent or severe acute bacterial sinusitis in order to achieve a pressure. rhinorrhu.. and tooth pain: rc:~iotw of acute rhinosi-
more rapid clinical cure. nusiti$.JA.WA 2009; 301: 179$-1807.
times the maternal titre may be given, depending on 10. Gr.lySlon JT, ctol. A new respiratory troa patho&cn: Chlamydia
how successfully the mother was treated dwing preg- If antibacterials arc considered necessary, treatment should pncum®ioe main TWAR. J lnfee1Dis 1990; 161 : 61$-lS.
nancy: be given for an adequate length of time, usually I0 to J4 11. Zalm.anovici A. Y1phc J. Intranasal steroids for ac\.ltc l inushis.
Available in Tiie Cochrane Database of Systematic Reviews: Is·
• one of lhc above IJUtment regimens or days;•A7 however, in a mela-analysis' of 12 studies, no sue 4. Chichester: John Wiley; 2009 C•=d 28/04/JO).
• a single intramuscular dose ofbem.athine benzylpenicillin significant difference in efficacy was found between sbort- 12. Harvey R. et al. NaSll n line iniplion.s for lhe symptOm5 of
37.5 mgikg(SO 000 unilSlkg) oourse (defmed in various sludies as 3 to 7 days) and long- dlronic rhlnosinusitis.. Available in The Cochrane Da1abas.e o(
SySlem1tH: Review$; Issue 3. ChiMcsttt: John Wiley; 2007 (ac-
Infants and children may be given: coursc (6 to 10 days) treatment in patients with acute, un- cessed 28/04/10).
• inttavcnous benzylpenicillin 30 mg/I(& (50 000 units/kg} complicated, bacterial sinusitis. When antibacterial thera- 13. Chtrry WB, Li JT. Chronic rhino•lnusllis in adults. Am J M•d
2008; 121: ISS-9.
every 4 to 6 hours for I 0 days. py is used, choosing the drug with the narrowest spccirUlD
Those who are allergic to penicillin should be desen- against the most probable ~thogens is prudent tO mini-
sitised if necessary. mise the risk of resistance. US guideline$4 recommend Skin infections
Sexual partners of patients with syphilis in any stage amoxicillin as first-choice therapy in adults and children; Bacterial infccrions of the skin and soft tissue (skin struc-
should be examined, tested, and trealed.2.3 co-trimoxazole can be used as an alternative in adults. In- tures) may result from invasion of skin .strucrures by en-
In the UK, 1 ii is advised that all cases of syphilis in HJV- creased resistance has been noted among causative organ- dogenous skin noro or by exogenous pathogenic organ-
infccted patients be treated as for the appropriate stage of isms, however, and local resistance patterns should be con- isms.1bey may involve any orall layersofthc skin, fascia,
infection as in HIV-negative patients; some experts recom- side.rcd. For patients who do not respond to amoxicillin, and muscle, and can ;-prcad giving rise to complications
mend treatment as for ncurosyphilis but the UK guidelines high-dose amoxicillin plus clavulanic acid (90 mg/kg such as endocarditis, Gram-negative sepsis, or streptococ-
note that evidence for this policy is lacking. The CDC1 and based on the amoxicillin compooen1, 10 a maximum of 4 g cal glomeru lonephritis.
WH02 consider thal scanclatd treatmem with a single intra- daily) is recommended. For those intolerant of amoxicil- Clinical assessment of the inf~tion is impor18nt for man-
muscular dose of bcnzathine benzylpcnici llin J.8 g lin, alternatives include oral cephalosporins (such as cef- agement and several classification schemes have been de-
(2.4 million units) is sufficient, but acknowledge that podoxime, cefdinir, and cefuroxime), macrolides, or nuo- veloped. Primaiy bacterial skin infections usually involve
some authorities recommend more intensive treatment roquinolones. If associated with dental disease, coverage areas of previously healthy skin and arc typically caused
regimens. for anaerobes and Gram-negative bacteria is indicated.9 by a single organism. Secondary infections occur in areas
(Briti~h A~ociatK>n for Sexual
I. Clinic111I EfTcc.livencss Group
Tetrocycline or erythromycin are the most effective anti - of previously damaged skin and are frequently polymicro·
lic:ullh 11nd HIV). 2008 UK national guidelines on \he man3gc- bac1erials against Chlbmydophila pnewnoniae. t0 bial. Skin infections have also been classified as uncompli-
mcnt or syphilis. hnp://www.bashh.org/documents/1771 (ac-
Jntrana.c;al corticosteroids reduce innamma1ion in the nasal cated or complicated (when they involve deeper skin
cessed I SlllSIOS)
2. WHO. Guidehnes for the ma.nagcment of sa:v-ally tnnsmincd mucosa. A systematic review11supported the use of intra- structures, need surgical treatment. or occur in immuno-
inrcctions. Oencva: WHO. 2003. Also 1vaihblc a1: nasal corticosteroids for acute, uncomplicated sinusitis compromised patients). Another classi fication system di-
http:/!whqlibdoc who. in1/ publica1ions/20031924 I S4 6263. pd r confirmed by radiology or nasal endoscopy, either as vides skin and soft tissue inf~tions into 4 classes based on
(~ 23103/07)
monotherapy or adjuncts to antibacterial treatment; al- the severity of local and systemic signs and symptoms of
3. COC. Sexu:1Uy transmiued disca.scs treatment guidelines 2006.
MMWR 2006; SS (RR·I I): 1-94. Also availableal: h11p:// though the authors noted that data were limited and the ob- infection, and the presence and stability of any comoroid-
ities.1
www.cdc.gov/mmwr/PDF!rr/n SS 11.pdf (•cceucd 23/03/07) served eltects were modest.
Failure IO treat acute sinusitis that does not resolve sponta- • Class I patients: arc a febrile and otherwise healthy and
S higellosis neously can result in chronic sinusitis or rarely in compli- usually can be managed with topical or oral antibocteri-
See p.185. cations such as orbital cellulitis, intraorbi1al abscesses als on an outpatient basis
(whic!1 may lead to blindness), cavernous sinus thrombo- • Class 2 patients: arc febrile and have an ill appearance,
sis, ostcomyelitis of the frontal bone, extradural and sub- but have no unslable comorbidities. Oral antibacterials
S ickle-cell disease dural ernpyema, brain abscess, or meningilis. 1 may be helpful in some ofd1ese patients but most will
For prophylaxis against pneumococcal infection in sickJe- need parenteral antibacterial trcaonent
cell disease, sec under Spleen Diso~ p.209. Management of chronic sinusitis is based on rcducin" ob·
struction of the sinus cavity using antihistamines, decon- • Class 3 patients: have a toxic appearance, at least one
gestants, anti-inflammatory drugs (including cortieos1cr- unstable comorbidity, or a limb-threatening infection
Sinusitis oids), and saline washes as appropria1e.1-' A systematic and need treatment with parenteral antibacterials
Sinusitis or inflanunation of the paranasal sinuses can be review 12 concluded that intranasal saline irrigations, either • Class 4 patic:nts: have sepsis syndrome or serious life-
caused by viral, bacterial, or fungal infection or may be as monothcrapy or as adjuvant treatment, arc beneficial for u1reatening infections, such as necrotising fasciitis (see
secondary to Olhcr disorders such as allergy. Sinusitis rare- symptomatic management of chronic sinusitis, although p.193) and always need treatment with parenteral anti-
ly occurs without rhinitis (minosinusitis). they appear to be less cffcclive than intranasal corticoster- bacterials; some patients will also need surgical treat-
Acute sinusitis often results JTom viral upper rcspiratory- oids. The usefulness of antibacterials is more conten- ment
tract infections. About 2% of cases arc complicated by tious, 13 although some clinicians advocate prolonged Trearment of ski n infections is hased on knowledge of the
bacterial inf~tion; 1 the most frequent bacterial pathogens courses as part of initial trcatmcnl7 As well as 01cir estab- likely infecting organisms and patterns of resistance. t,l
arc Streptoccccus pneu111011iae and unencapsulated Hae- lished antibacterial effect, it has been suggested that mac- The majority or skin and soft tissue infections are caused
mophilus injl11enzae, with Moraxel/a catan-halis (Branho- rolides also have immw1omodulatory effects that could be by aerobic Gram-po6itive cocci, such as SJaphylococcus
mella cotarrhalis) increasingly important in children. Oth- useful in the management of respiratory diseases including a11re11s and streptococci. Increasing drug resistance of
er bacteria I causes, especially in adults, include mixed chronic sinusitis but large placebo·cOntrolled studies arc Gram-positive organisms and the rising incidence of noso-
anaerobic bacteria (usually associated with denial disease needed. Surgical intervention may be necessary for select- comial and more recently commwtity·acquired MRSA is
and more frequent in chronic sinusitis), Staphylococcus ed patients if medical treatment fails. causing concern and complicating treatment options.
oweus, Streptococcus pyogenes, and Gram-negative bac- Exacerbations of chronic sinusitis arc treated as for acute Treatment alternatives for infections with UlCSC organisms
teria including Enterobacteriaccae and Pseudomonas aer- infection. arc discussed under Slaphylococcal Infections, p.210.
uginosa (in nosocomial sinusitis). About 5% of primary I. Ah-Sec KW, EvanJ AS. Sinusi1js and its rn:rn.agcment. IJMJ Guidelines and recommendations for the management and
sinusitis in young adults has been associated with Ch!omy- 2007; 334: 3SS-61. diagnosis of skin and soft-tissue infections have been de-
dophi/a pne111noniae (Chlamydia pneumoniae). 2. Ahovuo-S.10t11nCa A, ti ol. Antibiolic:S for acute maxillary Ji. veloped in u1e USA.1.3
nu.sitis. Available. in The Codvanc Data.base of Systcmalic: Re-
Acute sinusitis usually resolves spontaneously, and symp- views~ lssue 2. Chiehes1cr: John Wiley; 20-08 (accened Impetigo is a superficial skin inf~tion that consists ofdis-
tomatic relief with simple analgesics is considered the 19/Ct/08). crete purulent lesions usually on exposed areas of the
mainstay oftreatment. 1Although antibacterials arc wide- ). NICE. Respiratory tract infcc:tion.s-ontibio1ic prescribin~: pre-- body, most frequently the face and extremities and occurs
scribing of tuuibiotics for self-limiting respiratory tract 1nfcc-
ly prescribed for acute sinusitis, their use is controversial dons in 1duhs and childrm iri primary cue (ijjucd July 2008). most commonly in children aged 2 to 5 yeaIS. It is caused
given the self-limiting nature of the condition and the rel- Availoblc at: hllp://www.nice.of3,.uk/niccmtdia/live/120 1SI - by ~-haemolytic streptococci and/or Staph. Oll,.eus, and is
atively small propoltion ofcases where bacterial infection 41323/4 1323.pdf(occcssed 26l04/IO) highly contagious. The infection- may be nonbullous or
4. Slavin RO." ol Aoncrican College of AllcrJY, Auhma and Im·
is con finned. A systematic review of 57 studies concluded anunology. Joint Council o( Allergy. Asthma and lmmunok>gy. bullous in appearance; bullous impetigo is caused by
that any treatment efTecl of antibacterial therapy was The dia~is ltld management or sin.usitis: a pt'actlct pan.me- Staph. OlllT!US. Staphylococcal scalded skin syndrome is a
All cross·rcfen:nces refer 10 e111ries in Volume A
 Antibacterials 209
severe manifestation ofbullous impetigo caused by infec- me), an intravenous first- or second-generation cepha- (fo1111erly callee DF-1). which may cause opportunistic in-
tion witl1 su-ains of Staph. ai11ws producing exfoliative ex- losporin. 01· an aminog,lycoside depending on the severity fections in splenectomised patients after animal bites.~
otoxin~. The 1e1m toxic cpidennal necrolysis is used lo of lhe infection . TI1osc wi th polymicrobial infections Borde1e/la holmesii, and tick-borne E/111.ichia spp.3 There
CO\'er both !his syndrome and a morphologically identical (without anaerobes) may be treated with an aminoglyco- may also be an increased risk of falcipannn malaria and
syndrome of more varied aetiology. A syndrome resem- side plus either intravenous benzylpenicillin (if streptococ- babesiosis. 2.•
bling sc2rle1 fe\'er may also occur. ci are cu ltured) or a penicillinase-resistant penicillin (if Infections in asplenic or hyposplenic individuals are large-
For palienls with a limited number of lesions, topical ther- staphylococci are cultured). Ceftazidime and the Jluoro- ly preventable, the geneJ'al approach being through vacci-
apy with mupirocin may be considered; 3« other topical an- quinolones are effective against both Gram-positive and nation and the use of antibacterial prophylaxis. Practice
tibacterials, such as bacin-acin and neomycin arc consider- Gram-negatil'e bacteria.6 Patients witl1 mild, polymicrobi- guidelines based on publ ished evidence and expect opin-
ably less effective.; Topical retapamulin is licensed for the al infections (with anaerobes) may be treated with oral ion have been published in countries including Australia
treannent of impeligos due to either S!aph. aZ1reZ1s or S1rep- amoxicillin plus clavulanic acid or a fluoroquinolone (cip- and New Zealand3 and the UK. 2.S
1ococc11s pyogene$. rofloxacin or levofloxacin) plus either oral clindamycin or Jinmunopropbylaxis. Immunisation with polyvalenl
Patients with many lesions or those who do not respond to oral men·onidazole. Moderate lo severe infections may be pneu·mococcal vaccine is recommended for all asplenic
topical drugs should be given oral antibacterials. Penicilli- treated intravenously with an aminoglycoside plus clin-
patients and those with functional hyj)osplenism. Haema-
nase-resistant penicillins (dicloxacillin, flucloxacillin, or damycin or metronidazole, or monotherapy with a second-
philus injluenwe (H ib) vaccine is recommended for all pa-
cloxacillin) or a first-generation cephalosporin (cefaJexin) er third-generation cephalosporin (cefoxitin or ceftizoxi-
tients who have not prel'iously received lhis vaccine, and
are preferred; 3•4 alternatives include fuacrolides, clin- me), a carbapenem (imipenem, meropenem, or ertapen- influenza vaccination should be given annually!.5 Menin-
damycin, and amoxicillin with clavulan'ic acid.1•3 Intrave- em), a beta lactam with a beta-lactamase inhibitor (pipera-
gococcal vaccine is also recommended; however, the
nous benzylpenicillin, intramuscular benzathine ben- cillin with tazobactam), or tigecycline.6 Antibacterial
group C conjugate vaccine routinely used in some coun-
zylpenicillin, or oral phenoxymelhylpenicillin may be treatment is usually continued for J0 to 14 days or until
infiammation resolves,4 but uncomplicated cellulitis may tries (including the UK) does not protect against N. meni11-
given for infections likely to be caused only by streptococ- gi1idis serotypes A, Wl35, or Y; therefore, patients travel-
ci. '-6 be treated for 5 days.3·7 ling abroad to areas where these serotypes are endemic
Cutaneous abscesses are collections of pus within the Antibacterial resistance among S1aph. a11n1us (meticillin should receive additional vaccination with an appropriate
dermis tnd deeper skin tissues and are typically poly- resistance) and S11: pyogenes (erythromycin resistance) is polyvalent meningocoocal vaccine. 1s
microbial (containing normal skin bacteria and organisms problematic because both of these organisms commonly
cause a variety of skin and soft-tissue infections. 3 General- Antibacterial prophylaxis. Prophylaxis with a suitable
from adjacent mucous membranes). Staph. aureus is found antibacterial should be offered to asplenic and hyposplenic
as a single pathogen in about 25% of cases. Treatment in- ly meticillin-sensitive Staph. aureus (MSSA) infections
patients, and alt:1ou2h opinion varies on the opt imal dura·
cludes ir.cision and drainage, and systemic antibacterials mav be treated wid1 oral antibacterials such as cloxacillin,
flucloxacillin, dicloxacillin, or cefalexin; for penicillin-al- tion, UK guidelinesh consider that prophylaxis should be
are rarely necessary but 01ay be needed for those wilh mul- lifelong; it is considered particularly important in patients
tiple lesions, cutaneous gangrene, severely impaired host lergic patients clindamycin or a macrolide (erythromycin,
with underlying immunodeficiency, in children up to the
defences, extensive surrounding ccllulitis, or severe sys- clarithromycin, or azithromycin) may be given.' Jf
parenteral antibacte1ial 1ream1ent is needed a penicillinase- age of 16 years, and for the first 2 years after splenectomy.2
temic symptoms ofinfection.3 Phenoxyn1ethyl?enicillin is usually given, but amoxici llin
resistant penicillin (nafcillin or oxacillin) or a cepha-
Folliculitis is an inflammation of the hair follicle which losporin (ccfazolin, cefuroxime, or cefuiaxone) may be (wid1 or withoul clavulanic acid)2-' may also be used, par-
may result in superlicial infection with pus only present in given; clindamycin may be used in penicillin-allergic pa- ticularly in adults, as amoxicillin is better absorbed after
the epide1mis. Furnncles (abscess or boil) are infections tients. MRSA infections may be treated with oral antibac- ornl doses and has a broader spectrnm of activity. Erythro-
of the hair follicle in which suppuration extends through mycin is a suitable alternative in those unable to tolerate
terials such as co-lrimoxazole, doxycycline, minocycline,
the dcnnis into the subcutaneous tissue, fonning a small clindamycin, or linezolid.45 Oral rifampicin with either penicillins; 2.S roxithroinycin, moxifloxacin, cefuroxime,
abscess.3 A ca1·buncle fom1s when the infection extends doxycycline or co-t1imoxazole has also been used.~ The and co-trimoxazole have also been suggested 3 although
to involve seve1-al adjacent follicles, producing a coales- fluoroquinolones (levofloxacin and moxifloxacin) have specific choices should also be informed by local resist-
cent infinmmatory mass wirh pus draining from multiple been used in patients who could not tolerate any of the otl1- ance pattems. On a practical level, compliance with life-
follicular orifices.3 These skin infections are usually er drug choices,4 but some advise against their use as re- long prophylaxis is difficult, and guidelines frotn Australia
caused by S!aph. aureus. Folliculitis and small funincles sistance to them develops rapidly in Staph. aureus.s and New Zealand1 have therefore suggested that, in th~ ab-
may respond to the application of moist heat to promote Parenteral vancomycin is the drug of choice for moderate sence of impaired patient imll1unity, die need for ongoing
localisat'on and drainage of pus. Topical antibacterials to severe infections; appropriate parenteral alternatives prophylaxis can be reconsidered after 2 years of use. There
such as mupirocin, clindamycin, Cl)1hromycin, or benzoyl may include clindamycin, daptomycin, tigecycline, line- is also evidence to suggest that, in children who have re-
peroxide may also be used for management of folliculitis. zolid, and quinupristin/dalfopristin depending on whether ceived pneumococcal immunisation, there is no benefit in
Larger furuncles and all carbuncles require incision and the infection is hospital- or community-acquired.4.S continuing penicillin prophylaxis beyond the age of 5
drainage. 3 Patients who are febrile or also have extensive years,6 although indefinite prophylaxis has been recom-
cel lulitis may be treated with systemic antibacterials as for For details on other skin and soft tissue infections. see un- mended for those who have had a previous pneumococcal
impetigoH In patients at risk of recurrent furunculosis der Acne (p. 1717), Bites and Stings (p. I 72), Rosacea septic event. 7 fears that prolonged propJ1ylaxis could en-
topical o; systemic antibacterial therapy has been tried for (p.1724) and Surgical Infections (p.21 I); ~-ystcmic infoc- courage the emergence of resistant pneumococci have not
emdicating nasal or extra-nasal S1aph. aureuscarriage (sec tions with cutaneous in volvement include Anthrax been substantiated. 8 although the preva lence of beta-
under Staphylococcal Infections, p.210). (p.171), Diphtheria (p.177), and Mycetoma (p.193). lactam-resistant pneumococci continues 10 increase. Pa-
I. Eron LJ. c:s a/. M:m:iging skin nnd 50fl cissuc infec1io1\S: -exp~1
Erysipelas (also known as St. Anthony's fire) is an infec- pnncl n:c-0mmend31ions on key decision points. J A111imicrob
lienls who are not ulhcrwise taking antibacterial prophy-
tion of tl·.e more superficial layers of the skin and cutane- C:hemofh<tr 2003: S2 (suppl I): i3-il1. laxis should be advised to do so during periods of tca"el
ous lymphatics characterised by abrupt onset of fiery-red 2. Breen JO. Skin 3nd soft 1lssue iniec1ions in immunl\COmpctent abroad, wia1 resistance pattems in tr~vcl destinations be-
palients.. Am Fam flt_l•sic;on 2010; 81: 893-9. ing used to guide the specific choice ofantibacterial,2 Ma·
swelling of the face or extremities; it is mostly caused by 3. Stevens DL, eta/. fnf\."Clious Diseases Society of AmcricJ. Pr:1c-
ll-haemolytic streptococci (usually group A). The treat- 1ice: guidelin.:s for che diagnosis and m:inag(mem of skin :ind !aria prophyla~is is also necessary if travel to endemic ar-
ment of choice is a penicillin, e.g. intrave11ous benzylpeni- sofi-lis.sue infc::ctions. Cli11 ln/C'!ct Dl12005: 41; 1373-1406. Cor- eas cannot be avoidccJ. 2.3
cillin, intramuscular procaine benzylpenicillin, or oral phe- rectioos. ibicl; 1830 ~ nd ibid. 2006; 4?: 11J9. (dosc crro-r) Aho Antibacterial prophylaxis reduces, but does not complete-
avaiJ<\blt 3(; h11p:!/www.journ3 ls.uch icago.edu/doi/pd(/
noxymethylpenicillin depending on the severity of the IO.IOR61497143 (ate<5"ed 06108/08) ly eliminate the 1isk of infection, and prol,'!"<:ssion lo over·
infc::ction.3·6 Clindamycin or erythromycin are alternatives 4. Eron U. ~f of. Ccllulitis ""d soft-tissue: infcc:tions. Ann Intern whelming se1J5is can be rapid. Patients should therefore be
for those allergic to penicillin.6 If Sraph. a11re11s is suspect- Med2009; t50: lTC l·l-ITCl-15. advised to keep a supply of a suitable antibacterial for im·
S. Daum RS. Skin :ind sof1.;isst1e infectio1\Scaused by inethicilti11-
ed a pemcillinase-resistant penicillin or~ first-generation rcsi~ta nt Srap:1y/ne()U11s tnm!lls. N Engl J .lvli!d 2001: 357:
mediate use should symptoms of infeciion occur, aod be
ccphalosporin should be chosen.3 3S0-90. Correl·Cit111. ibid.: 1357. fdo$e t!rror) instructed to seek medical advice ur<,iently. 3·5 Suggested
Cellulitis is an acute infection, initially affecting the epi- 6. Fish ON. el of. Skin <ind soft-li$suc infections. ln: OiPiro JT. ct drugs are generally similar to those used for prophylaxis.
al. eds. Pharm.1cQthtrop)': 11 pm/Jop/J.1·1iologic oµprotJc•l1. 7th ed.
de1i11is and de1mis, but may spread within the superticial I. M~lles DC. de Marie$. Pre,·cnlion of infi.-ct>ons in hyposplcnic
New York: M<:'Gnn.,•·Hill. 2008: 1801-17.
fascia. lt may also spread through the lymphatic tissue and ttnd asplenic ~tcms : an upd:uc. Ne1/J.I Med2004; 62: 45.-52.
7. Hepburn IVIJ, ~' nl. Comparison of shon-wur~c (5 doy~) ::me.I
.., Working Partyof1he British Commiucc for $i;,mfords in Hacma-
to the blcodstream. Cellulitis is must commonly caused by st:anda1•d { 10 da)•S) lrc:l.lmCnl for uncOmplic:ucd cclluliti.s. Areh
1olog.y Clinical lf:temalol<>.t:Y T:ask f'orec. CuKJclincs for 1hc pre-
lntt'm Med2004; 164: 1669-14 .
. beta-hacn1olytic sn·eptococci and S1aph. (IU11'us although \·cntion :.ind trc31111cnt of infection in JXlti~nts wilh an abscn1 or
many other bacteria may cause infection. Parenteral drug dysfonclional spleen. B.>.tJ !996: 312: 430-4.
abusers 2rc most often iofcctcd with S1aph. aureus, while Spleen disorders 3. Spelman O. ,., ttl. Austr.ilasi;rn $('1Cidy for lnf<Xtious Oi$e3scs.
(iuiddincs for 11e prcwmio1l of sepsis in asplcnic and hy1~s­
mixed aerobic and anaerobic infections generally occur in Patients with asplenia (due to splenectomy or cougeoital plcnic ~1icn1s. /111ern Med J 200S: 38: 349- 56.
diabetic patients. Mild infections caused by unidentified defecl} or functional hyposplenism (associated with, for 4. Wi!litun BM. <!I al. Hypo."'plenism: a comprehc:nsive revitw. P:in
Gram-positive organisms or staphylococci may be treated example, coeliac disease, haemalopoietic stem cell trans- Ir: cliniC'31 nu,inifestations. di3gnQsis. :lnd m ~nttgement . Hcma-
with oral penicilli nase-resist<Jnl penicillins or first-genera- plantation, or haemoglobinopathies such as thalassaemia to/o!,!_.-2001: 12: 89-98.
S. British Conm1i11.;.: for Stand~rds in Haematology Working Party
tion cephalospo1ins, while intravenous nafcillin, oxacillin, major or sickle-cell disease) have impaired immunity and, of the Hoema10-0n~ology Task Fcrcc. Upd:ue o( guidelines (or
or ccfazclin are given for moderate to severe infections."' like other immunocompromised patients (p. !86), are at in- 1he prcvcnuon a11d 1rc1nmcn1 ofinrcc1ion in pn1icn1s. wifli an ilb·
Clindamycin and vancomycin are alternatives in those creased risk of infection. 1 Children are at special risk. Fre- s~1H or dysfut1t1ional spletn. Clbt Med 2002~ 2: 440-3. Al:,:o
availahk al: http://www.bcshgu ide l ines.com/pdfi
with life-threatening penicillin all~y.3 Documented mild quently, infection is caused by encapsulated bacteria such SPL£EN21.pdf .,:w:c.ssed 2110$104)
streptococca l infections are treated with ora l phe- as Haemaphil11s i'!{/11e11we, Neisseria meningitidis, and 6. F':illcua JM. tic./, Discon1inuing. penicillin proph~laxis in C'hit-
noxyrnclhylpenicillin or amoxicillin or intramuscular pro- most commonly, S1rep1oco<x11s pneumoniae, 1-' which drcll with sickl(t.:c!ll anemia. J Pedfrnr l99S: 127: 685-90.
caine benzylpenicillin; intravenous benzylpenicillin is giv- may cause seve!'e overwhelming infection that is rapid in 7. Hongcng S, tt ol. Recurrent S1reptococ:cus pncwnoniac sotpsis in
en to those with moderate to severe infections. Infections onset and sometimes fatal. S"l111011ella spp. are also impor- children with si<klc cell disca"'c. .I Petliou· 1997; UO: 814- 16.
(Orl'i:'Clio11. ibid.; 131: 2~2.
due lo Gram-negative bacilli may be treated with an oral tant patl1ogens in childrer1 with sickle-cell disease.• More 8. Norris CF. 1.•1 oi. l)ncu1nooocc;;il coloniiation in children with
second-generntion ccphalosporin (cefaclor or cefuroxi- unusual organisms include Capnocytaphag" canimorsus sickle cdl di.~:as.e. J Pediu1r 1996; 129: 821-7.
210 Antibacterials
Spotted fevers agulase-positive, and Staph. epidermidis and Staph. sapro- needed.3 CA-MRSA infections appear to be resistant to
Rickettsial infections of the spotted fever group are trans- phyticus, which are coagulase-negative. fewer antibacterials than HA-MRSA infections; CA-
mitted to man mostly by ticks and have also been called Staph. aureus colonises the skin and mucous membranes MRSA isolates are generally resistant to beta lactam peni-
tick typhus. Tuey include Rocky Mountain spotted fever, naturally and many people, including neonates, may be cillins and cephalosporins and macrolides (erylhromycin,
due to Rickettsia l'ickettsii and occurring especially in the staphylococcal carriers from time to time. Localised Staph. clarithromycin, and azithromycin). Resistance to fluoro-
USA but also in Canada, Mexico, and Central and South aureus infections may follow surgery or trauma and com- quinolones and tetracyclines occur.;, and may be increas-
America; boutonneuse or Mediterranean spotted fever, monly result in abscess fonnation. Staphylococcal.skin in- ing.3.S Most CA-MRSA isolates are susceptible to co-tri-
due to R. conorii and occurring in Mediterranean countries fections include impetigo, carbunculosis, and furunculo- moxazole, gentamicin, tetracycline, and clindamycin3.s
including the Middle East, Africa, and India; African tick- sis. Co nditions associated with staphylococcal For more serious infections vancomycin is the drug of
bite fever, due to R. africae and occurring in sub-Sahar.n extracellular toxin production include staphylococcal choice. 2•4
Africa and the Caribbean islands; Queensland tick typhus scalded skin syndrome, toxic shock syndrome, and staphy- For eradication of nasal carriage UK guidelines for the
or Australian spotted fever, due to R. australis and _occur- lococcal food poison ing. Staphylococcal septicaemia is control of MRSA in healthcare facilities recommend
ring in Australia; north Asian or Siberian tick typhus, due usually a consequence of local infection and may some- mupirocin nasal ointment Eradication at other colonised
to R. sibirica and occurring in Siberia and Mongolia; and times be associated with intravascular or intraperitoneal sites is more difficult: antiseptic detergents ma~ be used
oriental spotted fever, due to R. japonica and occurring in catheters or with intravenous drug abuse. Septicaemia of- for skin and liair washing.7 A systematic review has con-
Japan and Korea. Rickettsialpox, due to R. akari is trdlls- ten results in staphylococcal endocarditis. Other possible cluded that there is insufficient evidence to support the use
mitted from mice by mites and occurs in the USA, Russia, complications of septicaemia are pneumonia and bone and oftopical or systemic antimicrobial therapy for eradicating
and Africa. Flea-borne spotted fever is due to R. felis. It is joint infections, although in these cases aspiration or local nasal or extra-nasal MRSA in colonised patients. A later
transmitted by cat fleas and probably occurs worldwide. trauma, respectively, may be the cause. systematic review 16 to detennine the efficacy of topical or
Infection occurs after exposure to tick-infested environ- Staph epidermidis is also a natural inhabitant of skin and oral antibacterials, or both, for eradicating MRSA carriage
ments or animals. The rickettsize concentrate in the walls mucous membranes and an important nosocomial patho- found that short-term nasal application of rnupirocin was
of small to medium blood vessels causing vasculitis. Gen- gen. Many infections are hospital-acquired and are often the most effective treatment, with an estimated success
erally, symptoms begin 4 to I 0 days after a tick bite and associated with indwelling catheters. There has been an in- rate of 900/o l week after treatment and about 60% after a
may vary depending on the rickettsial species. Fever and creased incidence of bactcraem ia due to Staph. epider- longer follow-up period. Drug resistance during treatment
headache are characteristic. As the infection progresses, an midis in neonatal units. was reported in !% and 9% of patients receiving mupiroc-
eschar al the tick bite site and/or a msh may develop. My- Staph. saproplrJ.1icus is a common cause of urinary-tract in and oral antibacterials, respectively. Another systematic
algia, malaise, nausea and vomiting, and lympbadenopa· infedions in young women. review" found that in tl1ose who are nasal carriers of
thy can also occur. Sequelae may include thrombocyiope- Staphylococci were sensitive to benzylpenicillin when it Sl.aph. aureus, use of mupirocin ointment significantly re-
nia, encephalopathy, respiratory and renal failure, and was first introduced, but the majority of strains are now duced the level of Staph. aureus infections. A randomised,
myocarditis. Rocky Mountain spotted fever is the most se- resistant as a result of penicillinase production. Meticillin double-blind, placebo-controlled study 12 concluded that
vere of these fevers, but others are also potentially life- and other penicillinase-resis1ant penicillins such as flu- rapid identification of Staph. aureus nasal carriers fol-
lhreatening. cloxacillin were developed because of their activity lowed by treatment of nasal and extranasal sites with
The treatment of choice for all tick-borne rickettsioses is against these resistanl staphylococci. However, meticillin- mupirocin nasal ointment and chlorhexidine soap respec-
oral or intravenous doxycyclin~ in both adults and chil- resistanl staphylococci soon emerged. Both coagulase- tively, significantly reduced the risk of HA-MRSA infec-
dren.1 Tetracyclines are generally contra-indicated in negative staphylococci and Staph. au1·eus resistant to met- tion, especially among swgical patien1s. Although there is
young children; however, the ri>k of tooth staining with a icillin are generally resistant to all beta lactams and often no data to support the use of mupirocin with or without
single short course of doxycycline is considered negligi- have multiple resistance to other antibacterials (see Meti- chlorhexidine body washes to elimir.ate colonisation in
ble.•·3 Susceptibility to rifampicin varies by species.3 cillin, Antimicrobial Action, p.325). More studies have people with CA-MRSA,2-4 .5 decolonisation treatn'lclll may
• Chloramphenicol is a Jess effective alternative for Rocky be used in those with recurrent infections, or in high-risk
been published on MRSA than meticillin-resistant coagu·
Mountain spotted fever, used when doxycycline is not lase-negative staphylococci, but both types are a serious patients.2•5
available or contra-indicated.1" A fluoroquinolone has problem in hospitals around the world. Resistant strains Isolated reports from around lhe world ofMRSA with in-
also been suggesled,4 althoug)l experience is limited. 1 may be endemic lo a single hospital or may be epidemic termediate resistance or reduced susceptibility to vanco-
• Alternatives to doxycycline in patients with Mediterra- causing outbreaks of infection al more than one hospital. mycin initially emerged in the late 1990s,'3 · 11 and in re-
ne.an sportedfever include chloramphenicol1 (although Colonisation of hospital statfand patients with meticillin- sponse tl1e CDC produced intctim 16 and later 17 guidelines
relapses have been reported after treatment5) and cipro- resistant staphylococci is an important factor in the spread for preventing tl1e spread of vancomycin-intermediate
floxacin. 1 Macrolides such as azilhrom{;cin and clari· of these infections. Current trends are towards healthcare Staph. a11reus (VISA) and vancomycin-resistant Staph.
lhromycin arc alternatives in children; " ·6 josamycin is al home rather than in hospital and there are reports sug- aureus (VRSA). Newer antibacterials such as daptomycin,
also useful for pregnant women.1Short 2-day courses of gesting that MRSA is becoming more prevalent in lhe linezolid, quinupristin/dalfopristin, or tigecycline may be
ciprofloxacin or doxycycline were also curative for community.'_. Community-associated (community-ac- effective and may assume increasing importance... '~ Other
Mediterranean spotted feveJ in adults whose disease quired or community-onset; CA-MRSA) MRSA has clin- antibacterials, either recenily approved for use or in devel-
was not severe, although there was a more rapid re· ical, epidemiologic, and bacteriologic characte1istics dis- opment, tl1at may be effective alternatives to vancomycin
sponse to doxycycline.7 ti nct from hospital -associated (hospital-acquired) are the glycopeptides (dalbavancin, oritavancin, or tela-
infections (HA-MRSA).1 CA-MRSA refers to an MRSA vancin), ceftobiprole, and iclaprim. 18
• Infection with R australis has been treated successfully
with ciprofloxacin.8 infection with onset in the community in a person with no Staphylococcal vaccines have been used for the prophy-
• Rickettsialpox can be mistaken for chickenpox. It will established risk factors for HA-MRSA, such as recent hos- laxis and treatment of staphylococcal infections.
respond to tetracycline althovgh patients have generally pitalisation, surgery, residence in a long-term care facili?.;· For the management ofstaphylococcal infections in gener-
recovered without treatment' dialysis, or the presence of invasive medical devices. .s al, see under the specific disease headings.
J. Parola P. et n/. Tid:-bomt rickeusioses ~round the world: emerg- The spectrum of disease caused by CA-MRSA appears lo I. Salgado CD. er of. Community-acquired inc1hicillin-rcsistant
ing cJiscast:.S chalJc.nging old concepts. Clin Microbio/ ReY 2005: be similar to that of other Staph. aul"eus infections, al- StaphylococC'US aurcus: a mtta-anaJysis or prev3Jcncc 3nd risk
factoJ$. C/in !11/ea Dis 2003: 36: 131-9.
18: 719- 56. though some manifestations such as skin and soft tissue 2. Zctol3 N. cl ul. Community-acquired meticillio-resistanl Sto-
2. Chapman AS. ct ol. Tickbomc Rickcnsi31 Diseases Working infections are more common.4.S pl1ylococcus oureus: an cm~rging: lhrcat. Loncc1 ln/tct Dis 2005;
G1oup. CDC. Diagnosis and management oftickbome ricke-ttsial 5: 275-86.
diseases: Rocky Mount.,,in spon.ed fever, chrlichioscs, .'.Ind ana- Guidelines for the control ofMRSA are available in many 3. Merman RA," al. Etiology and treatment of community-asso-
plasmosis-United States. A practical guide ror physieians and c-0untries.6 In the UK, revised guidelines7 for the control of ci:ited methicillln-resist::rnt S1opliylococcus 011rcus. Am J
orhe-r hcalth·care and public he:tlth professionals. MMIYR 2006; Heo/ll,.Sy.11 Phann ZOOS; 65: 219-25.
SS: 1-27. Also available at: hup·//www.~d c .gov/mmwr/PDF/ HA-MR SA were produced by a joint working party of the
4. P111el M . Communi1y-associa1cd metieillin-resisl3nt $Jophylo-
rr/rr5$04.pdf(acccsscd 28/01/09) British Society for Antimicrobial Chemotherapy, the Hos- cocc11s oureus infec1ions: epidemiology, 1ccog.nition and man-
3. Buckingham SC. Tick-home i1lfecrions in children: epidemiolo- pital Infection Society, and the Infection Control Nurses •gemtnt. Dnigs 2009; 69: 693-716.
gy, clinica1 manifestations. and op1imal management s.tra1eg;cs. Association in 2006. They advise prompt isolation of in- 5. Gorwitz RJ. ti of. Strategies for clinical management of MN.SA
PeJlotr Drugs 2005; 7: 163-76. in 1hc community: summury or on exper1s' meeting convened by
4. Abramowicz M, ed. The choice of antibacterial drugs. In: Horul· fected or colonised patients, screening of patients and staff fhc Centers for Dist.3SC Control and Prevention (March 2006}.
book of ontimicrobial therapy. l 8th ed. New Rochelle NY: The in conlact with such patients, the use of protective cloth- Avail:ible at: http:f/www.edc.gov/ncidod/dhqp/pdffarf
Medical Lcucr; 2008. 74. ing, handwashing with an antiseptic detergent, and the use CAMRSA ExpMtgStrotegics.pdf(occcsstd 24/05110)
S. Shakt:.d Y. et al. Relapse or rickcllSial Mediterranean spoued fe- by all patients of an antiseptic detergent for washing and 6. HumphrcyS H. National guidelines for lht control and preven-
ver and murine typhus after treulmcnt wi1h cMoramphenicol. J tion of mcthi<:iJJin.-resis1ant Staphylococcus aurcus-what do
llifecl 1989; t8: 35-7. bathing. lhey tell us? C/in Microbial Jnfttt 2007; 13: 846-$3.
6. Cascio A, et ol. Clarithromycin \'crsu~ azithromycin in the treat- Although ciprofloxacin may be used to treat infection, the 7. Joint Working Pany of the British Society for An1imicrobial
ment of Mediterranean spotted fc'1,er in children: 3 randomii.ed Chemotherapy. the Hospital Tnfcction Society and the lnrection
<:ontrolled 1rial. C/fo lnfec1 Dis 20Ct2~ 34: IS4-3. emergence of widespread resistance in meticilli n-sensitive Con1rol Nurses Association. Guidelines fer the control and pre-
7. Gudiel F. et al. Randomized doutle·blind cvalu3tion of cipro- and meticillin-resistant Staph. aureus limits its usefulness vention of mc1icillin-rt-s:is1ant Staphylocoocus auttus infection
'1oxacin and doxycycline for Mcditernnean spotted fever. Ami- (see p.268). Combination therapy may be helpful. Rif- in healthcare facilities. J Hosp Infect 2006; 63$; SJ-$44. Cor-
111icr0b Agems Chemother 1989~ 33: 987-8. rec.tion. ibid. ~ 6-4 : 97- 8.
8. Hudson BJ. ct ol, Cipronoxacin trl!:ltment fol' Australian spotted
ampicin is highly active against MRSA, but it must always 8. Nathwani 0, et ol. British Society for Antimicrobial Chemo-
fever. MedJ AuJt 1996; 165: S&&. be used with another drug to prevent the emergence of re-- therapy Working Party on Community-onset MRSA Infections.
9. K:iss EM, et of. Rkkettsialpox jn a New York City hospital, 1980 sistaoce. Combinations of rifampicin with gentamicin, Guidelines for UK pr.i<:tice for the c!1agn~is and mnnascment
o f met1licillin-resistant Staphylococcus aureu.s (MRSA) infec-
to 1989. N Eng/J M•d 1994; 331: 1612-17. vancomycin, co-trimoxazolc, fusidic acid, quinoloncs, or Lions presenting in the community. J A111imicmb Chemo1her
novobiocin have been tried. 2008; 61: 976-94.
9. Loeb M, et ol. Antimicrobial drugs for t~ting mcthicillin-re-
Staphylococcal infections . Guidelines for the management of CA-MRSA have been sisiant Sraphylococc.us aureus colonizatiDn. Availabk in The
Staphylococci are Gram-positive bacteria pathogenic to developed in tl1e USA 5 and in the UK.8 Skin and soft tissue Cochrane 08111bnse ofSyslematie Review$; lss,uc 4. Chiches1er:
man. Species may be differentiated by various methods, infections associated with CA-MRSA can usually be treat- John Wiley; 2003 (•ccessed 16105/05).
10. Ammerh1an HS. Cl ol. Eradica1ion or methicillin•'1!Sistant S1u-
including the coagulase test. 'foosc species of clinical im- ed with incision and drainage, with or without topical an- ph1•JococcuJ 011re11s carriage: a systematic review. Clin Jn/eel
portance are Siaphylococcus aureus, which is usually CO· tibacterials; in some cases systemic antibacterials may be o;, 2009: 48: 922-30.
All cross-references refer to entries in Volume A
 Antibacterials 211
I I. ..·an Rijcn M. "' nl. Mupiroein OllrtntCnl roe J)cC\•t:ntiny Su1yh)'• phan11acokine1ic propenies should be such that adequate ~ I s~ ;)\•aiJQ;b ~c
at; hup:liwww.idsoticly.ors/Work.-\rcai
loc:oe:cus 21urcus infccuon' in na~t nrricrs.. Available in The
serum concentrations are maintained throughout the surgi- ~·~~~·:~f'"?lmkldc-n11fiC'r-id&1:emlD• IS966 tic-ccned
Cochrane. 03t11bose o(Systematie Reviews: lssur 4 Chichcs:wr
John Wiley; 2008(acccs<cd 2.a/OSJIO). . . cal ~dure. 1 Additional doses may be necessary "11C11 7. Henry SL.. Ci1ttlow:iy KP. Loc::al antibac.cri:il therapy tOt lhc
I~ . B~ LGM. d al. Preventing surgic;il-s:ite in(eclions in nus.al surgery 1s prolooged, when there is massive blood loss, or n:iatl"1.g~tucnt o.r or1hopo11:dic inra.1ioo;,: ph:,1rmacoti11t"1ic con·
~~'[;~of Slop1trlococc11.t011re1u. N F.,,gf Ju~ 2010: ~62: udtf'IUons. Clm PhamttK'okinct 1995: 29: l6--4S.
when an amibacrcrial with a shon half-life is used. More 8. Wininscr DA. F:ass RJ. An1ibiotic.1mprtsn:ted ccm.:111 :ind
13. ~DC. Upd3Jc: Staph)'lococcus Aurcus wi1h reduced Jusccptibil- C?ntrovcrsial rout~s have included topical or intra-inci- beads for onhoptdic infec1ions. ,.f,,rlmbt>b A•ent.s Cl1Cmo1l1l'f
~f3~1t1ncomyc1n-Unired Statt>s. 1997. MMU'R 1997; 46: S101_1al USC; and pentoncal lavage. Giving non-absor~able 1996; 40: 2675-9. ~
anubactenals orally to suppress the intestinal Oora was tra- 9. Dc~li~:cr E~. et ol. Q\;11li1y standard for antiruicrobiil prophy-
141 • Srni~b TL,'' nl. Emc11.cncc of.. ancornycin resistance in St:tphy· la~us m surpcal procedures. Clin Inf'-"' O~ 1994; t8: 422-7.
lococ<us ourcu•. N Engl J Mtd 199!>; 340: 493-501. dilional before large bowel surgery, and neomycin with 10. ~DC. ~ccommcndaliOM (or preventing the spre21d o(\"31\COCnV·
15. Rybak MJ. Akins RL.. Emcricncit or mcOticillin-rni,;tant Su~­ Cf)'lhromycin is still given for this putpase in the USA. For c1n res1slancc: r«omrncndat~.s of the Mosp11A1 fn(cc:1~ Coft.
~y~us .aurcus with intcrnlediatc glycope;ptide resistance: reference to selective digestive tract decontamination irol Pr:tc~ie<s ~dvisoryC~miuce(KICPAC) . MMH'J! 1995;44
~~~~cal SJgn•ficance and treatment op1ioes. D"'t' 200 1; 61: (RR·l2). 1-b. Also 1va1lable ar: hup://ww"'.edc.gov/mm""T'
(SDO), sec under lnlensive Care, p.187. Other dosage POF!n/rr44 l2.pdf (m:mcd 21/0S/04)
16. CDC. l!'ttri~ g_uiddin~ for P!C\COtion and ~~rol or staphylo- fom1s include bone cement and chains or beads for im- 11. Wilson ~PR. ~ntibio~ic P.rophylaxls al'ld infcc:1ion con1rol
coccal _rnfcctJon assoc:1tttd w11h reduced suscep4ibi1i'1. to van-- plantation! both contai_ning gcntamicin and used prophy- measures 1n mfnunally mvauve SUfiCfY J Anfbmc1"0b Clltm1oth·
comycin. MMWJ! 1991; 46: 626-8, 635. Also 1vail•ble al: er 1995; 36: 1-5.
http:llwww.cdc.gov/nH'D"·r1/pttvicw/mmwrhunl/000483B4.htm l~c11cally m olf:'1opa~1c surgery,7.8 and topical and some-
(accmed 21/05104) t11nes subconJunc11val antibac1crials for ophthalmic
17. CDC. fn\•e.itigation and co:it:rol of '"•ncomycin.int.ermcdiatc
artd resistant Sw11hyltx.'OCC11S CTUITHI (VISA/VRSA): a guide for
surgery.3 Syphilis
hallh departmen1s :u1d infeotion control personnel (updated Choic~ of antibacterial. The most commonly used anti- See under Sexually Transmitted Diseases, p.207.
Sepicmber 2006). Available ot: bllp:/lwww.cdc.gov/ncidod/ bat!erials are ccphalosporins, aminoglycosides, and met-
dh~p/J>df/arl\ ;,._ vrsa_guidc.pdr (acoe<s<d 20/05110)
romd~le. In the UK, 1he BNF 59 recommends that gcn-
18. M1ock ST. Allcmat1\•es to v~ncomycjn for the 1r011mcnt of me• Tetanus
thicillin.res.stant SlaJJh.Woeo«11.t °'"~"s infections. Clin /nf«.t tamicm, cefuroxime, or arnoxicillin with clavulanic acid is Tetanus (or lockjaw)1"3 is caused by the ncurotoxin, tetano-
Dis 2007: 45 (JUppl 3): Sl84-Sl90. g~~en before stomach or oesophageal surgery; before open
spasmm, produced by Closlridiwn teloni, a Gram-positive
b1hary surgery metronidazolc is given with either gcn- anaerobic spore-fanning bacillus present in soil and fae-
Surgical infection . tamicin or cefuroxime; before colorectal surgery or hyster- ces. The spores arc resislllnt to heat, desiccation, and disin-
lnf~o_n is an impo~nt cause of postoperative surgical ectomy mctronidazole is given with either gcntamicin or fectants and can survive for many years. Tetanus can be
morbidity and mortahty and antimicrobial prophylaxis is cefuroxime, or amoxicillin with clavulanic ncid may be prevented by ac1ivc immunisa1ion with tetanus vaccine or
one of several sl!ategics used to reduce the risk of infec- given alone; ifthere is a high risk of infection with MRSA passive immunisa1ion wi!h tetanus immunoglobulin.
tion. The value ofinfection prophylaxis is well established d~ng these gastroinlestioal procedures, va'ncom)•cin or Nowadays It occurs mostly m those who arc unimmunised
in certain types of surgery, especially abdominal surgery te1coplanm should be added to the prophylactic regimen. or panially immunisc-.d; it may also occur in 1hose who
an~ where prostheses arc implanted, altlioug)l recommen- Before .ei~d~ic relro!\f3de cholangiopal_!crea!ography have been fully immunised but have not received further
dat1ons as 10 the choice of antiooc1e1ial and the route. 1im- genlam1cm or c1profloxacm may be given; before transrcc- booster doses. Tetanus generally follows 1r.1uma, particu-
ing, and duration oftrealment may vary. Surgical wounds tal pros1atc ~iopsy ciprofloxacin or gentamicin is given larly deep pe11etnti~g ii~juries; patients with bums. surgi-
arc ~lassified as ~allowing clean, clean-<;0ntaminated (po- with mecromdazole, although for l!ansurethral resection cal wounds,. body p1crcmgs, or a his1ory of injected drug
t~t1ally contamm~led), contaminated, and dirty opera- ciprofloxacin, ge?~micin, or cefuroxime may be given abuse are at increased nsk of developing tetanus. Infection
tions. Clean operations exclude those involvino the gas- alone; and beforeJOmt replacements, including 1he hip and may also develop postpamun in the uterus (maternal leta-
trointestinal, gcni1al, urinary, or respiratory tracts.
Clean- knee, cefuroxime or flucloxacillin is recommended. In the
USA! cef~lin is commonly given before surgery, except
n~) and i~ lh~ newborn (tetanus neonatorum}. Tlic mor-
contaminated operations include those where the gastroio· tality ralc m mild lo moderate tetanus is about 6% and in-
tcs1in~I, genital, urinary, or respiratory tracts arc opened. lhat mvolvmg the lower gastrointestinal tract, for which creases to about 60% in severe disease; it m:iy be 80 to
~ut ~lhout unusual cootaminali?". Contamina1ed opera- cefoxitin or ccfotctan are used to provide activity against 90% in newborns even ifb-cated.
tions include 1hose where there 1s acute inOammation or anaer~ l.2.9 '."-llematively, ccfa:toli11 may be given with
The _goal oftrealment is to relieve muscle spasm, prevent
spillage from a hollow viscus. Dirty operations include metr_omdaz.ol~ m colorectal suigery.3 The choice of proph-
ylaxis for pauents unable to tolerate cephalosporins is less respiratory and metabolic complica1ions, neutralise un·
those where there is pus. gangrene, or perforated viscera. bound orcircula1ing toxin. and eliminate 1he source oftox-
In addition, surgery to repair compound fractures and lac- well ~tablished. Aztre.ooam has been suggested as an al-
temattve to cefazohn with !he addition of clindamycin or in. Treatment includes the use of tetanus immunoglobulin
erations due t~ aniim:I or human bites is considered dirty. to neutr11lisc any circulating toxin (p.2448} and the use of
The use of ant1bactcnals for the management of contami- metronidazole if activity against anaerobes is nccessary. 1
However, the use of ~narn plus metronidazole may antibacterials to stop lhe produc1ion and release of toxins.
natoo or dirty surgery is considered to be therapeutic rather Benzylpenicillin ms tradition:illy beeo used, given inrra-
than prophylactic1.1 and should con1inue for several days provide inadequate act1v1ty against Gram-positive cocci.9
veno_usly or int~muscularly for 7 to 10 days. but many
postoperatively.J Another suggested altema1ive to ccfazolin is vancomy-
consider metromdazole to be the dmg of choice· 1-1 oivco
cin.3 but the rou1ine use of vancomycin should be avoided
Guidelines for the management of surgical infec1ions have rectally it causes fewer spasms than when given ~itei·­
been dcvclopcd in the USA1•3and in lhe UK.•S Additional because of the risk of inducing resistance.'° Vancomycin
al~y.1 Ery1hromycin, a to:tracycline such as doxycyclioe,
guidelines for the diagnosis and manaoement of compli- ~ay be indicated for high-risk procedures ifMRSA infec-
uons are prevalent,' 0 and combination with aztreonam or chndamycm, vancom~m, or chloramphenicol are sec-
cated intra-abdominal infections have"bee11 produced in ond-line altcmalives. 1·-
1he USA by the Sursical Infection Society and the Infec- an ~minoglycoside ~as been suggested to provide activity
aga111st Gnnn·ncgallve organisms.9 !fvancomycin is used Wounds should be cleaned and dcbrided. Dn1gs used to
tious Dise<1se Society of Amcrica.6 treat muscle spasm, rigidity, and seiZllres include scda1ive-
for prophylaxi~ no more than two doses should be given.'o
A1'TIMICROB•AL PROPHYLAXIS. Strictly speaking the term hypnotic agents, genera l anaesthetics, centrally acting
Orher alternatives for colorectal procedures include an
'p_rophyl~is' should be.confined to cle:c1ive procedures muscle relaxants, ~nd neuromuscular blocking agenlS. For
aminoglycoside with either clindamycin or metronida-
with no evidence of sepsis at the time of operation. If pos- zole.9 further mformat1on on the treatment of rigidity and
sible any pre-existing infcc1ions should be IICated before spasms, see p.2065.
The ~eccssity for antibacterial prophylaxis in minimally
admissi~ for ~ery. Fa~ prophylaxis it.is customary to
give an11baetcnals systemically as a single prc-opera1ive mvas1ve procedures such as laparoscopy and endoscopy is I. :;:r;;i~)~~ ."'·TctMo.s. J N~lll'OI N~11rw111r. P~',l'chiatr_~ 2000;
dose ~hcreas more prolonged use is neoessary when 1hey ollen not clcar. 11 US guidelines1·9 suggest that s1andard ~. Cook TM. c-tol. Tetanus: a rt\oicwofiht httm 1u~. Br J A110C!Jtlr
are given therapeutically. Antimicrobial prophylaxis is prophylaxis should be used pending funher evidence. 2001: 87: 477-87.
Certain_ c~te~orics of patienl continue to be at long-tenn ;. Brook I. Cuncnt conccpls in 'he manoc.emcnt or Clos1ridium
~sed in cle_an.oontami~ated opera1ions and in clean opera- let..,f'i in(cction. £.'(~IR~,, Ant; lnff'ct T/wr !008; 6; ;:?7-36.
tions that involve the 111semon of prostbelic materials or risk of mtect1on after surgery and include splenectomised
when an infection, however unlikely, would be catastroph- patients who have impaired immunity and arc at risk of
1c.1 pneumococcal and other infections (sec under Spleen Dis- Tonsillitis
Co!1taml~atio_g or~anisms. Tiie choice of prophylactic orders, p.209}. Opinion has changed as to whelher patients See Pharyngitis. p.199.
1111t1bactcnal will be inOuenced by the likely contaminants at special nsk of endocarditis require prophylaxis before
for a pa11icular surgical procedure. The most frequently dei1tal and surgical procedures (sec Endocarditis, p.178). Toxic shock syndrome
isolated pathogens include Staphylococcus aurtus, coagu- I. Mt1~Qr•n1 AJ.'1 of. Guideline ror prevention of surgic::al site i11-
(ct'1on, 1~9. lnfttt Counol llosp Epidemiol 1999; 10: lS0-78. Toxic shock syndrome (TSS) is an acute, toxii1-mcdia1cd
lase-ncgat1ve staphylococci, Emerococcus spp., and Es- Also nva1fobl~ at: hup:l/www.joumats.uchicago..<duldoUpdf/ systemic illness often leading 10 multi-organ failure;• i;
cherichia coli. lnfcc1ions with antimicrobial-resistant I0. 10861501620(ac:ccsscd IM>6/IO) may be characterised by shock. fever, rash, and gastroin-
pathogens including Ctmdida nlbicans and MRSA arc in- 2. Am<:'ictt"!_ S~i e1y o( Jleafth-Sys;1cm Pharm:1c:ists. ASHP thtt'3·
pct1uc iu1dcl1nC$ on ontimicrobial prophylaxis in 11urgcry. A111J
testinal or CNS disturbances.2 ahhougl1 bactcracmia is not
creasing.1 The most conunon source ofinfec1ion is the en- Hca/1h-S_u1 Pharm 1999; 56: 1839-88. always presem.1 TSS has most commonly been associated
dogenous Oora of the patient's skin, mucous membranes 3. Abr.lmowtt"z M. ed. A111imic:robial prophylaxis for surgery. In: with Staplrylococcus 011reusand its bac1cria l exo1oxi.'1, tox-
or viscera. Thus. aerobic Gram-positive o~nisms (for ex: Ho~ ofonrlmicrobhll ,Mropy. I&th td. New Rochelle NY:
The Mcdoe.I Leclcr, 2008: 125-139.
ic shock syndrome toxin-I (TSST·I), or wilh group A
ample staphylococci) arc common infecting organisms 4. Scot~~ lntcrcoUcg;atc Guidelines Ncl""Otk. Antibiotic proph- streptOCOCCi (which .produce streptococcal pyrogenic exo-
when the source is the skin and mucous membranes while ylu1s 1n sulcry: a national cli1,ic1I ~uideline (issued July toxins A. B, and C).· More recently however, otl1er bacte-
infections with enterococci, Gram-negative aero~ (for ~°?.% ~s:Jti~i 11: hnp1:www.si~n.ac.oklpdf7signl04.pclr(oc- ria including Closrridiwn spp.,3 Pse11domonas spp., and
example £. coli}, and anaerobic bacteria (for example S. NICE. Surgical .site infcc11on: prcven.1ion and 1rcain1en1 of sur- Klebsiel/o spp. have also been implicated, and TSS is now
Bacteroides fi·agilis) can arise from the gas1rointestinal 11cal site infcc1ion (inued October 2008). Available at: considered to be a global io1mu11c response that may be
tract. hiip:/lwww.nicc.ors-uklnie<medi>llivefl I 743/42379/42)79.pdf caused by several different triggers.2 In the early 1980s,
(l<ecss«l25/0$/10)
~oulc of adminis~alion. Systemic dosage, usually by the 6. ~lomkin J~. ~f '!'·.Di~JtTIC?S•S and m.anaJf!"Cnl of complicated T.SS was repo11ed mainly in meiistruating wom•'ll u~ing
ml!avenous route, 1s generally preferred. The chosen anti- 1n1ra-a~nrnal 1nJcct100 .'ll aduhs and c:h1ldrm: •uidtlil\Cs by h1gh-ab~rbency 1ampons, but it is now appreciated that
the Sutg.1cal lnf«t1on Society and the ln(ectiou.s Otse:ases Soci· other foci of ~fection such as surgical wounds, bums, ab-
~terial is usual!! given ~ a single dose intravenously •.•Y of Amoricl\ C/i• lnfe<t Dis 2010: 50: 13)--64. Al$0 pub·
JUSt before operation at the mduclion of anaesthesia. The hshcd tn Suri In/tel (lorchmt) 2010: 11 : 79-109. scesses, and sinuses orcoflen rcsponsible.'-S Non·menslru-
212 Antibacterials
al cases now occur more frequently than menstrual,? and junctivitis, p.193) and in adults is associated with sexually 11 . Solomon AW, tt al, Mass trutmcnt ¥i1th sinsle·dou uihhromy-
cin for tnc:honio. N Enrl N•i<d2004: 351: 1962-71.
mortality may be higher.6 transmitted genital C. trachomatis infection and can
/\s with any case of septic shock, the first consideration in progress to trachoma when thetc is persistent or recurrent ll. ~~~~ Z}f~/~~~s ~~:!i'fct':rc:a~!;1;'!~i~~ct~~!=~i;
1

the management of patients with acute TSS is rcsuscit'.i- eye infection. Gambian community: a Jon&11udin1I siudy. lun,·et 2005: J6S:
132H!.
tion and stabilisation. For the general principles used in First infection generally occurs early in life, leading to a 13. Chidambaram JO. n al. Errtc1 of a single mas" antibiatic: diatri·
the treatment of shock, see p.1304. A thorough investiga- usually scif-limiting conjunctivitis. Re-infection is com- bu1ion on the pJ'C\-alt:noe or inrec1ious 1rachoma. JAM.A 2006:
tion to find the infective focus, followed by effective mon, and over many years leads to conjunctiva! scarring, 195: tl42-6.
14. Wt.11 SK. .i nl. Infection with Chlamyd11 &rachoma-1is ;1rtcr mass
source control is also necessary, and may include local causing the eyelashes to tum inwards and scratch the cor-
measures such as ranoval of tampons or packing. wound nea (trichiasis); eventually irreversible corneal damage ~r~!~';~:~f!.~ :~~~T;n~~{~t~~6:c;>~Q6. Tantania: in
debridement, or drainage of abscesses. and visual loss may occur. 15. Solomot1 AW. ~IOI. T\YO doses orazi1hromycin 10 eliminate lr.a-
choma in 1 Tanunian communiry. N Eng.I J Med 2008~ 358;
Appropriate, immediate antibacterial therapy is essential Blindness can be prevented by several interventions, and 1870-1.
to eliminate toxin-producing bacteria. Where the infect· an Alliance for the Global Elimination ofTrachoma (GET J6. Mc:lcse M. er al. Co1npari.son o( annual and biannual 1nass 1n1i 0

ing organism is unknown, initial regimens must cover both 2020) was launched under WHO leadership in I 998 with bioc.ic adminisiration for chminauon or infecl i ou~ 1r1choma.
JAMA 2008: 299: 778-14.
Staph. aureus and S. pyagenes; generally a beta lactam the goal of eliminating blinding trachoma by 2020. Inter-
plus a lincosamide is considered appropriate. Where the ventions are also promoted by the International Trachoma
causative organism has been identified, the following Initiative and follow the WHO recommended SAFE strllt· Trench fever
pathogen-specific regimens have been suggested:' cgy: lid surgery for,trichiasis, antibrdctcrials to treat infec· Trench fover is a louse-borne Gram-negative bacterial in-
• Group A streptococcus: bcnzylpenicillin plus clindamy- .tion and suppress transmission. facial cleanliness, and en- fection so nanied because of its prevalence among soldiers
cin vironmental improvements.3·4 In endemic areas, in the First World War. It is caused by Bm1one/la quilllana
bcta-lactam intolerant patients: either a macrolide or community-wide antibacterial treatment is m:omrncndcd (formerly Rocha/imaea 911intat10) which was previously
where the prevalence of active trachoma in children aged classified as a rickensia, B. quintana and B. hense/ae have
nuoroquinolonc plus clindamycin
I to 9 years is 10"/o or higher;3·' where prevalence is be- also been implicated in bacillary angiomatosis, especially
• Macrolide-lincosamide>streptogramin-B-resisiant in immunocompromised patients, and B. henselae is con-
(MLS 8 phenotype) group/\ streptococcus: benzylpeni- tween 5 and 10"/o, targeted ireatment may be considcted.3
Oral azithromycin regimens (usually a single oral dose or sidered to bca cause of cat scratch disease (p.175). Con-
cillin, plus either vancomycin or teicoplanin temporary B. quintano infections (also known as utban
beta lnctam intolerMt patients: vancomycin or teico- 3 oral doses at weekly intervals) have been shown to beat
least as eflective as topical tetracycline in resolving active trench fever) have a global distribution and are mainly as-
planin sociated with poverty, alcoholism, homelessness or dis-
infectionM and some studies,.. have reported that mass
• Meticillin-sensitive Staph. aw-eris: either cloitacillin, placement, and body-lice infestation.
treatment of communities with oral azithromycin once
nafcillin, or ccfa:zolin, plus clindamycin The disease varies from asymptomatic to severe. Clinical
weekly for 3 weeks resulted in a lower incidence of tracho-
beta-lactam intolerant patients: clarithromycin plusclin- ma at one-year follow-up than topical tetracycline given manifestations include fever, headache; weight loss, and
damycin daily for 6 weeks. This may be in part due to the fact that leg pain. Many patients have be.:n found to have chronic
• MRSA: clindamycin or linezolid plus vancomycin or topical tetracycline docs not treat extra-ocular reservoirs of bacteraemia, and some patients have been diagnosed with
teicoplanin infection, and its long trcaonent schedule has led to poor Bartone/la endocarditis,
• Glycopeptide-resistant or intermediate Siaph. aureus compliance. Mild or uncomplicated infection can be treated with a 4- to
linezolid plus clindamycin (if sensitive) WHO therefore recommends die use ofazithromycin, giv- 6-week course of an oral tetracycline such as doxycycline,
Newer antibllcterials ~uch as linezolid, daplomycin, and en as a single annual oral dose of20 mglk,g (to a ma~imum oral erythromycin, or oral azithromycin. 1 Patients wilh
tigecycline, that are effective against Grnm-pcsitive organ- of! g) fora minimum of3 years. Afterthat, the prevalence chronic bacteraemia should receive oral doxycycline for 4
isms, may be considered for third-line use. of active disease in the community should be re-assessed weeks plus intravenous gentamicin for 2 wc:c:ks,2.3 mainly
Continuing antibacterial treatment for I 0 days during the to determine whether treatment may be stopped. For those to prevent the development of endocarditis. 1lJe recom-
convalescent phase to reduce the risk of recurrence has who cannot take azithromycin (including infants Jess than mended treatment for documented Bartane//oendocarditis
been recommended.• The use of prophylactic antibacterial 6 months old) or whetc it is unavailable, tetracycline 1% is oral doxycycline for 6 weeks plus intravenous gen-
therapy has been suggested in bums paticnts,7 but this is eye ointment can be used twice daily for 6 weeks.1"' Preg- tamicin for 2 wecks. 2•3 If gentamicin cannot be used, rif-
controversial. nancy and breast feeding arc not considered to be contra- ampicin is an alternative. For suspected Bartone/la endo-
Provision of passive immunity through the use of fresh indications to the use of ordl azithromycin.• Azithromycin carditis, intravenous gentarnicin is given for 2 weeks wid1
froz~n plasma or intravenous normal immunoglobulins is I .5%eye drops, given twice daily for2 or 3 days, have also intramuscular or intravenous ccftriaxone for 6 weeks; dtis
consideied by some to be one of the most important meas- been used successfully in the management oftrachoma,9.oo regimen may be ~ven with or without a 6-week course of
ures to stop the inflammatory escalation associated with and may present a possible alternative to the standard oral doxycycline.·
TSS and prevent further tissue damage.? In a comparative WHO-recommended treatments. I. Ohl ME, Sp1d1 DH Bononell:a quint:1~ 31\d urban trench rever.
CUn Infect D/12000, 31: 131-5.
observational study, improved 30-day survival w3s noted It is uncertain how often, and for how long mass ireatrncnt 2. Rolain JM , rt al. Rtcommcndations for lrtllmmt of human 1n--
among patients with streplococcal TSS who were given needs to be given in endemic communities.to achieve dis- fcc1ions c::1tuscd by Banom:lla $p:cies. Arttimicrob Aznts CNm-
intravenous immunoglobulins.1 It has beeo suggested that ease control. 1 Although several studies have reported sig- otl>cr 2004; 48: 1921-)3.
such therapy be considered in cases where there has been nificam reductions in the preva lence of disease and infec- 3. Foucault C. "al. Banonella quintan.1 chanclerisiics and clink1l
m1n.aacmm1. Emerg lnftt.:I D/12006: 12: 217-23.
no cliniCDl response' within the first 6 hours of aggressive tion afier mass treatment with a single oral dose of
suppo11ivc therapy.' azithromycin, 11 •12 recurrence of infection within I 2 to 24
Toxic shock syndromes may be associated with neaotis- months has been reported. 13·14 Infection may have been Tuberculosis
ing fasciitis (see p.193). eliminated in a Tanzanian community 3 years afier the Tuberculosis' refers to disease caused mainly by Myct>-
L Lappin E. Ferguson AJ. Or1m·posi1ive toxic shock ayndrmncs. completion of 2 rounds of mass azithromycin treatment, bocJerium 111ben:ulosis and occasionally by M bavis or M
Llma:t lnf«t D;1 2009; 9: 281 90. given at 24 month i111ervals; 15 the authors concluded that africanum. Infection results from inhalation of infected
2. Yov.n.g AE. Thornton KL Toxic ahock ~rOC'l'le in burns: diag· one or two rounds ofhign-coverage ma-;,; treatment might droplet nuclei. Primary infection is usually asymptomatic
nosis and m;rnagemcnt. An:h Dis Child £d11c Prac1 Ed2001: 9·2:
cp97~p l00. be sufficient to eliminate infection in communities with and in more than 95% of ilnmunocompetent individ11:1Js is
3. Cohtn AL., CJ nl. Toxic shock ~ssoci:itcd with Clostridium sor· moderate disease burden. Mass treatment with oral azi. controlled by acquired (cell mediated) immunity. Tiie im·
dtHii 31\d Clostriclium perfrinscns ancr med leaIand SpOontaneOUS thromycin twice a year was noted to be significantly more mwie response, however, is unable to eradicate the tuber-
aboriion. Ob11tt Gyil«Of2001; 110: 1027-33.
4. Todd JK Thcr.1py of toxic sh()(k $yndromc. DrHs,s 1990; 39:
effective in reducing infection prevalence than annual cle bacilli, and these bacilli may gjve rise to progressive
856-61. treatment in communities with high prevalence of infcc- primary infection (ifdisease occurs within 2 years of initial
S. WilliAln$ GR. The IMic shock syndrome. BMJ t990; 300: 960. tion.16 infection) or post-primary (reactivated) tuberculosis (if
6. Descloux £. rl ol. One in Ove ITIOrt(llJi1y in non-mi:nsu~l toxk. I. Bunon MJ. TrGchom:a: An ortr\'i<:w. Br Med Bull 2001; 8.. : disea~e occurs years to decades afier initial infection).
shock syndrumc YCTJ\IS no morl1lity in mc:nsaruel cases in a bal·
anccd Frmch series o(SS c11$C'S. Eur J Clin Mkroblol /11f~c1 Dis
99-116. Young chi ldren and immunocompromised patients are at
2. Wrigtn HR, tt of. l'rochoma. La1>e<12008; 371: 1945-54. increased risk ofdeveloping active disease. The most com-
2008: 17: 37-43. . 3. WHO. Repon of the 2nd global scicmitic meeting on trochcuna
7. Ruh id A. ttt uJ. On lhc u~c uf p•of>1•ylactic 1ntibio1K-s in prc\·cn~ (WHOIPBDIGET 0).1). Otncva: WHO, 2003. Avatloblc at· mon manifestation of tuberculosis is pulmonary discnsc,
1k>n oflo:<ic shock syndrome. 81uns 2005; ll: 981-S. h11p://www.who.intlblindncJS/2.C%20GlOBALV.20SCIENTl although almost any orvan may be affected. Patients usu.
I. Ktul R, •t oJ. lnltavenous immunog.Jobuhn therapy for s.1repto· flC%20MEETJN0.pdf (KCCSSCd OU04i'09)
coccal 1oxic $hock synd1om<-1 comparative observational 4, WHO. Trachoma control:'a guide (or programme managers. Ge·
ally present with cough, fever, night sweats, and weight
s1udy. Clin luf<et Dis 1999; 28: 800-7. nevo: WHO. 2006. Avail3ble tt: lmp://whqlibdoc.who.intl loss.
publications/2006i9241 s.46905 _ cng.pdf ("'ccssed 06.~/09) During recent years the incidence of tuberculosis in many
S. Bailey RL, •t ol. R.andomis,cd controlled lri1l orsinglc-dost az.i-
Trachoma 1hromycln m &rt:atmtnt of 1~choma. Lonc~t 1993: 342: 4S;-6. countries has increased along with the increasing preva-
Trachoma' .2 results from chronic eye infection with cer- 6. M~bcy 0, ~' cJ. An1ibiotic.s for trachoma. A~ilable 1n The Co· lence of HJV infection. Supervised rifampicin-based
chral'K' Oatat-se of SyS4eml\tic Reviews; lssut ~- (.'hk:he.slcr: (short-course) therapy, using fixed-d05C combination~
tain Chlamydia rrochomatis scrotypes aod is an important John Wiley ~ 2005 (occcsscd 06l04J09).
cause ofpreventable blindness. It is endemic mainly in Af. 7. Schachter J. '' ol. A:dlhromycln in c:oaurol of trachom1. Lortctt ICtS, is recommended by WHO to improve cure rates and
rica and the Middle East, and also in parts of Asia, Latin 1999; 354: 630-5. reduce the emergence of drug-resistant tubcrculosis. 2
America, and the western Pacific. The reservoir is chronic &. frucr-Hur1 N, et iJI. Efficacy of oral llithromycin vet1us t<'p•· WHO applies the tttm DOTS (Direc~y Observed Thera-
<'111 tetraeyc.line in mas~ trel\M('l\t o( endcmk tl'3choma. 81Jll
eye infection and transmission occurs ea<ily via contami- WH0200 1: 79: 632-40. py - Short Course) to its tuberculosis conrrol s!nltegy,
natecl fingers, personal effects., and flies that come in con- 9. Coi:hcr~u I, t.1 al. Efr.cacy arMI safety ur short durA1ion a.nthro- which includes standard.s for diagnosis, supervised thera-
mycin eye drops ''USUS azithrom)':in 1ingle ural dose for lhc py, ensuring secure drng supplies, and regular evaluation
tact with the eyes or nose. Infection tends to cluster in fam- treatn1co1 of 1r1c:homa in children: D rolldomised. controlled.
ilies and communities, particularly where water shortage, double-masked clinical 1ria1. Br J Oph1hnlmol 2001; 91 : of the tuberculosis control programme. The feasibility of
poor sanitary conditions, and overcrowding occur. Al- 667-72. implantable dosage fonns has al59 been investigated.
10. Hugucl P. ~' oJ. Mus 1rca1mcnt of1r-;1chorn.a with Utlhromvcin • First-line tl"CatmenL Multidrug treannent for 6 to &
though trachoma is not n sc.xually transmitted disease, in- 1.5% eye drops in the Republic of(.'amaoon: feasib1l11y, 101er·
clusion conjunctivitis in infants {see under Neonatal Con- ancund dftttivcncss. BrJ Ophihalnwl 2010. '4: t57-6-0. months is required to cure tuberculosis, reduce the risk of
AII cross-references refer to entries in Volume A
 Antibactenals 2 I 3
relapse. and prevent the emergence of dntg-resisiant dis- antin1berculous dnigs. Tiicse drugs are generally less ef- use of eitl1er daily or inten11ine111 d~ing schedules in HIV-
ease. Treatment regimens recommend an initial intensive fective and more toxic than standard therapy and need to infected patients, •9.20 \\IH07 advises against intennittei11
phase of2 to 3 months that is aimed at achieving rapid spu- be taken daily. They include injectable drugs such as the dosing due to higher risk of treatment foilure ~nd relapse;
tum conversion followed by a continuation phase of4 to 6 aminoglycosides (amikacin and kanamycin) and the dosing tlu-ee times a week may be acceptable during the
months to eliminate residual bacilli and prevent rclap~e. fX'lypeptidc capreomycin, as well as further oral drugs continuous phase of treatment if doses are directly ob-
ll1e choice of regimen depends on local patterns of drug such as the fluoroquinolones (lcvofloxacin, moxifloxacin, served. Treatment failures in HJV-infected patients have
resistance and the availability of drugs, and are embodied and ofloxacin) and bacteriostatic agents (aminosalicylic also been associated with reduced d1ug concentrations due
in national and regional trealmentfrotocols in many coun- acid, cycloscrine, ethionamide, protionamide, and teriz- lo malabsorption of anti1nycobacterials.:n
tries including those in Europe, the UK,4'5 and USA. 6 idone). WHO advises that regimens should consist of at In HIV-infected patients with tuberculosis, adjunctive pre-
WHO recommended treatment regimens are based on lea~1 4 drugs with certain or almost certain efficacy, based ventative therapy with co-trimoxawlc has been associated
disease severity and history of previous tuberculosis treat- 011 factors such as previous antituberculosis therapy, DST with substantially lower mortality; WHO therefore recom-
ment: (where available), and country-specific drug-resistance mends that co-trimoxa7.ole be started as soon as possible
• new cases of pulmonary or extrapulmonary cuberculo- patterns. Specific drugs should be chosen in hierarchical after a diagnosis of tuberculosis, and continued for the du-
sis are generally treated with an initial phase consisting order based on potency and likely effectiveness; any suit· ration oftreanncnt.1 Thioocetazone should not be used in
of rifampicin (R), isoniazid (H), pyrazinamide (Z), and able first-line oral drugs should be considered first, then HIV-positive patients because of the polential for severe
elhambutol (E) for 2 months, followed by a continuation addition of an injectable drug, a fluoroquinolone, and if skin toxicity.
phase with rifampicin and isoniazid for 4 months, such necessary, 1 or more oral bactcriostatic drugs. Drugs that In antiretroviral-naive patients, the issue of when to SUlrt
a regimen being described as: 2HRZE/4HR. Although a have potential for cross-resistance should not be used 10- antirctroviral treatment is controversial.7 •19-21 Although
regimen using ethambutol in the continuous phase in- gcthcz.7.I Cross-resistance between rifampicin and rifabu- WHO has advised that antiretrovirnl treatment should be
stead of 1ifampicin (2HRZf/6HE) has been used to re· tin is common and rifabutin is therefore not recommended started a 509n as possible after, and within the first 8 weeks
duce COSIS, it is no longer recommended by WHO due as a second-line drug, Cross-resislance between amik.acin ofstarting, tuberculosistrc:nmcnt,7concerns include over-
10 an increased risk of relapse and death. All firsl-line and kanamycin is also common, while =-resistance is lapping d1ug toxicity, drug interactions, pill burden. and
drugs can be given intermittently if doses are directly variable between the fluoroquinolones. Cross-resisranoe is risk for immune recoostirution syndrome; some clinicians
observed (3 times each week), however, WHO advises complete between elhionamide and protionamide, and be- may instead choose to base die decision on when to start
that daily use is considered optimal. In tuberculous mcn- tween cyclose1ine and terizidone. antireuovirals on the immtuie status of the r,ilicnt. 19.JO In
ingitis ethambutol should be replaced with sttcpcomycin Extensh·ety drug-resistant tuberculosis (XDR-TB) is an open-label, randomised. conll'Olled study-3 of642 HrV-
and an extended continuation phase of up to I 0 months defined as tuberculosis that is resistant to isoniazid and rif- infected patients with CD4+ T lymphocyte counts
\\ith rifampicin and isoniazid is often recommended. ampicin and also resistant to fluoroquinolones and at least < 500 eellslmm3, start.mg antiretroviral therapy during tu-
Cure rates of greater than 90"/o are typically achieved in one of three injectable second-line drugs(amilcacin, capre- bereulosis treatment (during, or up to 4 weeks after com-
patients infucted with drug-susceptible organisms who omycin, or kanamycin). 11•12 XDR-TB can develop when pletion of the intensive phase) led to significantly im-
adhere to therapy. the second-line drugs are misused or mismanaged and by proved survival. The use of rifamycin-based regimens to
• patients previously treated for tuberculosis are at high· early 2006 cases were being reported from every region in treat tuberculosis is recommended as response rates are
er risk for dtug-resista111 infee1ion, ond wherever possi- the world. 13 A report from the KwaZulu-Natal province of better compared with non-rifamycin-based regimens.
ble. treatnlC!lt should be guided by drug susceptibility South Africa highlighted the risk for rapid death in H1V- However, drug interactions between rifamycins and
testing (DST). Where DST is not available or is delayed, infected persons with XDR-TB. 14 In this local case series, antiretrovirals complicate the co-administration of HIV
an initial empirical 1-egimen should be chosen based on all but one of 53 patients died, and where the date of death and tuberculosis tre~unent?0·21 .:!4 and certain combina-
the perceived risk of multidrug-resistant infection, could be confim1ed the median survival was 16 days from tions may require dose adjustment or be contra-indicated
which is based on both patient-specific factors and the the time of diagnosis. There are very limited clinical data (for details of the interactions of rifampicin and antiretro-
degree of resistance seen iu the commw1ity. Those con- available 10 guide treatment of XOR-TB, and management virals, see p.355, and for those witl1 rifabutin, see p.352). It
sidered to be at low'" •11edium risk may be empirically should always involve expert consultation. Although is important to note that guideline recommendations are
re-treated with first-!mc drugs; the initial treatment WHOs guidance for choice of treatment follows similar based on phannacokinetic studies, often performed in
phase includes rifampicin, isoniazid, pyrazinamide, and principles to those for MOR-TB, it may be impossible to healthy subjects, rather than on studies of treatment out-
etl1ambutol given for 3 months with streplOmycin being construct an adequate regimen from among the usual first· come in patients. Paradoxical worsening of tuberculosis
added for the first 2 months, while the continuation and second-line drugs. Additional diugs such as clofaz. symptoms is common in HIV-infected patients who statt
phase includes 3 drugs (rifampicin, isoniazid, and imine, linezolid, amoxicillin with clavulanic acid, tl1ioa- antirctroviral lherapy2S and incidences of up to 35% have
etbambutol) and is extended lo 5 months cetaz.one, imipenem with cilastatin, or clarithromycin may been noted.24
(2HRZESll HRZE/SHRE). For lhose considered to be have some activity against tuberculosis and should be con- • Adjunctive therapy. The inflammatory response to tu-
at high risk for multidrug-resistant infection, a regjmen sidered in these cases, although tlicir benefit remains un- berculosis can cause considerable tissue damage and ad-
incorporating the use of second-line drugs is recom- clear. junctive conicosteroid therapy may be used to counter
mended (see below). • Children and infants cw be treated with generally sim- this. Conicosteroids arc of little benefit in uncomplicated
first-line drugs such as isoniazid, rifampicin, and panicu- ilar regimens to adults but with afsPropriate dose adjust- pulmonary tuberculosis. Howevtt, a systematic review-'6
larly pyrazinamide may cause severe and possibly fatal mcms for age or body-weight.<A While cthambutol is found that in tuberculous meningitis, adjWlCtive corticos-
drug-induced hepatitis. Further details covering hepato- not usually given to young childreo because of the per- teroids reduced the risk of death and disabling residual
toxicity and special precautions for use in patients with liv- ceived difficulty in deteeting ocular toxicity (see p.298), a neurological deficit in JllV-negiitive patients. Systematic
er disorders are given in the respective drug mono- literature review 16 on its use in children found almost no reviews of rubereulous pleurisY27 and pericarditis,is have
graphs-see lsoniazid, p.314; Rifampicin, p.355; and ocular toxicity at daily doses of 15 to 30 mg/kg and it was concluded dl8t there is insufficient evidence to support the
Pyrazinamidc, p.349. UK4 and US6 guidelines recom- considered safe in children of all ages. use of corti~eroids in these conditions. Nevertheless,
mend stopping all potent.ially hepatotoxic drugs if scrum • Pregnancy, breast feeding, and the neonate. Tubercu- WH0 18 suggests that corticosteroids may be useful adju-
transaminases rise to more than 5 times the upper limit of losis, and especially drug-resistant tuberculosis, during vants to antituberculous therapy for die monagement oftu-
no1mal or 3 times in the presence of symptoms of hepatitis pregnancy poses a serious risk to the mother, fetus and ne- berculous meningitis, pericarditis, pleural effusion, laryn-
or elevated bilirubin. Cautious sequential n>introduction onate if oot detected early and treated properly. 17 WHO gitis. tuberculosis of the renal tract, adrenocortical
ofthe same drugs (with or without pyrazinamidc) after res- recommends that pregnant women with tuberculosis are insuflicicncy due to adrenal gland tuberculosis, and mas·
olution of the biochemical abnormalities is often possi- treated similarly to oon-pregnant patients. 7 Fluoroquinolo- sivc lymph node enlargement in botl1 HIV-positive and •
ble....6·7 Patients in whom therapy is interrupted may be ncs, aminoglyeosides, ethionamide, and protionamidc arc negJ1tive patient~. Conicosteroids may also be useful for
given streptomycin, ethambutol; o.nd a fluoroquinolone best avoided. Liver enzymes and symptoms of drug-in- hypersensitivity reactions to antitl.lberculous dt'ugs. For
until hepatotoxicity has resolved. duced hepatitis should be monitored.4 ·"-17 Most antituber- further details on the possible role of corticosteroids as an
Management of drug-resistant disease. The incidence of culous drugs may be used during breast feeding, but drug adjunct to antituberculous therapy, seep. 1653.
d1ug resistance amongst M. tuberculosis straios has in- concentrations in the breast milk are too low to prevent or Srudics have suggested that injection of suspensions of
creased over recent years typicalll. in countries with poor treat tuberculosis in infams. WHO recommends that once killed Mycobocteriwn vaccae improved immune respon·
tuberculosis control programmes. ·9 Jsoniazid and strepto- active neonatal ruberculosis is ruled out, neonates of moth· sive11css in patients witl1 pulmonary tuberculosis, although
mycin resistance are the most prevalent. Multldrug-re- ers with ruberculosis should receive preventative treatment a systematic review29 concluded that M vaccae immuno-
sistant tuberculosis (MOR-TB), caused by stn1ins resist- with isoniazid for 6 months; 7•15 alternatively, isoniazid tl1er.1py was of no benefit.
ant to both iso niazid and rifampicin, requires a may be given for 3 montl1s after which time tbe need for •Prevention. Studies have found that BCG ml~·i11e offers
combination of first- and second-line drugs for at least 18 funher treatment can be evaluated.15 BCG vaccination is protection against serious forms of ruberculosis in chil-
to 24 months (see bclow)."64 Drug-resistant tuberculosis recommended when isoniazid is stopped.1,ll dren, such as miliary and meningeal tuberculosis, but has
is a reflection of poor tuberculosis management, control, •Co-infection with HIV increases the risk of patients de- l'ariable efficacy ngainst pulmonary rubcrculosis in adults.
and unreliable drug supply; it is difficult.to treat, a11d 11ot veloping both pulmonary and extrapulrnonary tubccculo- In high prevalence areas, vaccination is recommended for
infrequently fatal, panicularly in HlV-infected patients. sis, and mortality is higher than in HlV-negative patieuts in children at birth, except for children with HIV infection.
Whereas the WHO DOTS programme may limit the de- the absence of antiretroviral therapy. HJV patients (i11clud· For further information on BCG vaccine, see p.2411.
velopment of MOR-TB, different strategies are required in ing children) with active pulmonary tuberculosis respond Tubcrculoois skin testing may identify persons with latent
areas where multidrug resistance is already established. to short-course chemotherapy similarly to HIV-negative M. n1bem1/osis infection. Treatment of tuberculosis skin
These have been formulated by WHO in the DOTS-plus tuberculosis patients, and most can be treated with the test-positive persons (also referred to as preventative ther-
sua1egy for countries with well functioning tuberculosis standard 6-month regimen. 4.I&-~• For most extrapulmonary apy or chemoprophylaxis) reduces the risk of developing
control programmes. 10 infections, 6 to 9 months of therapy is recommended; 9 to (reactivation) tubcrculoois. Treatment is beneficial in HlV-
Patients with suspected orconfinned MOR-TB should re- 12 months is suggested for infections involving the bones infected patients, contacts of active cases, persons who
ceive a DOTS-plus re&imen, which includes second-line and joints or CNS.20 Although some expertS endorse the have recently become tubetculoois skin test positive, and
214 Antibacterials
persons at high risk of disease. Chcmopropbylaxis is not America. MMWR 2009; 58: (RR·•): 1-207. Ai.o avoibblc a1: Typhoid and paratyphoid fever
http;/iwww.cdc .aov/mmwr/ pdf/1r/rr.S804.pd( (;,cccsstd
recommended routinely in developing countries where the 08/02110) Typhoid and paratyphoid fever are systemic infections
priority is to detect and treat patients with active tubercu- 21. CDC. Manag-int Orug 1nteract ioo$ 1n 1M Tre111ment of HIV-kc· caused respectively by Salmonella ryphi and S. poraiyphi
losis.1Uo Lall:nt tuberculosis has been treated with isoni- la1ed Tuberculosis (issued December 2007) Avail•blt al: hllp11 A, B, or C, Grarn-nega1ive bacteria belonging to lhe En-
www. cdc.gov/1bfTB_ HIV_ Drug1/POF/1bhlv.pdf (accused
aijd or rifampicin given alone, or with rifampicin given 29/07/08) terobacteriaceae family. They are sometimes lermed col-
with either isoniazid or pyrazinamide. Daily isoniazid for 22. Gurumun.hy P. rl ol. Decreased bioavailabllity of rifempin
other an1ituberculosis drup in p1tien1s with advanced human
and lectively 'enteric fever' but, although initial infoct.ion is in-
6 to 12 months reduces the risk ofactive tuberculosis by 60 testinal, dissemination in the blood leads to more
immunodefich~ncy viru.'i d tJCaS(. Anlimlcrob Agtnt.f Charnothar
to 900fo1.31and in HIV-infected, tuherculosis skin test-pos- 2004; 48: 4473-5. widespread systemic effects. Typhoid and pllr'dlyphoid arc
itive persons isoniazid for 6 montJ1s has also been shown 23. Abdool Karim S.S. ~I ol. Timing or inilialion of a.ntirc1rovil"'t1I endemic in many developing countries in Asia (particular-
lo provide short-tenn protection against tuberculosis.32 drugs during 1ubcrculo.<is 1hcrapy. N Ens/ J Mtd 20 10: J6l: ly the southern regions), Africa, the Caribbean, and Cen·
697- 706.
However, the combination of rifampiein and pyrazina- 24. Poznisk AL. cl al. Bri1ish lllV Anocia1ion. BlllVA 1rutmen1 tral and South America, where they arc associated with
mide has ri:sulled in scvi:re and falal liver damage in HIV- guidelines for TB/H IV inftelion. febru1ry 200S. Av1i!lble oi: poor water supply and sanitary conditions. Mos! cases OC·
negative persons and is no longer recommended for tuber- hup://www.bhiv1.org/riltslrilclOO I S77. pdf (1ccuscd curring in developed countries arc contracted abroad. In·
OS/10/07)
culosis prophylaxis.31 .ll.3• The American Thoracic Socie- 25. Breen RAM, ~' al. Paradoxic.al reactions durina rubcrculosis fection is usually transmitted by ingestion offood or water
ty and the CDC,31.33 and NfCEs have issued detailed rec- treatment in pitienls wi1h and wi1hoU1 HIV co·infeclion. Thorax contaminated with the faeces of infected individuals and
ommendations for treatment of latent tuberculosis 2004; 59: 7()4.7. the incubation period is generally 7 to l 4 days. As well as
26. Prasad K. Singh MB. Con..ieosicroids for 111a.n1iinc 1uberculous
infection. Briefly, UK recommendations for HIV-negative non-specific symptoms such as fever and disturbances of
adults and children over 2 years old are for either isoniaz.id ~~~!;s.l~~ll~~'C~~c~~~f~~~c z~~~:'loO~sr.::=~~ bowel function, characteristic rose-coloured skin lesions
alone for 6 months or isoniazid with rifarnpicin for 3 11/02110). may appear on the cbest, abdomen, and back, and neu-
27. Engel ME. <t al. Coruco11eroids ror 111bcrculous pleurisy. Av11f·
months; isoniazid alone for 6 months should be given to all able in The Cochrane Database of Sys1em1ltc Reviotws: tssuc 4. ropsychiatric symptoms may occur. Severe ~id report-
HIV-positive patients. In 1hc USA either isooiazid alone Chichts1cr. John Wiley; :?001 (occu.<ed 19A>M>S). edly develops in up to !Oto 15%ofpalients and may be
for 9 months (or 6 monlhs in I IN-negative patients) or rif- 28.=. !~i1~b~-i~~·c:;~r:n~ Da~ ~t~rcue!:~tcTC:
0 associated with serious complications including gastroin-
ampicin alone for 4 mo111hs is recommended. 4.
views; ls$Uc John 2ori (acc.essc-d
Chichcs1cr: Wiley; testinal bleeding, intestinal perfocation, and typhoid en-
I. Fried<n TR. ti ol. 1\lbcr<11losls.1Anct12003; 362: 887-99. 02mll06). cephalopathy.1"'
2. Blombctg 8, F-ie D. Fixed·dost comb1..1ion dNg:s r0< Wbcr· 29. de Bruyn 0. Gamer P. Mycobad<fium voccoc immunolhtrapy
e:ulosis: 11P1>1ic1tion in 11ambrdiJt.d trutmenl rc-gimcn.s. Drvgs for 1ruijng tuberculosis. A\.-a1lable in The Cochr1nt Database o( Treatment of typhoid fever has traditionally been with
2003; 63:' s;s-ss3. Sys1Cmatic Review>; wuc I. Chichcs1er. John Wiley; 2003 (1c- chlorampbenicol or alternatively amox.icillin., ampicillin,
3. Drockm1ns Jf1 ti al E~an fn1ncwortt. for tuberculosis con.- «SS<d 02A>3i06). or co-trimoxazole. 1 However. there has been a spread ofS.
trol and ~limination in countries with a low incidence. Recom· 30. Akolo C. e1 al. Trc:a1men1 of latcn1 tuberculosis infection in HJV
~lions or lhc World Hc1lth Qrsanizauon (WHO). Jn1erna- infected pcr$Ol"I$. Available: ln TIM: Coctiranc Database of Sys-. l)lphi strains simultaneously resistant to all of these drugs
1ionol Union Apioll Tubtrculoiis 1nd l.<101 Oiscuc (IUATU>) lcm.atic R~vie-ws; l1SUC' I. Chlche,ttr: John Wiley• 2010 (ac- (tenned MDR strainsf.S in virtually all cypboid-cidemic
and Roy1l Ne1herl1nds Tuberculo.sis Auocia1ion (KNCV) cessed 11!02/I 0). areas. 2 With widespread use of the lluoroquioolones to
Worlting Group. E11r R11plr J 2002; I': 76S-7S. Also available
~~~~~.cnjoum1ls.coml<1ilt<pnn1/l 9/4n6S.pdf (accessed
ll .~:::,~ ~a~;n~ l~~~io~~~~~l::n~M~~i~~l ~;~~ treat typhoid; resistance to lhese drugs is an increasing
I-SI. Also published in Am J Respir Crll Core Mtt/2000; 111: problem as well, particularly in Asia. Resistance may be
4. Joinl Tubtrcufosis Commhttc of 1hc Brlush lnoracic Socjcty.
~?c~~:;~~"~~~!17~:~o:!~.~:~ t~~=O:,~'~)'mmwr/ total or partial; in the latta case, nalidixic acid-resistant
Chcmo1l)Crapy and m11in11emcnl o( 1u1>ctculosi.s in 1hc Uniled
Kingdom: re<ommend11ioo1 1998. Tltoror 1998; 53: 536-4&. 32. Johnson JL. t1 ol. Ounuion or efficacy of treatment of l1ttnt (NAR) isolates typically appear sensitive to lluoroqui-
(Although lhcse guidelines were replaced by ones issued by tuberculosis infeclion in f-HV.infcctcd adults• .AJDS 200li 15: nolooes, however thcrdpeutic use often results in clinical
HICE in 2006 the lotter do not ..txplain 1ub•rculo1is or its 2137-47. failure. As a result, some experts recommend nalidixic-
1reo1men1 in dtloil .. and thcrtrorc tcrcrcncc to the earlier 33. CDC. Update: adverse event data and revised Amcri<:an Thorac-
acid resistance testing as a means of predicting reduced
~~opc)~~~~~i:e;::~~~~so:,::~~tl 17:b:::u~!~!'~~~~
guidelines has been rtloincd/ Also available 11: hnp:ll 1
www.brit thora,c:ic.0rg.uk/Pon1 1/0/Clinic11%20Jnfonn1t1on/
0 lluoroquinolone susceptibility.2 Interestingly, there is
Tubcrculosis/Ouidtlincs/Chcmo1hc1•py.pdf(1cecss<d 29/07108) 1ion-Uni1cd Sblcs, 2003. MMWR 2003; S2: 73S-9. Also ovoil·
able at: hllp:l.'www.cdc.gov/mmwr/POF/wlc/mmS23 l.pdr (ti~· some evidence that as fluoroquinolone resistance spreads,
5. Na1ional Collabo1a1lnc Ccn1rc for Chronic Condi1ions/NICE. sensitivity to some of the older drugs used to treat the dis-
Tuberculosis: clinic.al diagnosis and management oftuberculo· ccs.•ed 05/ I 0/07)
sis~ prevention aOO control (issued March
and measures for ils
2006). Available 11: h11p://www.nice.ora. uk/oictmcdia/pdfl
34. Jasmer R.M, cl al. Shon·couru rifampin and pyn:-dnamidc
compared with isoniazid for t31cnt tuberculosis in rt-ct ion: a mul-
ease, such as chloraqiphenicol, may be retuming.6·7
cg033guideline.pdr (1<:eesscd 19/08/08) ticenter clinical trfol. Anff lnttm Mtd 2002~ 131: 640-7. Treatment recommendations2.S,S emphasise the use of a
6. American Thoracic Society, CDC. and Che lnf<."<!liou1 DiscasH fluoroquinolone such as ciprofloxacin or ofloxacin for in-
Socic1y or Amttic1. T!utmcn1 of 1uberculosis. W.fWR 2003; itial treatment of both fully-sensitive, and MOR typhoid.
S2 (RR- II ): 1-77. A lso 1v1i11ble 11: hnp:/fwww.cdc.gov/ Tularae mia Cbloramphenicol, amoxicillin, and co-trimoxazole are
mmwr/PDF/rr/rrSll I .pdr (•ceemd 2410S/04) Corrcclion. ibid. Tularacmia14 is caused by the Gram-nega1ive bacillus now considered second-line drugs against fully suscepti-
200S: SJ: 1203. (d..e)
7. WHO. Tno1t11,11f o/1ubc.rc11IOJi1; g11ld1llnts-'th tdition. Ge-- Francisella tulareusis, an organism that mainly affects ro- ble strains, although there appears to be little sound evi-
ncvo: WHO, 20 10. Av•il1blc ot: hup://whqlibdoc.who.int/ dents and rabbiis but may be transmitted to man, usually dence that fluoroquinoloncs arc more effective again~1
public11ions/20I 0/9789241 SH833_•n&·pdf(ICCtssed 08/02/I 0) by handling infected animals or carcasses, or by the bites such isolates.s.9
S. WHO. G11ideli,,a for the proiroftmtatlc monogcmrnt ofdmg• of insect vectors, or by ingestion of contaminated food or
rrsistonl n1Mrc.t1lo11J· rmrrgtlfCJI MJ1dot1 JOO&. Ccne\·1: WHO. Azitbromycin, or third generation ccpbalosporins such as
2oos. Av1il1ble •1: hup:/iw!lqlibdoc.wllo.inll)blicouons/2008/ wata. Tularaemia may also be caused by inhalation of air-
9789241S47S81_eng.pdr(accesscd 08'02110 borne bacteria; lhecc has been some concern about the po- ccfiximc, ocfotaxime, and ceftria.xone, are possible alter·
9. WHO. A111i-mbucA1losis drug rcsiJto.nu m the w<1rld· #th 11~ tential use of airborne tularaemia as a biological weapon. natives for both MOR and Ouoroquinolone-resistant infec-
bal ,.,-. Ocnevo: WHO. 200K tions.10 A systematic review found that azithromycin was
Available 11 : b11p :l/whqlibdoc.who .1n1/hq/2008/ Symptoms usually appear 2 to 6 days after exposure, but associated with reduced clinical failure and shortec hospi-
WHO_HTM_T8_2008.394_eng.p4f(occascd O&IOl/10) can take up to 3 weeks. They depend on lhe route of expo-
JO. S1ctfing TR. n al. lmpa<t of DOTS ._red with DOTS-plus talisation times than 1hc fluomquinolones, and reduced
on mullidrug r~sistant tubcrcul0Ji1 and tuberculosi.s duth.s: de· sure and may take several forms, tbe most common of rate ofrelapse compared with ocftriaxonc.11 For infections
cision onolysis. BMJ 2003; 326: S74-9. which is the ulcei-oglandular. This is characlerised by rash, caused by NAR isolates, 1hc Ouoroquinolones are still sec-
II. oc~°j;1~1":~~u':!..~~:;~~~t:n1%6". .:."i!"!~~::."t£
1 ulceration at the site of inoculation. sudden onset of fever,
chills, headache, muscle and joint pains, and lymphaden-
ond-line alternatives, but higher doses and longer courses
hUp:/lwww.edc.govhnmw.IPOF/wk/mmSS43 pdr (accc»<d of treatment arc advocated. Combination regilllCtlS have
07/12!06) opathy. A glandular fonn without skin ulcers and a typhoi- been investigated,8 but a study in patients infected with
12. Mad.ari3.ga MG.~' al EJ1:lmsively drug reshtan1 tubcrculos11.
0
dal (septicaemic) fonnarealsoseen, asarcoculoglandular,
14,,,J Med200I; 121: SJS-44. strains showing both multidrug resistance and reduced
13. CDC. E.mcrgcoce of Mycob;,ctc-rium wbtrculosis wilh cxtC"n· oroph:uyngcal, and pneumonic fonns. Possible complica- suscep1ibility to lluoroquinolones found that azithrom¥cin
sive rcsis1.ancr to second-line drugs-worklw;de. 2000-200'4. tions of infection include endocarditis, hepatilis, meningi- alone was preferable to azithromycin plus ofloxacio.1•
MMWR 2006; 55: 301-S. Also 1v1il1blc a1 : hllp: // tis, pericarditis, peritonitis, pneumonia, osteomyelitLc;, and
w\.\.w.cdc.iov/mmwr/PO f/wk/mmSS 1 l . pdf (accessed
sepsis and septic shock. Most treatment options used for uncomplicated typhoid
07112/06) arc also considered suitable for severe cases, bu! again
J4. Ga.itdhi NR, d cl. E.x tcn~ivcly drug~ rcsiSt;int tubcrwlosis as a Parenteral streptomycin or gentamicin are considered lhe higher doses and longer ttcatmcnt are recommended, and
cause ofdc3th in p411icnts c~inftcttd wi1h tuberculosis and HIV antibacterials of choice; treatment is usually given for
in a rural •rt•
ofSoulh Africa. IA,.ctt 2006; 368: IS7S-80.
about I0 days.14 Tobramycin is not recommended. A tet-
initial parenteral therapy is advised until at least 5 days af-
IS. WHO. Guidance/or natfortol 111~rc1dosfs JW0gronmt11 on tit~ ter fever subsides.2
management of tuberculosis In chlldrc'n. Geneva: WHO, 2006. racycline (such as doxycycl ine) or cbloramphenicol have
Avail•b le •I : hllp ://w h ql ibcl oc.w h o.i nllhq/2006/ been given as alternatives but clinical relapses are more Allhougli Ouoroquinolones are not generally indicated in
WHO. HTM_T8_2006.37 l_en~.pdr (11ccc'5<~ 19108/08) children because of potential toxicity, WHO considers that
16. WHO. EthombuJol efficacy tmd toxicity: littu•o1u1'6 rt11l~w ond frequent than with the recommended aminoglycosides; 1·l
cblorampheniool is generally not recommended except in lheir benefits in typhoid fever ouiweigh any putative risk.s
~:::~~~~:~~,~{~~1~~ri::,~ ~~~,~;:~~·~~,~~i,·d:~~~:rn~
1
the treatment of tularaemia meningitis.3 Fluoroquinolones Azi1hromycin may also be given.s In pregnancy a beta-
hq/2006/WHO_HTM_TB_ 2006.; 6s_ cng.pdf (occcssed lactam such as ampiciUin or one oflhe cephalosporins may
OlVl2/06) have shown promise in treating tularaemia and cipro-
Ooxacin, usuall! givLTI orally for I0 days, is another suita- be preferablc,s although there are reports of the successful
17. ~l~~:;~~s~~,\~~mD~t~:'Sofe~;c;J~~~4~";~lS~'nan· ble allcmativc, _. especially for those patients who are al- use of fluoroquinolones. WHO also suggests that although
18. WHO. TB/HIV. A c/i,,icol mo,,ual 2nd ed. Genna: WHO. 2004.
lergic or intolerant of other treatments. there is no evidence to suggest bann, az.itbromycin should
Available a1: hllp:/lwhqlibdoc.who.in1/publico1ions/2004/
9241546344.pdf(accc...,d 02103!06)
not be used in pn:goant or nursing women if aliematives
Oral doxycycline or oral ciprolloxacin given for 14 days are available.s
19. CDC. Guidclitlcs for the prevention •nd 1n:.1umcnt of opporwun-
istic: infections among HIV-exposed and HIY·infeGled children: are reeommended for postex.posure prophylaxis.1
Patients who develop mental changes should be evaluated
rccommenda1ions from CDC, lhc National 1n$titultS of Hcehh, A tularaemia vaccine is available in some countries forao- for meningitis; if typhoid meningitis is suspected, bigb-
fhe HIV Medicine Association o(thc lnfcetious Oiscasu Sod- tive inununisation against the disease.
cty o f America, the Ptdi>1ric lnfectioui Discues Society. and dose intravenous dcxametha~onc should be given in addi-
!he American Acacletr>y of Pcdi•ITics. MMWR 2009; 58 (RR- I. De.Mis D'f. ~I al. Tularemia as .a biological 'WC.apoo: medica' md
public hcallh m•na.i:emtnLJAMA 2001; 185: 2763-73.
tion to antibacterial treatments
11): 1-166. Also .,..ilablc •I: h11p://www ..!c sovlmmw#PDFI
rr/rr~S11.pdr(acuSS"d 08/02/10) 2. EllisJ, et ol. Tulorcmia. Clin Micn>biol Rr-2002; JS: 631-46. On recovery, typhoid patients may continue to exc-ete S.
20- CDC. GuidclinC$ for prC'\'cnlion and trtalltlCJlt of opportunist_ic 3. Ehasson H, et ol. Tubrc.mia: current epidemiology and dise:ise typhl in the faeces or urine for several weeks. Unlike these
infce1tons in HIV.infected adults a:ndldoles«nts: rccommcnd1-
1ions from COC, lhe Nati0<>al ln!l~ultS orHeahh, tnd !he HIV
manaieme.nt. ln/ttl Dis Clin North Am 2006; 20: 2&9-311.
'· Hepburn MJ. Simpson AJH. TuJ11emia: current diagnosis and convalcsccot carriers, some I to·5% of patients become
Medic.inc Association of the Jnfe-ctiou1 Disuses Society of trtalm<:nt options. &~rt Rev A1J1i luft!Cl Tbtr 2008; 6: 23140. chronic carrierss who may excrete S. typlii for y~ with-
All cross-references refer 10 entries in Volume A
 Ant1baae1ials 215
out any symptoms. Eradication is difficult and prolonged canno1 be made treatment for both infections should be acute pyclonephritis inpreg11on1 women and should there-
b·eatment is nece~sary. bul regimens using ciprofloxacin or giv~n together otherwise postgonococcal urethritis due 10 fore be lreated.
no11loxacin for 4 weeks. or co-trimoxazole or a combina- C rracllomotis may follow the cure of gonorrhoea. For the Urinary-011ct infeclions in men arc less common and are
tion of probenecid with either amoxicillin or ampicillin for n-eatment ofgonococcal urethritis see Gonorrhoea (p.206). often associated with abnormalities of the genito-urina1y
6 to 12 weeks have all reported ly been effective. 1·3.5 For gencr11 I management of chlamydia! infections sec tract such as prostalic hyp<.'l'plasia. Acute bacte1ial prosll!-
Typhoid vaccines are used for the prevention of typhoid p.175. ' titis is usually caused by organisms similar to tliose re-
fever. for details see p.2450. No vaccine prO\~des com- Guidelines produced by WH0,1 by an expert group in the sponsible for cystitis in women Chronic bacterial prosta-
plete protection, however, and strict altention to personal, UK,2 and by the CDC in the l!SA3 for the treatment of titis is difficult to treat; the antibacterials used must be able
food. and \\ ater hygiene is important in preventing infec- urethritis arc as follows: to penetiate into the proslatic fluid. For other genit0-uri-
tion.3 • WHO: for chlamydia! ureihritis: nary inftttions in men, see under Epididyrnitis, p.180, and
Pan:styphoid fever is less common and generally milder • oral doxycycline 100 mg I\\ice daily for 7 days.°" under Urethritis, above.
than typhoid fever. Treabnent is similar; no licensed vac- · uinile oral dose of azi1hromycin I g In p!'CSChool childrrm, especially girls, asymptomatic bac-
cines are currently avai lable for prevention. altemative regimens for 7 days, are: teriuria with vesicoureteric reflux can result in renal scar-
I. Parry CM . ., t1l. Typhoid (evtr. N E•gl J Med 2002: 3 47: oral amoxicillin SOO mg ~m:e times daily ring and should be treated; the use ofprophylactic antibac-
1770-82. 1erials is complex and controversial. Long-tenn follow-up
2. Bhan MK, ti 111. Typhoid r.nd paratyphoid fe\•t:r. Lancet 200~; oral crythramycin 500 mg four times d•ily
366: 749-62. oral onoxacin 300 mg twice daily of girls who have had asymptomatic bacteriuria suggests
3. Sasny111 B. ('I ol. Enltric (ryphold) ltvtr in l ruvcl~rs . Clin/;iftct orol tc1racycline SOO mg four times daily 1hat new kidney damage does not occur after 4 years of
Di12005;41: 1467-72. . . age, but highlights tl1e importance of diagnosis and treat-
4. Ro"''C B, <'f al. MuUidrua·rtsistant Salmonella typhi: a world· Unless it can be excluded, patients should also he trcaled
wide epidemic. Cli• l>iftfl Dis J997; 24 (suppl I): SI06-S I09. concurrently for gonorrhoea (p.206) ment in younger children.
5. ~~~·n8:~::~i~t~:~(i:;~~!r~~~¥00~~: 1r~unenr and pre· UK: for nongonococcal urethritis: The significance of asymptomatic bactcriuria in old age is
Avail.able at: hup://W'W\\'.Who.tntJ\•:tccine_r<"se.arch/docurnc-n.ts/ • esingle oral dose ofazi1hromycin I g. or
disputed, but most consider treatment to be unnecessary.
cnAyplioid_d1>anosis.pdr(1cc<SSed 20/64/09) • oral doxycycline 100 mg twice daily for 7 "'1ys Infections associated wilh imlwelling bladder catheters
6. Gogia A.~' ol. Qmnolonc·rcsi.ttant typhoid (ever. lr.<lia11 J Mttl occur in both men and women and probably account for
Sci 2006i '9: 319--90 ahemative regimens are:
7. Cllitnis S. a ol Ciprolloxacin thenpy ror typhoid r...,r nttds the majority of hospital-acquired urinary-tract infections.
oral erythromycin SOO mg iv.;c:e daily for 14 days
rccoosidcnlion. J /life.ct Clt<tMO'I~, 2006; 12: 402~. Treatment. Antibacterials used to treat urinary-tract infec-
• oral oflo.•acin 400 mg daily in one single or l\>.o di,•idcd do$-
8. :J,';:/('.;;.";:;}'i%'ft3 ~n7~~~!ft0Sis and 1.-.a1men1 or cs for7 d•ys tions need to be excreted in adequate amcentrations in the
9 Persistcm or recurrem nongonococcal urctluitis should urine. For acute 11ncomplicatttdiefectio11s oral amoxicillin,
· ~h:~ ~~:~~~:~~f.~":)~ ~i~:,;:;~1?~::~a:b::
0
be 1rea1cd with: ampicillin, co-trimoxazole, nalidixic acid, nitrofurantoin,
hast n( Sy~fe.m"llC Kc\ it\\' £ ls.wt 4, Chichester: John WilC'y: or trimetboprim (preferred to co-trimoxazole in the UK)
2008 (ICCUS<d 20/0<l/09). oral azithromyein 500 mg to sian then 250 mg daily for 4
10. Threlfall EJ, ,., ol. Ahcmiuh•es 10 ciprofloxacin use for cntcric days 11/us oral mcrronidiuole 400 mg twice tjllily for 5 days, have been given, although the choice will depend.on local
fe"er. United k.ingdom. £mtrg Jnfcc1 Dis 2008: 14: ~60-1. or panems of bacterial resistance; J::. coli resistant to arnpicil-
11. Effo EE. Bukirwa H. Aiilhromycin for lrea1ing uncomplicated orol Cl)llhromycin 500 mg four limes doily for 21 days plus lin and amoxicillin is widespread. Allcmatives when re-
lyphoid :ind pnr:uyphoid (ever (cnteric fo\'..!r). Available in TI•c
Lochranc Dtt1al,ase: ofSvstcma1ic Reviews: Issue 4, Chichester: oral metronidozole 400 mg !\vice daily for 5 days sistance is prevalent include amoxicillin with clavulanic
John Wiley: 2008 (accessed 20/04/09). An alternative, second-line regimen is: acid, oral cephalosporins, nuoroquioolones, or fosfomy-
12. Parry CM. ct ol. Ran®mitcd con1rollcd comparisou of • oral moxinoxacin 400 mg once daily for I 0 days plus oral cin. In pregnant women, nitrofurantoin or a beta-lactam
oOoxacin, ui1h1~mycin. ond on onoxttcin-azilhromycin combi-·
11atAon foe treatnl"U o( inultidrug•l'C'Sislanl :and ll:tlidixic acid· mclronidazole 400 mg twice daily for 5 d•ys 3ntibacterial ~n be used. Standard treatment schedules
1esisuint 1yphoid feve r. Antinti<'IVJb Ag#11l.1Chtmtulrtr2007: SI: • USA: nongonococcal ured1ri1is: have been for S to 7 days; 3-day or single-dose regimens
~19-25
• OS for the U K can also be effective and may be preferred in women. Sin-
alternative regimens for 7 days, are: g)~-dose treatment may be associated with reduced effica-
Typhus oral crydtromycin 500 mg four times daily cy compared with 3-day regimens. Urinary alkalinising
Rickettsial infections or fevers of th¢ typhus group are oral tr)1'tromycin elhylsuccinate 800 mg four limes daily agenlS such as potassium citrate and sodium citrate have
transmitted to man by various insa.1 v~tors. Louse·bome or.ii oflo•acin 300 mg twice daily been given orally to relieve lhe pain of cystitis caused by
or epidemic typhus, due to Ricke"sio prowazekii, and flea- oral levoOoxaem 500 nig uncc daily lower urioary-u11e1 inf~tions. Recurrent infections may
borne or murine typhus, due to the closely related R. typ/ri Persistent or recurrent nongonococcal urethritis should require long-terrn low-dose antibacterial prophylaxis.
(R. mooseri), have occurred worldwide. Scrub typhus is be treated with: Acute pye/011ephrirls may require broad-spectrum
due to Orie11tio ts11t.mgomuJhi (R. 1S11tsugomushi), trans- • • sill'.;lc oral dose of either rnell'Onidar..ole 2 3 or tinidaz.ole parenteral treatment initially with, for example, aztreon-
mined by mites, and occurs mainly in Asia, Australia, and 2 g plus oral aiithromycin I g (if it was not used in the initial am. cellazidi mc, cetilroxime, ciprofloxacin, or gen-
the Pacific Islands. treatment regime11) tamicin.
A tetracycline, ofien doxycydine, or chloramphenicol is Sexual partners of patients with urethritis should be lesled Chronic boc1eriol prostalftls may require treatment for
the treatment of choice for these infections although and treated.13 several weeks wilh trimethoprim, e1)1hromycin, ora fluo·
strains of 0. ts111s11gom11shi resistant to doxycycline and I. WHO Guidtlincs for th.: m:rnag.cmcul ur )C'(U:lll)' tnn :m1 iu~d roquinolone.
chloramphcnicol have been reported in Thailand. 1·2 Cipro· infcctif'lns. Ge ne' :i: Wl-10, 2003 . Also :iva ila:bl<" at: Catheter-rotated bladder mfec1ions may sometimes re-
hll p:lfwhqlibdoc. who.inl"publ ications/2003/9241 S46263.pd r
floxacin may be an effecti"e alternative? and rifampicin (tcccssc<I 23!03/07) spond to localised 1re:umcnt with bladder washouts con-
has been sll0\\11 to be more effective against scrub typhus 2. Clinical Effcc1h·encss Group (British Associ:uion ror Se;,ual taining chlorhexidine.
than doxycycline.' AzithromycinM and telithrornycin' Heahh and HIV). 2007 UK national &uidehnc on 1hc m:anai~­ General refettnccs.
have also been rcpo11ed to be effective. Prophyla.'(iS for ment O( l)C)ft-g:onococcal urtthriti'-'lpdaCcd 0....'"'tcmbtt 200..~.
Available at: hnp://w\\ow.~shh.orgldoc.umml5'19SS (KCf$.Kd I. Nicolle LE. Utinary UXl in1'i.."Ctlon: tradiuonal pharmace>JoSie
scrub typhus '"th doxycycline has shown promise when 0!-/0)110) th<rapits.AntJ M.,12002: 113 tsuppl IA): 3SS-44S.
started hefore exposure to infection.' 2. Nicolle L Bc1t ph~rmxolo1ie1I practice-: urinary traa idftt·
;8i"·~~oo~: ~~·CR';'.~ l~i~::. ~~"::!;t~~t ~~\~:;
3 1
tions. faprrt Opin PharmMOlher 2003: ~: 693-704.
I. \\':t.n Ci."' o/. Scrub 1yphus irtf\!Ctions pootly: .~poru1rt 10 :uui· ·
3. Miller LG. Tans AW. Ttteoncot of uiK:Ompli~tcd urinary l~cl
biolic;-s in nonhcm Thailand. l•.tmcd 1996: 348: 86-9. \n\"\..Cdc.so"·/mmv.·rlPDFl1T/n'S511.pdf (acccs.JC'd 23101:'07)
infcc:rions in an era orincn:n1na 1n1irnic:n:>bial resistance. /tkt.t'tJ
2. P111p;111ich R. Qamer P. An1ibio1ic:s for trcatins $trub typhus. Cl!n Prot: 2004: 79: I048-$).
A"1ilable in The Ccx:hranc Oatabnc ofSys1cmiuic Rcvte-ws: I!!· ~.Carson C. N1ber KG. Role of lluoroquinolonts in lhc trca1mc:m
sue l. Chichtstcr. John Wiley; 2002 (occc,.ed 16/0SJOS). Urinary-tract infections of scri-ous b.ic1erial urinary trnct inf1.-c1ions. Drugs 2004; 64:
l. E.i1011 M. "' nl Ci1)(00oucin 1rc11mcn1 ol'typhus. JAMA 1989~ Infections of the urinary tract are especially common in 1359-73.
262: 712-3. women. TI1ey are frequently due to cn1eric b~cteri:i, in por- 5. Bloodc:rn JM. Curttnt issues in the m1:Jn11gemen1 ofurimuy tract
4. W11u G. ut ol. Doxycycline :ind (ir:ampicin for mild sctub•typhus infections: -:xu::ndcd·rCIC'l'SC c iprolloxotcin as a novel tre:11mtn1
infec1io111 io northc011l1ailand: o randomised 1rial. Lnnc~t :?000: ticular Esdrerid1ia coli, although a common cause in option. Drugs 20\).I; 64: 6 11-28.
356: 1057-'11 . young women is Staphylococeus soprop/1)1tlci1s, a roagu· <i. Hooton TM, "'"'· Acute uncomplicalcd cystitis io an era ofin-
S. Kim Y·S. Pf fil. A compuativc trial of a single dose o(nithro· lase-neg;itive staphylococcus. Other urinary palhogens in- cteasini :intibiotit' .ruistancc: :>proposed awoach 10 empirie.al
m~cin \'crsu~ duxy~ycfiitC' fot lhc trealtTh:'nt of mild scrnb l)phuJ.
clude Sroph. epidermidis, enterococci, and Pse11domonos thc,.py. C/i1> lnf<M'I Dis 2004: J9: 75-80.
o;,
Ctin 1"fi.-c1 2004: J9: l329-;s.
spp. An arbirrary definition of urinary-tract infection has
1. Nicoll~ LE.t'lal. ln(ctliCIUI 01)casesSocietyof America guide·
6. J>himd3 K, ti ol Ooxyc.)"Clinc VC.l"SU$ uithromyci.n ror tn:a1mt·1n lints fOr 1hc diagnosis anid lrC'alment of asymptomatic bacttriu·
o(JcptospirosiJ and scrub typhu.s.. An1i111krobAgV1U CM11t01hcr been significant bacleriuria with 1Ol or more colony form- ri:i in aduftJ.. Clln /11(«' DJ,, 200$: 40: 643-54. Co«cction. ibUl;
2007: SI: 3?59-63. I SS6. Also a\•:tilable :11· http://w''"'Journals.. uchicago.nlu/doil
ing unirslmL of a midstream urine specimen; some also pdf1t0.IOS6/42i507 (m0$$cd 031t161101
i. Kim D·M. "al Cone rolled tritl of a S-day coorw of 1clitht0my· consider lower counts to be indicative of infection. Most S. Gurhnts SE. #t al Op11m.ahsncn V3t'I hd antibtoticabclcid in
c1n vets.YA do'ycych1..e far treitmc:nl of mild 10 modcr.ttc Rrub
t)phlb. A1ttlllfitTol>Atrnu Ctwmo1fwr 2007; SI: 2.011-IS. urinary-tract infections are isolated uncomplicated infec- Nederland X: SWAB·riehtl~n ""°' ant;microbiflo tltt111pit bij
iecomplicccrde urinC'•·csrnfcclics. li«I TiJdschr Gtut'ntd
S. Tw:inl JC. rt tzl Oo'ycycline P'"Phyla.:itis (or humati KrUb 1y-- tions of the lower urinary tract. Recurrent infections may 1006; I SO: 237()..6.
1'hu<.J /1>ftc>1 D/1 1981; 146: SI I-IS. be due to relapse., or more often, re-infection, and are more 9. Pohl A. Mocks of tdmini1&n1ioo of antibia1ics for sympton\lhc
seoious. Patients with complicated urinary-tract infections sc"·~rc urinary u~a inrecaions. A\•ailabk in The Cochrane OaLt·
lx>st' or Sy.SlCn\:lliC Re"i~ws; lssuc •. Chichc:S.lCI': John Wiley;
Urethritis associated with urinary-tract abnormalities or diseases 2007 (lccmd 071081081.
Urethritis or urethrnl inflammation can result from infec- such as diabetes mellitus may be at risk of kidney damage. 10. Nic:ollc LE. Shon..u,:rm thcmpy for urinary tract infection: suc-
cess and (:.ilut'C. Im J Anlfmi(m/I AgtnLt 2008: JI (suppl I):
tious or noninfectious conditions. Infectious urethritis is a Infections of the lower urinary tract in women generally s.IO-S4~ .
sexually transmincd disease seen most frequently in men. present as cystitis (inflammation of1he bladder) and symp- 11. Nicolle tE. Uncomrlic1lcd urinary 1rac1 inf~c1io11 in adultc: in·
~~d i;'fs~~:~'2'.plica1cd pycloncphritis. l..l,.o/ Clin North Am
Th~ most common causes are Neisserio go11011'ilo'"'e and
Cltlomydio n·achomotis (termed nongonococcal urethritis
toms include dysuria, frequency, and urgency with pymia
and significant bacleriuria; the urethr~I syndrome is simi- I~.
8
Norris 01. ~ Youn; JO. Urin:uy tract in fection~: diagnosis an<.l
or non-specific urethritis). Other organisms implicatC'd lar, but there is no significant bacteriuria. In the upper uri- ~~;.~~s~::c200i8: i~~ :~)~fO~cy dcp3rcmcn1. Em<"rg Mttl cu,,
have included .'v(vcoplosmo genitolium and Ureaplosmo nary tract. acute pyelonephritis may occur as a complica-
13. M:a,son P. ,., 11/, Mct1·111aly:ses in prevtntion and lte:nm:IU. ol'
ureolytieum. Gonococcal and chlamydia! infections fre- tion of cys titis or, more rarely, may result from tirinary itact infcct1on1. lnfttl Dis Cli11 Nor'h Am 2009; 13:
quently occur together and if a specific clinical diagnosi.s septicaemia. AsymptOmatic bactcriuria may progress to .m-u.
216 Antibacterials
Cathete!'-relate d. References to catheter-related uri- Pregnancy. References 10 urinary-tract infections in to 2 years. 1·3 An alternalive oral main1enance regimen for
nary-tract infections and their management. pregnancy and their management those allergic to sulphonamides is doxycycline and hy-
I. Tambyah PA. Maki OG. The relation.ship between pyuria and in· I. Maclean AB. Urinary t.raCI infection in prcgnanc~·. Int J A111;m1- droxychloroquine for more than 1 ycar.3 Other alternative
fecc.ion in pa1icnts wi1h indwellina urinary calhcLCrs: " prm-pec:- aob Agems 2001; 17: 273-6. oral antibacterials that have been used for maintenance
tive study of761 p.1licnts Arch lttt~,,, Me</2000; 160: 67l-i. :?. Krcmery S. aJ ol. Treatment of toY.<er urinary trac1 infec1ion in treatment arc minocycline. 1etracycline, phcnoxymethyl-
2. Tambyah PA. Maki DG. Cathc\cr-auociated urinary tract infec- pregnancy. Im J A"1imicrob ••gems 2001; 17: 279-82.
tion is ~rely symp1om•1tc: •prospective srudy of 1497 catheter- 3. Win• DA, Pyc1onephri1i1 in pregnmcy: llt2tmcnl Options for op-
penicillin,1 or chloramphcnicol. Art exclusively oral treat-
ized patients. Ard lllltm M•d 2000; 160: 678-82. tim1I O\rteomcs. Drop 2001; 61: 2087-96. ment regimen of doxycycline and hydroxychloroquine for
3. Hooton TM, t.t of. Oiq.:nosis. prevention.. and lreatmcm of c:a1h.- 4. Yuquci JC. Villar J. Treatments ror symptomatic urinary tract more than I year has been tried in some patients without
ctcr-3.$.$0Ciatc:d urinary tnct 1nfcc1ton in ad'uhs.: 2009 inl.Cml- infcctioris d4'ring pregnancy. Available 1n 1bc Coc:hra.ne Daia. CNS involvement; it has been suggested that in those with
tional dinicat pqc1ice guidelines from the Infectious 0iSC:1$e'S ha.<e of ~)"Cemalic Re..,1ews: Issue 4. Chichester: John Wile)-:
Society of America. Clin Inf.ct Di.s 2010; 50: 62~3. Also 2003 (accessed 20/05110~ CNS involvemcn1 high dose sulfamethoxawlc (which
available al: hl1p:/lwv.•w.journ1l1.wchicago.cduldoi!pdf/ ~. ~;:~~/~~,;~~:· .}!~ lnet infections in pr~gnancy Clm
may be given as c:o-trimoxaiole~ or sulfadiazinc should be
10.108616504.82 (K"C<SS<d 0)/06/10) added to the trcam1ent regimen . .J
6. Maccj)(o AM. Schaeffer AJ. Asymptomatic bact~riuria and
T he elderly. References to urinary-tract infections in the symp1oma1ic urinary trac1 infections during prea;~ncy. Urol Patients who relapse as a resu 1t of inadequate trcatmcni
elderly and their management C/fn North Am 2007; 34: 35-42. may be re-treated with intravenous ceftriaxonc or intrave-
I. Abrutyn E. et al. Docs H)'tnp1om:nic bacleriuria prcdicl monal·
7. Sina.ill F. Vazquu. JC. AntibiotiC"S for asymptomatic bac1criuria nous bcnzylpcnicillin for 4 weeks, followed by an oral
icy and docs antimicrobial 1re1tmcm rt:du<:c monality in elderly
in prc1n1ncy. Av1ibble in The Cochrane Dat3bue of Systema1ic maintenance regimen for more than I year.3 A patient with
Re,•lcws; Issue 2. Chiches1cr: John Wiley; 2007 (Aeceued
ambufatory women? Amt lnt~rn Mtd 1994; 120: 827-33. Cor- 07/08/08). chronic Whipple's disease involving the CNS wid refrac-
rec1H>n. ibid.: 11 1: 901. tory to antibacterial lhcrapy was successfully treated wi1h
2. Nicolle LE. Urina:ry Intel infection in the elderly. J AmimiCf'Ob Wom en. References to urinary-tract infections in wom- an induction course of cefiriaxone and chloramphenicol
Chemo1her 1994; 33 (suppl A): 99-109. en and their management.
3. Ouslandcr JG. et ol. Docs endie11int bac:tenuria affect the sever-
followed by long-term maintenance lrealment with c:o-tri-
ity of chronic urinary ineonrincncc in tnming home residents? I. \Vo~ JW. tJ al. Infectious Diseases: Society o( AmcriCI. moxa7..ole supplemented with interferon gamma.5 Adjunc-
Ann /Rlem Med 1995; 122: 749-54. Guidclinc.s (or 1ntimicrobiaJ 1rca1ment of uncomplic&lrd acute tive treatmcnt with inteiftton gamma has been suggested
bacterial cystitis and acute pyc:Jonephri' is ln \\'Omen. Clitt !tt/«1
4. Abrutyn E. i!t ol. Dou trcatmtnl or uymp1omatic bac.tctiuria in Dis 1999; 29: 74S-SS. for patients who relapse despite appropriate treatment and
older ambulatory women reduce s.ubscqucnt symptoms of uri- who do not have inflammatory focal cerebral lcsions.3
nary 1nct infeetion? J A., G...,,,,,
Soc 1996; 44: 293-5. 2. Hooton TM. RC(.'lUTCnl winary tr.ad inrcc1ion in women. /ttl J
Anlf.,krobAg<nlr 2001; 17: 259--a. CortiCOSleroids may be given to patients with cerebral lo-
5. ShonlilTc I.MD. M<Cl>e JD. Urinary 11ac1 inr«•ion ai the•&<. J. Fihn SO. Acute uncomplicated urinary lract inrtction in wom-
utrcmcs: pcdi•tric< tnd gcri&lri<S. Am J Jokd 2002; 113 (suppl en. N £nrt J Mtt/2003; J.49: 259-66. sions and to those with continued high fever aftec stBrting
I A): 55S-66S. 4. Alben X.110/. Anlibiotics for prcvtntingrccum:nlurin;wyu-.cl antibacterial treatment.;
6. l utte:rS M. Vogt-Ferrier NB. Antibiotic duratk>n for treating un- infection in non·pregna.nt women. A"-ailable in The Cochr1ne I. Marth T. Raouh D. Whipple'• di,..1se. Lonc<t 2003; 361:
complicated. symptomatic lower urinary 11'1CI infccHons in clc:J.. Oa11basc of S)'$lema1ic Rtviev.""S; Issue 3. Chichc.q u: John Wi· 239-46.
c:rly women. Available in The Cocht11ne Dalabase of Systematic ley; 2004 (acc...ed 20/05110). 2. Fcnollar F. et al. Whipple's disuse. N £111/ J M•d 2007; 3S6:
Reviews; Jssuc 3. Chichester: John Wiley; 2008 (accessed
'19/08/08). S. ~~~ ~rf~ao/. ?~~lj~~~:1ii~a:::~~~~~j~~~l~°i;'Th';1~~:, 5S-66.
chmnc Dat~se of Syslema1ic Review$; Issue 2. Chiche!ltr: ; . Schneider T, ~t al. Whipple's disease: new aspecls or palho&cn-
esis and tre:nm<nt. Lanett lnf«t Dis 2008; 8: 179-90.
Infants and children. References to urinary-tract infec- John Wiley; 200S (•cccncd 07/08/08).
6. K~Hchm1n EA, <JI al. Thrce..day i;s longer dura1ion ofaf'ltibiotic 4. Feurle GE. et ol. Efficucy o(cenriaxone or mcropenem as initial
tions in infants and children, and their management. thcr~pics in Whipple's disease. GostrtHnr•rology 2010; 138:
trea1mcnt for cystitis in women: systematic rcvicv.• and meta·
t. Williams G, et ol. Anribiotics (or 1hc prcvcnlion of urinary tract •naly•is.AmJM<d200S; 118: 119G-i07. 47&-86.
infection in children: a systemtt>c review of randomized con- 7. Nicolle I.., tt al. Uncomp1tu.ted urinary tract infectk>n in wom· S. Schneider T. t!f ol. Treatment of refractory Whipple disease wi1h
trolled trials.J Pedialr 2001; 138: 868-74. en; current pr1C1ice and the effecl ofantibiotic rc.sistancc on em· intcrleron·1. Arm Jntun Mod 1998; 129: 87S-7.
2. Tran D, a ol. Shon..course ver.ws conventional Ieng.th antimi· piric trealmcnt. Con I-Om Phys;c;on 2006~ S2: 612-8.
crobial thcnpy (or uncomplicated k>wcr urinary 1raa infections 8. F•l~g•• ME, rt al. Probiotfcs for prevention o(l"C'Currcnt urinary
in diitdrcn: a meca~analysit of 1279 pAhenU.. J Pediotr 20C:H: tract 1nftdt0nt in women: a review of the evidCllCC (rom mkro· Yaws
139: 93-9. bioloaial ind clinical studi... Or11g> 2006: 66: 125)~1. Sec Syphilis, p.207.
3. Shon.litre LMD. MC.Cuc JO. Urinuy tr.ct in(cction zt lhc age 9. Car J. Urin1ry IDC1 infeccions in women: diagnosis and manage·
mmncs: pcdi1trics and S<'iatncs. Am J J.f<d 2002: 113 (suppl mcnc in pnmll)I core. BMJ 2006: 331: ~4-7 .
IA):55~. 10. FoAcr RT. Uncotnphcated urinary tract infections in womew.
4. Michatt M. ~' nJ Shon Vtt'\US standard dvrataon oral antibiotic Obltct G>--« C/m ND'1h Am 2008; JS: 235-48. Yersinia enteritis
lhcrapy for acute urinary lracl infccaion in (hildren. Available in II. Andre M. MOl'1ad S. Nya riktlinjcr fllr urinv1gsinfclttion hos Seep.185.
The Cochrane Database of Systematic Reviews; Issue I. Cbich· k.. nnor. Lllkartid11lng•n 2008; IOS: 1107-9.
C$1et: John Wiley; 2003 (1<ttsS<d 16/0S/05). 12. Pcnoct1 C. 11 ol. OcJ*rogens for preventing recunent "'inary
5
• ~1t1 i~~!a':;·,~c~1in'f~~~1~'f.! !i'iil~~~~~s1~;Ka':~i~in1\crecc"!: met infCC1ion 1n postmcne1rau.ul women. Availab&e in The Co-
chrane DatabQse o( Sy&tcmatic Reviews; Jswe 2. Chichester:
A cediasulfone S o dium (rlNNJ
chranc Database of Systcm111ic Reviews; Issue 3. Chichtsler: John Wil<y; 2008 (1cceued 20/05/10).
John Wiley; 2006 (accc"cd 07/03/08). 13. Guay DRP. Contemporary managemenl of unromplic11cd uri · Acediast.Afona s6dica; Acediasulfonc Sodique: Acedtisi.Afonnatri-
6. Hodson EM. ct of. Antibio1icg for ocutc pycloncphritis in dlil· miry 1ract infections. Dn1gs 2008: 68: 1169-205. um: Acedasulfonum Natricum: AsediasulfoninatA.rm; Sodii.m
dren. A..·aiJabJc in The· Cochrone Database of Syslcmatic Rc- 14. f Hlagas ME, 111 t1l, Antibiotics \'trSUS placebo in the tre~1me1u of
"iews; Issue 4. Chichester: John Wiley; 2007 (accessed women wi1h uncomplic:tlcd cystitis: e mc1a-analysi$ C'lf rand- Di.lpl>enytsulphonacetate. N-p·Sulpnanilyfphcnyfglycine sodium:
19/08/08). omized controlled trr•ls. J lnf•<'t 2009: 58: 91- 102. AueN<acyN>Cj>oH HaYp,,.;:;
7. Beetz R. e1 ol. H:amwegsinfektionen im S~ugling,s- und Kinde-
saltcr: Kon5Cnsuscmp(chlungc.n zu Diognotllk, Thcropic und C14H1iN,Na0 15 = 328.3.
Prophylaxe. Ur'Olog< A 2007; 46: 112-23. W hipple•s d isease CAS - 127-60-6.
S. \Volff'O. Maclenn1n C. £\llCk:nce behind lU WHO guidelines: \\/hippie's discasel-1 (also known as intestinal lipodystro- UNll - M45G7SJL52.
hospital ca~ for chitdren: whit is the appropriate empiric anti-
biotic therapy in uncomplicattd wrinary U'Xt infectio.1s in chil· phy) is a rare, chronic, multisystcm condition associated
drm in dc~op1nJ countr;.s? J Trop PMimr 2007; SJ: ls-0-2. with infect:ioo wilh the Gram-positive bacillus 1i'oplrery-
9. Agenoc franpise de ~riti Uflll&Jre ~ prnduiu de sante. Di- ma whipplei (formerly T. whippelii). It most often affects
agPOStic ct anlibiothCrapic dc:s infcc.11ons urinaires blcttticnncs
communatJU;ires du nourris.son ct de l'cnrant. Jr;kf/ Mol Jnf«t the gastrointestinal system but other OrgitnS Iha! may olso
2007: 37: 64~) . be infected include the CNS, heart, joints, and eyes.
10. Ochoa Sangrador C. Milap Gucn<ro S. R<eomendacioncs de Whipple's dise:isc mainly affects middle-aged white men
~~~=r~;:~;~!s~l~~~;~ri~~~o ~~~~~J~~r;~~~;~
0
and clinical signs and symptoms vary depending on lhcor·
utr (Bare) 2007; 67: 517-2S. gan system a fleeted. Symptoms include diarrhoea, stcator·
11. National Collabora1io& Cen1re for Womens and Chifdrtns rboca, abdominal pain, loss of appetite, weight loss, mal·
Hcahh/NICE. Urinary tr~ c l infection in children: diagnosis.
treatment and long-1erm manaacmcnt (issued Augu,st 2007). absorption, fever, and weakness. Arthritis, arthralgi:i, and Profile
Available a1: hllp://www.nlcc.ora..uk/nicemedia/pdf/ myalgia often occur several years before gastrointestinal Accdiasulfone sodium is reported to have antibacterial properties
CG54follguidclinc.pdf (•cccucd 20/0S/IO) symptoms develop. About I0 to 40% of pa1ients may also and is an ingredient of f'"CPllra1ions used IOpically in lhe treal·
12. Conw1y PH, et ul. Rccumm urinary uac1 inCcctions in children: have neurological symptoms such as confusion. dementia, tnent of local infections of the ear.
risk factors and association wi1h prophylae1ic a1Himictobials.
JAMA 2007; 29& 179-86. headache, memory impairment, or decreased level ofcon· Preparations
ll. Sedberry-Ross S. Pohl H<l Urintry 1..01 infections in children. sciousncss.
Crrrr Urol Rep 2003; 9: 165-71. Proprietary Preparation• (dctoils arci:ivcn in Volume B)
14. Mot1tini G. u ol. Prophylaxis 1ner first febrile urinary tract in-
Undiagnosed and untreated disease is progressive and fa- Multi-ingredlent Austria: Oop"n cum ANes:l"-ot. Rn.: Ocpin
fection in children? A muhic:Cl'lltr, randomized. cnntmlled. non- tal. However, appropriate long-term treatment with anti- nm ANesthelia>t. Swl<>-: Ooprn cat
infcriority trial. hd;atri<:< 2008; 122: 106-4-71. bacterials results in rapid symptomatic improvement and
IS. Mcrgucria.n PA, ~I ol. Urimiry net 1nfccuons in c-hiklrcn: rcc- lasting remission. Tetracycline was once considered the
ommendatK>ns ror an1ibiotie prophy1.axi1 and evaluation; an ~v­
id<nce-bas<d app.-11. Curr Ul"O/ Rq12010; 11: 9&-108. treatment of choice but relapse rates. especially CNS n>
16. Dai B. d ol. lon,·lcnn 1n1ibioti« (or 1he prevcn1ion of recur- lopse, were high (up to 35%) and antibacterials that cr05s A mikacin (BAN. nNN)
rent urinary tr.ic:t 1nfci:1ton in childten~ 11 systcniatic review ~nd the blood-brain barrier are now generally recommend- Amicacina: .i>.nil<acina; Amil<.lcinas; Amikad~ Amkacinum;
meta·analysis. Ar<!r Dis CJrlld2010: 9S: 499-508. ed. •·3 Induction treatment consists of a 2-wcek course of Amlkacyna; Amikasiini 6-0-(3-Amino-3-deoxy..:t·O-glucopyran-
Men. References to urinary-tract infections in men and an intravenous third-generation cephalosporin such as osyt)·4·0.(6·amino-6-deoxy·a·O-glucopyranosyt)·N1·[(2S)-4-
their management ccftriaxonc, or a penicillin (eilher as intravenous bcn· amincr2-hyd-oxyi;!Jtyryl]:2-deoxystreptamine.
I. JoJy-Guillou M-L, Lury S. Pruc1ical rccooimendations fot the
zylpcnicillin or intramuscular procaine benzyl!JCnicillin)
drug lrc~lmcot of baclcria1 in(cclions or the male genii.al tract with or without intramuscular streptomycin. 1· lntravc· 11Mi<K3t»<H

including urethriti$, cpididym it i~ :.nd proMatitis. Drugs 1999; nous mcropcncm has also been used successfully.4 Pa- C11H1iN~013 = sa'S.6.
S7: 743-5-0. tients allergic to ccftriaxone or penicillins may be treated CAS - 37517-28·5.
2. Ullcryd P. febrile urinary tract ln(eedon in men. Int J Am imlcrob with oral co·trimoxaiolc plus intramuscular streptomycin ATC - D06AXl 2; j0/G806; SOIAA71.
AgenJS 2003; l l (suppl 2): ~93 .
or
3. Lipsky BA, et ol. Tu:itmenl bacterial prouatilis. C/i11 Infect for 2 wecks.3 The induction course is followed by long- ATC Vet - QD06AXI l; QJO f GB06; QSOIM2 I.
Dis 2010; SO: 164 l-S2. 1cnn maintenance treatment with oral co-trimoxazolc for I UNI/ - 84 3 I 9SGC3C.

All cross-references refer 10 cnrrics in Volume A

 Acediasulfone Sodium/Arnikacin 2 17
and staphylococci have been reported, 2nd it is gener- tients according 10 plasma-amikacin concentrations,
ally reserved for infections resistant to other aminogly- and this is particularly important where factors such as
cosides, although reports differ as to the extent and age, renal impainnent, or prolonged therapy may pre-
speed of the development ofamikacin resistance where dispose to toxicity, or where there is a risk of subthera-
it has been widely used. peutic concentrations. For discussion of the methods of
0 References. calculating aminoglycoside dosage requirements, see
1. Ho VII. n ol. ln·\';lrO AC1ivilics o( aminoglycosidc-:irninocyclic· Administration aod Dosage, under Gentamicin, p.309.
ols igainst m~obacttria. J Amimirrob CbemoihC'•' 1997; 40: See also Administration, below. As with some other
27-32.
aminoglycosides, once-daily and extended-interval
!'hannacopoeias. In Chin.• Eur. (seep.vii), /11/., and US. f>harmacokinetic.s dose regimens have been used successfully with ami-
Ph. Eur. 6.8 (Amila::ii). An antimiclobial substance oblained As for Gemamiein Sulfate, p.308. kacin withou1 increasing toxicity, but local guidelines
&om kanamycin A. A while or almost while powder. Sparingly
On intramuscular injection, peak plasma-amikacin should be consulted (see also Once-daily and Extend-
soluble in water, practically insoluble in alcohol and in acetone; ed-interval Dose Regimens, p.309).
shghtl) soluble in methyl alcohol. A 1% solution in water has a concentrations of about 20 micrograms/mL occur I
pH of 9.5 to 11.5. hour afte r a 500-mg dose, reducing 10 about A 0.25% solution has been insti lled into body cavities
USP ll (A<r*a::ii). A while cl)IStallioc powder. Sparingly sol· 2 micrograms/mL 10 hours after injection. A plasma in adults.
uble in water. pH ofa 1% solution in waler is between 9.5 ond concentration of38 microgramslmL bas beeo reported A liposomal formulation of amikacin is under investi-
11.5. Store in airtight containers. gation.
after the intravenot,1s infusion of 500 mg over 30 min-
Amikacin Sulfate (llSAN. tlNNM) utes, reducing 10 18 micrograms/mL 1 hour later. Ami· Administration. It has been suggested that in patients with se-
kacin has been detected in body tissues and nuids after ''cre sepsis or septic shock, in whon1 the volume of distribution
Atrul<acin Sulphate (6ANA<); Amii<.Kin-disutf~t: Amikacine. SIJl'.ate may be markedly increased, an initial llltro\'CflOUS loading dose
cf: Amikacini Disulfas; AmilG;cini Si.11!"5; Amikacino sulfat.os; ,,.,,._ injection; it crosses the placenta but does not readily
of amikacin 25 mg/kg total body "-ci~ht should be given. since
Q(nS\Jlfat: Amikaci1H2Vlfat ~ siaioan; Amilcasinisul- penetrate into the CSF, ahhough substantial penetra- standard doses of I5 mg/kl!, may not achi~ therapeutic peak
;aat".i; AMikasin S<ilfat B8·K8: Sulfato de amikacina. tion of the blood-brain barrier has been reported in chil- conccntr:Jtions~ however, evidence from a prospcclivc open
A.-1..au-a Cyr.~~ dren with meningitis. study in ICU patients' suggested that even with the hi~ lklsc.
C12H,,N,Ol},2H2SO, :: 781.8. A plasma half-life of about 2 10 3 hourli has been re- serum conce11l1'3lions or a1nikacin were loo low in abouc one-
CAS - 39831.55.5, lhird of the p<1tients. Subsequeni doses should be de1em1ined on
ported in patients with normal renal function. Most of the basis of therapeutic drug nionitoring.
ATC - D06AXI 2; JOIGB06; SOIAA21 .
ATC Vet - QD06AX I 2; QJO I GB06; Q;O I Ml I
a dose is excreted by glornerular filtration in the urine I. Taccone FS, t:I nl. Revisiting lhe loading dose nf omikadn ror
within 24 hours. pauc.nas ~ilh M\C1'e sepsis and St.'ptic sWck. Crlt C<1re 2010; 14:
UN/I - N6M33094FD. . RSJ
Pharmacopoeias. In Chin.• Eur. (sec p.vii), /111•• Jpn. and US. O References. Administration in children. An:iikaein is licensed for use in
Ph. Eur. 6.8 (Arril<am ~te). A white or almost wbite pow- I. Vunh:ieverbttk M. a al. Ptu1rm::icokinclic.s of onoe-d:3ily ami.. neonates, infants, and children and may be given by inttamuscu·
der. It loses not more than 13.00/e of its weight on drying. Freely k1cin in tlderly patients. J AmiruiC'rob C1'ttn0lh~r 1993~ JI:
18$-7.
lar/Jf intravenous injtttion or by inlJ'avtnous infusion. for stwe:1c
soluble in water; practically insoluble in alcohol and in acetone. i11/tt1io11s calJSl!d by su:rr~ptlble bacteria in children btyond the
~. Oailt:Jrd J-L. er of. Certb<os.p1n~I Ouid penclralion of am1btin
The pH of a I% solurion in water is between 2.0 and 4.0. Store in children wilh commun11y..acquired b1>ctcri:.'tl meningitis. Autf. newbom period. !he Amcri= Academy of Pediatrics (AAP) 1
m airti~I containers. u1i<l"f.lb Agcmti Cl1M10(htr 199S: 39: 2S3-S. suggests an intravenous or intramuscular dose of amikacin of IS
USP 33 (Ami<acin Sulfate). Amikacin sulfate having a molar ro- 3. Srcssolle f, " nl. Popul31i<'n ph~rmacokinc l ics of 1mik1cin in 10 22.S mg/kg daily, in 3 divided doses.
tio of amikacin 10 HzSO, of l:2 conlains the <quivolcnt of not eti1ically ill pa1itn1J, A,,,imiett>b Ag.ems Cht:mot,,ttr l996; 40:
For the lrcatmcnt of Jerious Gram·negaiivc i11/«tio11s resis/0111
less than 674 micrograms and not more than 786 microgrJms of t68l-9.
4 . Cani.r F. ~ nl. Plmnn:icokine1ies and btNchial dirfusion of sin· 10 gentomic/11 in infal\ls and children the BNFC 21110111 sug-
amikacin per mg. calculated on the dried basis. Amikacin sulfate git dad) dose amikacin in cys1ic libros.1.1 patients. J Amimiaob ges1.1:
having a niolar ratio of amikacin to H1SO, of I :1.8 contains the ~31 - J.
ChC'mot/10- 1997; 39: • a multiple daily dose regimen ofamikacin by slow intnn•e-
equivalent of not less than 69 1 micrograms and llOI more than S. Tod M, Cf(t/. Populalion ph:iirmacok;l\Cltc 11udy of~mlbcin ad · nous injection over at le3st 3 to S minlllcs
806 111ic1ogn11ns of amikacin pct ma, calculated on the dried tx.- ministered onct Of twice d~il)' 10 rrbrilc-. $Cverdy neutropc:.nic • in those I month to 12 years of age: 7.5 inglkg every 12
sis. oduhs.AmitnicrobAgt1111Ch.:motliar1998; ~2 : 849-56.
6. Tr~ l uyer JM, ~'of. Nonp.aran1ctrlc population pha.rmacokinc:t1c hours
A "'hitc crysllllline powder. Frttly soluble in water. pH of a 1%
solution in water is betwccn 2.0 and 4.0 (I :2 sail) and 6.0 10 7.3 analysis of omikacin m ntona~'· inf:m1.s, 3nd c hildren. Alllimi· • children 12 years of age and older: 7.5 ma/ks every 12
croh ,4gc111.t Cluuuolhfor 2001; 46: 138 1-'. hours; in S1We1'< infections the dose may be increased to
! I :1.8 salt). Store in airtight containas. 7. Okusanya 00, ti al. Pharmacokinetic and phann.codynamic 7.S mg/kg e''CIY 8 hours lo • ma.~imum dost of 500 mg
Incompa tibility. For discussion of the incompatibility of cvalu;i1ioo o( liposo1n1I amikacin for inhalalion in cystic fibrosis
pat~h1S with chronic pKudornon;il i.nf.ec:t.ion. A11ll11tlcr'Ob Agen11
every 8 hours for up 10 IO days, or
aminogl)'COSides. including amikacin. with beta lactams, see un- CM-l1tr l009-. 53: 384 7-54. • a unc•~daUy dose regimen (other than for endocardiris or
der Gentamicm Sulfate, p306. Amikacin is also reported to be meninajtis) given by intl1\lve1>0us injection or infusion of
incompatihle with various other dmgs. Howewr, reportS are con· 15 mg/kg adjusted according 10 scrum.amikacin c.1ncentra-
tradictory in many cases, and other factors, such as the strength Uses and Administration
llOll in those from J month of oge
and composition oftbc ""hicles used, may play a role. Amikacin is a sernisynthetic aminoglycoside antibac- In the management or pscudomonal lung infection in C)"11ic ft·
Stability. Solutions may darken from colC>W'less 10 pale yellow
terial derived from kanamycin and is used similarly to b1-osis the BNFC 10/()//J sugi:ests a multiple daily dose regimen
but diis does not indicate a loss of potency. gentamicin (p.308) in the trcauncnt of severe Gram- of 0111ikacin given by slow intravenous injection or infusion, of
negative and other infections. Tt is given as tbe sulfate, I0 mg1kg every 8 hours (to a maximum dose of 500 mg every 8
Adverse Effects, Treatment, and Precau- and is generally reserved for the treatment ofsevere in- hours) in those from t month of age.
tions fections caused by susceptible bacteria that are resist· For neonalal se1uis the BNFC 20 IOI/I SU!)gCSts;
ant 10 gentamicin and tobramycin. Amikacin has also • an extended-Interval d - regimen of I 5 mgllcg every 24
As for Gentamicin Sulfate, p.306. Peak plasma con- hours by slow intravenous injection or intrnvenous infusion.
centrations of ami kacin greater than 30 to been given with anlimycobacterials in the treatment of or
35 micrograms/mL or trough concentrations greater nontuberculous mycobacterial infections (p.194) and • 1 multiple daily dose regimtn of 10 mg/kg as a loading dose.
tban 5 to 10 mierograms/mL should be avoided. Com- multidrug-resistant tuberculosis (p.212). As with gen- followed by 7.5 mg/kg c""•Y 12 hours by intramuscular or
parisons with equipotent doses found that amikacin af- lamicin, amikacin may be used with penicillins and slow intra~'!lous injection or by infosion
fects auditoty (cochlear) function to about the same ex- with cephalosporins; the injections should be given al An altcmati"" regimen bnscd on the age and birth-weil!hl of the
neonate is suggested by the AA P:
tent as gcntamicin. · separate sites.
• for all ncona~ ""i~hing less than 1.2 kg; 7.5 mg/l<gevcry 18
Effects on the eyes. A report of retinal damage after inlr3•it- Doses of amikacin sulfate arc expressed in terms of 10 24 hours
n:al injection of amikacin.1 amikacin base; 1.3 g of an1ikacin sulfate is equivalent • for neonates less than I week of age 3nd weighing t .210 2 kg:
I. Jxl son TL~ Williomsop TH. Amibdn rcunal 1oxicily. Br J to about I g of amikacin. Adu lts may be given 7.5 mgfkg every 12 hours
· Ophtho/NtOI t999: 83: 1199-1200. • for neonates less than t \'ICCk of age and weighing more than
15 mg/kg daily in equally divided doses every 8 or 12
hours by intramuscular injection. ln life-threatening in- 2 kg: 7.5 to I0 mg/kg e\'ety 12 hours
interactions • for nC<Jru1tcs I week ofage or more and weighing 1.2 10 2 kg:
As for Gentamicin Sulfate, p.307. fections, the dose may be increased up 10 a maximum 7.5 to IO mg/l:g every 8 or 12 hours
of 500 mg every 8 hours. A dose of7.5 mg/kg daily in • for neonates I "-eek of age or more and weighing more than
Antimicrobial Action two divided doses (equ ivalent to 250 mg twice dai ly) 2 kg: IOl1lJlkg every 8 hours
As for Gentamicin Sulfate, p.308. Amikacin is active may be given for the treatment of uncomplicated uri- I. Aincrtc1n Actdcm)' o(Pcdiitrics.. 1{)ft9 Rctl ~ . Rcpor1.o.f1hc
Conumllf!I on llf/ttlkm.t Dit«J.tCI. 2gth ed. Ell Orovc Vdlngc.,
against a sim ilar range of organisms although it is also nary-tract infections. The same doses may be given by lllin·ois, USA. Arnrric.:1n Ac;,uJcmy of Pedi:nrics..1009.
reported 10 have some activity against Nocardia aster· slow intravenous injection over.2 to J minutes, or by
Preparations
oides, Mycobacreri11m tuben;idosis, and some atypical intravenous infusion. BP 2010: Am·kac"1 ~
mycobacterial strains. Amikacin is not degraded by For details of doses in children, sec below. USP 33: Amikacio 5-Jfote tr,.con
many of the common enzymes often responsible for Treannent should preferably not continue for longer Proprien.ry Prepan.tions (dcl>ib arc given in Vo!Ulll< 8)
~ Sikint: G'cini: AAl·nal<: AlfWO/.i Ami>jnt. Austria: 8ldirc S.fs•
acquired aminoglycosidc resistance. In consequence, than 7 to I 0 days, and the total dose given to adults """"1t Stoz.: Amicae>lf; """"""t· """'""" Ar.Wlocinat: Klc:bid: Ne·
.,..,.... Cor>0d.: knol<int. Ct.: Amion: /v:Wczilt; MNcnj: Rn.: Sildit\ Fr.:
cross-resistance with gentamicin and other aminogly- should not exceed 15 g. Peak plasma concentrations Arrc"!cL.,, G.<.: SMn; Gr.: Am>eiJ!O\ Afflcl!K Miil<on; Bior:W.: 8ricin:
cosidcs is infrequent and amikacin may be effective greater than 30 to 35 micrograms/mL or trough plasma Sruc.:rt: Cllqft Con•umOf\lt; C>..-ocrc FV<l(lll: fitxotite; Fromemyt
against strains resistant 10 other aminoglycosides. concentrations greater than 5 to 10 micrograms/mL K.lncir>-c.p: '--">'<"" L~c::mycirc Lil<adn. ~ M;cilpl'!" O'lob•n:
Rembt fbowdtt s.taxa: Uzi>< X)lan>t H0<>f Konr; Aml<in: ~Int:
However, resiswnt strains of Gram-negative bacteria should be avoided. Dosage should be adjusted in all pa- Huni.: ,.,.,.n: ~ lndlo: Amcin: Arrctn AmOcx ~cir( lndon"

The s~mbol t denote~ a preJ1313tion no longer actively marketed

218 Antibacterials
and in ctlicr. Its ~olu1ions decompo•c slowly and darken in col- cxcrc1cd as 1he acel)'lated metabolite. The half-life of aminosali-
our. Prepare solutions within 24·hours of use. Under no circum· cylic acid is about 1 hour.
s1aoccs should a solu1ion be used if its colour is darker than thDt Aminosalicylatc is dis1ribu1ed in10 breast milk (sec under Pre-
ofa freshly prepared solution. pH ofa 2% solution in water is be- cautions, above, for more details).
lwccn 6.5 and 8.S. S1orc in airtii;J-it containers at a tempcn1turc
U ses and Administration
not exceeding 400. Prolcct from light.
Aminosalicylic acid and iis salts are second-line antimycobac1e-
Stability. Aqueous solutions of aminosalieylates are 1.W1Stablc rials given orally in the trealmCntofmullidtus-rcsistant tubercu-
and should be fresh!)' prepared. losis (p.212). They should llways be given with other antitubcr-
Solutions of sodium aminosalicylate in SO<bitol or syrup degrad- culous drugs.
ed more quiclclr to m-aminophcnol than those in gl)'Cmll or pro- Aminosalicylic acid may be gtl'efl as the acid or as the sodium
pylene gl~o!. Colour developed in all solutions but was nOI salL Sodium aminosaJicylate 1.38 g is equiv1fcnt to lbout I g of
foood to be ao accunttc indicator of dcoomposilion of sodium aminosalicylic acid. How•vcr,a usual daily oral doseof810 12 J!
aminosalicylate as it reflected only oxiclaiion ofm-aminophcnol. in 2 or 3 divided doses has been recommended boch for produels
I. Olake Ml, "al. EfTect or vehicle on the stabili1) (lf sodivm 1mi- containing the acid and those containing the sodium salL
Aminosalicylic Acid noulic~l11e in liquid dos~sc fornis. AmJ Hosp Phtwm 1973~ 30: For details of doses in children, sec below.
«1-3.
Acidum AminosalicyiC\JfT'C Aminosalic~ico. acido: 4-Aminosakyt· Aminosalicylate sodium is afro given rec1ally in 1hc trea1meot of
ic Acid: Aminosalicyl>yra: /\minos.llisyylih3ppo: AminosalAim: Adverse Effects and Treatment ulcerath·e colitis (see lnflamma1ory Bowel Disease. below) in a
Para-arrVno5aliqAic Acid; PAS: Pasalicylum. 1-Amino-2-hydcoxy- Aminosalicylic acid and its salts may cause the adverse cffccls of usual dose of2 g once daily.
salicylatcs (see Aspirin, p.21). AUemplS have been made in fonnulation to overcome tbc bulk
~Moic acid.
Gastrointestinal effects arc common and include naui:ea, vomit- and e•ecedingly unpleasant iaste of 1hc aminosalicylates. The
AMMHOca."1U11/'0WI K11CAOT3
ing, and dianlloea; they may be reduced by giving doses with salts appear to be bener 1olcrated than the free acid and solutions
=
C,H,N03 153.1. food or with an antacid but occasionally may be se-oerc enou3b in ic<:d waler prepared immodia1cly before use may be less un-
CAS - 65-49-6. lhat therapy has 10 be stopped. Altcralion of gas1t0intcs1inal pleasant to take.
ATC - j04AAOI. function may lead io malabsotptioo of viramin Bo?• fol11c. and
ATC Ver - QJ04AAOI. lipids. ORcfer<n=
UNll - 562658E.ON2. Hypc1$Cnsitivity reactions have ~ rqiortcd in S IO I 0"4 of
I. Anonymous. Pa.ra-.aminosalicylic 1cid. T•bo-tulrui.s (Ed1i ib)
2005: 88: 137-8.
1dults, usually during the lirsl few weeks of 1rcatmcnt. and in·
Administration. A small study suggested that giving ami·

A;oH
elude fever, skin rashes; less commonly, anhralgia, lymphaden-
opathy, and hcpatosplcnomcgiily may occur and. nircly, 1 syn· nosalicylic acid in a dose of 4 g twice daily produced adequate
drome resembling infectious mononucloosis. Olhcr adverse seNm con«ntrations (well in excess of I microgmnlml, a typ-
effects which have been anribulcd to a hyperscnsi1iviiy n:action ical MIC against Mycobocrerillm 1ubcm1/osis) for up to I2 hours
aflcr each dose.1 The drug was raken with an acidic bc\'crage
y to aminosalicyla1e include jaundice and encephalitis. Blood d,ls-
orders reported include haemolytic anaemia in p:1tiems with
G6PO deficiency,agranulocytosis. eosinophilia, leucopenia, and
1hrombocy1opcnia. Psychosis may occasionally occur. Pro-
such as fruil juice to prevent early release in 1he stomach. A sin-
gle 4-g dose was nOI sufficient 10 mainiain seNm concentrations
for 1he full 24-hourdosage interval. '!be authors had subsequent·
longed 1reatmen1 may induce goitre and hypo1hyroidism. Crys· ly changed their prac1ice lo use a twice-daily regimen for ami·
1alluria may occur. nosalicylic acid in patients "ith multidtug-rcsistanl rubetculosis.
NOTE. Dis!inguish from S·aminosalicylic acid <M= lazine, I. Pe:lo9yin CA, Cl al. Onct:oodaily ind I\'- ice-daily dosing of p-omi·
p.1898). Effects on tho liver. Drug-induced hepatitis occurred in 0.32% n~hcyJic add granules.Am) Re.'lplrCritConMed 1999~ 159:
Phannacopoelas. Jn US. of7492 patients receiving antiluberculous drugs; omino.<alicylic 932-4.
USP 33 (AminosaLcyic Acid). A " 'hitc or practically while, acid was the most common c.ause.. 1 Adminirtration in children. For the treatment ofdrug-resist·
bulky powder lhat darl<ens on CApo5W'C to li&l>t and air; it is I. Rossovw JE. SaundtrS SJ. H~paticcomplicationso(anhtubm:u- ant rubcn:ulosis in infants. chilcftn, and edolcsccnts the Amcri·
odowlcss or has a slighl acetous odour. Slightly soluble in water lous 1henpy. QJ ..Utd 1975; 44: t-t6.
can Academy of Pediatrics' and WI 102 suggCS1 an oral dose of
and in ether; soluble in alcohol; pnctically insoluble in benzene. Precautions pani-aminosalicylic acid 200 to 300 mg.11a daily, given in 2 lo 4
Under no ci=msLanccs should asolution be used if its colour is Aminosalicylic acid and its salts should be used v.ilh gnoit care dil<idcd doses, to a nwcinium dose of 10 edaily.
darker than that of a fi'eshly prepared solution. pH ofa saturated in P1lien1S with hepatic or renal ionpairment and in patients with I. Amerinn Academyorfcdiotrits. 1009 /ltd Boo.t; ll'f'O"oflh•
solution in water is betw= 3.0 to3.7. Store in ainightconraincrs pstric ulcer. They should be given with cau1ion to patients with Committee on ln/eclious Dluosn. 28th cd Elk Grove Vi11agc.
at a temperature not excecdina 30•. Protect from light. G6PO deficiency. The sodium salt should be used witl1 caulion Illinois, USA: Americ11n Academy o( hdia1ri~ 2009.
in palienu with heart failure. 2. WHO. Guidelines for th(! programmork mo11ag~menf of drug·
1Y1iJ1ttrfl 1ub~rn1lo.'li.f' emergency updot• 10n&. Gcnc\'a: WHO,
Calcium Aminosalicylate Aminosalicylatcs inlerfere wilh tests for gly<:osuria using copper 2008. Available at hup:/lwhqlitxloc.who.int/p<>bticolions/20081
Aminosalicilato calcico; An'W1osaliC)l1ate cakiurn: Aminosal)".alco- reagents and for urobilinogen using Ehrlich's reagent. 978924 t54758t _c:ng.pdf (ac«:.,cd 08/06110)
um; Arnnosalylkakium; Aminosaly)'fikalsium; Cakii Aminosalicy· Breast fee ding. Small amounls of aminosalicylic acid 11re Administration in renal impairment. It has been recom-
izs: Calco Para-aminosalicyla3; Calcium Paraamroosalicylate: Calci· present in brca sl milk. A maxim um concentration of mended lhal aminosalicylic acid should be avoided in patients
um PAS: Kakiumaminosalicylat Kalsiumam'nosaijsylaatti. Calcium I. I microgram/ml has been reported in the breast milk of a lac- wi1h renal imp::iiim1ent' An increase in pla1Mna clearance of ami-
4-amiio-2-hydroxybcnzoate trliydr-dle. lating woman 3 hours aner a 4-g dose of amin0$alicylic acid.1 nosalicylic a<:id (attributed to increased hepatic metabolism) has
I. Holdint'H MR. An1i1ubcn:ulu~is drup and brciSl recdmJ. Affh been ootcd in patients with renal impailT!lent, hence allcmpting
AM.MHOcaMUW.aT l<at-bUh•
lnitr11 M•d 1984; t44: t 888. to give aminosalicylate in reduced doses to such patients may
(C7 H 6N01) 1Ca.3HP 398.4. = Pregnancy. The use ofaminosalicylic acid or its salts is not reo- lead to subthcr.>peu•ic serum conccntrations.1
CAS - I JJ. I 5-J (anhydrous calcium ominoso1icylote). I. Appel GD, Nw HC. 11.c ncphroto>.1city 0(1.n1imicrobial agc:n1s
ATC - )04AAOJ. onunendcd in pregnant pa1icn1s due IO gaSlrointcsrinal 1ntoler-
ancc.1 ln addition it has beci noted that a study published in 1964 (fir11 of1hrc• parts). N &,g/J MM t911; 196: 663-70.
ATC Vet - QJ04AAOJ. 2. Hoktincss MR. Clinical phartnacoldMtits of1he anhluberc\Jlos.i~
UNll - 9VFl6M7FWU suucs1cd firs1-1rimcstcr e.•posure might be associa1cd with con- drucs. Cli11 Pharmorokin.r 19!4; 9: 51 1-4-1.
gcnital dcfec.1s, although other studies had not found similar cf-
Pharmac~ias. Jpn includes lhc hcptahydratc. fcctS.2 Inflammatory bowel disease. Dcrivatil'esofS-aminosalicyl-
I. Snider 0 . Prcanancy ond 1ubc1<ulosis. Chnr 1984: 86: tOS t 3S. ie acid and corticosteroids arc the main.stays of the lrcatmcnt of
Sodium Aminosalicylate 2. Briggs CO. 11 al Dr,,gr /Jr pnguancyand loc-101ion. Sth ed. Phil· inflammatory bowel disease (p. J846). Ilowcvcr, aminosalicylic
1dclphla, ~SA: Lippincou Williai1l$ and Wilkins, 2003. acid (4-aminosalicylic acid) has also been investigated, and bcn·
Aminosalicilato s6dco; An'wlosalicylan so<lny dhydr.lt Aminosal· cficial results hove been reported with both encmas 14 and oral
ocy!ate Sodium: Am1nosalylna1n..m: Monosodium 4-Aminosali- Inte ractions dose fonns5 in ulcerative colilis. Three patients who developed
cylatc Dihydrate; N~trii Aminosahcytas; Natrii aminosalicybs di· ll1e adverse effects of aminosalicylates and salicylA1cs may be acute pancrcatitis while laking mcsal3iinc (5-aminosalicylic
hydricus: Natrii Paraaminosalicylas; Natn1 Para-aminosaricylas: addi1ive.1'robenecid may also increase 1oxici1ybydelayint: renal acid) for inOammalory bowel disease, la1er tolcra1ed treatment
Natrio aminosalicilatas dtiidr.it.as; Natricmaminosalicylat; Natriu- excretion and enhancing plasma concentra1ions of aminosali· wi<h 4-aminosalicylic acid encma.s.6
cylate. The activity of aminosalicylic acid may be an1agonised
maminosali<yiatdohydrat: Natriumaminosa!isylaattr. Natriumami- 1. Cainpieri M, c1 ol. 4~Amin<1~::1licylic a<:1d (4-ASA) and S-ami-
by es1er-type local anaesthetics such as procaine. nosolicylic acid (5-ASA) in 1opical 1rcatmtnl u( ulcc.nuivc coli1is
nosal1Sylaattidihyd-aatti: Pasaficylum Solubile; Sodium (aminosali-
cylate dej dhydra1C; Sodi"'-n Para.aminosa&cylate: Sodium PAS; Antimicrobial Action patients. Go1n'O~nltrologj· 1984; 86~ I 0j9.
Arninosalicylie 1cid is bac1eriostatic and is acti"e against M. 111- 2. G1mbcrgAL.e1a/. Trdlmtntofler1.sided u1ccrathccotitis with
Sodu aminosal<ylan. Sodi<.rn ~ -amino-2-~te dihy· '4•1minosalicylk: acid coemas: 1 doubk·blind. pl1ctbo-con1roJ..
chtc. bereulosis. Other myoobacreria are usually resistant. lt has 3 rel- led <rial. Ann ln1<m Md I983; I08: I95-9.
atively weak aclion compared with other antitubcrculous dn1p. ) . Sharma MP, Oupharc HV. ~-Aminosa1te) lie acid totrnas for ul-
AM11HOCa 111<w••aT HnpM•
Resistance dt1 clops quickly if aminasalicylic Kid is used alone. ce:rati'\-t- colitis. Lmlf:~t 1989; i: 4SO.
C,H,NNa0:>2H10 = 2 11 I. ' · O'Donnell LIO. er al. Doubl• blind, con1roll<d 1nal of 4-ami·
CA5 - I JJ. I 0-8 (onhydrous sodo:rn ominosolicy:a1e): 0 References. noalit.') lie: :sciJ ~nJ ~dniwlo~ cnt'"" in d1s11l ldC"Crlhve col·
60 18- I 9-5 (sodium omonosclocylo1e dohydrcte). L Rcngar1j1n J. ~f al The fola.tc: p:!thw.iy is a 1:>.rget for misunce
lo tht: dru9 para.-.1mmonlicylic xN:S (PAS) in nlycoblt1eri;1 Aloi
i1is.c., 1992; )): 947-9.
S. D<cken W, ~' ol. Controlled 1ri1I of 4·ASA in ulcttaitvc coli1is.
>TC - j04AAOZ.
ATC Ver - QJ04AAOZ. Mlrroblol 200-C; 53: 27~ . Dig Du Sci 1997; 42: 354-8.
6. Daniel f, d al Tokn.t'k."C o( 4·-aminoHticylic acid C'ncm:i.s in pa·
UNll - 53869W6AXW. Pharmacokinetics 1icnl$ with inflammi\tory bowel disc:asc ~nd ' ·•minosalicylic-in·
Pharmacopoeias. Jn Ch/11., Eur. (step.vii), and US. When gil'cn orally, aminosalicylic acid and its salts arc readily duced :acute pancrc~ t itis. /nflnmm Bou~/ Dis 2004; JO: 2SS-60.
Ph. Eur. 6.8 (Sodium Aminosalicylate Dihydrate). A slightly hy- absorbed, and peak plasma concentrations occur after about I to
4 hours. Manganese toxicity. Intravenous aminosalicylic acid, given a.s
groscopic, white or almo.~l white, crystalline powder, or white or 1he sodium salt in a course of 6 g daily for 4 days a week, for
almost white crystals. Freely soluble in water; sparingly soluble Aminosalicylate diffuses widely through body tissues and fluids. r.neen courses, produced significan1 benefit in a patien1 with par-
in alcohol, pr•ctically insoluble in dichloromcthane. A 2% solu· although diffusion inlo the CSF occurs only ifthe meninges ore kfosonism induced by chronic occupational manganese cxpo-
tion in water has a pH of 6.5 10 S.S. Store in airtight containers. inflamed. Aboul 15% of the sodium salt. and SO lo 70"/e of the sure.11l1e patient remained well on prolonged follow-up. 0 1hcr
Protect from light. acid, is bound to plasma proteins. cases of benefit had been reported in the Chinese literature.
USP 33 (Aminosarocylate Sodium). A white to crcam-coloun:d, AminosaJicylatc is me18boliscd in !he intestine and liver prima· I . Jiang Y·M, ti ol. EITtetiw: trc:mncnr of manatnc.sc·induced <M:-
practically odourless crystalline powder. Soluble I in 2 ofwater; lily by llCC1)'l1tion. Urinary excretion is rapid, and 80'/e or more cupaLiooal Partinsonism with p-amin0$llkyhc acid: 1 case o(
sparingly soluble in alcohol; very slighlly soluble in chloroform ofa dose is C.'<Crctcd within 24 hours; 50"!. or more ofthe dose is t 7-year follow-up ••udy. J Dtx•p Environ .Utt/ 2006: •8: 644-9.

All cross-references refer 10 entries in Volume A

 Arninosalicyiic Aad/Amoxicillin 219
Preparations Hepatitis and cholestatic jaundice have been reported colarrholis). and B1ll'kholderio pseudomallei (Pseu-
USP 33: Am<"""Sc1l•1< ~ T>IU;,; Am'"IO>llocyl c Acicl Tlb'o-s with amoxicillin plus clavulanic acid (sec below); the domonas pseudomallei). However, Ps. aeruginosa.
. Proprietary Preparadons (dcWls aro :iivcn in Volumo 8) clavulanic acid component has been implicated. f.ry- Sen·atia morcescens. and many other Gram-negative
Chile! A1otcl Cz.: Quold!~ Fr, Qw'"'4 Ge-.: Pas.fa:el N; Ito!,
Q1.Gldr.u¢ S.ll·P•<. Port. : P..-..~ R'"" l'a!.·fJtol N (IUc· thema mu ltifonne, Stevens-Johnson syndrome, toxic bacteria remain resistant. Transferable resistance has
Cl>&T.... It) l'i«onat (Tl•'1<C...T); PW< (OACY.): Pa<k-Alcri cnae<·AKP"~ epidermal necrolysis, and exfoliative dennatitis have been reported in H. py/oi·i.
Tho/.: flO.S SodU.-C Turk : PAS; Ulv, PlllCONt (l°ba<oooT); USA: Pase<
also been attributed occasionally to the use of amoxi·
Mulri·invedient India: lnapn.
cillin with clavulanic acid. Pharmacokinetics
Use of amoxicillin with clavulanic acid during preg- Amoxicillin is resistant to inacti,'<ltion by gastric acid.
nancy for premarure ruprure of the fetal membrane has It is more rapidly and more completely absorbed than
A moxicillin (BAN. rlNN) been associated with an increased risk of neonatal ampicillin when given orally. Peak plasma-amoxicillin
Amol<sisilin: Amol<s1s11fi"' Amoxicilina; Amo>OaW1ne; Amol<ici'li- necro1ising enterocolitis. for fun her information, see concentration~ of about 5 microgramslmL have been
nurn Amoxydhn. (6R)-&-{o.-0-{'l-Hydroxyphenyl)glycylami- under Premature Labour, p.202. seen I to 2 hours after a dose of250 mg, with detecta-
no]pencatan'c acid.
Brea.st feeding. Although amoxicillin is cxcn:tod in breast milk
ble amounts present for up to 8 hours. Doubling the
AwOil<CMUMM"" tn small amoun~.' the Amcncan Academy of Pcdianics COOSld- dose can double the concentration. The presence of
c.,H ..N,OsS = 365.4. cn that it is usually compatible wilh breast feoding.l food in the stomach does not appear to reduce the total
CAS - 16787-78-0. amount absorbed.
ATC - ]OICA04. I. ~~!~s~t4!~~~.~~~!'J:ed';o~~~~: ~~~ ;~~tc1llin
ATC Ve1 - QG51AXOI; QJOICA04. 2. AmcricanA..SCmy orPodi•tri"'. Tbewnsferordrup and •th· Concentralions of amoxicillin after intramuscular in-
UNll - 9E.\.t05• I OQ9.
er che"mtcab lntO hu1mJn milk. pttJ;orrks 2001; 108 ~ 776-89. jection arc similar to those achieved with oral doses.
[Rctircd May 20101 Comc1ion. Ibid.: 1029. Also available 31:
ht I p ://11 ppol icy.a 1 p pu b I ica 1i ons .or.lc&ifcon I en 1/fu 11/ About 200/o is bound to plasma proteins and plasma
pcdiau ics%)bl08131176 (accessed 24/0SIO•) half-lives of I to l.5 hours have been reported. The
Effects on the liver. Hcpalilis nnd cholestatic jaundice 3SSOCi· half-life may be prolonged in neonates, the elderly, and
atcd wioh the combination amoxicil!in with clawlanic xid (co- patients with renal impainnent; in severe renal impair-
11noxiclav) have been n:por1cd1.. and by J993 thc UK CSM hOO
=ei~ 138 reports of hepatobiliory disorder.;, 3 of which we<e
ment the half-life may be 7 to 20 hours. Amoxicillin is
fo1al' It warned that, ollhough usually reversible, the rcaclioo of· widely distributed at varying concentrations in body
ten occum:d after stopping tha-apy wilh a delay of up to 6 weeks. tissues and fluids. It crosses the placenta; small
fl appeared tbat the clavulanic acid was probably responsible. amounts are di stributed into breast milk. Little amoxi-
Rctrospccti-c anoiy,is of cases reported in Australia6 and a co- cillin passes into the CSF wtlcss the meninges are in-
hon srudy in the UK7 found increasing age and prolonged Creal·
melll to be major risk faclors for jaundice af\cfco-amoxiclav; flamed.
Amoxic:illin Sodium ~ W.N. rlNNM) male SC< is also a risk factor. By 1997 the CSM considered that Amoxicillin is metabolised to a limited extent lo pen-
choleslll1ic jaundice occurred with a frequency ofabout I in <iooO icilloic acid which is excreted in the urine. About 60%
Amob'Cilino natrio druslca; Amobsihn Sod)Ull: Atroksisillini·
adult patients and that the risk of aculc liver injury was about 6
natriuTc Amoksycylina sodQ.11a; Amo>oc1li1' sodlli set Amo><icii· times gr~atcr with co--a.moxiclav than with amox.tcillin alone.
of an oral dose of amoxicillin is excreted unchanged·
1\1 s6di:a: Amoxicilline sodique; Amo><'c~linnat6um; Amoxicilin- Therefore il recommended thal w-amoxiclav should be n:sctVt:d in the urine in 6 hours by glomerular filf!"atioa and
tiAtrum: Amoxici'linum natricum; AmoX'JCilin Sodium; BRL· for bacterial infections hkely to be caused by amoxicillill·mis1- tubular secretion. Urinary concentrations above
2333AS-S. Nari .o.moxici1inum ant str•ins, and that treatment should no1 usually e<cecd 14 300 microgramslmL have been reported after a dose of
1-laTpi.lH AMolcc•'\IMMMH days.• Use is also considered contra-indicated in pa1ien~ with a 250 mg. Probenecid reduces renal excretion. Amoxi-
c , .H,.N,NaO~S =387.4. history of jaundice or hepatic dysfunction associo1cd with co-
amox iclav or Olhcr penicillins. cillin is removed by haemodialysis. High concentra-
C..r\S - 34641-77-8.
ATC - ]OICA04 I. Srricket BHC. n of. Cho lesiatic hepatitis due '°
11n•ibacter ia I tions have been reported in bile; some may be excreted
A:"C Vet - QJO I CA04. combin11ion of amoxic iHin and da\•ullnk: acid (Augmcntin). in the faeces.
UNll - 544Y3D6tAYH. Dig Dl1Sci1989: 34: 1~76-80 .
2. Wons FS. et al. Au;mcntin-indueedjaundice. MedJ A1u1 1991: Amoxicillin u,irh clavu/anic acid. The phannacokinet-
Ph>.rmacopoeias. ln Chili :ind Eur. (seep.vii). 154: 698-701. ics of amoxicillin and clavulanic acid are broadly sim-
Ph. Eur. 6.8 (Amoxicalin Sodl.rn). A while or almost while. \'cry 3. Larrcy D. et al. Hcpati1i1 usocuted with ainOx)·cillin-clnutaoic
hygroscopic powder. Very soluble in water, sparingly soluble in acid combination report of 15 cases. Gut 1 992~ 33: 368-71 . ilar and neither appears 10 alfect the other to any great
dchydra1cd alcohol; very slightly soluble in acetone. A 10'1. so- ~. Hebb:. rd GS, et al. Au;.menlin-induud jaundic-c with a f~tal out- extent.
came. M<t!JAuSI 1992; 156: 285-6.
lution in water has a pH of8.0 to 10.0. St~ in o.inigh1 contain- S. CSMt'MCA. C h~l esuuic jaundice "Aith ~amo:<ich1v. Cu1'1-ent ORcrerencn.
ers. """"'"" 1993: 19: 2. 1. Sanchei N:.wamo A. New fonnu.la1ions ot',mo.'<icillin/ctsvulanic
6. Thomson JA, ct al. Risk faoloB tOr the dc~clopment of a mo<ty- acid: a pharm3cokinclic and pbam1~codynamic review. Clin
Amoxicillin Trihyd rat e (CJANM. rlNNll) ('illin<tavulanic 3Cid nssoci:itcdj111undi« MMJ An.sl 1995: J 62: P/Jor,u~oklittt 2005: 44: 1097·11S.
63l-10.
Amol<sicr•nas tnt.dr.uas: .'\mok~sri1n Tflhidrat Amolcsis.1i'n.'tnny- 7. Rodriguez LAG~, ol. Risk or acute liver inj\Ky a.s.5<>Cia1cd with
d~tb: Arnoksycytina tr6jwodi;i: Amo>Oci!in llih-p.it .'\moxicili· 1he combin3lion of amo.xicillin And cb.\'ulanic xid. Arch fottf'll Uses and Administration
na trihickato: Amoxralln {USN-If. Amoxici!linc trih)<lmte: l'rnox· M«f 1996: 156: 1327-3:1. Amoxicillin is the 4-hydroxy analogue of ampicillin
8. CSMiMCA. Revised mdiea&ions for co-amoxiclav (Augntentin).
din-trihidra~ Amoxdimt¥-.l Amoxicill'num trill)'dricum. Cun~nr Pt'()/>J~m.1 1997; 13: 8. (p.222) and is used similarly in ruscep1ible infec1ions.
Amoxyciltin Tii'lychte: BRL-2331
Effects on the teeth. Too<h discoloration associated with the
These include actinomycosis, anthrax, biliary-tract in·
Aw.ot<OIU>IMHH Tp~l'>IAPaT use of amoxicilli11 with eb,'Uhmic acid has been reportod in 3 fections, bronchitis, endocarditis (particularly for
C 16H ,.N)05S.3H20 =119.~. children.' prophylax is), gastro-enteritis (including salmonella en·
C/1S - 61336-70-7. I. GJtCi,..LOpcz. M, et al. Amu:<yallin-clavulanic acid-related tcritis, but not shigellosis), gonorrhoea, Lyme disease,
ATC - JOICA04. tooth ddcok>ration in chi1drtn. PodH>tr.u 200 I; 1OS: 8 t9-20.
AiC Vet - QJOICA04. mouth infections, otitis media, pneumon ia, spleen dis-
Sodium content. Each g of amox1cillin sodium contains about orders (pneumococcal infection pr0phylaxis). typhoid
UNll - 804816}1HU.
2.6 mtnol or sodium.
NOTE. Compoundod prqiora1ions of amoxicillin may be repre- and paraiyphoid fever, and urinary-tract infections.
sented by the following names: Interactions The beta-lactamase inhibitor clavulanic acid (p.272)
• Cc>-amoxiclav xljJ (BAN}-amoxicil)in (as chc uihydratc or As for Ampicillin, p.221. widens amoxicillio 's antimicrobial spectrum and a
tbe sodium sail) and polassium c4'vulano1e; x and y arc the combined preparation (co·amoxiclav) can be used
strengths u1milligrams ofamoxicillin and ctavulanic acid rc- when resistaocc 10 amoxicill in is prevalent, for exam-
spec1ivcly Antimicrobial Action
As for Ampici llin, p.221. ple in respiratory-tract infections due to Haemophilus
• Co·>.mci.1clav (P£~amoxicillin nihydr:11c and potassium injluenzoe or Moraxello corarrho/is (Branhnmello ca·
clavul•nalt. · Amoxicillin has been reported to be more active i11 vir-
torrholis), in the empirical treatment of animal bites, or
Pharmacopoeias. In Chi11., Eur. (see P.'ii). /nt.. Jpn. US. and ro than ampicill in against Enreroax:cusfaecalis, Heli·
Viet. cobacrer pylori, and Salmonella spp., but less aC1 ive in melioidosis. For details of these infections and their
Ph. Eur. 6.8 (Amc»cici(n Triiydrate). A while or allt10$l white. treatment, see under Choice of Antibacterial , p. J70.
crystalline powder. Slightly soluble in water; very slightly solu-
against Shigella spp.
Amoxicillin is also given as pa11 oftreannent regimens
ble in alcohol; pncticallym.10lublc in fa ll)' oils. II dissolves in di· Amoxicillin is inactivated by beta lactamases and com-
Jule acids and in dilute soluiions ofalkali hydroxides. A 0.2% so- plete cross-resistance has been reported between to eradicate Helicobac1er pylori infection in pnlicnlS
lution in waler has a pH ofJ.5 to 5.5. Store in airtight containers. amoxicillin and ampicillin. Tiie spectrum ofac1ivi1y of with peptic ulcer disease (p. 1851).
USP 33 (Mioxicillin). A white, practically uOOurl~ crystalline amoxici ll in may be extended by use with a beta-lacta· Amoxicillin is given orally as the trihydrale and by in-
powder. Sli¥hlly soluble in waler and in methyl alcohol; insolu· jection as the sodium salt. Doses are expressed in terms
blc in carbon tetrachloride, in chloroform. Ind in benzene. pH of mase inhibitor such as clavulanic acid (p.272). As well
a 0.2% solution in water is between 3.S and 6.0. Store in ainigh1 as reversing resistance to amoxicillin in beta-lacta- of the equivalent amount of amoxicillin; 1.06 g of
containers. mase-producing strains of species otherwise sensitive, amoxicillin sodium and 1.15 g of amox icillin trihy-
cla..1.1lanic acid has also been reported to enhance the drate are each equi valent to about l g of amoxicillin.
Adve rse Effects and P recautions activiiy of amoxici llin ag;iinst several species not gen· The usual oral dose is 250 to 500 mg every 8 hours, or
As for Ampicillin, p.221. erally considered sensitive. These have included 500 to g15 mg every 12 hours. Higher oral doses of
The incidence of dialThoea is less with amoxicillin than Bacre1vides, Legionella, and Nocardia i;pp., Haemo- amoxicillin, either as a single dose or in short courses,
ampicillin. philus injlue11me, Mora.-cel/o calarrholis (Bronhomello are used in some conditions. For example. a dose of3 g
The symbol f deno1cs a preparation no longer actively marketed
220 Antibacterials
repeated once after 8 hours may be used for dental ab- BNFC 2009 also recommends lhe following in1ra..,mo1« dose
scesses. A 3-g dose may be given for uncomplicated ranges for neonales and children;
acute urinary-tract infect.ions, and repeated once after neonates: 30 to 60 mg/kg, given every 12 hours for neonates
less than 7 days old and every 8 hours for those 7 to 28 days
JO to 12 hours. of age. For meni1111ilis, 100 mg/kg per dose is recommended
A high-dose regimen of3 g twice daily may be used in children from I month of age: 20 to 60 mg/kg every 8 hours
patients with severe or recurrent infections of the respi- (to a maximum of4 g daily). for meningitis, group B s!Tepto-
coceal infection. and endocarditis, SO mg/kg every 4 10 6
ratory ttact. Amoxicillin has also been given as a single hours (lo a nwumum of2 g every 4 hours) is recommended
dose of 3 g, with probenecid 1 g, in the treatment of In the USA, the follCl"'ing licensed oral doses att recommcndec!
uncomplicated gonorrhoea in areas where gonococci fot amoJ<ieillin depending on infection severity;
remain sensitive. • nconaicsand infants less lhan 12 wcclcsofagc: a maximum of
For the prophylaxis of endocardilis in patients at risk, 30 mg/l<g daily in divided doses <"Very 12 hours
• children from 3 months of age weighing less than 40 tea: 25 10
amoxicillin 2 or 3 g may be given about I hour before 45 mgllc11 daily in divided doses every 12 hours, or 20 10
dental procedures. However, in Lhe UK the BNF 59 40 mg/leg in divided doses every 8 hours
and NICE now suggest that such prophylaxis is unnec- • children ftom 3 months weighing 40 kg or more: as for adulls
essary (see p.178). (s« Uses ood Administr:ltion, above)
For the eradication of H. pylori, amoxici llin is given Ahcmalively, for children from I month of age the American
Academy of Pediatrics (AAP) 1 recommends oral doses of2S 10
with either metronidazole or clarithromycin and a pro- SO mg/leg daily in 3 divided doses for most infections.
ton pump inhibitor; usual doses ofamoxicillin are 0.75 For orltis media, the BNFC 2009 recommends thar children
or J g twice daily or 500 mg three times daily. from l month ofagc may be given oral amox:icillin 40 mg/kg (lo
An extended release fonnulation containing 775 mg of a maximum of 3 g) daily in 3 divided doses; alternatively the
AAP =ommcnds 90 mg/kg daily in 2 divided doses. Where
amoxicillin as the trihydratc is available in the USA for compliance may be a challenge, \JK licensed prodllCI infonna-
the treatment of tonsillitis and pharyngitis due to Strep- rioo suggests an allanative cowsc of 750 mg twioe daily for 2
tococcus pyogenes in patients aged 12 years or older. It days for children from 3 to l 0 yean; ofagc.
is given orally in a dose of775 mg daily for JO days. For prophyla.tls of tndocarditis in childreri al risk. US cxpcnsl
suggest a si,.ie oral dose of 50 mg/kg 30 lo 60 minutes before
Amoxicillin is given by Intramuscular or slow inlr~­ high risk proecdures.
nous injection in doses of 500 mg every 8 hours. In se- For doses in children wilh renal impoinnent see below.
vere infections, 1 g of amoxicillin may be given every I. Amcric>n Academy of Pe<Hatrics. 1009 Red Book: Report of1he.
6 hours by slow intravenous injection over 3 to 4 min- Commlttt• on Jnftctious Diseases. 28lh ed. Elk Gro,·e Vil11jt.
Jllinois, USA: Arilerican Academy of Pcdi3trics, 2009.
utes or by infusion over 30 ta 60 minutes. 2. Wilson W, ot ol. Prevention of infective endocarditis: guidelines
from the ArMrlcan Hean As.soc-iation: a guideline from the
For detai ls of doses in ch ildren, see below. Amc.ricen Heart Association R.hc:u~tic Fever, Endoc.orditts, and
Doses may need to be reduced in moderate to severe Kawasnki Oi1eue Committee. Coun-cil on Cardiov-aiscular Dis·
ease in the Youna. and 1hc Council on Clinical Cardioloay.
renal impainnent (see below). Council on Clrdlovucular Surgery snd Ane.sthcsia, and the
Qu•J;ty of Care and Outcomes Research lntc!disc;pli""ry Work-
Amoxicillin wirh cla1mla11ic acid. Amoxicillin com- ing Group. C1"ra./01k>n 2007; 116: 1735-54. Corr«1ion . •~.,I.;
bined with clavulanic acid (co-amoxiclav) is given e375-7. Also avall•ble 01: hup:/lc;.c.2hajoumals.orglc;ifr<priN/
orally in a ratio of amoxicillin (as the trihydrate) 2, 4, I 16/IS/1736 (KC<$5Cd D/08/09)
7, or 14 parts to 1 part of clavulanic acid (as the potas- Administration in renal imp~nnen~ O<al closes of amox-
icillin should be reduced in patients Mtb modcr.olc to severe re>
sium salt), or intravenously in a r3tio of 5 parts of nal impainncnt according to creatinine clearance (CC):
arnoxicillin (as the sodium salt) to I part of clavulanic • CC 10 ro 30 mUminule: maximum 500 mgcvuy 12 hours
acid (as the potassium salt). Doses of the combination, • CC less lhan JO mUminutc; maximum SOO mg every 24
calculated on amoxicillin content, are similar 10 those hours
for amoxicillin used alone. • haemodiolysis patients: 250 10 500 mg every 24 hours and an
addilional d= both during and after lhe dialysis session.
0 References. In children weighing less lhan 40 kg and up 10 10 years of ai:c
t. Speller DCE, :1 "'· · cdJ. Cl11\'Ulana1elP,.laNam antibiotiC"$: fur- with renal impainncn4 UK licensed product infonnarion recom-
ther cxpcrienc.e. J Amlmlcrob Cltcmo1h•r 1989; 24 (suppl B):
mends dosai:c as follows:
J-ll~·-
2. Todd PA. Bc11ficfd P. Amoxicillinlclavulunic add: an update of • CC I010 30 mUminutc: l S mg/kg (maximum 500 mg) c\'Cry
its antib3ctcrial ac1ivi1y. ph:armoeokint-lic properties and ahen· 12 hours
peu1;c ""'· Dr•gs 1990; 3': 264-)07 ·CC less than lOmVminutc: 15mg/kg(maximum SOOmg)
). Malik Z ~ Lllmln N. Amp1C'11lin and amoxicillin. Pttlia.tr R~v once daily
2006; 27: 4)4~.
Dose rcductionsboukl also be considered whcngivingamoxicil-
4. Geddes AM• ., ol lmrod1Jc110•1: his!Orical perspect;,~ and d<v<I·
opment of amosicillinlclawlanatc. ,,,, J Anliw1ierob Agen11 lin by parenteral routes.
2007; JO(suppl 2): SI09-Sll2 Pre parations
S. BaH P. The clinical development and launch of amoxicillin/cb·
vuh1~te (Of the 1rca.tmen1 of a nn~ of commumry-acquirtd in-
BP 20 I 0: ~ c_... Amc»ociln lf1«tion: Amo>ciciln Onl s.,,.
rec1ioos. /»1J Amimlcrob Agm111 lC07; JO (suppl 2): SI 13-SI 17. ptn$'()r(~v~Co-""""""3v0nl~Co-amooc•
idav Tableu; ~ Co-omo<ic:lav T&U;
6. Thanaviraran3nich S, tt ol Once ot 1wic.'"C daily vcnu:s three USP 33: Am00<aln and 0.VU.ntte f\JussM"n for Oral S..1pe0.-;
times daily amoxicillin with or without clavulanatc for the treat- Amoo<i<:i""' and C - t e f'bl4SWm Tat'iets;AmooOclW.~; Nnol<·
ment of acute otitis mcdi11. Available in The Cochrane Database ~ii"' lor Oral ~ Arnoxiclln Tal:leu: Amoxicillin T•blc:u (or 0-..
o( Systematic Reviews; Issue 4. Chicheiter. John Wiley: 2008 Suspension.
(occesscd 06/08109). Proprietary Preparations (details arc given in Volume B)
7. Salvo F, et ul. A1noxicillin and l\moxicillin plus clavulanate: a Ar,.: Abiotylt: Abram<»<; Almorsan; Arrixcn: Amox-G: AMCllC( Amox1bi-
s3fety review. Exput Ophi Drug Sofaf)' 2009i 8: 111-S. ott. Amo>ocilW>a Duot; hnoxiOOa: Amoxicle<: AmooOda\ Amoxidul Duo:
AmQ)(i~nd: Amoxipcnil: M>~tent; AmO><Jttric Am:»cot Amoomo><f:
Administration in children. Amoxi<:illin may be given tone· Alrivatt: Blowne>x•lt: llo><lina; Oofame»< D•rVlt. O\Jnox: Fobom:»<. Aern-
orates and children for the 1reanncn1 of infections caused by sus- oxon fullcilwla 0..::>t, F.ik.olITTat, Gmo\ Glinsil D._.. Mi>dn1: Moxilnl:
ceptible organisms, and for the propbyla.•is of endocarditis. It Nobact"'"' ~mooc: ~Pim•»< T8nox; Tril>mcx; Tr.Gmox Duo:
may be given orally, by intromuseular injcc6on, by slow intrave- Xalotinat: AurtNI.: ~ Amohex.it: A'flOldt Bp-nilt 0...-
nous injection over 3 to 4 minutes, or by intermirte:nl inlravcnous Fisomox: lbiamox; Ma>camox: Moxacin; M<l'Cic:lav; R.rvnoxy. Auurio:
Amo>calt: An-1le>otAmoxW<A.~ ~~Os­
infusion over 30 lo 60 minutes. ~ ~ a.11.: ~ 8oaime:t Oamcocyt Doumo>od:
In the UK, licensed orol closes for children up to I 0 yeatS of age Attr.c»ort Hiconcij: ........,.t: ~ ~ Bnu.: And.oc
range from 125 to 250 mg every 8 houts depending on the type AAlox: AITocadtM: Amaci-Ped: Amc:ocilnln; Amo.ia;>t Amoo<ic:omf:
Amocldt Alno<llr.-AmcHned;A;noxnt: ~,.,,,,,,,..
and ~ty of infection. For childrcn S years and older, up to
""'~ ~ llimo>cn1: Crnoxnt: Ductod"no: Duzirric:int,
500 mg e\'ef}' 8 hours llas been suggested by the BNFC 1009 for Fill"MO><t """"'-'t: Hx:O<lCit Hn:omox: lbamoOOlt: L;.llon, Lifamoo<t:
the treatment of severe infections including uncompl i<:ated C-Om- t1<lo<il*.os; Ncmoodlt, Neo Moxiriin; ~ ~ No;oocif. Cltrln:
munity·acquittd pneumonia, invasive salmonellosis, and exac- "-'<iint; Pn.rmcoc Pblibocf: f'blimc.at PtobOOI Prcdoool: R.'f'ic:~nt: Tri-
mox: Ulnimco¢ Un• Amooc Vetamaoc C..nod.: Amooc ~Arnoxr. t..n-
erbations of cystic fibrosis (7 years and older). Amoo¢ Nov..,..,.;,. N"'"""°'"= ChUe: At>olex: Atnobioti<:: Amoval; Nn-
Additionally, d:le BNFC 2009 suggests the following oral dose oval Duo; Amoxipenit Mo>cil•nic Optamo:oc: Cz.: Am0<len: Amozalt:
range for neonates and children up 10 l year of age: Amo.ohexal: Apo·A1noo<1t: Duomox; Gonof0<mt: Grunatn0xt; Wecto-
Moxf: Ospomox: Oenm.: Oemoxio; lmacirn; rnadrax Fin.: Atnorioo;
• nconalcs: 30 lo 60 mg/kg, given every 12 hours for neonates Amoom: Flerno>Ont. Fr.: A-Gra"" Amod<><: S.ctox: Bnst2moxj: Oarno><yl:
less than 7 days of age and cvcry8 hours forthose 7 to 28 days flet-ro>Mcj: 1-kO<lCiJt: Ger.: Amagesan: Amc·Purent: /lmoxi: Amol<i-Oio-
lan: AmooU·Hefa: Amoxj.fV.....,t: Am0><;.Tab:<>e,,. Am0><;·Wol~ Amoxib<·
of age U; Arno>odoc; Amoxiht><>t Amoximerd<t: Amoxypen: Fl.J;.Arnolocirn; ln-
• children I monlhto I year of age: 62.S to 125 mg31imesdaily
Licensed fXJrt!nl<!lvl closes for chilc!re11 up to I 0 yws of age in ""'°"'t Jl/WTIOICL>mbem:
'fectoMo>c
~ lzoU
Si&amC>Pe•t: Gr.: Amospes: Amoxil.
~ Ovomoxyt o..rincp.:o; ~ Onnus; flc:moxilt
M>wedrn Ospamo>c P¥>dm><l Prev...t
~

the \JI( range from SO lo I00 nig/11& daily in divided doses. The Pmcimox; se..;,,inc; Ste..enafrc 5'mlag>t Trioc!inO< w..tem. l-l""f

All cross.references refer 10 entries in Volume A

 Amoxicillin!Ampicillin 221
C; Al~lee. Ambre,,_.'\. Nnoblt Q.; Amcv.ibrort A1~.t, ~~ Ampicillin Sodium !~ u>~N ofN1'/.I) mononucleosis develop ~ maculopapular rash when
~ Ov0; Apoclw- ~ Av..o<ian· !!oovi<A'TI E><: 'loblnc<f:
~ Bo""""I: Sron'<><erc &oa>o>ot Broxoiom·AMf: llnrMx: Cbo'>- Amirrobenzylotndin Socji.rn; Ampid•in sodfw ~: Ar.picilr.a treated wirh ampicillin. and patients with other lym-
.t 0..-.l Oomo>U" c..,,,,~ C...x,d. ~' °'"""" Cri= &- s6d ca: Ampici!ono na1r-.o dn.'Ska: Ampdine sodiq~: ~t!ir>­ phoid disorders such as lymphatic leukaemia, and pos-
hlf'lott &-..ec~ &o:: Fcrlc..-x. Grr~brot Grama:ic": Hloraf'l'IOx·M: Loe)(()(Y'I
FC: Lot"°"' fS; Wm<»<bron S: M•mtt ~ Moxlin 0.V: Mu~
••tnum Amp:c!lin-nit"urr~ Al'rllr<•llonum natro {um: Anpicyt:r,. sibly those with HIV infection, also appear to be at
Am:»o M.r.0>0na: P,,,zmox M. Pe~ ~ Ropiclzv. Ra"°iar:
sodo.-'ll. Amp1Sil'i·ninotriun·: Natri. Ampoci finvm; Sodyum A...,,;. higher risk. More serious skin reactions may occur and
~dlSlf': ~Amax~ Sep;Mi'\ Amt::#:i ~ Setv~JOOX ClV, s3on. crythema multiforme associated with ampicillin has
Sonvl"lll: S*b"<>: Too«* Tn!,mox IBL: V•ldai>r: V:lnrT'c<olj: Neth• Amoc· Hil'pW AMn>u<M11H
Ian: Amudar' AuVr-.in< Socx:!Md: for«! P•moflt<: HZ: Alpi'la·Amox)'· occasionally been reported.
div. Augmerotin: ia..oo HP 7t: Losee Hp7: S~ Philipp.: l\a<cmt'"C =
C, 0 H:iN,NzO,S 37 1 .~.
Gastrointestinal adverse effects, particularly diarrhoea
/\moclav. Anboc)n: - : ~~I'< Augmcx: ~ llac1>< Bocto- CA5 - 69·51-3
dav. Biocla" Biocl,..;¢ C.X Cbmc>Ad: Clone<.< a.-.A: OMnl.I'< 0.-n· ATC -)OIC/101 . SOIAA/9. and nausea and vomiting, occur quite ofien, usually af·
mox: Cl...,.,..>< Cl"'°"'">e CQ..ac ~ °"""'"< ac..IN>C Em¥nooc ATC Ver -QJOICAOI; QSOIAA f9. ter oral use. Pscudomembranous colitis has also been
Emancorc E""'1: Giob.in1n Gloda¥: l<lM:: N•V.'l()O(! N...i..r. O/IC t\>7t.
Periw>c:t: P>oociclav. A.lone><: S.....cx ScNl.n: S"1iiv•n Svplenl,..t; U.-.. UNll - JFN36L5581<. reported.
moc; v..Jmocelf: V..'f\O>e; Xl.lf'ic: p~ Amod¥'1; Amol<sl<lw, Aull""'J< Pharmacopoeias. In Chin. Eur. (seep. \1ii), "11.. Jp>. and US.
~ Betamo><: Cla"""""" °"""""
Curam. Forod: FWnoclav. Ta.~ Pon.: ~m: hnpla"""' PIJs:
Forod: Nqrlam: ?enii.n: l!ui.:
i\mo<W>~): AAloksiklav (AMo"-~Niet ~): Aug<nc'l\on
Ph. Eur. 6.8 (Arrc>'cillin S<xium). A white or almoSI while hy·
grotCOpic powder. Freely soluble in w1uer; sparingly soluble in
Effects on the liYer. Ampicillin has been associated with he·
ixuic injury. Self-limiting cholestasis was rcponed in a 23-ycar·
old man who received oral ampicillin:' recurre1><:c followed each
(Ayn••..,..,.): Flemocl•·' (CDAC..O<Mt): Lidav (.ll•«Ma): Medo<lav ~!OllC: practically insoluble in liquid paraftin and in fatty oils. of 2 subsequent exposures to the drug. A case of chronic
(M•AC*I..,~ l'>nld3v (ila>t<All): R.nclov ~~ Rap;div (l'M•"""~ A 10'1. solution in water has a pH of8.0 to IO.O. Store in •irtight cholest.asis associated with ampicillin use has al$0 been ttpOC\·
Trif•mox iSl (l'~ 1161\): S.Afr.: Adco·Amcdw. Amodan: Au&· containers. ed.:
maxd: Auu-m liio-~v. Oamcmr< a......rr..ct. Co-A"'°')" USP 33 (Ampicil11 Sodium). A white to off.white, odourless or
c1av: Curam Fomct H<oncil-NSf: Haer_... ~ McocycJ~ flan. S<:vere and pl'Olooged cholcstasis has also ~n 1'Cponed afttt
d•«: F:olab·Amoclavt; Supr•pen: Singapore: Amodl, ""'"'ontin: proctically odoutless, hygroscopic, crys1:1lline powder. Very sol·
trcatmcnt with ampicillin plus sulba<:lam; aradu•I resolution of
~: Clamone>e O.mowcl: Cura"' Enhancin, h;p>bn. l"lo>Oclav. uble in water and in isotonic sodium cl1loridc and glucose solu·
the condmon occurred over 7 months.' ·
Spain: Amocbvo: Alr'C>O Gobens Muc.,..;cot; AmoxyplJ>t. Ardnc !lrcn- tions. pH of a solution in water containing the equivalent of amp-
qo.salf: Mi!neclavt:Aupntroe: S-OOC:o Tonic: ~ Clamo><)'I ~ J. K6kla S. tt al. Recurrent cholcs1uis due to atnpicillin. Ann
icillin 1% is between 8.0and 10.0. Store in ainight containers.
loco: CIMpcnt; Clzvucidt; ~ Ouonm: Eupccl•:•ct. E-...,e.' l'han#UC'ollwr 2003~ 37; 395-7.
eranqu;,tt. Kelrope<i: 06on\Ollio1Jc l'l.ln1o Ooit>>l.in: Remisao Mucol<lcc; Incompatibility. TI1c incompatibility ofampicillin sodium Wld 2. C3v:mzo FJ. tt nl. etironic chatestasis. paucity of bile chrc-1s. red
S>Mp<n Mucolruco: Swed.: llioclMd. ,..,.,.,_.,, Hp: Speklra.'TIO>< Sw/u.: aininogl'ycosides is well established lncompalibilities ba"" also ctll oplasia, and lhc Stt>vens--Johoson syndrome: an ampi<illin·
Amocosdt; Au;p-.ent>l: Aro.v. o......_ dr....buant; Co-A:nc:"': Co- b.:cn R:portcd with m3ny Olhet dnigs, induding other antibclcte- ilSSOCi:ttc:d C.JSC. GosllWHl,'1"0fOS,l' 1990: 99: 8>4-6.
Amoxdine: Tboi.: AMK; Amod>t: Amd<stdav. An.!licyrc Avgclav. Aut- 3. KOldU S. ct of. P,..b4< s;ul01ctant1tunpicillin-uso-:i:u.cd pro-
men~ Au;p<r< Cawmooc: Cl>wnoo<y. ~ Unm: Kl•moiu< Man-
rials. alld appear to be more pl'Onounc:ed at higher concentrthons
longed c:hole51uis. ""''" PhonnMOJh<>r 200~: 38: lOSS-8.
clalTlin<: Moxidov. Mc:J.icl<: f'oncla: Ranci..r.- T""°' Amol:la,,r.:Au?,· and in solutions also containing glucose.
menw't. Siomen~ ~ He!ipak l(l~m~ KY-l\l"lat: IO.awpcfl: Trio;
Stability. Tiie stability of solutions of ampicillin S<ldium is de· Precautions
UAE: JulmorA.i'c UK:~: Augmentirt ~ Helicleart:
Ukr.: Amol<sillav (A..Ol<O<!Wt): Avgmcntin (Ayr.....,..,.): Bctak!av pendent on many factors including concentration. pH, tempera-
1t1rc. and the Mture of the vehicle. S!Abilily decreases in the pres-
As for Benzylpenicillin, p.232.
(6e•..w•~ Flomocl>v (<li.~t. Klamox (iw..o.c~ Pytob>ct Neo
(llw.¢6al<T Heo). USA: M>ooorc AugrTl<!f>li" Prevpoc: Vcnu.: ~ ence of glucose, fructose, inven sugar, dcxlnns, hetasiarch, Ampicillin should be stopped if a skin rash occurs. It
tt'< Augrncnt•n B:dt: 0 - x : C...atr< Ful£1'i 1'f\, sodium bicarbonate, and lactate. It is recommended thaI reconsti- should preferably not be given to patients with infec-
llrted solutions ofampicillin sodium for injection sh<luld be given
within 24 hours of preparation, 3nd should be Slored at 2" tor
tious mononucleosis since they are especially susccpli·
but sho11ld no1 be frozen. Solucions for infusion are stable for var· ble to ampicillin-induced skin rashes; patients with
)'ing periods and derails arc giYCn in licensed product intbnna- lymphatic leukaemia or possibly HIV infection may
Ampicillin (BAN. uSAN. rlNN) tion. also be at increased risk of developing skin rashes.
References.
Myasthenla gravis. The symptoms of a woman with myasihc-
I. Lynn 8 . Tht u~biri ly and administration of intr.tv<nOU$ peniciJ.
Am'l'lobentffpe<>ic~lin; Ampicifo: Ampicilina: ~•hnas. bev-
lins. BrJ l111rm·~,, Th~r 1981: l <M:irt: :!2-39
nia &JllVi$ were ex3cerbatcd when she "'as given ompicillin.1
andenis, Ampicllon. mtenfii:-.; Ampici!lit>e: Anll'olne arih)'dre: I. -*'~' z. f!t ul. Ampic:illin may aJgrl"~'' dinical nnd cxptr-i·
Ampicminum: AmpioCr...n zrtiyclncum: ~ bezl,,ocina: n\Cnt01l myasthtni:a ~vis. !Jt~h Nta1rol l9'6: 43: 2SS-6 .
Ampicillin Trihydrate(8ANM, rlNN.Y<)
Ampisilrr: Ampisllliiri; AmpisOlini. ,oedct6n: Anhydrous Ampicillin: Sodium c:ontient. Each g of ampieilhn sodium contains about
A~icilin tfilydrat; Ampocilina triNdrato: Ampialnas trihidraus:
AY·6108: BRL- 13~1 ; NSC-528986; P-50: Vizmerte< ampdn 2.7 mmol ofsodium.
(6R)-6-(n·D·Phenfjl!ycylamoono)penicilfaoic arid. Ampic1U1n; Ampiciline tmydratee: Amprc~lin-tnhictat; Ampicol
lintnhydrat; Arr.,dil'AJtn trih)'doicum: Ampicylina ~:
Ampisinnnitn'hydraatti. Interactions
A>m"''"''"MH Tp~r1<.opn
As for Benzylpcnicillin, p.23~.
C,.H 19N,O,S =349.4 . c,.'"l,cNJO,S.3H~O = 403.S. Antigout drugs. An incieased trcqncncy of ~kin rashes has
CA5 - 7177·~8·2. been reported in patients receiving ampicillin or amoxicillin.
CAS- 69 5:;.4 wuhal/opul'inol, comporcd wirh those receiving the antibacterial
ATC -)OICAOI: SOIAAl9.
ATC ~et - Q;OICAOi; Q501AAl9. alone.' but lhis could 1101 be conflmled in a subseq11ent slUdy.~
ATC - JOICAOI : SOIAl\19.
UNll - HXQ6AIN 7R6. 1. J1cL. H. Po.-tcr JB. Potc:n1i ..1iun or .mipidlliu $kin r~ac:tiuns by
ATC Ver -- QJOICAOI: QJSICAOI ; QSO I AAl9. :ill<"rurinol or hy~ruritcini:21 . J C/i,, Pharut(J<.ol 19SI; 11:
Pharmacopoeias. In £11Y. (sec p.\•ii), Jp11, and VH1t. In Chin. 4~64.
under 1he title Alnpicillin /111. and US pennit anhydrous or the 2. Hois::.nC R. ct al ~currcnce of cx:11'tlhems in re1.:tition to nmi~
UNll - 7C782967RD trihydratc under tlie title Ampieillin. nopCnkiUin prc-pMliljons and a llc•puriuol. N £'¢/ J J.litd 19&1;
Fh. Eur. 6.e (~ll:n Trif¥Jrate). /\ white or almosi white.. 316: 1217.
~stalline powder. Slightly soluble in waler; ponctically insolu.
Antimalarials. The absorption of ampicillin hos been ~
blc in •lcohol and in fatty oils. It dissolves in dilute solutions of
in heal1hy subjects taking c/1/oroq11i110.
acids and of alkali hydroxides. A 0.25% solution in water has a
I Ali HM. Reductd ampicillin bioa\"11l1\\ili1y fC\llowing Qra) co~~
pH of3.S to S.S. Store in oinight containers.
ministration with chloroquine. J .•mimit','Ob C//emo1Mr 19SS;
USP 33 (Arl'piclln). It is anhydrous°' conlllins thr<e molecules 15: 78t-4.
ofwate1· of hydration. A white, practically odourl<ss cry•talline
powder. Slightly soluble in wolcr and in methyl alcohol; insolu-
ble in carbon tctrachloriclc. in chlorofonn, 3nd in benzene. pH of Antimicrobial Action
a 1% solutiorrin water is between 3.5 ond 6.0. Store in 3irti&hl Ampicillin is a bcla-lactam antibacterial. It is b.1ctcri·
containers. cidal and has a similar mode of action to that of bcn-
zylpenicillin (p.232), but as an aminopenicillin with an
NOTE. Compounded preparations of ampicillin niay be represent· Adverse Effect$ amino group side-chain attached to the basic penicillin
cd by 1hc following names: As for Bcnzylpenicillin, p.231. structure. ampicillin is better able to penetrate the outer
Skin rashes arc among the most common adverse ef- membra ne of some Gram-nCll.ativc bacteria and has a
• Co-Ouampicil (BAN)-llucloxaeillin I part and ampicillin I
~rt(w/w). fects and are genera lly either urticaria) or maculopapu· broader spectrum of activity. -
lar; the urticaria ) rcac1ions arc typical of penicillin hy- • Ampicillin resembles benzylpenicillin in its action
Pharmacopoel;;:s. In £11r. (seep. vii). Jpn, and YICI. persensitivity, while the crythematous maculopapular against Gram-positive organisms, includ ing Sll'epto·
fut. and US permit anhydrous or the llihydmte. eruptions are chan:ic1erisric of ampicillin and amoxicil- coccus pnewnoniae and other strcptoc<>Cci, bul, with
Ph. Eur. 6.8 (Amp alin. Anhyct'ous; Ampicillin SP 2010). A lin and often appear more than 7 days after starting
white or alnmsl white, crystalline powder. It exhibits polymor-
the possible exception of activity against En1erococ-
trealm~nl. Such rashes may be due LO hypersensitivity c11s.faecolis, it is slightly less potent than bcnzylpen-
phisn1. Sparin11ly soluble in water; i:nctically ,insoluble in alco-
hol, in ecetonc, and in fatty oils. It dissolves in dilute solutions of to the beta-lactam moiety or to the amino group in the icillin.
acids and of alkali hydroxides. A 0.2S% solution in \\llltcr has a side-chain, or to a toxic reaction. The occurrence of a Listeria mo11ocy1oge11es is highly sensitive.
pH of3.S 10 S.5. Store at a temperature noc exceeding 30" in air- maculopapular rash during ampicillin use does not
tight conlaincrs. necessarily preclude the subsequent use of other peni· • The Gram-negative cocci Moraxella catan-halis
USP 33 {~).It is anhydrousorcont:1ins1hrtc molecules cillins. However, since it may be difficult in practice to (Branhamella ca1t11Thalis). Neisseria gonorrhoeae,
ofwa1cr ofhydnation. A white, practically odour)= crystalline
distinguish between hypersensitive and toxic respons· and N. meningitidis are sensitive.
powder. Slightly soluble in water and in methyl alcohol; insolu-
ble in carbon tetrachloride. in chloroform, and in licnune. pH of es, skin testing for hypersensitivity may be advisable • Ampicillin is more active than bcnzylpenicillin
a I% solution in water is between 3.S and 6.0. Score in airtight before another penicillin is used in patients who have against some Gram-negative bacilli, including Hae-
containers. had ampicillin rashes. Most patients with infectious mop/11/us mjlue11we and Enterobacteriaceae such as
The symbol t denotes a preparation no longer actively marketed
222 Antibacterials
Escherid1ia coli, Proteus mirabiliS, Salmo11el/a and tarrhalis), Salmonella infections, shigellosis, and in- follo"1ng oral dose range for neonate~ and children up 10 I year
Shigella spp. It is inactive against Pse11domo11as aer- fections due to Escherichia coli. For details of these in- of age:
uginosa. fections and their treatment, see under Choice of • neonates: 30 10 60 mg/kg. given ev<'I)' 12 hours foe- neonales
Jess than 7 days old, e""')' 8 hours for !hose 7 10 2 1days old,
• Ampicillin also has activiry similar to benzylpenicil- Antibacterial. p.170. •nd every 6 hotn for those 21 10 28 days old
lin against other organisms including many anaer- If beta-lactamase-producing organisms arc present, • children I monlhto I yearofagc:62.Sto 12S mg4timcsdaily
obes and Actinomyces spp. ampicillin can be given with a beta-lactamase inhibitor Recommended intravmous dose rangC!t in ncona1es and children
Activity with other antimicrobials. There is Synergy such as sulbactam (see below) or a penicillinase-resis1- arc as follows:
against some beta-lacwnase-producing organisms be- ant drug such as cloxacillin, dicloxacillin, or flucloxa· • neonates: 30 to 60 mglkg. given e\-ety 12 hours for neooates
cillin (known as co-fluampicil). ll may also be used less lhan 7 days old, e'-ery 8 hours for lhosc 7 to 21 days old,
tween ampicillin and beta-lactamase inhibitors such as aud every 6 hours for those 2 l to 28 days old. For tJcaunent of
clavulanic acid or sulbactam, and also penicillinase- with an aminoglycoside to increase the spectrum of or- meningitis, JOOmglkgpcrdOiSC is ~mended
stable drugs such as cloxacillin or flucloxacillin. Syn- ganisms covered; it is advisable to give the injections • children &om l mooth of age: 25 lo SO mg!kg every 6 hours.
ergy has also been show n between ampicillin and sepaMely. For listeria) meningitis, group B stn:p1oooccal infte1ion, and
aminoglycosides against a range of organisms, includ- The dosage ofampicillin will depend on 1he severity of entcrococcal endocarditis, SO mg/kg every 4 10 6 hours (to a
ing enterococci. Variable effecis ranging from synergy maximwn of2 g every 4 hows) is recommended
the disease, the age of the patient, and renal function. In lhc USA, the American Academy ofl'acdiallics1 suggeslS the
10 antagonism have been reported between ampicillin Ampicillin is usually given orally as the trihydrate and following doses given intramuscularly or intravenously:
and other beta lactams, bacteriostatic drugs such as by injection as the sodium salt. Doses are expressed in • all neona1cs with a birth-weight Jess lh•n I.2 kg, and those less
chloramphenicol,'and rifampicin. terms of the equivalent amount of ampicillin; 1.06 g of than I week old and weighing 1.2 lo 2 kg; 25 to SO mg/kg eve- .
Resistance. Like benzylpenicillin, ampicillin is inacti- ampicillin sodium and 1.15 g ofampicillin trihydrate ry 12 hours
vated by beta lactamases, although other mechanisms are each equivalent to about I g of ampicillin. • neonates Jess than I week of age wilh a birth-weight of more
may be responsible for resistance in some species. lhan 2 kg.and~ I weelcofagcoroldcrwilhabirlh-weigh1
The usual oral dose is 0.25 to I g every 6 hours taken of 1.2 to 2 kg; 2S to SO mg/kg evesy 8 hours
There are geographical variations in the incidence of at least 30 minutes before or 2 hours after food. For • neonates l wcdc of age 0< older wilh • birth·...~ight of more
resistance, but most staphylococci and many strains of urinary-tract infections, ampicillin 500 mg is given than 2 kg: 25 to SO mglkg e--ery 6 hows
E. coli, H. influe11ZLJe, M. cotarrhalis, N. goncrrhoeae, orally every 8 hours. The usual dose by injection is • children 1 month and older. l00 to ISO mg/kg daily in 4 divid·
and Salmonella and Shige/la spp. are resistant. 500 mg every 4 to 6 hours intramuscularly or by slow ed doses (to a maximum of 4 g daily). For sevtte infections, a
intravenous injection over 3 to 5 minutes or by infu- 10ta1 daily dose of200 lo 400 mg/kg (lo a maximum of 12 g)
Pharmacokinetics is n:commcndcd
sion, although for severe infections higher doses are of- Alternatively, for mild to moderate infections in cllildren from I
Ampicillin is relatively resistant to in_activation by gas- ten used. monlh of age, 5010 100 mg/kg ornfly, in 4 divided doocs, may
tric acid and is moderately well absorbed from lhe gas- For typhoid and paratyphoid fever where Salmonella also be used.
trointestinal tracl after oral doses. Food can interfere typhi strains remain sensitive to ampicillin, an oral Anipicillin is also used in some coun1ries in children 10 eradicate
with the absorption of ampicillin so doses should pref- close of 110 2 g may be given every 6 hours for 2 weeks chronic carriage ofSalmonella typhi and S. paro(yphi, which can
erably be taken at least 30 minutes before meal~. Peak cause typhoid and paratyphoid fever respectively; an i11tramus-
for acute infections, and for 4 to 12 weeks in carriers. culordosc of 10 mg/kg (to a maximum of2SO mg) every 6 hours
concentrations in plasma occur in about I to 2 hours
and after a 500-mg oral dose are reported to range from Ampicillin 2 g given with probcnccid I g, as a single foe- 4 to 6 weeks has been rocommcnded.
oral dose, has been used in the treatment of uncompli- 1. American Academy of Pediatrics. 1009 RM Book: R~port ofthe
3 to 6 micrograms/mL. Comm;utt On lnfeclious Dist4SU, 28th ed. E•k Grove Vi113g.~.
cated gonorrhoea in areas where gonococci remain Illinois, USA: Am<rican Academy of P,,diamcs, 2009.
Peak plasma concentrations of ampicillin after a 500- sensitive; repeated doses are reoommended in females.
mg intramuscular dose given as the sodium salt occur Admlnlsu-adon in renal impairment. ll>edoscofarnpicil·
In meningitis, higher parenteral doses may be used; !in should be reduced, or lhe dose intc:n-al increased, in scve.-c
within about I hour and are reported to range from 7 to renal impainnent (c~tinine clearance lc$s than 10 mUtninule).
14 micrograms/ml. 12 g daily given intravenously in divided doses every
4 or 6 hours has been suggested for listeria! meningitis. Patients undergoing dialysis <hould recei11e an additiooal dose
Ampicillin is widely distributed and therapeutic con- after lhe session.
centrations ean be achieved in ascitic, plewal, and joint For intrapartum prophylaxis against group B strepto-
Preparatio ns
fluids. It crosses the placenta and small amounts are coccal infection in the neonate, a maternal dose of2 g
BP 2010: Ampkilrl ~ An'!><•llin lrjectkln: Ampicii"1 O"l Suspcn·
distributed into breast milk. There is little diffusion into by intravenous injection initially then I g every 4 hours Jion: Co lluampicil C.psules. Co·lluampicil 0..1SuSP<"'soon:
0

until delivery has been suggested. USP 33: ~in ard Proll<n!<<I (0< O<al S..spensoon: AmpK~•n ¥1<1
the CSF excepl when lhe meninges are inflamed. Sulbactam for qe::fon; Ampi<il!,n C1p wle•: ~in for lojectllble Svs-
About 20% is bound to plasma proteins and the plasma For details of doses in children, see below. ir::~ Ampicilin (or lsiectlOIX Ampacalin for OraJ Susptns.IOl"C Ampiciliin
half-life is about 1 10 J.5 hours, but this may be in- Ampicillin has been given by other routes, usually as a Pt0prietary Preparations (details arc &iven in Volu1nc B)
creased in neonates, the elderly, and patients with renal supplement to systemic therapy. Intrapcritoneal or in- Al'f·' AJpcMx: Ampi·Bi~ ~:i.rt: Ampieen Ampiarandt. Ampincx;
impairment; in severe renal impairment half-lives of7 trapleural injections have been given in a dose of Amp~- Ampixcrt Atcdinaf; Boctino: Oc<Honlf: FaboP<~;"" G"'mpe-
to 20 hours have been reported. 500 mg daily dissolved in 5 to 10 mL of water. For in-
"'tt: H;.cperc Trifacilina; Trm:rot, Vlll!ltK•liNj ; Aunrol.: AJpnacint:
A~icyn; Auslrap<r< !b;mCyn; Austria: Stonclk•l~rc Bole.: A:ntrexyl:
Ampicillin is metabolised 10 some extent to penicilloic tra-anicular injection, ampicillin 500 mg daily has Broz.: AnlJ( ~ Ampiul<Jynlt. Arrc>iot Ampoallb: ~;Jose;
Amp<i\bf;A,...X~~lon:~~~--
acid which is exacted in the urine. been given dissolved in up 10 5 mL of water or a solu-
Renal clearance of ampicillin occurs partly by glomer- tion of procaine hydrochloride 0.5%. ~~=~=l~
GtomdN; Li'..orn.t. Not>tinf: l'n1ici.nf: Conod.: Apo-'°"'lJI: l'bAm-
ular filtration and partly by tubular secretion; it is re- Ampicillin benzathine has also been given by intra- P< C..: Aj»Ampif; llemubllf; Stondatilnf: O.nm.: Ool<udllint, f'cn.
tr<X)t Fin.: A·l'er< Fr.: Toc.;><nt Ger.: 8incut Gr.: AbmlhorcAd&opet<
duced by probenecid. About 20 to 40% of an oral dose muscular injection. ~on:~~Ccnv..-.lin:Ccpt<(Jlo>c~f,.te­
may be excreted unchanged in the urine in 6 hours; uri- Ampicillin with sulbactam . The sodium salts of ampi- linr. fraxici.ino; bticline; ~ Plc:iln. Spiroci!O-'c Stopon; To>Upcr<
Xonline; Hong Koni : ~ut /\mpre>c)t Aj»/Vrpt. Pameol; Penoditf;
nary concentrations have ranged from 0.25 to cillin and sulbactam (p.363) may be given intramuscu- Pr.ntrexylt. l.Jri.Ampicin: Huni.: P,,nsubolj; S.,,,.;~lin; SW1docllrc lndlo:
I mg/mL after a dose of 500 mg. After parenteral use larly or intravenously in the treatment of infections due Ampiln: ~: Arr9>l""< Ati~lin: &ocmn: ~ic~ht'( lpac;iint. Ros-
c;lr< Synthotlirt In don.: Arrbiop( Amdllonf: 1\rr9: Arcociionf: Binotat B.-
about 60 to 80% is excreted in the urine within 6 hours. to beta-lac1amasc-producing organisms. Doses arc ex- opensyM:; Cet1.cillif>t; Corsacllit>; KJ!picilin: O?<c•llh'li Parpitillf>t; ~ict:
Ampicillin is removed by haemodialysis. High con- pressed in tenns of !he equivalent amounts of ampicil- Ponbrrtint: Phopin: Polypen: Pri,,,.,.nf: 541npicll'ort S""'4acill n; U1lr•P"nt.
VKdllin: X.p;icillW>: lrl.: Oo"""4" Nowapenj: Pon:lritont. Rn>acol•rt brae~
centrations are reached in bile; it undergoes enlerohe- lin and sulbactam; available injections contain ampicil- A:nibrin: Ital.: Ampi""= Ampiplus Simplex; Amp!itat NTlj>h<?<: lbimicynt :
patic recycling and some is excreted in lhe faeces. lin and sulbactam in the ratio 2: 1, respectively. The A:nlrCX)I: Molaysfo: Am?ln: l'ame<il; Stllncloc>'lir< Mex.: Aolmcd< Alp·
haperc All.<edrin; Alr>hr; Ambidrin: Ambootol; Ampe>c: ~Quil11(Ampi-
Ampicil/in with sulbactam. TI1e pharmacokine1ics of usual dose is ampicillin I g with sulbactam 500 mg
ampicillin and sulbactam are broadly similar and nei- every 6 hour.;; doses may be doubled in severe infec- ~~~'.tf'00t>t"'t=.~~Ao=~=~t..:~~
~ Fi.miOni: ~""F: lq'.X•iN: L~: ~t Marovlina:
ther appears to affect 1he other to any great extent. tions. M~ ~ 1-f~ Clnril>er-< l'el>ot Pcnbru'c i'mNe-: ~
tr<X)t Proci&v; Fnxlifer. f'rome(h: ~ S>Nplon: Tronex: Ya.
For oral use sultamicillin (p.373), a mutual prodrug of
Uses and Administration ampicillin and sulbacwn, may be given. ::t:..z~~~rw~~~'.
Ampicillin is used in the treatment of a variety of infec- -a.::r'" ~ OO>d &rocin; &dit famacA"< GIWToOt ~
0 References. Mlcroclin: Olxxt P.waa: ~~ Papkt l'bl)perc Ratoarl;
tions due to susceptible organisms (see Antimicrobial
Action, above). They include biliary-tract infections,
I. M1lik ZA. Li1man N. Ampicillin and 3moxicillin. P~tliat,. R1t1 SNnopcrc ~ T""""""' l/Jt>cit; Pore.: Aml>'fr; ant; Estrep!O-
btt>n(ol: Hi;nrbiotico; Hjperb.atico Retard, Rus.: Sund~cdlir.
2006; 27: 4)4-6.
(C--~ S.Afr.: AcuplliTf; ~t. Ampop<r< Jlml)sall: l!e-
bronchitis, endocarditis, gastro-enteritis (including sal- 2. Rafailldis Pl. tr of, Ampicillin.'sulbactam: cun-cnl 1:e-a1us '" H- Mlpid: ~ P<tritet. ~cidln: ~ Sptc112dj: Sin(OP•n•.:
vcre bacccrial infcclions. Drwgs 2007~ 67: 1829-49. Ampiron; P>ociln !'>med: Sund.JCillin: Sporn:~ Anlot>opeof; B<·
monella enteritis and shigellosis), gonorrhoea, lisierio- l . Lode HM . RaLion1t antibiotic lhc:rapy and 1he position ofampi- iupert Got><m:uia; Nuv.per< Swed.: O<ll<tadhr< Thal.: Amc:illlnf: Am(:;.
sis, meningitis, perinatal streptococcal infections (in- cillin/sulbottam. fnl J Anlimicroh Ag"'"' 2008; 32: 10-28. lin: Jlmlinf; Mipac; Amp( Ampi Fnc Ampi.Ora~ Atrc>icirc Ampcyn Amp;.
trapartum prophylaxis against group B streptococci), ho(: Ar.-¢« Ampill"': A1r9im)C1rt Ampopoc: Atrj>ra( ~ Miprot:
Administradon In children. Ampicillin may be given 10 neo· Er.itillint; M.OCillin: fen!Nii.rt; P.ncotrcxt. F\:ntr~ So~cilj; Sumap-
peritonitis, pneumonia, septicaemia, typhoid and para- na1es and children for lhc 1roiunent of infections caused by sus· ont: Utoc;n.,, Vacillir< lioccilO; Tu,f<.: A lfa$ll"' Amplsld. Arnpisina; Ncosi1"1:
typhoid fever, and urinary-tract infections. Resistance ceptible bacteria and may be given orally, by intramuscular injec- f'enb;sirt S.-iin: Sl&>i: UAE.: J~apen: UK: Mappert PenbriU>: Rima·
to ampicillin is increasingly a problem in some infec- lion, by slow lutravcnous injection over 3 10 5 minu1cs, or by <•"- USA: Pri:>cipeo; Venn: Alampert Ampent; ~<W\I! ~;g•f;
in1enniltcn1 inlTavcnous infusion over 30 mioulcs. Ampian: Atcocilin; Fbopcnt; "'1t>pl!t\t: Ne..mpicolt.
tions, for example, gonorrhoea, pneumococcal infec- In the UK. licensed orol doses foe-children up to 10 years of age Mutti·invedient: Arg~ Aminoxidin SublcWn; Amp.Bi• FU: Mipigcn
tions, respiratory-tract infections due to Haemophilus are 125 to 500 mg every 6 hours, depending on lhe 1)1"' and se-
SI!; /\ITpbbenutin Bn>nqi.Oat Ctonop~r> S.l..mico: M<'lito~ p,,,,,..U"lasy-
Nt. Austria: lhsyrt Btaz.: Ant>ezeut ~\ llenzolat Cornl:>aruort
info1en:zae or Moraxella cararrhalis (Branhamella ca- verity of tbe infec1ion. Additionally, lhe BNFC ]()(}9 su~ts !he 0....,.. Oplaci'n: ~ ~"""' Svbxtert; UNsyn lkopielooc
All cross-references refer 10 en1ri~s in Volume A
 AmpicininiAvoparcin 223
Pharmacopoeias. Jp11 includes the trihydnne.
Profile
Aspoxicillin is a urcidopcnicillin Iha! hAS l>ecn given intrave-
nously in the trcaUnent ofs~plible infec1io11s.

Astromicin Sulfate (VWI. ol\N\'IJ

Abbott-44747. As\l'omicin S<Apl-.ate; Astromcine. Su'fate d': As..
tromcr. SUfas: Fortimicin A Su%Jhatc: "(:Y>/-1 OiO: Sulfato de as-
troma'la. 4-Arnno-1-(2-amino-N-methylacetamdo}- I.4-didc-
o><y·3-0-(2.6-diarrino-2.3,4,6,7-pentadeoxy-11-l~·"o-.'>cpto­
pyranosyt}-6-0-melhyk-dw·o-joositol sulphate.
ACTpo M~ U""3 Cy""9<n'
=
C 1H 3sN 50 •.2H 1S04 60 1.6.
CAS - 55779-06· I (osvomicin); 72275-67-3 (ostromicm
(orbekoCJll) sul(o1e): 66768-12-S (J<H1SO.).
UNll - POY3SOT38D
Apramydn (!IN'( tMN. rlNN) Pharmacopoeias. In Jpn.
47657: ApramiclNI: Apramycine: Apramyci<urc EL-857: El- Profile
657/820: Netnmycin Factor 2 4-0-((2R,3R,1a.S,6R.7S.8RJlaR)-3- Arbekacin is an aminogl}'l:oside an1ibacteri1I derhoed from
Amirlo·6-(1·amino-'\-deoxy-a-o-g\Jcopyranosyloxy)-8-hy- dibekacin and has general properties similar to those of g<:n·
droxy-7-me1hylaminope~3.2·b)'yran-2-yl]-2-de­ tamicin (p.306). It has been 11$ed as the sulfate in the inatment or
oocysvep1aminc. serious infections doe to mc:ticillin·n:sistanl Sloplryloax:cus ou-
t't"lts.
Anpa-
C2 1H.,Ns011 =
539.6.
Arsanilic Acid (SAN. rlNN)
CAS - 37321-09-8.
Acide Arsanilique: Addo amnlico: Acick.m ArYnihcum: Am~
AiC Ver - QA07M92; QJOIG890: QJSJG690. narsonic Aod: AS- IOI. p·Aminobenzen~ acid; 4°Am1-
UN/J - 388K3TR36Z. nophenyiarsoRC ieid.
Apca"""°"" ~n
C,H,AsN01 = 2 17.1.
CAS - 98-5:1-0.
UNll - UDX9AKS7GM (osuom1cin)

Pharmacopoeias. lnJJ"'.
OH Profile
HzN
-0- ~=O
OH
Asuo1nicin is on aminoglyeosidc antibacterial 1iroduccd t:r1 Mi-
CTOm<»IOSpora spp. and wid2 adions Md uses similar to thase of
gcntanticin (p.306). Ast1·omici12 sulf•te ru1:1 been giv.:n by inllll·
muscuLv injection or intrnveuous infu.ion. D.JMge should be ad-
NOTE. The code AS-101 has also been used fot an immunomod· justed ba5ed on serum-astromicin concentration monitoring.
ulator investigated as an antineoplns1ic and antiviral.
Preparations
Pharmacopoeias. lo US for \11.'lerinary use only.
USP 33 {Arsanoic Acid). A white lo oft:whitc crystalline pow- Proprietary P,-epuatiocu (details att' ,given in Volumt 8)
/pn: Fortimic'in.
der. Soluble i11 hot water, in amyl alcohol, and in solutions of al-
kali carbonates; slial•lly soluble in cold water, in nlcohol, and in
Apramycin Sulfate (nNNM} acetic acid; insoluble in aeetonc. in cblorofurm, i11 ether, in btn-
z.enc, and in d1lu1c mineral acids; sparingly soluble in coucenuat- Avilamycin /BAN. 'JWJ,lffl)
Apramydn s.Aphate (8ANM) ; Aflra"¥tt. S.Nte d': Apramycin1 ed minml acids. AVlamicina: Avilamyc.ine: Avt~ LY.048i~O (aVl~n
Sulfas; Apramyons.Jfat ApramysuniS\Jlfaau~ SuM'ato de apramici- or avUTly<in A}
na. Sodium Arsanilate (SANM, ffNNMJ AeHMM....uHH
Afl>aMMUMHa Cyllb'j>aT
Ars~n~ate oe Sociu."IX Arsanil'1to s6dico; Nalri! Ars>niLls: Sodi·
um Aminarsonat~ Sodun Aniiarsonatc. soo;....,., 4-arrinophe·
c.. HnCl20n (avil•inycin A) =I io-4.2.
CAS - f/051-71· r (ovilomycin); 69787-79-7 (oVIJOmycin
CuH., Ns0 11 .2';2H 2SO, = 781.8. n')'larsonate. A); 69787-80-0 (ovilomycin C).
CAS - 41J94 . J6-S. HaTP,,.;; ApcaHw1aT
c,H,AsNNaOJ "' 239.0.
UNJI - 8UYL6NAZ3Q. CAS - I 27-85 -5
Pharma.:opoelas. ln BP(Vel). Pharmacopoe ias. Fr. includes the anhydrous subslon« and
BP(Vet) 2010 (Aprunydn S<Aphate). The sulfa~ of an antibiot- die trihydnite.
ic produced by certiin strains of Srrep1om,t'Otl tenebrorius or by Profile
other means. Tbe polet>C)' is not k ss 1han 430unitspet1ng, cal- Arsanilic acid and sodium arsanilate arc used in \'eterinary m<.-d·
culated wi1h reference 10 the anhydrous substance. A light brown icine for the prophywis and treatment of enttric infections in
hygroscopic powder or granubr material. Freely soluble in wa- pi&> and also as growth•promoting agents.
ter; practieally insoluble in alcohol, in acetone, in ether, and in
methyl alcohol.

Profile Aspoxicillin (flNNJ

Apramycm is on aminoglycoside antibacterial used.,. the sulfate A$poxici! na: Aspoxidline; AspoxicilruTt TA-058. (2S.5R.6R)-6-
in veterinary pmctice fol' Uie treatment or su=ptiblc infections. {(2R}-2·((2R)·2·Amioo·3·(~propionamidc]-2·
(p-~)acetamido)-3.3·dmethyl-7-oxo-4-thia- l-
wbicydo(120]-heptanc-2-calboo<yk aod
/VJ)()KCl.fl~~

Arbekacin Sulfate (IN'IM) =

C 11HnN507S 493.5.
CAS - 63358-49-6 Profile
AS'<. (atbekacin): AHB-06K (arbelcacin): Arbekacin ~le: Ar· UNI/ - OH5KN026) A\·ilamycin 1s an aniioocterial that has been used in \'ttcrinary
belcac¥1e. Sulfate d': Arbekacri Sut!as: HABA.Dibekacf\ (ar· medicine as a IJ'Owth promoter.
bekacin): Sulfato de arbdcacina. o.·J-Amino·3·deoxy-n~·
copyranosy!·( I-t4)·0·[2.6-diamino-23.1.6-tetradeoxy·a·O·
eryJvo.he>«>war>osyl-( 1-.6))-N'·((25)-1-amm-2-l'lydrox-/bu·
tyryf}-2-<leoxy-L-streptamine sulphate. Avoparcin (llAN. IM/lt •MJ
Avoparci~a: AVCJPdr<ine: Avoparcinum: Compound 251.
Apf>e•aU""3 Cy""4>aT
Aaonaf>U"H
C22H, 1 N,0 10.xH1S04. CAS - 37132 -99-3.
CAS - S 1025-85-S (orbekocinj. Profile
Avopal'Cln is a glycopeiitide antibacterial usually produced by
J\TC - JOIG812. Amycoloropsis colorodensis (Srrepron9v:n condiclus). It has
ATC Vee - QJO IGS I 2. been incorporated into animal feedstuffs 10 promOle growth.
The symbol t denotes a preparation no longer actively markcied
224 Antibacterials
o There is evidence of cross·rcsis1a11cc between avopan:in and given or•lly as the sodium salt in the 1rca1men1 of ~uscep1ibl e (28%). In general, adverse effects were asoocialed with higher
vancomycin. 1 Suggestions thal vancomycin-resistanl O<ga11isms infections. TI1e polassiurn sail has also been used. serunMszitluomycio concentrations.
could enter the human population from the food cm in as a resull P reparations I. Brown BA. ~ al. Reluionship o( •dvc:rsc: cvenas 10 scrum drug
of the use of avoparcin as a growth promotor in animals?:; were levels 1n paaicnlS rcc:ti\•ing high~o1eazi1hromyein for mycobac-
disputed by the manufacturers of l\'Oparcin,•_, but such use has Pt"Oprietar"y Prcpa_rations (dc1alls are given i:n Volume R) terial lung dis.case. Clin lnf«t Dis 1997~ l-4: 9SB-64.
now been banned in many countries. A flcr a ban in lhe EU on the G•1.: Jnrtclolkllo Hf.
Effects on the ears. Re"crsible sensorineural he.ring loss was
use of •'wan::in as a growth promotor in animals thac ha• been reponed in 3 patients gi""n oral aziOvomycin 500 mg daily with
some evidcnce6-7 ofa deac&SC in the prevalence ofvancomycin· clofaziminc and ethambutol for the treatment of disscmillllled
rcsiSWlt c.iterococci in animal and hwnan flora but othaSIUdies
Azithromycin (BAN. USAN. tlNNJ Mycoboclerium m•um complex infection 1 lncvcrsible hearing
in various countriess.to have indoc:au:d considerable persislence loss has also been rqxirted after low-dose exposure tO oral azi..
of such organisms. AtWomysoni: Azltlvomycine: Azithromyc....-n: Az~ana tluomycin.13 A pa1ien1 who had had 8 days of trcaDDcnt with
I. ~l~t;:~;!'t.;cl:!~~~~~~·~u-2.c:r:.~;~~= AlitromionaJ; AzitromS:O: Azivomµ:ir.: ~: CP-
62993. XZ-'150. {2R.3S.4R.5R.8R.IOR.l IR.125.135.14R)-13-{2.6-
intravtnous azitluomycin SOO mg daily fot pneumonia n:portcd
complete deafness, which had resolved 20 days after stopping
biol L<:11 l99S; 125: l6S-72
2. Howarth F. Poulter 0. Vancomycin resis•a,-.c:e: time \o bon Dideoxy·3-C·3-0.d~>i;4·ci-t.·ribcrhex09yranosroxy)-2-~nyl· the drug.'
avoparcin? Lanett 1996; =44'7: 1047. 3.4.1O·Vihydroxy-3.5.6.8. tO. I 2. I 4·heptamethyl- I 1-(3.4.6·tride· See also Incidence of Adverse EffcQ5, above.
3. Wisc R. Avoparcin and anhnal fccd.11Uff. Lancet 1996; 347: oxy· 3-dimethylamino·ll-O·xy/o·hexopyranosytoxy)· I-oxa-6-aza· I. Wallace MR. el <JI. Olotoxicity wi1h uithl"Oll'l)'C1n. /..om:et 1994:
183S. 343: 24 1.
4. Mudd A. Vancomycin ~sistence nnd avopt~nin. Ltmc"t 1996; cydopcntadecan-1S-one dny<i'ate: 9-Deoxo·9a·=·9a·methyt· 2. ReM BO. Gross EM . lrrt'versible sensorincural heitrina los.s as a
347: 1412. 9a-homoerythromycin A dihyc!rate. resull of aiithromycin ototo)'.K:ity: a cast rc:porl Ann 010/ Rhi110/
5. Mudd AJ. Is it lime to ban •11 untibiotics a.s animal groW1h-pro- A3MTpo~MUl-tM , 1..t>1yngol 2000: 109: 435-7.
mo1ing agents? I.Ancel 1996i 348: I4S~S. 3. Mick P, Westtrbe:rg BO. SenSOfin.eur1I hearing Joss Ha probable
6. Pantosti A. e1 al. DecreaK or vancomycin-rcs11tant cntc-rococci CnH12N10 1z.2H:0 :: 785.0. serious adverse dru3 reSiction U50Ciated wi11l low-dosc oral ni·
in pouJtry meal afltr avoparcin ~n . Lo11ea 1999; 3S4: 741-2. CAS - 83905·01-5 (anhydrous :izirhromycin); 117772· lhromycin. J 010/oryngol 2001; 36: 257-63.
7. "'8TI den Bogaard AE, el ol. The: cf'r«I or binning a"'oparcin on 70-0 (azrthromycin d1hydra1~). 4. Bi1jak ED~ ~t ol. Jntravenous a:zithromycfo.inductd 0totoxici1y.
VRE carriage in The Nelhcrtands. J Anlimic""'b Chent01hu P/tarnroco,herap;11 1999; 19: lH--8.
2000; 46: t46-7. ATC - )OIFAIO: SOIAA16.
8. Manson Jf\.t_ e1 ol. Persistence or '~ncomyc-in·ruistant cntrro-- ATC Vet - QJOIFAIO: QSOIAA26. Effects on fluid and elec1701yte homoeostasis. The syn·
cocci in New Ze-~land broilers 1ner discontinuation of drome ofinappropriatc anlidiun:1ic hormone secretion was asscr
avoparcin US<. Appl En>"in>H /.t't<t'Obio/ 2004: 70: 5764-S. UNll - F9~0W58Y8V (owhromycm): )21<LZWUI M (on-
ciatcd wilh azithromycin ireaunent in a petienL t.l
9. Sorum M. 11 ol. Prevalence. persistence, and molecular cha:tac· ltydro.is oz11hromyc1n): )i£4MNNIMD (oz11hrom~in
lerization of glycopcptick-.rcs1s1an1 cntcrococci in NOT"llo·cgiat1: 1. Cadle RM. e1 ol. Symptomatic syndrome: or lntppropriatc anti·
monohydtote): 5f0 I 131175 (ozithromycm di~ydro1e) diuretic hormone sccretion associated " ·iih uhhromycin. Ann
poultry and poultry rarmers 3 10 8 years aflcr 1he ban on
avoparcin. Appl &vi11M Microblol 2006; 72: 5 16-21 . Phormaco1her 1997: 31: 1308-10.
10. Lim SK. ct nl. Pcn i~tence of vanA·t)'~ En1eroc:occus faecium 2. Kintz.cl PE. CorrcctiC'-n: symptomatic s~rome of inappropriate
in Kore.an livestock aftCT OOn on a..,oparcin. Mic.rob Drug R~isr antidiurctic hormone secre1ion associated with atit.hromycin.
2006; 12: 136-9. Ann Pharmocorher 1998: 32: 388.
Effects on the kidneys. Acute inlerstitial nephrilis leading 10
irreversible renal failure has been reported' in a p•lient who re-
Azidamfenicol (8AN. rlNN'J • ccivcd azilhromycin for 9 days. A later report2 described a pa·
tienl who developed recurrent acu1c in1emi1ial nephritis after
Azidamfeni<ot Azidamfenicolvm; Aziclamol>enicot Azidanleni- courses of azitluomycin. Repeated exposure n:sultcd in persist·
cot Azidoamp"ienicot &yer-52910. 2-hioo.N-[(.,R,~RH-hy­ cnt renol damage; lcucocylosis and eosinophilia were still
droxy-<1-hydroxymefyl·4·rVtrophenelhyl)3cet.'.Jmide. ~ent I year taier.
A3J.wl1"4ieHMKOA I. Mansoor GA. ~' al. Azi1htomy<:in·induced ~cu1e intcrsliti~I nt·
C11H11NsO; =
295.3. phri1i>.A•11 lmem Akd 1993; 119: 636-7.
2. Soni N. a ol. Recumnt acU\c in1crs1ilial nephruu induc~ by
CAS - 13838-08-9. IZJlhromycin. Paliorr Jnfttr DU J 2004, 2J: 96s-4.
ATC - SOIAA15.
ATC Vet - QSOIAA25. Hypersensitivity. A syndrome ch1rac1erised by eosinophilia.
UNll - 40257685UA. ar1hralgja, fever, and rash was associated with ujtluornycin or
roxitluornycin ueatment in a patient on sepuate occasions. 1 The
authors believed the condi1ion represented lhe Chorg..Suauss
syndrome, although this w:is disputed by olhtrs1 and anributed
Pharmacopoeias. In 01in. and JptL to !he eosinophilin-myalgia syndrome.
Eur. (seep.vii) includes 1he anhydrous fonn. A falal case of DRESS {drug rash wi1h cosinophilia and systemic
US includes lhc monohydrate and 1he dihydr•lc. symploms) syodrome and hypersensitivi1y myocarditis associat·
Ph. Eur. 6.8 (Azithromycin). A while or almost white powder. cd with azithromycin use has been rcported.l There h:is also been
Prac1ically insoluble in water; freely soluble in dehydrated alco- a report' of vanishing bile duel syndrome associuled wilh the use
hol and in dichloromcthane. A 0.2% solulion in a mixrun: ofmc· ofazitluomycin and developing• montl1 after inilial presentation
thyl alcohol and ''"•ICr ( I: I) h:is a pH of9.0 to 11.0. Store in air· - of Stevens-Johnson >yndromc; the p•liont t\'enlually required
light conllliners. liver transp!Mtation.
Profile USP 33 (A%ithrom)'clll). A while or abnost white powder. J>rac. 1. HUbner C. et al. MacroJM2e--induccd Churg·Str1uss syndrome m
Q patient with ~ topy. Lcnc.'t.t t997; JSO: S6l.
Azidamfcnicol is an antibaclcrial tbal is related suucturally to Jically insoluble in "-•ter; freely soluble in anhydrous alcohol
2. Krinke B. Ab<n:r w. Mocrolidc·inducecl Clwra·Sl,.u>S •rn-
chloramphcnicol (p.260). h has been used as 1% eye drops in the and in dichloromcthane. It is :tnhydrous or contains one or IWO drome in patient wilh 11opy. /..t>-r 1997; 350: I 55t-l.
trcaunent of bacterial eye infections. molecules of waler of hydration. pH of a 0.2°/e solution in a mix· ) . Pursnani A. ei al HypCTSCnsitivuy myocatditiJ auociatcd with
Preparations lure of methyl alcohol and water (l:J) is between 9.0 and 11.0. au\hromycm exposure.. •.fnn ltrtun M~tl 1009: 1SO: 22S-6.
Store i11 ai1tiah1 con1ainers. 4. Danica J. ~t ol. Vanishing bite duct S)ndrome auoci1ted with
Proprietary Preparation$ (Ool•ih arc &i"°" in -..,1~ B) nilhromycin in a 62·~ar.old man. 801lc Clir1 PAorwwcol Ton·
ez.: Optd--A.~: G•r.: ll<li<«ilt: f'bo<rmco.'t, Thi:x..doft: <ol 2010: 106: 62-~.
Gr_. rr.i'oc:oC Adverse Effect s and Precautions
Overdosage. Bradyeardia with complete heart block was
As for Erythromycin, p.293. reported' in a 9-month-old infant who had been iMdvertcntly
Gastrointestinal distuibances are the most frequent ad· given aboul 50 mg/kg of azilhromycin inlr3venoosly.
Azidocillin Sodium (eANM. rlNNM) verse effect of azithromyein but are usually mild and I. TUtlli JA. ~I {I/. Lifc.-threalening bt1dy1rrh)•lh1nia after musi\l'e
~.zid00enzy!peniciU1n Sodium: Azidod1na s6dica: Azidociline nzithromycin Ovetdosc. Phormm;o11t(Jrcpy2006; 26: 147-50.
less frequent than with erythromycin. Headache, som·
Sodqie; Natrii A2idotillinum. Sodium (6R)-6-(o-2-azido-2-pi>e- nolence, and taste disturbances may occur. Severe hy·
nylacetamido)penicillanate. Interactions
persensitivity reactions occur rarely but may be pro- for a discussion of drug interactions of macrolide anti·
HaTp1~ A3"1AOUH.VJ+f
longed. Th rombocytopenia and mi ld' transient
C,6H16N;Nao.s 397.4.
(i'.S -
=
! 7243-38·8 (ozidocillin): 35334- 12·4 (ozidocimn neutropenia have been rarely rep01ted in patients re·
bacterials, see Erythromycin, p.295.
Giving azithromycin with antacids containing alumin-
sodium). ceiving azithromycin. Pain and inflal)lmation may OC· ium or magnesiwn salts can reduce the rate, but not the
ATC - JOICE04. cur at the site of intravenous infusions particularly at
ATC Ve1 - QJO I C£04. extent, of its absorption; azitluomycin should be given
high concentrations. Azithromycin may aggravate
UN/I - OXPT6W6670. at least I hour before or 2 hours after the antacid.
muscle weakness in patients with myasthenia gravis
and new onset of myasthenic syndromes has been re- Antlretrovirals. Azithromycin scrum concen11111ionure mark·
edly in~d when it is gi¥Ct1 \\ilh ntljilJa\lfr, 1 but the clinieal
ported.

OJ
significanu ofthis is Ullcertain. US licensed proc!uct information
H H Licensed product information states that azithromycin for azithromycin states that dosage adjustment is not n:quited al·
should be used with caution in patients with hepatic or though lhe patient should be closely monitored for adverse ef-
, N
H : J! t S CH3 tects.
renal impairment. It should not be given to those with
N3 N_)<CH3 severe hepatic impairment as safety has not been estab· J. Amsden GW. et of. A study of 1he phannacokintlics C"lfntilhro-
m)'cin and neHinavir when coadministercd in ht311hy volunteers.
0 .. lishcd. Although plasma concentrations may be in· J CUu Pharmo~ol 2000; 40: 1522-7.
COOH creased in renal impairment dosage adjustment is not
usually required. Antimicrobial Action
As for Erythromycin, p.295. Azithromycin is less ac-
Incidence of adverse effects. In 39 patients given azilhromy-
Profile cin daily long-1em1 for inycobacterial infections,' g3.Slrointesti·
tive than erythromycin against ·streptococci and sta·
Azidocillin is a scrnisynthctic penicillin wi1h actM>ns and uses lllll disorder$ occuired in 32 (82"4.), hearing impairment in 10 phylococci, but has greater activity than erythromycin
similar lo those of phcno•ymdhylpcnicillin (p.341). 11 has been (26,.o), linnirus in 18 {46%). and poor balance or dizziness in 11 in vitro against some Gram-negative organisms such as
All cross-refettnus refer to entries in Volume A
 Azidamfen1coVAzithromycin 225
Haemoplti/us injluenzae and Moraxelfa cararrhalis I gfollowedby500mgdailymaybegiven,ot I gmay mild to modctltc l)'phoid caused by multidru:;·rc>i>1u111 s1rains in
(Bra11hamella calarrftalis), as well as having acti\'ity be given once a week for at least 3 weeks, until all le- !hose aged 6 months and over.
against some of the Enterobacteriaceae such as Es- sions have completely healed. US guidelines for the prevention and lrnlment of opportunistic
inlt'Clions among HN~d and Htv-infeeled children sug-
cherichia coli and Salmonella and Shigella spp. Azi- In the USA, a modified-release preparation given as an gest that for prophylaxis of disseminaled A~1'CQbaclerivnc al'ivm
thromycin is al.so more active than erythromycin oral suspension is available. The product delivers a sin· CClll1plcx infections, azidvomycin 20 mg.ol;g (lo a maximum or
against Chlamydia 1rachoma1is and Ureoplasma urea- gle 2-g dose and should also be taken on an empty 1.2 g) oocc weekly or S nig/lc& (to a maximum of250 mg) onc:c
~Jllicum, and some opportunistic mycobacteiia, includ- stomach. It is licensed for the treaunent of acute bacte- doily may be given. 1 For aeauncn~ to 10 12 mg/l;g (lo a ma.<i·
ing Mycobacterium ovium complex. Ji has activity mum of SOO mg) once daily should be given \vilh Olhernnthny-
rial sinusitis or community-acquired pneumonin in cobactcrials.'
against the protozoa Toxoplasma gondii and Plasmodi- adults. t. CDC. Guidelines ror 1hc J)f'c\'Cntion and 1rra1.rncnt of opponun-
um falciparum. For prophylaxis of disseminated MAC infections, az.i- i51lc infc«1ons among HIV-exposed 1nc:I HIV·inrcc1cd children:
rtcommcndMioa.s from COC. the N:utona.1 ln"itu•es of Health.
Resistance. TI1e pattern of resistance 10 azithromyein is similar thromycin 1.2 g may be given once weekly. For treat- the HJV Medkine Association or1hc Infectious Diseases Society
toth:lt seen with elaritbromycitl (p.271). ment or secondary prophylaxis, 500 to 600 mg (de- or Anlcrica. I.he Pediatric lnfcc1ious 01SClSCI Society, and 1ht
American Academy of P~diatrics. MMWR 2009; 5S (RR.-1 I):
pending on the fonnulation used) should be given once 1-166. Avaibblc a1 hllp:1/1idsilifO.nih.gov/conren1files!
Pharmacokinetics daily, with other antimyoobacterials. Pcdiuorie_Ol.pdr(1cc.:SKd 04/06110)
Azithromycin given orally is rapidly absorbed and For mild or moderate typhoid caused by multidrug- Babesiosis. Jn a proopective. randomised study' involving 58
about400/o bioavailablc. Absorption from capsules, but resistaiu strains, 500 mg once daily may be given for 7 patients with babesiosis (p.907), azithroniycin with atovaquonc
not tablets or suspension, is reduced by food. Peak days. was found to be as effective as, and associated with fewer ad·
plasma corn:entrations occur 2 to 3 hours after an oral vcnc cffe<:ts than, standard therapy with quinine a11d elindamy-
dose and 1 to 2 hours after intravenous dOIS3ge. How- For details of doses in children, see below. ein. Azitluomycin 500 to 1000 mg on day t followedby250 mg
Azithromycin dihydrat.e may also be given initially by once datly thereafter, with atovaquonc 7SO mg cwicc <1'1ily, bolh
ever, azithromycin is extensively distributed into the orally for 7 to I0 days, has been rcco1 nmcndcd by somccxpc1ts3
tissues, and tissue concentrations subsequently remain intravenous infusion to adu lts in doses equivalent to in lhc USA for the lreatment of babcsilllSiS. Jmmunocompro-
much higher than those in the blood; in contrast to most 500 mg of 37.ithromycin as a single daily dose in the mis~tl patients should be given higher doses or azithromycin
other antibacterials, pfasma concentrations are there- treatment of community-acquired pneumonia and pel- (600 to 1000 mg daily). Otildren may be given azithroonycin
fore of little value as a guide to efficacy. High concen- vic infla1mnatory disease; treatment should be changed 10 mg/kg (maximim 500 nig) on day I followed by Sm8/l(g
to the oral route after at least 2 days in pneumonia and (maximum 250 mg) once daily thereafter, with ato\•aql10ne
trations are taken up ~1to white blood cells. There is 20m~g(maximum 750 mg)l\,iccdaily.hoth orally for7to lO
little diffusion into the CSF when the meninges are not after I or 2 days in pelvic inflammatory disease. It may days. Azitlvomycin with quin~ was rcponcd to be clTcctive
inflamed. Data from animal studies indicate that az.i- be given either in a solution containing I mglmL over in 2J"'iclllS who had not responded to quinine plus elindamy-
thromycin crosses the placenta. Small amounts of azi- 3 J1ours or in a solution containing 2 mglmL over 1 cm. .
thromycin arc demethylated in the liver, and it is ex- hour. I. K1ause PJ, el al. Atov3quonc omd azilhromycin for the crc:itmcnt
of b1besiosio. N £ngfJ M•tf2000; 30: 1454-S.
creted in bile mainly as unchanged drug and some In the USA, azithromycin is avai lable as 1% eye drops 2. Abramowitz M. ed. Drugs/or f)'1rosftlc Fnf«tions. 2nd ed. New
inactive metabolites have also been detected. About for the topical treatment of conjunctivitis caused by Rochelle NY:~ Mediul Lcucr. 2010.
6% of an oral dose (repiesenting about·200/o of the susceptible strains ofbacteriA. J. Wormscr GP. ti ol. The clinicol :isscs.s1nent. 1rca1mcnt. 1nd pre-
vention of Lyme d'i.SC"uc, hum1n granulocy1ic anapJasmous. and
amount in the systemic circulation) is excreted in the ORcvicws. babcsiosis: ciinlc.al practice 1uKfclines by the lnfechous Oi$0'"'
urine. The tenninal elimination half-life is about 68 I. Pcurs OH. ct al. Azilhromycin.: a n:vit\\· of its antimicrobfal cs Socic:1y or America OiR hifrc1 Di.s 2006; 43: t089-1134.
3C1"'ity. pharm1c~kinccic properties and clin~1I efficacy. Dn1gs Also available 11: tutp:l/W¥o'Yojournals.uchica;o.cdu/doi/pdf/
hours. 1992; «: 750-99. tO. IOS6/S08667 (1cco.scd 12\lSlllS)
0 Reviews and references. 1. ~ngtry HO. Balfour JA. Azithromycin; • review or hs use in 4. Shaio MF. Vane KO. Ruponse ofbobe:s1osis 10 ~combined ttg·
iC'lt:n of ~uininc and azithromycin. Tru11s R Soe Trop Med H)"g
pacd11mc inrccl~s di~e:ise. Drug.f 199&: ~: 2'7 3-97.
I. L1lak NJ, Monis DL Azithromycin c:linical ph.armac:okioetics. 3. Qucy KW. Amsden GW. Intravenous n.ilhrom~i.n.. Ann PIUJr- 1997,91:114-lS.
C/in Pllom;ocoltim:t 1993; 25: 3-70'*"'4 . marorhu t999; 33: 218-23. S. Sluh C-M, Wang C-C. Ability of a1.1thromycin in combination
2. Luke OR, rt al. Safuy_ t<Jlcration. and phannacoldnctics ofintr11~ 4. lo.-nnidis JPA.ttol. Mcta-at1alysi11 orr1Momiudcontrolled eti- with quinine for the elimination of ba.b«:i•I infection in humans.
venous aiithromycin . •if111itnkrob Ag,1111 Chrmothcr 1996; 40: als on the comp.wativc cffi4;acy 1md nfety or azilhromycin AmJT>op~dHJ1, 1998;59: S09-12.
2577-81. 1$1'.!inSt Olhe:r antibM>liCS (Or up~r ceipirAl01)' lr3ct infeclic)ns.. J
3. Ripp RP. Phannacokinctics 1ttd pharmacodynamics or i:llr&\'e· Anrlml~rob Chemothu2001; 48: 677-89. Cholera. Azithromyein has been 1ric:d1·i in the ttealmcnl of
nous and oral azithromycin: ~need tissue ac1ivi1y 11nd mini- s. Contopou1os-Jo;:innldl.S DG.'a ul. MetOHanalysis or random1z.cd cholera (p.183). A sin2led06Cof 10 or20mg/kgwas f<iund to be
mal drv!; interactions. Ant• PIHtrm«:Ol~r 1998; 32: 785-93. controlled tri:ils on the compwative efficacy :lOd safety of Hi• effective in cl1ildrcn1Faild I gin adults.;
4. Chandra R, d ol. Clinic11I ph:irrnacotine1ics and gru1roinlcit1n1l 1hromycin a&ainsl other anobiocics for lower respiratnry tract l. Khan WA. ct ol Comperison of singlc·d0$C A)'.1lhrom~in ind
m!cn.hility of u nuvtl c:xu:ndcd~relc:asc microsphtre (orn111lotion infeel ions. J A111imiuob Chtl#Olher 2001; 48; 69 J-'703.
ll ~dosc, 3 ~day erythrom~in for c-hildh"od <:huleri: 111 nn-
of•zi1hromrdn. Clin Phormorokima 2007; •6: 241- $9. 6. Law C. Amsden OW. SinsJe--dose 3:iilhromycin fo1· rt:Spir.atory domi~d, double-blind trial Ltmcet 2002; 360: 17,:?-7.
tract infections. Amt Phor1noeo1/1tr 1004; 3S! 4J3-9.
7. Blum<t JL. Evolu1ion of a new dru& formulltion: the rutionalc 2. Ob:auach::uya MK, et ol. Anthn>m)Cin in 1ht trcs11ncnl ofchol·
Uses and Administration forhi;_h-dou. short..course ther:ipy wilh 1ti1hcomycin. lflf J A11· ua in children. Ar.in Pntdintr 2003; 91: 676-S
Azithromycin is a nitrogeo-containing macrolide (aza- timlcrobAs<mJ 2005: Z6 (suppl 3): SIO-St47. ). S:tha o. ,., ol. Sing.le-dose az.uhromytjn for the trealmcm of
8. Sw1ina.1on Hanison T. Ktam SJ. ALithromyicio cJl:tcndcd n:· cholera in adults. N E>:gl J M...12006; 354: 2452-<>2.
lide) with actions and uses similar to those of erythro- lea$t': 1 rcvie"¥.· or its use in 1h<: 're:ument of acute bacterial 1i·
nu~i1is and c·ommunity-acquirc:<I pneulTk)nia in tht US. Drug.,
Hyperplasia. For reference 10 the use of azithromycin to con-
mycin (p.296). It is given in the rreatment of respirato- 2007; 6 7: 773-92. trol ciclosporin-induccd gingival hypccplasia, sec: p.1983.
ry-tract infections (including otitis media), in skin and
soft-tissue infections, and in uncomplicated genital in- Q, :~:rfi~f~~i~1~1~ ~~i~=~-~~~~~~a3::~a~:: ~~~~~o~
1
lschaemic heart disease. Maerolidc antibacterials, including
fections. Azithromycin may also be used for the proph-
atic Rcview5; lswc L Chimrstcr: John Wiley; 2008 (1!C«$Sed °'
azithromycin,'_. clarithromycin,.S-9 and roxitluomyc1n, 1 1,. have
181%/0S). been in,·cs1i~1cd in the prevention of ischaemic bean disease,
ylaxis, and as a component of regimens in the treat- 10. Erra EE. Bukirw1 H. At.ithromycin for 1rcati11; tineomplicated b:ised on a SU!l8cstcd link between alherosclerosis and infection
typhoid ind p1ratyphoid Ccvu(cntcric fe,'Cr). Avail11bJc in The
ment, of Mycobacterium avium complex (MAC) COcMnc 01t:abasc of Systematic Rcvt<ws; ls.sue 4. Chichc.s1cr: -.i1h Clilomydophila p11e1m1011i« (Ch/011(1Yiia pneum<mioe) (sec
infections. It is used in some countries for the prophy- John Wiley: ZOOS (accessed 2Gt'08/09). p.11S). Although preliminary results from some pilot srudid
11. Zuckerman JM.~t al. Macrolidc5, keio1Hlr$.1nd glycylcyclinc5: were promising, longer-letm s.tudics in IMgc nur~lbcrs of pa.ticnl'S
laxis of endocarditis in at-risk patients unable to take nithromyein, cl~rithromycin, lclithroinycin.. tigeeycline. hrfttt were disappointing and none o( the tbrcc macrolides decn:ased
penicillin. It is also used in the management oftracho- Dis Cffo lionh Am 1009; 23: 997-1026. ischacmic events or provided clinical benefit; indeed, in one
ma and typhoid. Administration in children. Azithromycin is licensed for use study' an wicxpectcd increase in cardiovascular mOJ1alil)' was
in infants and children for the treatment of infections caused by seen in those takin11 clarithromydn.
For details of all these infections and their treatment, susceptible organisms. The usual oral dose in those over 6 I. Andcr!;Oll Jl. rl ol Randomized second:try prevention ui:tt of
see under Choice of Antibacterial, p.170. months ofage is 10 mgllcgonccdailyfor3 days, or an initial~ azi1hr1Jlt'lycin 111 p:nknts wilh coronary artery d1scuc )nd KT<l"-
Azithromycin has been tried in protozoa! infections of IO mg/kg onay be followed by 5 mg/kg daily for a furthct 4 logical evidence ror Oil3mydi:1 pneumoniae inftction: lht Azi-
1hromycin in Caronary Ancry Disease: Eli1r11n•tion or Myocar-
such as babesiosis (below), cryptosporidiosis (p.908), days; tho.. who weigh over 45 kg may be given the usual adult di1l ln(~c1ion wi1h Olbintydii{ACAOEM IC) ~udy. Clmilation
dose (sec Uses and Administration, above). A single dose or 1999;99: IS40-7.
and toxoplasmosis (p. 911 ). 30 fll&/kg may also be given for acute Olitis media. For pharyn· 2. Cercck B. cl al. E«w of sl'torMenn h't31n'ICnt with azilhron1y-
It is given orally or by intravenous infusion usually as gilis or to11silli1is in children aged over 2 years. 12 mg/kg once cin on rccurrem isc.htrtc:mlc C\·tntS In p:uifrus with acute coro-
na.ry syndrome in 1he At:ithtoen)cin in Acute Comntuy Syn..
the dih:r-drat.e; doses are expressed in terms ofthe anhy- daily for S da)'S may be given. Jn the USA. a modificd·releasc dronte (AZACS} 1ri~I : a raudo1n1Kd tontralltd trial. Lnrtttt
drous substance. Azithromycin dihydrate 524 mg is prcparatioo is available as an oral suspension; and may be used 2003;361: 809- 13.
in a single dose 0(60 mll/k& (maximum 2 g) for the 1rcatment or 3. O'Connor CM, e1 ul. Atithromyt:in foe &ht secondary prevcn·
equivalent to about 500 mg of anhydrous azithromy- communiry-~ui~ pneumonia among children 6 months of tion ofcoronary htan disease events.: the WlZARO study: o r&n·
cin. The capsule formulation should be given at least I age and older. domiud conuollcd orial. JAMA 2003; Z90: 14S9-66.
hour before, or 2 hours after, meals. ln the UK, lhe BNFC ](}()9 suggeslS that nilhromycm m~y be 4. GrayMon JT. tt al AzilJuoinycin for tJte K'COOCllry prevcntton
of coronary.,...,,.. N EngfJ Med 200S: 3Sl: 1637-4S.
The usual oral dose of azithromycin is 500 mg as a sin- used in penicillin allergic children for the prevention or second- s. Sini~,10 J, rt ol. Efftct or 3 1nonths or antinucro~a.I (fU\CICfl\
ary cases of g:roup A strep<ocoecal infection; those 6 months and "ilh clarithrornyc:in ia acute non-Q-W3\'C coronary syndrome.
gle dose daily for 3 days. Alternatively, an initial dose older may be given an oral dose of I2 ms/kg (to a maximum of Circulatio11 2002; t OS: I SSS 60.
of 500 mg may be followed by 250 mg daily for a fur- SOO mg)OflCc daily for S days. 6. Bc'l HF,~' al. Effea of darhhron1ycin on intlainmalOt')' martc-
ther 4 days. el$ m p:ltients with athuosclttOSis.. Cli11 Dingn Lob lm•mnol
For chronic Pseudomonas amJgino$a infection in cystic fibro- 2003; to: 525- &.
For uncompl icated genital infections caused by sis, d>e BNFC ](1()9 suggcsu that azithromycin may bo given 7. Berg HF. tt tJI. Trc:tuncn1 with cl11~hromycin prior to coronary
Chlamydia rrachomatis and for chancroid, I g of azi. weighingorally, 3 rimes a week. lo children from 6 Y"aIS or age. n oose arwy b)'l"'SS gran sur;cry does"°' prevent M>ti.cqucnt cardlOC
2S to 40 kg may be given 250 mg, while those weigh· events. Clin lnf«t Di1100S; 40: JS&-65.
thromycin is given as a single dose. A single dose of ing more than 40 kg may be given a doseofSOO llli· S. Berg HF, er ol. Efrect or clarithromytm lrtalment on Chloinydia
~!~r:~::~:;,,a;:~~~=~1:-~1~:d.l=::71~~·,~~i.1
1
2 g has been given for Wlcomplicated gononboea For The BNFC 1009al'° suggests giving az.ithromyan 10 mg/kg (to
the treatment of gmnulorua inguinale, an initial dose of a m.ximum ofSOO mg) once daily for 7 days in the IJcatlnent of Clin AlicrobioJ 200S: 43: 132S-9.

The symbol t denotes a preparation no longer actively marketed

246 Antibacterials
9. Jesper.:en CM, et ol. Randomi.s(d placebo controlled muhitcn- the plasma concentr•tion. Between 20 and 46% of azlociUin in
~7e ~:~a~~~5a~h~~!!~~ ~t~~:Cd':i~,f::. ':.~~"~~~i~\~~~ the circulation is bound to plasma proteins. The plasma half-life
is usually aboul l hour, but is longer in nconalcs; in pa1ients wilh
22-7. Conuaion. /b/d.: ISi.
10. Gurfinkc) E. et al. Tre1tmcnl with the antibiotic ro:iithromyein renal impairment half-lives of2 10 6 hows have been reported.
in patients wi1h acute n0on-Q..w1ve coronary syndr0mes: the fi-
nal r<:pon of Ille ROXIS Saudy. £11r Hcort J 1999; 20: 121- 7. Atlocillin is widely distributed in body tissues and nuids. lt
11 . WicsJj P, et al. Rox11hromycjn treatment preventspro,rcssion of crosses the placenta into the feal cireulition and small amounts
peripheral anerial occl1mve di.sou in Chlamydia pncumonl3c arc distribu1ed into breast milk. There is liale diffusion into the
scropositive men: a randomized, double-blind. placcbo-<:onuol- CSF except when lbe meninges arc inJlomcd.
led trial. Circulotwn 2002; IOS: 264~S2.
12. Zahn~ et ill. Antibiotic thcr1py after 1cu1c myocardial infarc- A2locillin is metabolised to a limited extent About SO to 70% of
t.ion: a prospective rindomizcd •udy. C1rnla1iott 2003: 101: a dose is excreted unchanged in the urine by gJomcrular filtration
1253-9. and tubular secretion within 24 hotn ofa dose, resuhing in high
ll. Sander D. tt ol. PrO"'Jession of earl) carotid athct0$Ctaosis is urinary conccntratioM. A21ocillin is partly excreted in the bile
only Lcmpor1nly reduced. a fter antibtocic trcatmCllt of Chlamy-
dia pncumoniacscroposftivi1y. C1'rculoti0tt2004; 109: 1010--IS. where i1 is also found in high concentrations.
I4. Kaehler J, 11 ol. A nndomiicd rri1I in patie:nts undergoing per- Plasma concentrations are enhanced ifprobcnecid is giveo.
culancous coronary 1n:.ioplasty: roxithromycin does not reduce
clinical re$lcno,is but angioplasty inc:.tca..cs antibody concen- A%locillin i<removed by haemodialysis.
lrations asainst Chlamydia pncumoniac. Am Ht(JrtJ2005; 150:
987-93. U ses and Administration ·
Mlocillin is a urcidopcnicillin and, like piperacillin (p.343), has
Malaria. Azithromycin has been srudicd1·' in die management
been used mainly for lhe trcatmenl of infections caused by Pseu-
of malaria. Srudies'·' have shown !hat an initial loading dose of
do171Qnas .o<iroginosa. It has been uSod particularly forsepticae-
750 mg of azithromycin on the first day followed by 250 mg dai- Azloclllin (BAN UWt rlNN)
ly !hereafter for 20 weeks was effective in 1he prophylaxis of mi'1, and infections oftherespirato.ry ond urinary tracts, and also
Atslosilliil10; Azlocihna: Aztocilline: Azlocillirum. 6-[N-{2-0xorn~ for peritonitis; fordet:Jilsofthcsc infccrions, seewiderOioiceof
Plasmrxfi11m vivar malaria; die drug was well tolerated and the Antibacterial, p.J 70.
most frequently reported adverse effects were heartburn, paracs- dazolidin-1-ylcarbony!}·o-phenyfgiycylamino)penicillanic acid
thcsia. and itching.' Asrudy$of1he ttcazmentofP. ,.;,...malaria ~ Azlocillin has genaally been used with an aminoglycoside;
found Iba! azithromycin l g daily for 3 days produced an 88%1
clinical response ra1e by day 7, but had a slower on.set of action
C20HnNso.s 161.5. = howe\'er, Ibey should be given separately as Ibey have been
shown to be incompatible (sec 1Jlcompa1ibility, above).
CAS - 37091-66-0.
than chloroquine 600 mg daily for 2 days 1hc:n 300 mg on day 3, ATC - )OICA09. A7JociUin has heeo gi'ml intravenously as the sodium salt Dos-
which produced a response of 99".4. ATC Vet - QJOICA09. es arc cxpr~ in terms of the equivalent amount of azlociUin;
Azilhromycin in various doses {typically SOO mg oue to lhrce UNll - HUM6HJ89WO. I.OS g of e:zlocillin soditim is oquivalent to about l g of azlocil-
times daily) with ()(her antimalarials, such as artesunate 200 mg
dailyl-1 or quinine l 0 mg/kg 3 times daily,'-1 given for 3days was
found to be effective in the trcaiment of wicomplicalcd multid-
rug-rcsistant P.falcipann11 malaria in Soulheast Asia. However,
a later study among 1lmzonian children• did not support lhe use
of azithromycin wilh rutesunatc to treal malaria or acute febrile
illness in children in areas of Africa with high levels of antima-
lariol drug resistance. ·
f\
HNVN'w"'N
II
0 0
II
60
· ~
HH
: :
NII VCH3
s
H_)-- N.._/ 'CH3
0 .
lin. A 10% solution in a suitllble diluent may be given by slow
injection for doses of2 g or less; higher d~ should be infused
011er20 to 30 minutes.
A typical dose is S g every 8 hows for life·lhreatening infections,
or 2 g every 8 hour.; for less severe infcc1ions and urinary-tract
infections.
for details ofdoses in children, see below.
Further studid are warranled, cspceially i11 children and prcg· I ,.,;::; COOH Dosage of azlocillin may need to be adjusted in patients wilh he-
nantwomen. patic or rcrial impairmenl (see below).
I. l'aylor WR. e.'
ol. M1lari1 prophylaxi1 us.ing azithromydn: a
Administration in children. Azlocillin has been used in ne-
double-blind, pblubo·conuollcd trial in Jrian Jaya.. Indonesi•.
C/in /nfect Dis 1999; 18: 74-81. Azlocillin Sodium (~tlNNMJ onates and children for the treatment ofinfections caused by sus-
2. Krudsood S. "al A midomaud dinial trial ofcombinations of ceptible org;anisms, given inrravenously in lhc following doses:
artesumu: and a:zithromycin for treatment or uncomplicated Azloo0na s6da; Azloci~ S<>dqJe: Az.k xalirun Natricum:
Plasmodiurn falc:iJ»Nm malaria 1n ThaJland. South~ A.sion J Azlocyina sodoNa; Bay-e-6905: Naw ~ Sod.nl • prematun: infants: 50 mg/leg twice daily
TropMcdl'Hblic HeolthllXIO; JI: 801-7. (6R}6-[o-2-(2~ l-<atboxamido)-2-phcnyta· • neonates less than 7 days old: l 00 mg/kg twice do.ily
3. Taylor WR.. et ol. Tolerabilily of uithromyc1n as malaria proph- cetamido]periollanate.
ylaxis in aduJu in Northcut Papua. Indonesia. Antlmicrob • infants between 7 days and l yeaz of age: JOO mg/kg 3 times
Ag~ts Chemolher 2003; 47: 1199-220>. · Hnp~,;,~ daily
4, Heppner DG. ct al. Randomiu:d, controlled, double--bJind trial of C10H21NsNa06S = 483.5. • chiklren up to 14 years of age: 7S mg/leg 3 times daily
d'ily oral azirhromycin in aduhs for the prophylaxis of Plasm~ CAS - 37091-65-9.
dium vivax malaria in Wc:slcm Thailand. Am J Trop Med If.vs Administration in hepatic or renal impalrme.nt. The in-
2005; 73: 842-9. ATC- JOICA09.
5. Dunne MW, ti ol. A doublc·blind, randomized study of azithro- ATC Vet - QJOICA09. terval between doses of intravenous azlocillin may need lo be
mycin compared to chloroquine for lht ttc~tment of Plasmodium UNI/ - 0WV I E.FW947. increased to every 12 hours in modcnuc to severe renal impair-
vivax mabri:! in India.Am) Trop Med Jfyg 2005; 73; 1108-1 1. 1nent (crealinine clear.mce less lban 30 mUminule); addilional
Pham>acopoeias. In Pol. dooagc reductions may be needed in patients with both severe
6. Miller RS, et al. Efftetivc 1ru1mcn1 of uncomplicated Plasmodi-
um falciparuin malaria with uilhromycin-<juininccombinations: Incompatibility. AzlociUi11 sodium has been reported to be in- renal and hepatic impainncnt.
a randomized, dosc-rangini saudy. Am J Trop Mtd Hyg 2006; 74: compatible with aminoglycosides, ciprolloxacin, metroniduolt,
401-6. Preparations
7. :\oedl H. tt ol. Azil.hromydn combin:n1on lherapy with 2.ncsu- ond tetracyclines.
nale or quinine for the rrulmcn.t of uncomr-licated Plasmodjum Proprietary Prepantions (details 111e given in Volume B)
Adverse Efrects and P recautions
f1kiparum malaria in aduhs: 1 ran6omiz~. phase 2 clinical trial G<.: Ab.-odil
in Thailand. Clln /nf«I Dis 2006; 43: 1264-71. As for Carbenicillin Sodium, p.235.
8. Sykes A.~ al. Azith,omyc1n plu.s anauntlc wr$U$ artcmcthcr· Prolongation of bleeding time has been less frequcnt md less sc-
tumefantrioe (or tTCatrneft\ or uncocnphuiled malaria in T1nza· vete wilh azlocillin !hon with carbcnicillin.
nian children: a nndomiad, controlled I.rial. Clin lttfec.t DU
2009; 49: 119S-1201. Hyf>!>uriaemia. Rcpons of transient asymptomatic decreases Aztreonam (SAN. USAN. rlf\NJ
in scrun1-1..ic acid concentrations damng treatment with azlocil-
Respiratory disorders. For reference to the use ofazilhromy- lin.1.l Atstrconaamc AzthreoMm; Aztreotiam. Aztreonamum; SQ.
cin in the management of respiratory disordczs, sec under Eryth- 26n6. (Z)-2-(2-Arrinothia-Lol-4-yl-((2S,JS)-2-methyl-+oxo-1-
l. Faris HM, Potts OW. Ailocillin and $erum uric add. Ann "''trn
romycin, p.297. Med 198;; 98: 414. sulphoazetidin-3-ylc~rt>amoyl)meth)'leneamin<>0xy}-2-methyt­
Preparations 2. Em:.,r JA , Sy ER. Em~.c1ora~lociltin on uric add levels io scrum. p<opionic acid.
AntimlcrobAg111ts Clt1rmo1hur 1983; 24: 609-10 .
USP 33: A>.ithr(lmy<on C";il»IJ!e.: Azithromycn for In~ Azithromycn AlTpeOHaM
Tablets. Sodium content. Each g of azlocillin sodium contains about
2.1 mmol of sodium. As a2'.locillin sodium has a lower sodium C1)H11NsOaS2 = 435.4.
Proprietary Preparations (dca•ils arc given in Volume B)
Arg.: Ar?omicin: J>.zibictc; Azitt&I: Azi\rovlt. A2rtrolart .~ Azitrox. content than carbenicillin sodium, hypematraemia and hypoka· CAS - 78110-38-0.
CoW<im: Clws<>g; Cronopcn: Doyle: F•br.m:CiN: Fnivest Maci"om:ix: l•e•nia arc less likely to occur.
l'lo!.At&: Na>oocno: Neb'lc; Nifoslrr< N<M>Z~IOll Oot>o!ic: 5'.rox; Told'o· ATC-JOIDFOI .
Interactions
:;a.=:~~~~t.~~~ ks for Bcnzylpenicillin, p.232.
ATC Vet - QJOIOFOI.
UNll - G2B4VE5GH8.
~~::%~~~~=
i; l!ioDtromj;Cird&t Ems~ Moc /&Jr.~ -
Sdm.x: Se-
Antibacterials. For the elf~t of a:zlocillin on the ckarancc of
ajOtaxi,.,,,, and a repon of neurOloxicity, see p.247. For refct·
....... ~ SiltromOYt: Tnazit. Tromx T""'""'1: ZOn.x: ~ encc to azlocillin affecting the disposition of cipl'Oj/o.Tnt:tn, see
ZRit, Zcrom.x: ~ Zuonea c-.: Z-Pokf; Zit1n:>max: a.a.: p.267.
~ore Abz::r; Aziml: Azi:torrc ~ Trtx Zitm>ma>< Cz.: A2iDot;
"2itic>: ~ Zeumx: Zltrccrc Ot11m.: z.,.,.,._ Fin.; Zithromax Neuromuxular blockers. Azlocillin and othtt urcick>penicil·
Fr"~ N:ft<=<: Zit~ Ger.: AzitMxAzillYobcU: Azy\cr: Utre- !ins arc reported to prolong the action of competitive muscle rc-
Ott Zithromi:w; Gr.~ Azibic1ron; A:ir..-m: Azirox: Azin.itec: Azi'thr.11:
laxanls .such u 1""'11ronium (see Atracamwn, p.2067).
~,.,~~'"t:;~~~ly!~r;:::~fu Antimicrobial A ction
Zithro·Ouc: ZillY'obe<t: Z'lhro'Tll><: Zitlv'on«I: Zltlrcpon: Zitlr<ljllJs: z;.
ti'rotel: Zilllroxyn: Zrtrax: Zyramyc;n: Honi Kong: ZMromax; Zotax: Azlocillin has M antimicrobial aclion similar to th~I ofpiperacil-
Hung.: Ali: AW<ot Azioot 5'.lm>mtd: Zittocin< Zmax lnd;o: A<ee: Azj. lin (p.343). 11s activity;,, vitro against Enterobacteriaceae is gen-
b.>tt Azifa.t A<Mf•t Aziwolc ZMrocn; Zyc.n lndonc Anrin: Bino<)'t Me· erally less than that of met.locillin or piper•cillin, bul ii has com·
mm; Zarom. Zbomax: z;ct.o: Zdfl: ZS!lc ZllhrQ<'rla>C: Z)<:<>: lrl.: A2To· parable activity lo pipcracillin agains1 Pse11domonas oe111gl11oso.
n\ixt, Zithromax; Israel: .A.lenil: Zeto; Zithrotna><; Ital.: Azttrocin:
R;bwe>< Tm2odna: ZiVoma>< Moloy•io: ZJWomix Zmax Mex.: Amsa· Pharmacokinetics Pharmacopoeias. In Jp11 and US, which allows lhe anhydrous
tot Atoxilom; AziQoc Azidrat Aziplw: Azrte',&: AWocin: Azittohexolt: Azlocillin is not absorbed from lhe gastrointestinal JTact to any or hydrated forms. •
A.-o.Max Ci>oryn: K~ Mocrozit: Mar?NJC: Medoti: SO!o.-i: Te>Os; Tr<>
mUla: Truoca: Zerufn: Z1llv>n: Zitrolrelt Nella" N.odws;AzWf:Az)'ter: siaoificant C);tent. It has nonlinear dose.dcpendenl pharmt1COki· USP 33 (Aztreonam). A while, odour1ess crys.talline powder.
~rot: l'lx>n: ZMroma>c: Norw.: Azl!/'Cm&X: NZ: Zi".hrcma>< nerics. DoublinQatl intravenous dose results in more than double 'kry sliglttly soluble in dehydrated alcohol; pnictically insoluble
All cross-references refer to entries in Volume A
 Azlocillin/Aztreonarn 227
in chlorofonn. in ethyl ac>:tatt, and in toluene; solubl• on d1m•th· though UK liconud product mforma1ion recommends tha1 Aztreonam is removed by haemodialysis and to a less·
ylfonnamidc and in d1melhyt sulfoxide; slightly soluble in me- mothers should refroin from breast feeding while reoCl\ing a:are- er extent by peritoneal dialysis.
thyl alcohol. Store in ain~ coniainers. onam.
Small but variable amounts are absorbed after inhala-
I. flc1ss rM. fl <1/, .i\.ttrcona."TI in human scru1n ond hrc:at.t milk. Br
J C/In Plu,mnuc:tJ/ 1935; 1': 509-11. tion ofnebulised aztreonam lysine; about 100/o of the
Aztreonam Lysine (8MV-t US4.'t tlNNM) dose is reported to be excreted in urine, largely as un-
:?. Ain-trican Academy of Pediauics The transrcr o( drugs 3nd olh-
Altrcorwn lisina: Aztr.!onam lysine: Aztreonamum L)"inum: ct chemicals into hum11n milk P~diorrlcJ 2001: 108: 776-89. changed drug.
Co,.us· I020. (Z}2-{2-Aminothiazol·~ -y4-j(2S.3S)-2-mcthyi-1· (Rrhrcd May 2010] CmrcC'tion. rbitl. ~ 1029. Also &\•ailublc ai:
hn p://aa ppo I;cy. nap pub Iic al i On$.ori~c g i /conlc n tlfu 11/ 0 Reviews.
oxo-1-sulfoue'.idin- 3-ylca1bamoyl]1Tietilyleno...anil<>oxy}·2·
pcdialrics%3bt08131776 lac«:IS<-d 2SIO~I04) I. Mani~ H. Clinical ph1rm1cokiM1i~ of azlrtonam: on upd3tc
meth).1prnp1DrOC a:d l~ine. Ctm Phor••m-oki11.i 1994; 26: 99-106.
AnpeoHaM• /\Juo1H Hypersensitivity. A:nreonnm is said 10 show lntle cross-re•c· 2. Vinti AA . ti al. Ph11rmacokinclics of ll'lrtonam in hcahhy suf>..
livity "'ilh other bet> lac!Jlms, 1·l bul 1here ba'-e been isolaled re- jects and pauc:nlS '-'dlh cystic fibrosis and a-atu~ticm of dosc·cx-
CnH 11 N~0 6S7 .C4H , ,Nl0~ = 581.6. ports of immediate h)JlCrscllSitivily to aztrconarn in patients witb po-surt relationships using Monte Carin simulllion. A111imicrob
CAS- 877611.~9-4. a his1ory ofhyperscnsiti•ily to penicillin.•J Age1111CIH!-hu2007; 51: 3049-SS.
ATC-)OIDFOI. I. Saxon A. et of. Lacie or <Toss..rcactivit)' bctwee.n ttLrcocum~ a
ATC Vet - QJOIDFO:. ino11obac111m antibiotic. and pcnicillin in pc:nlcillin-..allergjc sub· Uses and Administration
UNI/ - XNM7LT65NP.
jcct•. J l'lf<et Dis 19S•: 10: 16- 22. Aztreonam is a monobactam or monocyc\ic beta-
2. Adkinson NF. lmmunogcnicity tnd ~-allcrge ni city o( 111tt.re.. lactam antibacterial used parcnterally for die treaunent
Incompatibility and stability. Allreonam has been reported onom. AmJ ,'>f<d 1990; 88 (suppl JC): 12S-lSS.
3. Pauiar~ Ci. ~t nf. Tolc:r:sbili1y o(az&rconam in ~tjcnls wi1h lg£..
of infections caused by susceptible Gram-negative aer-
lo be incompatibl• with cefradine, melronidazolo, na(cilhn, and
vancomycin. med:ioited hyp«1ensitivity to bct;:,•b.etams.. Int J lmmu1wpotlKJI obic organisms. These have included bone and joint in-
Ploormncol 2008. 21: 373-9. fections, gonorrhoea, intra-abdominal and pelvic in·
References. 4. Ah·~rez. JS. o ol. Immediate hypc1'$Cnsith ity 10 ntreon~m. Lt:m-
l990; »S: 1094.
fections, lower respiratory-tract inf~tions (including
I. Bell RG. et ol. Stabihly of 1nuavenous :.tdmi:inu~s of aztrcor13m C<lt
and ccfoxitin. gcntamicin. mcll'Onidai.olc. or lObnin1ycin. A• J 5. Hant~nn P, ct al. Immediate hyper~en sit1v;ty 10 azucona1n and
pseudomonal infections in patients with cystic fibro-
Ho1p Pllonn J9S6; 43: 14«-Sl. imipc11~m. BAU 1991: lOl: 294-S. sis), meningitis, septicaemia, skin and soft-tissue infec-
1. Rile) CM. Lipford LC. lntcrachoo of atuconam wi1h nafcillin in tions, and urinary-tract infections. For details of these
intravenous admi;durcs.. Am J Hosp Phor,., 1986~ 43: 2221-C.
J. B<llivcau PP~ et al. S1abiti1y of »Zlrconam and 3nlpicillii1 sodi· Interactions infections and their treatmcnl, see under Choice of An-
um·JUlbxum $odium in 0.9"'. sodium chloride injec1ion. Am J Caution is recommended in patients receiving aztrcoo. tibacterial, p.170. To broaden the spectrum of activity
Hosp Pile"" 1994; 51: 901-4. . am and oral anticoagulants because ofthe possibility of for empirical treatmentofinfections, aztreonam should
4. Triss.:11.A, M.artinczJF. Comp:uibilityof mrcona"1 with sclecc .. be used with other antibacterials. Use with an
ed drugs d'l.lting s1muhucd Y-:Sitc adminis&.ra11on. A"' J H~ttlth­ increased prolhrombin time.
Syst Pharm 1995: 52: 1086-90. aminoglyeosidc may be of benefi t in serious Pseu·
5. Tri,;~I tA, ~' ,,1 C'"nmp.1tibjlfty and ~1abili1y of a7Jreonam and
.Antimicrobial Action domonas aeruginosa infections.
vancomycin hydrodtloridt:. A111 J Heolllt·SJ'lt Phnrtrt 1995: 52:
216()...4. Aztrconam is bactericidal and acts similarly to the pen- Aztrconam is usually given parenterally by deep intra-
icillins by inhibiting synthesis of the bacterial cell wall; muscular injection, by slow intravenous injection over
Adv~rse Effects it has a high affinity for the penicillin-binding protein 3 3 to 5 minutes, or by intravenous infusion over 20 to 60
The advetSe effects ofaztrconam are similar to those of (PBP-3) of.Gram-negative bacteria. The adivity of az- minutes. Single doses over I g should be given by the
other beia lactams (see Bcnzylpenicillin, p.23 l, and treonam is restricted 10 Gram-negative aerobic organ- intravenous route. It is given in doses ranging from I to
Cefalotin, p.238). Hypersensitivity reactions, includ· isms, including bcta-lactamase-producing strains, with 8 gdaily (usually 3 to4 gdaily). in divided doses every
ing rashes, wticaria, angioedema, exfoliative dermati- poor or no activity against Gram-positive aerobes or 6 to 12 hours, according to the severity of the infection.
tis, eosinophilia, bronchospasm, and rarely anaphylax- anaerobic org3nisms. It is active against most Entero- Foe infections due to Ps. ae111ginosa, 2 g every 6 or 8
is and 1oxic epidermal necrolysis, may occur in patients bacteriaceae including Escherichia coli, Kle/Jsiella, hours may be given for initial treatment.
receiving aztreonam, although it has been reported to Proteus, Prol'idencia, Salmonella, Sl!ITatia, Shigella, A single intramuscular dose of I g bas been recom-
be only weakly immunogeuic. Gastrointestinal effects and l'ersinia spp. Some strains of E11terobaczer and mended for the treatment of gonOIThoea or cystitis.
include diarrhoea, nausea, vomiting, mouth ulcer, and Citrobacter spp. are resistant. Aitreonam has some ac- The dose of azireonam may need to be reduced in renal
an abnonnal taste. tivity against Pseudomonas aeruginosa, although most impainnent, see below.
Phlebitis or thrombophlebitis has been reported after strains of other Pseudomonas spp. are insensitive. .f\z- For de!ails of doses in children, see below.
the intravenous use of aztreonain, and pain or swelling treonam has good activity against Haemophilus infl11- Aztrconam lysine may be given by inhalation foe the
after intramuscular injection. er.zae and Neisse1·ia spp. suppression of chronic respiratory-tract infections due
Use ofa2:1re0nam may result in the overgrowth of non- Synergy has been repo11ed in vitro between aztreonam to Ps. aemginasa in patients with cystic fibrosis. The
susccplible organisms, including Gram-positive cocci. and aminoglycosides _!lgainst Ps. ooruginosa and some usual dose, expressed in terms of aztreonam, is 75 mg
Pseudomembranous colitis or gastrointestinal bleeding Enterobacreriaceae. given 3 times within a 24 hour period for 28 days; dos·
may develop. A:ztreonam is stable to hydrolysis by many bela-lacta- es should be taken at least 4 hours apart. Patients
should use a bronchodilator before each dose. If addi·
Other adverse effects that have been reported wid1 az. mases and appears to be a poor inducec of beta-lacla· tional courses arc required, a minimum of28 days be-
treonarn include jaundice and hepatitis, increases in masc production. Acquired resisiance has occasionally tween courses is recommended.
liver enzymes, and prolongation of prothrombin and been reported.
0 General references.
pa1tial thromboplastin times. t. 81'o&dcn HN, lled RC. A?1rcontm . ~ rcvic" nr ib 111\lbac:ttrial
Pharmacokinetics ac\iYil)', ph~rmacokinet.ic ptOpC-rhts and thero~u1ic use. Drugs
Cough, wheezing, nasal rongestion, feller, and occa- Aztroonam is poorly absorbed from die gastrointesti- 1986, JI: 96- JJO.
sional repons of bronchospasm have been associated nal tract and is therefore given parenterally. Absorption 2. Ntu HC. ed. Aztreonam '$role 1n the 1":1tmCJ1t o(Gr;1m-neµli\'C
with inhalation of 321rconam lysine. 1nrcc1ions.Am J Med 1990; GB (1uppl 3C)< l5-4JS.
after intramuscular injection is good; peak plasma con- J. Hcllingu WC. Bn:wer NS. Car~apentms and monobactams: ime
Effects on the skin. Rcfcronccs. centrations of about 46 micrograms/mL have occurred 1pc-ntnt. mtropencm, and 1tlrconum. Mayo Cli11 Pmt' 1999: 74:
420-34.
I. McDonald BJ, t.I ol. To.x1c epidermal nccrolysis possibly lmked within I hour of a I·g dose. Aztreonam bas a plasma
to ~01tnnl in bone: 1n1nuw 1nu~ph1nt p~llitnts. Am, Plwrmo-- Administntion. Refercnt<!s 10 the use of wreonam (•• oztrc·
<Olh<r 1992: 26: 34 s.
half: life of about 1.7 hours. The half-life may be pro· onam tysi11e) by inhalation in 1he treatment o( noway infeel ions
2. Gonzalo-Garijo MA. de Arg.ila D. Eryth1odc111M due to •z.t.1-.:on-
longed in neonates. in the elderly, in patients with renal in patients \\iOi c)'$1ic (1brosis. 1·•
am and clindamy<in. J /m·esltg Al/ago/ CUn /11m11mol 2006: 16: impairment, and 10 some extent in those with hepatic I. Gib,<('111 RL, ct al. MKrobio~. safc1y1 ond pJ1n11Tutcolinctics of
210-1 nl~om1m lysin:itc for jnhalJtion in palir:nci with cyscie: fibrosis.
impainnenl. A:z:trconam is about 56% bound lo plasma Ptdi<m· P1dmo11011006: 'I : 6$6-6S.
proteins.his widely distributed in body tissues and flu- ? . R~l~ch-Hug.unGZ. ~' nl. A phuc 2 stY<!y oraureomnn lys:inefor
Precautions ids. including bi le. Diffusion into the CSF is poor un- mhal31ion to tn:oil p:Hicnts wtlh cystic fibrQ.$i-S ilnd PscudCMnonu
Aztreonam should not be given to patients who are hy· nrus,inosa inltclinn. P#dltttr Pt.tlUlono/ 2008; 43: 47-58.
less the meninges are inOamed. It crosses 1he placenta l . McCoy .:.s. "ol. lnhak-d n1reon11m fy$.ln:: for chronic airv.1ay
persensitive to it and should be used.with caution in and enters the felal circulation; small amounts are dis- Psc-udohlOClas 11cruginosa iri cyStit fibros~. A1n J R.~!lpi1 Crit
lhose known to be hyperscnsi1ive to other beta laciams, Corr .Ved2008: 178: 92 l-S.
tributed into breast milk. 4. Reto;ch-Bopn CiZ. ~I ol. Efficacy and safety of inhaled :nlrcooe
although the incidence of cross-sensitivity appears to a1n lysine'°" airway pSC"udomon&S in c)'Jliic: rlbrosi> CM.:12009:
be low (but see below). Aztreonam is not extensively metabolised. The princi- 135: I223- l2.
pal metabolite, SQ-26992, is inactive and is formed by S. Elbom JS. Henig NR. Op1im3I 3irway a;uim1crobial 1herapy for
A:ztreonam should be used with caulion in patients opening of the beia-lactam ring; it has a much longer C)'SliC fibrosis: the rote of lohalcd az1rcona1n lysine. Expert Opin
with renal or hepatic impainnenL Phm·mnco1he,· ?010; II: 1313-sS.
half-life than die pareut rompound. Aztreonam is ex- 6. O'Sullivan BP, el al. lnhaJcd Ulte011am, /\'(If Rt-'' Drlff, D;sco.,
creted mainly in the urine, by renal tubular secretion 2010: 9: 3S7-~. ·
Breast feeding. !n a study in 12 heallhy women given aztrcon·
a1n, peak concentrations in btcasl milk were found to be less ihan and glomerular filtration; about 60 to 70% of a dose Administration in children. Azlr<onam may be gi•en to nc·
1%ofthoseinscrum and ibis wnsconsidercdsual!tStivcofa low appears within 8 hours as unchanged drug with only onates and children for Oic 1ZU11ncn1 ofinfeclions caused by sus-
risk of adYcrsc effects in breast-fed infants. rThc American c.cptiblc Gram-negative norobic organisms including Pst!u·
Academy of Pcdia1ncs slalcs that no adverse offcccs have been
small quantities of metabolites. Only small amounts of domonas oe-ugf1t0.ro, / locmuphi/us influenz<Ht, a11d Neissorfu
seen in breast-fed infants whose mothers received 11.!rCOnam and uuchanged drug and metabolites are excreted in the mmi11gi1tdu. his usually.given parentcraUy by clocp intra1nuscu-
considers it 10 be u$Ually compatible wi1h breast (oeding,? al- faeces. lar in_rection, by slow intravenous injoaiun uvcr 3 to 5 minutes,
The symbol t denotes a preparation llO longer oc1ively marketed
228 Antibacterials
or by inttavenous infusion over 20 to 60 minutes. Single doses white, hygroscopic, powder. Soluble in w•lcr and in dichlo· and in methyl olcoho~ the solution in the org31lie solvents usually
over I g should be given by the in1ravenous route. romethane; freely soluble io alcohol and in chloroform; very showing some insoluble residue; insoluble in acetone, in chloro-
UK. licensed product infonnation recommends that azireonam be slightly soluble in ether. pH of a 2% solution in water is between fonn, and in ether. Its solutions deteriorate rapidly at room tem-
gh'cn in the following doses: 3.0 and 4.S. Store in ainight containers. pcrature. ll is precipitated from its solutions and is inactivarcd by
• infants older than one week and children less thon 2 years of sails of many of the heavy metals. pH ofa solution in water con-
Adve rse Effects and Precautions ta.ining J0 000 units/mL is between 5.S and 7.5. Store in ainigbt
age: 30 mg/kg every 6 or g hours As for Asnpicrllin, p.221. Dianhoca has been n:poncd to occur
contai11C1S at a ternperaturcofs• 10 JS0 •
• children2to 12ycars:30 mglkgevery6or8hoorswbichmay less ftequently with bacampicillin.
be increased to 50 mg/kaevery 6or Shows inscvcieinfection
(to a ma.'timum total daily dOL<e of8 g)
In teractions Ba citra.cin Zinc ~'Al. tf'INM)
As for Bcnzylpcnocillin. p.232-
Although not lice.nsed in the UK for neon:i.tes less than one week Baa'non 2ine<natj komple>c; &c~ me: Bacitracir><inl
old,lheBNFC 20/0IJ/ su1l8"51sadoseof30 mg/kg given inllll· Antim icrobial Actio n Baotraonc Zincique: Bacivacine-zinc; 8aotracino en«> ~e­
venously every 12 hours. Bacampicillin has the antimictobial action of ampicillin in vi1IO lcsas; llacitracins Zinc Co.-nplex 8aatl"llcirun Zonoa.cn; Bacitrac-
In the USA. the American Acadctny of Pediatrics' suggesis the (p.221). It possesses no intrinsic activity and ncccls to be hydro-
ziOOJm: Bacytracyna cynl<owa; Sinld<ibisrtrasiin< Zinc Bad·
11'1\.1'1'1
following doses for anreonam: lysed to ampicillin.
traCtn: Zinci Bacitracinum: Zinkbacitracin.
• all neonates weighing less than 1.2 kg and those less than I Pharmacokinetics U,,H<a OaU>1Tp3U11H
week old and weighing 1.2 to 2 kg: 30 mg/kg every 12 hours Bacampicillin is more rapidly and completely aboorbcd from the
CAS - 1405-89-6.
• neonates less thon I week old ond weighing more than 2 kg gas1roin1cstinal tn1Ct than ampicillin, to which it is hydrolysed in
ATC - D06AX05; JOIXX IO; R02A804 .
and those I week of age or older and weighing J.2 to 2 kg: the intestinal wall and plasma. Peak plasma-ampicillin conccn·
trations occur about 30 to 60 minutes alter oral doses, and are ATC Vet - QA07AA93; QD06AX05; QJOIXXIO;
30 mg/kg C\•ery 8 hours QR02A604.
• neonates I wcckofascorolderand weig)lingmorcthan 2 kg: about 2 to 3 times those after an equivalent dose of ampicillin.
UNll - 89Y4M134ES.
The absorption ofbacampicillin from tablets does not appear to
30 mg/kg every 6 hours Pharmacopoeias. In Ew: (seep.vii), /nt.. and US.
be affected by the presence of food in the stomach. About 7S%
• children I montl1 and older; 90 mg/kg in 3 divided doses (lo a of a dose is excreted in the w'ine as ampicillin within 8 hours. Ph. Eur. 6.8 (Bacitracin Zinc). The zinc complex of bacitracin.
maximum daily dose of3 g) for mild to moderate infections,
or 90 to 120 mg/kg in 3 or 4 divided doses (to a maximum U ses and Administratio n
n1e pot<ncy is not less than 60 units/mg. calculated ,.;th refer·
encc to the dried substance. A white or ligllt-yellowish·gsey hy-
daily dose of 8 g) in severe inf~1ions Bacampicillin has actions and uses similar to those of ompicillin gioscopic powder. Slightly soluble in water and in alcohol The
lo the USA, aztreonam lysine is hceoscd for use by inhalation for (p.222) to which it is rapidly h)-drolysed in the body. It is given filtrate of a saturated sollllion has a pH of6.0101.5. Store in air-
the suppression ofchronic rcspiratory-uact infections due to Ps. orally as the hydrochloride for the treatment of infections caused
tight containers.
oeruginosa in ehttdren aged 7 ycan and older with cystic fibro- by SllSCCpllble bacteria in doses of0.8 to 2.4 g daily, in 2 divided US P 33 (Bacilr.lcin Zinc:). The zinc complex ofb<acitracin, which
sis; doses are as for adult$ (see above). doses. For details ofdoses in childrm, sec below.
consi~ of a mi~tun: of antimicrobial polypeplides, the main
1. America~ Academy of P~diairics. 2009 Rrd Boole R~port ofthr In uncomplicated gonorrtioca a single dose ofbacampicillin hy· components being bacitracins A., BI , B2, and BJ. It has a potcn·
ComJNiuu Olf l11/utfo111 Distosu. 28th ed. Elk Grove Village. drochloride 1.6 s with probeoccid I g may be given in orcas ey of not Jess than 65 units/mg. calculated with rcf=:icc to the
Jllinois, USA: American Academy or Pediatrics. 2009. where gouococci remain sensitive. dried substance. lt contains not Jess than 4% and not more than
Administration in renal impairment. Intravenous doses of Administration in children. In children, bacampicillin has 6% ofzioc, calculated with reference to the dried substance. A
aztrconam should be reduced in moderate lo severe renal impair· been used orally for the lrcatment ofsusccplible bacteriol infec. while or pale tao, hygroscopic powder, odourless or having a
ment. Patients with renal impairment may be given a usual initial tions, similarly to ampicillin. In children over 5 years of age, dos- slight odour. Sparingly soluble in water. pH of a saturated solu·
dose followed by a maintenance d= adjusted according to cre- es of25 to SO mg/kg daily, in 2 divided doses, have been used. tion in water is between 6.0 and 1.S. Store in ainigl>t containers
atinine clearance (CC): at a temperature of 8° IO IS0 •
Prepa rations
• CC JO to 30 mUminute: half the initial dose Incompatibility. Baeitracin was slowly inactivared in bases
US P 33: ~ Hydrochloride lor Or.ii S..'5per.sior\: 8ac""""iin
• CC less than 10 mUminute: one-quarter of tbc in iliaI dose Hydro<:htoride Tablru. containing stcaryl alcohol, cholesterol, polyoxyethylcne deriva·
• baemodialysis patienlS: a supplementary dose ofone-eighth of Prop rietary Preparations (details are given in \Olum• B) tives, and sodium Jaurilsulfate, and was rapidly inactivated in
the initial dosc may be &i"en after each dialysis session bases containing water, macrogols, propylene glycol, gl)'CCiol.
Austria: Percbl>cf: CL:~ IWnr.: ~Indio:~
Inhaled attreonam lysine should be used with caution in palicnls Ital.: 8oc.od; ~ 8aca"'1I: e.c-,: 8d<t 8'l<rnf: u.,,o-t: cctylpyridinium chloride, bcnzalkonium chloride, ichthammol,
whose serum ereatinine is more then 2 times the upper limit of P<nglobet. l'o5bo0t1<1: Reb1<olf: W~ M ol"'f• la: f'tnalobet. phalol, and tannic acid. 1
PllUipp.: ~Port.: Bot~ Spoin: ~ SW.d.: PW> I. Ploxco JM, Hus:> WJ. The dTect of v:ulous wbs1an<c< on the
nonnal. &lol><t. Tho•:~ Turi<.:~,-_ aollbacterial activity of b.aciua<.:in in ointments. J Am Ph.or.. A.s·
P reparations soc (>ci) 19S6: 45: 141-5.
USP 33:J'....-for~iorc-lnjtctm Stability. Bacitracin zinc was more stable than bacitracin and
Proprietary Preparations (details ate gi•"Cfl in Volume B) could be stored for 18 months at tempcrarures up to 40" without
Auwa L: Azaclomf: Austria: Au<Wrc 8el1.: Au<t>m; llruL: Azarum; Bacitracin (BAN. rlNN) appreciable Joss ofactivity. Lozenges ofbocittacin zincaod oint-
Chile: ~am; CL: Azaclamt: Ca~: o~nm.: Azactam: Fin.: Azactam:
Fr.: Azactun, Ger.: Alactam; Gr.: AndArrt Azcnam: Aztrcotk: Hong Bacitncina: Bacitracinas: Bacitracine: Bacitrac1r-...rrc Bacytncyna; ments and tablets containing bacitracin zinc with neomycin were
Kong: Az>rnmj: lndla: Azenam: Trezan'( lndan.: VE()oc: lrl.: Azactam; Basitrasiini: Bas~ras>n. more srablc than the corresponding bacitrocin preparotions.
Ital.: A2actam: Primbaictal'T't Jpn: Azacum: M e.it.: Honob:ac N orw.: Bacitracin zinc was less biuer than bacitracin and 1he 1as1e was
A.zactam: NZ: Azactam: Philipp.: Atactom: Az1nrn Pol.: A'11ctamf: 5au11Tpau11M
more readily disguised.'
~.L~~~;~:~=~/c'.;'~·~~~~~J%~~:: CAS -
ATC -
1405-87-4.
D06AXOS:JOIXXIO: R01AB04.
t. Gross HM. e1 al. Zinc bacitracin in ph1.rm1ccu1ical ptcpar.ilion.s.
Drug Cosmtf Ind 1954; 75: 612-13.
Uyston: Vent-Jo: Azxtam.
ATC Ver - QA07AA93; QD06AX05; QJOIXXIO;
QR01AB04. Units
Bacamp icillin Hydrochlorid e ~&.ANM. lMN. flN""'9 UNll - 58H6RW0511 (bocirrocin); ODAJRRXOP7 (bo<i· The second International Standard Preparation ( 1964)
troc•n A): 3968134COD (bocitrocin 81): A"'12VBLQG5X of bacitracin zinc contains 74 unitslmg.
Ampic& Elhoxycatbol'I)~ H)droc~ BK=picil- (bocttrocin 82): IRE2j07DT4 (bocitrodn 83).
ltt. chlo<hydrate de:~~~­
IW>-hydn:xhlorid: ~(lino l'ldrocNondas; Bakarrpidin-tic:l- Adverse Effects and P recautions
roklorid: Bak2mpic~oldorid; Babmpisiin Hidrol<!o<\1r: Systemic bacitracin may produce severe ncphrotoxici-

H3C~l
Ba:<ampisiDii..Ohydroldoridr. Carampocillin: EPC.272: Hid:odoruro ty, resulting in renal failure due to tubu lar and gJomer·
de bacampidina. 1-(Ethox)'tartorrfloc<y)ethyl (6R}-6-(Q·O-phe- ular necrosis. Renal function should be detennincd be-
nytglycylamino)penocillanate hydrochloride. fore, and daily during, therapy. Fluid intake and urinary
0
6aJ<aMn1<U>1M>1Ha r 'IA!>0Xllop"A output should be maintained lo avoid kidney toxicity.
H2N N_....." ' f
C2 1H21Np,S.HCI =502.0. Jf renal toxicity occurs, bacitracin should be stopped.
CAS 50972-17·3 (bocompic1llin); 37661-08-8 His-1>-Asp-Asn Leu
(bocompicillin hydrochloride). Use with other nephrotoxic drugs should be avoided
/ I 1
ATC - )OICA06. o-Phe E 1>-Glu (see Interactions, below).
ATC Ver - QJOICA06. '- I I Nausea and vomiting may occur, as well as pain at the
UNll - PM034U953T. lle-1>-0m-Lys ·a-lle
site of injection. Hypersensitivity reactions, including
(boci<rocin A)
rashes and anaphylaxis, have occurred with systemic,
and more rarely with topical, use.
Pharmacopoeias. In Chin., Em: (sec p.vii). /nl., Jpn, and US. Hypersensitivity. Refacnocs 1"' to hypefsensitivity reactions to
Ph. Eur. 6.8 (8acllraCi'o). Mixtun: ofantimicrobial polypeptides baeitracin, including anaphyJ;i.,i$.
produced by ocr1arn strains of Bacillus licheniformis oc B. .r11bil- I. Sood A. Taylor JS. Bacitracin:allergen of the yur. AmJ <Antoct
lis. The potency is not less than 60 units/mg, calculated with ref- O.rt•ot 2003; 14: 3-4.
erence to tbe dried substance. A white or almost white hygro- 2. Jacob SE. James WO. From ro:1d rash to lop 11lcr1en in a tl3$h:
bacitracin. D~rma1ol Smg 2004; JO: S2 l-4.
scopic powder. Freely soluble in water and in alcohol. A 1% 3. Fn:1lcr Jf. et al. Intraopwuive anaphyh~l!.iS to bac:hracin during
solution in water has a pH of6.0 to 7.0. Store at a tempcra!UIC of pacemakcrchang_c and laser lead cxlrnction. A1tn Alftrgy Asthma
8° to IS0 in ainight containers. lmmmwl 2005; 95; 389-93.
US P 33 (Bacitracin). A mixture of polypeptides produced by the 4. Greenberg K1 ~f ()/, Anaphylaxi$ to topical Mc:irrucin oinlment.
Pharmacopoeias. In Eur. (sec p.vii), Jpn, and US. srowth of un organism of the licheniformis group of Bacillus Am J Eme.g Med 1001; l S: 95- 6.
Ph. Eur. 6.8 (Bacan1picilin Hydrochloride). A white or almost subtl/is (Dacillueeac). The maio componenls are bacitracins A, s. Crec.nberg SB. et al. Succcssrul re.su11Ci1a1inn "''I raticnt who
white hygroseopie powder or gninules. SoJUble in water and in Bl , B2,aod B3. It has a polencyof nor Jess than65 units/ms, cal- developed cardiac an-cs-t from pulsed ulinc b»ch111ein lavage
during thoracic lamincc1omy and fuston. J Clln Antsth 2003; 20:
dichloromethane; freely soluble in alcohol. A 2% solution in wa- culated with reference to the dried substance. Ir is a white to pale 294-6.
ter has a pH of3.0 to 4.5. Store in ainight containers. buff, hygroscopic powder, odourless or having a sli(:ht odour. 6. Cronin H, Mowad C. Anaphyl•Clit 'readion to .,_,citracin oint-
U SP 33 {Baca~ H)odrodiloride). A white or pracrically Freely soluble in water; soluble in alcohol, in glacial acetic acid. mt:nL Cutis 2009: &l: 127-9.

All cross-references refer lo enlries in Volume A

 Bacampicillin Hydrochlotide/Bekanarnycin Sulfate 229
Interactions meni: Necxrn)'(h ~lt ll""CS B.lcitrac.r, O n:ment I~ s.J~t And
Ba.c.it:-acin Zinc Ointrncn:;, ~ e 5·.Jlfav.:: ar.d SkcrM:in 2l'IC Tc:ipical:
Additive nephrotoxicity would be anticipated if baci- Acl'OSol ?ol)'l'O)>C" B s.A!a" ind e.av.c;., Zinc T°"""OI ~
tracin were given systemically with other ncphrotoxic
Propriatary Pre p<i.ratio ns ld....~ils :11·c sivcn in Volume B)
drugs, particularly colistin, kanamycin, neomycin, pol-
C.O.W,c!.: Ba<"uerr.t: B~ Baatot USA: AA-r...cii·;: B•;S.H1; v......,
ymyxin B. and streptomycin; such use sbould be e.c.dem\
avoided.. Bacitracin is reported to enhance the neu-
romuscular blocking action of cenain dmgs, such as
neuromuscular blockers and anaesthetics, ifgiven dur-
ing surgery or postoperatively.

Antimicrobial Action •
Bacitracin interferes with bacterial cell wall synthesis
by blocking the function of the lipid carrier molecule
that transfers cell wall subunits across the cell mem-
brane. It is active against many Gram-positive bacteria
i11cluding staphylococci, sm)ptococci (particularly
group A streptococci), co1ynebacteria, and clostridia. It
is also active against Actinomyces, 7i·eponema palli-
dum, and some Gram-negative species such as Neisse-
ria and Hoemophilus injluenzoe, although most Gram- (motnomycm A)
negativc organisms are resislllnl.
Acquired bacterial resistance to bacitracin rarely °'" Profile
Oombcm1ycin is an aolibacttrial complex containing mainly
curs, but resistant sttains of staphylococci have been ~nomyci n A w.ld mocnomycin C and which may be obtain<d
detected. from cultures ofSrrep1on1)'Cf!S bambergiensis or by other means.
It is used as a growth promotor in veterinary practice.

Pharmacokinetics
Bacitracin is not appreciably absorbed from the gas-
trointestinal tract or from intact or denuded sk in, Baquiloprim 1'BAN. rlNN)
wounds, or mucous membranes; however, systemic Baki!opnmi: 8al<iloprrn: Saquiloprima; Baquolopnme: 82q.Jilopri·
absorption bas been reported after peritoneal lavage. It mum; I380U. S-(S.Dimeth)tlmino-7-me~S.quinolylme·
is rapidly absorbed when given by intramuscular injec- thyl)pyrimidn·2.~~iam.ne.
tion. Bacitracin readily dilf\Jses into pleural and ascitie 6a:x~.:..Onp1<1M
fluids but little passes into the CSF. About JO to 40% CnH10N4 = 308.1.
of a single injected dose is excreted slowly by glomcr- (AS - I 02280-35-3.
ular filtration and appears in the urine within 24 hours. UNll - 3DE.766VIG6.

Ba lofloxacin C"""-0
Use s and Administration
CaloOoxaci~: Balolloxacino; 8alo0oxacinum: Q-3S. (±} 1-Cydo·
Bacitracin and bacitracin zinc are applied topically (as propy1·6·0uoro- I ,4-dh)'dro-8-methoxy-7-[3-(metl.,y..Mo)pip·
a cream, ointment, dusting powder, or ophthalmic oint- erid.oo}4-oxo-3.quinomeca~ic acid.
ment), often with other antibacterials such as neomycin
and polyrnyxin B, and sometimes with corticosteroids, ~CaU'1H
in the treatment of local infections due to susceptible C~H2,FN10• " 389:4.
organisms. Typica l concentrations of bacitrac in or CAS - I 27294-70-6. NH2
bacitracin zinc in such products are 400 to 500 units/g. UNll - Q022B63}Pfvt.
Absorption from open wounds and from the bladder or Profile
peritoneal cavity may lead to adverse effects, although Baquiloprim is a diaminopyrimidine an1ibacu:rial used in ve1cri-
the dose-limiting roxicity of combined preparations is 11a1y nlcdicin<: with sulfadimcthoxinc or sulfadimidine.
considered to be due to neomycin.
Parenteral use of bacitracin is usually avoided be-
cause of nephrotoxicity but it may be given intramus- Bekanamycin Sulfate (rlNNM)
cularly for the treatment of infants with staphylococcal Aminodeoxylc.inamycon Sulphate: Bekanamycin Sulphate: 8'!l<a,-...
pneumonia and empyema due to susceptible organ- amyo~. Sulfate de: Beka<wnyon Sulro~ Kana,.,.,.1tin 8 Sllphotz
KOi".; NK-1006; Sulfato de bekanamlcina. 6·0·(J..,\mino-3«·
isms. For details of doses in children, see below. oxy-<>-O·glJ<:Opyr-dnosyl)-2-0eoxy-4-0-(2.6-d;;.mino-2.6-dide-
Baeitracin has been given orally in the treatment ofan- Oxy-<l-O-gllcopyranosyl)-e>-svepwnr.e 5Ulphate.
tibiotic-associated colitis due to Cluslridium difficile. Profile 6e-a..a..-tca Cy~ar
Balofloxacin is a fluoroquinolone antibacterial used in the trcat-
meni ofurin:iry-traet inftttions. = 728.7.
C,~HnNs0 1 c.2''>.HiS04
Administra.tion in children. In the USA, baciirocin 1my be CAS - 4696·76·8 (oekonomycir.); iOSS0-99-1 (bekon·
g,iven in1ramusc11larly for !he 1rcaunen1 of infan1s with staphy~ ORevlews. cmycin sulfate).
eo<cal pncumonio and empyema due to su:sceptiblc organisms. UNll - KB 7 IfA86HM.
Infants weig.hing less 1han 2.5 kg may be aiven n dose of I. Aiksnt l . Balo 0 ox3c:in Choongwx. C11rr Opht /m 1rs1ig Drugs
900 1.a1its/l;g cbily in 2 or 3 divided doses; those weighing more :ool: '' 224-9.
than 2.5 ~S m:>y be given 1000 uni1slkg daily in 2 or 3 divided Preparations
doses.
Propriecary Preparations (dei~ils.,. given in Volume B)
Preparations l(or.: Q·Ro<h

SP 2010: Poiymy><n and &"""""'Ero Oin'""""'~

USP 33: 8aci1rac1n""' ~ B s.Jfat• Topiol A('t'C)l(>I. ~ b ·
lr¢c1ion: Bacrtmin Oonll'llO"C; SJO"nUI O!>hwlmk Oirtmcrr, Blctr""'
Zr< ir<1 ~n B Sulfate O~ Baciln.cir. z;nc and~ B
s.K.o.e Op.-.ihatmic Oir.tmont Baci:r.«> Zinc 011tm0nc Neomycii ;and Bam bermycin (M~ po."INJ
l\ol\,,.,,..., 8 Sullr.es and B>cilrati\ OnvnM: ~ aod Polym:,,;., B
~mic:ina; Sambemlyciie: Bam~mycins (VIAN): ea,_,.__
(bekonomycin)
s.Ma~ and S.Wadn Oph~~ ~ Neom)<n ond Polymy>ion 8
Sullales .ir48'cvlci.' Zinc Ointment: Neomics> ir<I l'olfl'l¥<n BSu~fates ~ Flavophospr.c~ipot
one: BKIV°"" z:..., Ophlhalmic Ointment ~and Fl::fymyxin Bs.;. P harmacopoeias. In Jpn.
i.tos. Baccrooo l.ott. 2"CI H)drocor'•IOl'e keUte Optolholm< C>mmco>t: 6aM~utlH
'Jeomy<#1 illd ~ 8 SYl'atts. l\a<11J·ocin Z"n<. <nd ~or.ioone Profile
Oon\ment Neormon irod A>ymy>on 8 Sulfates, eadtraM Zn<. and 1-')<1<0- C,.H,ocNs01 4 P ~ I 582 .6 (moenomycin A). Bekanamycin is an aminC>Slycosidc 3Jllibactcrial and is a con~­
coriMOroe O phll>k'lc ClwUroe'll. Neomytn •nd Pblymp<l 8 Sukn. S.C• ncr ofl<anamycin. It has properties similar 10 those of gcn1amicin
vuii Z,nc, and L.dx>tt Clwtmont; Neomycin ar.d Pol)myul 8 S<lmes. CAS - I 1015.37.5 (bombermycin); 76095-39-1 (moen·
a.civotil, and H)<l<o<OtV.ono """''° Ointmerr.: Nton')•C<'I ind l\::oly-
l'llflO'l 8 S..ilatn. S.Cru'l""'and ~Ort~ A<elate Clf>ht""""" OW·
omycin Aj.
(p.306). It is given topically as the sulfate for the treatment of eye
infections. It has also been·given inn muscutarly and orally. It is
i=:>t !'Je~(in "'° Po~·my>m 8 s.ktes. Bacrncin. and Lidoa"" <'.Xt· UNll - PP922A42V2. reported 10 be mote toxic than kanamycin.
The >yinbol t denotes a preparation no longer acti\•ely marl<etcd
230 Antibacterials
Preparations Benzathinc benzylpcnicillin should not be injected in- penicillin is usually preferred. Benzathine benzylpeni-
Propr ietary Preparations (dc1ails arcgi,•cn in Volume B) travascularly since ischaemic reactions may occur. cillin 900 mg is equivalent to about 720 mg of bcn-
Pon.: Kanacf.t. zylpenicillin (1.2 million units).
Multi-ini-redient: ltal.:Vwsvc:lobtn~ V~e Antib'°"" Interactions
co. For early syphilis, a single dose of benzathinc ben-
As for Benzylpenicillin. p.232. zylperiicillin 1.8 g by dttp intramuscular injection is
given, usually as 2 inject.ions at separate sites. In late
Be nethamin e Penicillin (BAN t'.NN) Pharmaco kine tics syphilis, 1.8 g is given at weekly intervals for3 consec-
Benelhamil'le Penicilone: ~thamin1.m PenicilLOr>Jm; Penicina-
When benzathinc benzylpenicillin ls given by intra- utive weeks. Bcnzathine bcnzylpenicillin is not usually
benetamina. Ben..")'l(phendlyl)ammonium (6R)-6-(2-pheny!a- muscular injection, it forms a depot from which it is recommended for the treatment of ncurosyphilis be-
cetamido)penicollanote slowly released and hydrolysed to bcnzylpenicillin. cause ofreportS of inadequate penetration into the CSF.
6etteTaM~H nCH:MUW"""1M
Peak plasma concentrations are produced in about 24 For the treatmcnl of other treponemal infections, such
c,~H17N.C14H1eNiO,S =545.7. hours and are lower than those after an equivalent dose as yaws, pinta, and endemic syphilis (bejel), a single
CAS 75 1-84-8. ofbenzylpenicillin potassium or sodium. However, de- intramuscular dose of bcnzathine bem:ylpenicillin
UNI/ - OJS7RWT8R5. pending on the dose, benzylpenicillin is usually detect- 900 mg is given.
able in plasma for up to 4 weeks (but see below).
For streptococcal pharyngitis and the primary preven-
DiStribution into the CSF is reported to be poor. tion of rheumatic fever, the aduh dose is a single intra·
Due to the slow absorption from the site of injection, muscular injection of 900 mg. To prevent recurrences
benzylpenicillin has been detected in the urine for up to of acute rheumatic fever, 900 mg is given intramuscu-
I 2 weeks after a single dose. larly every 3 or 4 weeks.
Benzathine benzylpcnicillin is relatively stable in the For details of doses in children sec below.
presence of gastric juice, but absorption from the gas~ Admininration in children. Beozathine benzylpcnicillin
trointcstinal tract is variable. Plasma concentrations of may be gi'1Cn by deep intramuscular injeclion to infants and chil-
Profile
Benechamine penicillin is a poorly 50luble derivative of ben- benzylpenicillin after an oral dose are lower than those ~n for the 1rea1men1 ofsuscq>lible bac1erial infoctions, includ-
zylpenicillin (p.231) wich similar ae1ions and uses, although it is from the same dose of a soluble penicillin; peak con- ingcongeniial syphilis andSllep(ocoocal pharyngitis, and for the
noc recommended for chronic, se•=. or deep-seated infections. centrations are also produced less rapidly, but may per- prevention of rfiwmatic fe'1Cr.
Aflerdeepin1tamuscular injeclioo it forms a depot &om which it sist for longer. In the USA, the folJo,.ing doses have been recommended for
is slowly absorbed and hydrolysed to ben~ylpcnieillin. treatment of streptococcal pharyngitis and prim•ry preven-
8cnechami11e penicillin is usually gi'1Cn with bcnzylpenicillio so- Plasma concentrations. Bcnzalhine benzylpenicillin h'as tion ofrbevmalk fever by lhe American AcadcrnyofPcdiatrics
dium and also sometimes procaine bcnzylpenicillin 10 produce been given every 4 weeks for secondary prophylaxis against (AAP) 1and the American I Jean Association (AHA):I
both an immediale and a prolonged ellCCl; overall, the clrect laslS 1heumatic fe'1Cr, alchough 50one advocate gj~ it~ 3 weeks • infants and children weighing 27 kg or less: 450 mg
for 2 10 3 days. 10 ensure adequate plasma concentralioos of bcozylpcnicillin. (600 000 units) as a single dose
"JYpic:al conc:enlrations achieved after a single intramuscular in-
Preparations jection ofbeozatbine bcnzylpenicillin 900 mg have been cited as • children weighing more than 27 kg: as for adults (see Uses
Propri<otary Preparations (details arc siven in l.\>lumc B) about 100. 20, and 2 naoogramslmL on days I, 14, and 32 re- and Administration, abo'1C)
Multi-i<>gredient: r,, Bochroco:lintt Port.: - ....t. spccti\'ely. In one study' adequote concentrations (defined as Alternatively, WHO recammend:
20 nanograms or more per mL) were seen in more than SO°le of • children weiViing less than 30 kg: 450 10 6 7S mg as a single
serum samples al 3 wcd.-s, but in only 36% at 4 weeks. In a fur- dose
ther srudy, in which single doses of 900 mg, t .3S a and 1.8 g
Benzathine Benzylpenicillin (BAN.tWN) were con1parcd. it appeared chot doses higher rhan the 900-mg • children weighing 30 kg or more: as for adults
dose ofbenzathine benzylpcnicillin usually recommended might To prevent recurrence or acute rheumatic fever, the AAP and
Bensylpenicil6nbensatio; Bensytpenicollinbenzatir'( Benlsyylipen'sil· prolong lhe duratioa of prOteclive plasma concenl1lltionsofbcn- AHA rttxlmmC!ld lhe same dose as U5Jed for primary prevention
liinibeni.atiini: BenzatiW>-benzylpenicilin: Benl31hine benzylpeni- zylpcnicillin (defined as ~bove 2S nanognms/mL) and impr0vc be lP''CD once every 4 weeks.
cir.inc; Bcnzalhil".e Pendln; Benzathini ~ Benza- che efficacy of dosing every 4 weeks for prophylaxis against WHO make the following allernaove dose recommendations:
tin Penisiin; BenuUla bencilpcnicoina: Benzelhaat Bcnzilpenicili- rheumaric fever.
• children weighing less chan 30 kg: <150 mg once every 3 to 4
nas benzatona>: Benzi!peniciRina Benzatinica: Benzilpenicillin-benz- 1. Kaplan EL, ~' ol. Pharmacokinaics of bC'ntalhinc p-=nici11in G: weeks
antn; Beneylopenicyl:na benzatyr\C>Wa: Benzylpenicilinum Ben- scrum levels during lhc 28 days after inlram\l$Culu injection of
zantllirun; Benzyfpcnicifoum benzatli'un: Penidlin G Benza- t 200 000 uniu. J P•diorr 1989; 115: 146-SO. • children weighing 30 kg or more: as for adults
!Me: Penisi'n G Benzaun: Penuet/Wun G. NN'-Oibcnl)'le\hyl- 2. Currie BJ. cl al. Pe.nicillin c.onccnamtions after increased dOMs For trea1men1 of yaws, plnta, and bejel (endemic syphilis) in
of b~m:a1hinc~ penicillin G (or prevention ofsecondary rhcumallc
enerumroniom bis{(6R)-6 (2-phenytaccwnido}penicillanatei (e\·u. Antimicrob Azimi# Cla,morl1tr 1994; 38: J203......t. children, 450 mg as a single dose is recommended by WHO.
6'Hla'Tl1Htl EieH3~/\neHM:UV..MMM For doses used 10 treat congenilol syphilis in infanu, sec p.207.
Pregnancy. The pharmacokinctic.~ of benutltine benzy1penicil·
c ..H10N1(C,Ji 1sN104S)i = 909.1. !in appear 10 be altered in Ja1e pregnancy. Or lOhealthy pregnant 1. Amutcan Academy of Pcdiattics.1()()9 Red Book.: R~porl offlrr
Comn1i11~t on Jefecti011s Dl1tost1. 2Sth C"d. Elk Grove Village.
CAS - I 538-09-6 (anhydrous benzothine b'nzylpenicil- women given benzathine bcnzylpcnicillio 1.8 g inrramuscularly 111;nots. USA: American Academy of Pediatrics. 2009.
lin); 5928-83-6 (benzorhine benzylpenicillon monohyd:ote): before caesarean secrion, only 4 nchie•'Cd adequate serum con- 2. Gubcr MA, ti al. Prevention u( tftnma1ic fever and diagnosis
4 i 372-02-5 (benzo1hine benzylpen1cil/m 1e1rohydro1e). ccn1r1tions of benzylpenicillin (for syphilis, at least and 1re1tment of ocute St~p1acoce1J pMryngilis: 1 sc-icntific
ATC - jOICE.08 18 nanogramslmL) for 7 days. 1 s.taleme:nt frorn lhe Americ.an Heart As.soclntion RheurNtic Fe-
1. Nathan L. 11 ol. Penicillin le" ck follo,,,in~ lhe 1d1ninistr1tion of -_·er, Endoc1rditis. and K.awnaki Disuse Commi11ec of the:
ATC Vet - QJOICE.08. Council on Can:tiovas«1far Disease in the Young. the ln•t:rdlsci-
benza1hinc penicillin Gin pttgl>M<y. Obmr Gynrcol 1993, 82. plin3ry Council on Function.al Gct1omics and Tn.nst11tonal Biol-
UNI/ - R/T82F58GK. 338--42.
og)'• and the lntcrdiSC1phnary Council on Oualiry of Cuc and
Oulc:omct Resc:irch. tndors«l by lhe American Academy of
Uses and Administration Pediatrics. Cirailo1io11 2009; 119: JS41- S1. Also available tU:
hHp://circ.ahajoumals.ors/cgilreprint/ 119/l l/IS41 (accc~scd
Bcnzathine benzylpcnicillin has the same antimicrobi- l)I08/09)
al action as bcnzylpcnicillin (p.232), to which it is hy-
drolysed gradually after deep intramuscular injection. Preparations
This results in a prolonged effect, but because of the USP 33: Ptridlin (; 8e11Za1Nno and ~c; !'Towne •nr-ct<lble Susptn-
relatively low blood concentrations ofbenzylpenicillin
"°"' l'!!r.cilf"' c; Benzathine ~ ~ Pe1>:ot1n c; l!cnutlW>e
Onl Suljiemion: Pcnicoll;n G ecnz,~.,.,. T.tkt>.
produced, its use should be restric1ed to micro-organ- Proprietary Prcparati...;s (details are givett in Volume B)
Pharmacopoeias. In Ch/11., Eur. (seep.vii), and /111. isms that are highly susceptible to benzylpenicillin. In Arg.: Benzetacit Gatt.rnicillc Fwl ci B<ti: Rot"l"'rc Auruat: 8dlro l-A;
acute infections, and when bactcraemia is present, the Austrio: ReU<pen: Belr.: ~ Broz.: 8actopcn: eenz..,.,,. SenMuc;t
Jpn and US include the tctrahydrale. Bcpebcn: LOf1&il<fo: Nco ~t. Pcrd 6' Canad.: Biciln l-A; C1.: P.n-
Ph. Eur. 6.8 (BEnzylpcnicili\ Benut/line). ll contains a variable initial treatment should be with benzylpenicillin by in- depoo Compos<u-n; Reatpent. Fr.: E><tencoU:nc: Ger.: ~ Gr.: Fen>-
quantity of waler. A white or almOSt while powder. Very slighdy jection. dur: Hone Kone: Pan-Senza:hine G: Huni.: lletilpeflf: India: Pcncont
soluble in waler; slightly soluble in alcohol; freely soluble in l'l::nidure /rrod: Ounllx>tk: /tol.: o:om:ncc:-h ~rat: Mol<Tysla:
Infections treated with benzathine benzylpenicillin in- Roi.rpen: Mox.: Benicilintj: S.nc<>lin: 8onzafu1: &!nl>nil 5'Tlplet Ben·
dimelhylformamidc Md in fom1amide. Srore in airtight contain- zetooi. lp<n>on: lentop.nt l.k,;QJ 6:3:3: u.al l -A; Ndh.: ~ NZ:
ers. clude diphtheria (asymptomatic carriers), pharyngitis Bdn l ·A. Pf>iNpp.: Pcnadur; blpen: Pol: Ool>«)'1onl: Pon.: Lenroc;ron
USP 33 (F'enic& G Bcnzathine). The letr0hydro1e is a while, (Slreptococcus pyogenes; Arcanabacterit1111 haemo- S: f'enacUt: Rus.: lkillin-1 (Gou..,..._!~ E>otenc•tt (3'<cTeHlWW'.H):
odourless, crystalline powder. Soluble I in SOOO of woter and I RetJtpon (P"rapne>1); S.Afr.: Bicilln l-At: l'eri!d1te LA: Slnropore: R<>-
in 65 of ale-Oho!. pH in a solu1ion prepared by dissolving 50 mg
lytiann (Cary11ebacteri11m haemolyticum)), and syphi- ta;>c« Spain: Benzelael Cep.an.: ThoL: Pcnadurt; Turk:
~ 63.3: Ooposir.., ~ 633: Pe:-..dur: Peoadur 63.J: l'etUc
ee.-.
in 50 mL of dehydrated alcohol, and adding SO mL of worer is lis (including non-venereal treponematoses). It is also Ukr" Retarpen (PenpncH~ i.tSA: Bicilro L-A Flormapcn: Venn.: Ben.
between 4.0 and 6.5. Store in airtight containers. used for primary and secondary prophylaxis of rheu- macol l·A: Silcopent.
matic fever. For details of these infections and their Mul ri~ingredient: Aurtrio: Reurpen composit\.rn; ~.: ~int:
Adve rse Effects and Precautions treatment, see under Choice of Antibacterial, p.170. Ger.: Retacillin compca(.-T.,dcx<lirt ltol.: Tri-W)~ Mu.: Bence·
lin Combin>d<x Benzw C""'!'ucstoj: B<.-n~ Conti>odo: Peciva><.
As for Benzylpenicillin, p.231. Bcnzalhine benzylpenicillin is given by deep intramus- Pc~ ~ Net~.: Ptridural Otft: Por<.: len:ockc Penadur
Non-allergic (embolic-toxic) reactions similar to those cular injection, sometimes with procaine benzylpeni-
6.J.Jt.11.,, ~3 (OMw;w,"'3): E!icl5n·S ~s~ s.Afr.: Pcni-
lente Fortet. Ul:r>ciir-c S,,,Un: BoNetoc• Compuem: Cep;ocaina 633: Pe-
associated with procaine benzylpenicillin, p.347, have cillin and benzylpenicillin itself. It has been given oral- nil"'-d RelW USA: Bocilhn C·R: Venn: Bcllleucl 3-3: Ben:d>cil 6-3-3.
been repot1ed rarely with benzathine bcnzylpcnicillin. ly for mild infections, although phenoxymethyl-
A II cross-rcfcren~s refer lo entries in Volume A
 Benethamine Penicillin/Benzylpenicillin 231
Benzathine Phenoxymethylpenidllin practicnlly insoluble in fatty oils and in liquid paraffin. A 10'.4 anaphylaxis occasionally occurs and has sometimes
Be-lzabn Fenoksrne:il Per.isiJ•'l: Benzatru ""10.-netilpen1c1lona: solution in water has a pl-I of5.5 to 7.5. S1orc in airtigln contain- been fatal.
Pendin V Bet>zathine (UWJ): Phenoxy:nclh)ipenic:illini Di- ers.
USP ll (Penicillin G Potassium). Colourless or "ilile ciyslllls, or Gastrointestinal effects such as diarrhoea and nausea
belll)'laelh)lcndaminum. N.N'-Dibenz)'lethylencd.ammonium
white Cf)'Slallinc powder. II is odourless or praciically so, and is are the most common adverse effects after oral use of
!:>•s[(6R)-6-(2-;iiienoxydCetamido)pcnicilana:e]. modctately hygroscopic. Very soluble in water. in sodium chlo-
6ew3aT"1}1cf>e11()1(()UJoe'1"\lW\CH:.tl.!MA""'H
benzylpcnicillin; a sore mouth or tongue or a black
ride 0.9"A, and in glucose solutions; sparingly soluble in alcohol. hairy tongue have occasionally been reporled. Pseu-
CAS1 - 18 5928-84-7 (o~hydrovs b•nzoth1no phenoxymerh·
(C - H N,O}S)i.C,.H~~ = 941. 1. Its solutiOllS recain substantially full potency for several days a1
iemperarurcs below 15", but are rapidly inactiva1cd by acids, by domembranous colitis has been associated with the use
(lperucil!in): 63690-57-J (ben;zo!luot ph•r1oxyme1hylpeni- alkali hydroxides, by glycaol, and by oxidising agents. pH of a of most antibacterials; an1picill in or amoxicillin are the
clllin teuohyd101e). 6% solu1ion in waier is belween 5.0 and 7.S. S1orc in airtight con- most frequently implicated penicill ins (see Antibiotic-
ATC-JOICE.10. tainezs.
•4TC V•t - QJOICE.10. associated Colitis, p.182).
Incompatibility and stabilit)•. See Berrzylpenicill in Sodium. Other adverse effects have generally been associated
below. with large intravenous doses of benzylpenicillin; pa-

0~..A.w ~ \! s
0
..
N-i--f'"' )<CH,
] (·NH,_,)0
L
0 Benzylpenicillin Sodium (6!\Nlll, lfNN,VJ
Bendlpenicil"a s6dica; Ben~illinnatriu~ ~li­
tients with renal impairment are also at increased risk.
These adverse effects include haemolytic anaemia and
neutropcnia, both of which might have some immuno-
[ •NH~ ,,inabiun~ Benzifpenicilino natno dl\JSl<a: Benz11penicilin-ni!tri..,,,

'coo·
HJ-if--/ 'CH,

0 ' v Benzylopenicyiina sodowa; llenzy!penicilin sodni ..:A: Bel'IZ)'lpen-

ic:iline sodiqve: Benz)'lpenicir.-...n natriwm. Natrii Benzyipe'licil-
l1run: Peniolina G s6dica; Penialin G Sodiurrc Sodyum Penisilin
logical basis; prolongation of bleeding time and defec-
tive platelet function; conV\Jlsions and other signs of
CNS toxicity (encephalopathy has followed intrathecal
Pha rmacopoeias. In US. G. dosage and can be fatal); and electrolyte disturbances
USP 33 (Pcnio"lin V Benntt-ine). /\ proClically white powder HaTpM~ 5ei<JOW>CM1!MMH>< because of the large amounts of potassium or sodium
havingacharacteristicodoor Soluble 1 in3200ofwater, I in330
C,•Ho?N1NaO,S =356.4. given when benzylpenicillin potnssium or sodium, re-
ofalcohol, 1 in37ofaCCIOnc, I in42ofchlorofonn,and I in910
of ether. pH of a 3% suspension in waler is between 4.0 and 6.S.
CAS - 69-57-8. spectively, are used.
Store io airtight comaincrs.
ATC - JOICEOI; SOIAAl4 Hepatitis and cholestatic jaundice have been reported
ATC Vet - QJOICE.01; QSOIM14.
Profile UN/I - YS5LY7JF4N. rarely witl1many penicillins, notably pcniciUina»re-
Scnzalhine phenoxymcthylpcnicillin has actions and uses simi-
Pharmacopoeias. In Clnir.. Eur. (seep. vii), Int., US. and Viet. sistant penicillins such as flucloxacillin and oxacillin,
lar to those ofphcnoxymclhylpcnicillin (p..341) and is &iven oral· and also combinations of amoxiciUin or ticarci llin with
P h_. Eur. 6 .8 (Benzylpenicil§n Sodium). The sodium sall of a sub-
ly in the treatment of susceptible mild to modera1e infections.
stance produced by growing cer1ain srtains of Pet1icil/ium no- clavulanic acid.
Dose$ nrc cxpress<d in tams of phenoxymelhylpenicillin.
tutum or n:latod orgllllisms or obtained by any Odier means. A Nephropathy and intersliti.a l nephritis, which may have
Preparations white or Alrnost white crystalline powder. Very wllble in warer,
VSP 33: Ptndn V S..Valhi><Or".i ~ practically insoluble in fatty oils and in liquid paraffin. A I O'.I. some immunological basis, have been especially asso-
Proprietary Preparations (de11ils are: gi.,.c1l in Vf.llU1'11c B) solution in \\'lllLT has a pH of S.S 10 7.5. Slore in oir1igl11 con1ain- ciated with meticillin, but may be produced by other
Aunrol" Abbociln-V: c;1.,.ino V: Austria: Os;ien: Conod.: f>,en-Vce: Cz.: ers. penicillins.
Ospe:. Fr" ~h Gor.: 11\fectoBidUn: Gr" °'Pct< HUt>f" 051><"'< Ox· USP ll (PeniciHin G Sodum). Colow1css or while crysials, or
)'!liont. Pol.: ~ Rus" Ospen (°"""'): Spoln: l!enorit Sw;tz., Os·
white to sliglltly yellow crystalline powdet. II is odourless or
Some patients with syphilis and other spirochaete in-
pen: Tu rk.: floA.0.: U/u" Ospen (O:n.,,.): Von ...: ~ fections may liavc a Jarisch-Herxhcimer reaction
praclically so, and is moderately hygroscopic. Its solutions lose
potency fairly rapidly al room temperalUrt, but retain substan- shortly after starting treatment with penicillin, which ·is
tially full potency for several days at lempcrnrures below I;•. Its probably due to the release of endotoxins fro1n the
Benzylpenici!lin (BAN. rlNNJ solutions are rapidly ill3Clivated l>y acids, by alkali hydroxides, killed treponemes and should not be mistaken for a hy-
by oxidising agenlS, and by pcnicillinase. pH of a 6% solution in
Benolpendin<: Bensylpenic1Un Bentsy)'lipenisill•ni: Benza Penisil- water is between S.O and 7.S. Store in airtigh1con1ainers.
persensitivity reaction. S)111ptoms include fever, chills,
iin: Bct-~icillir.e: Bel'\Z)•penicilln.im: Crystall.ne Penicilin G: headache, and reactions at die site of the lesions. The
Penocilina G: Penialin: Penitilin G: Penisiin G. (2S.5R.6R)-3.3- Incompatibility. Benzylpcnicillin h.as been reported to be in- reaction can be dangerous in cardiovascular syphilis,
Dimetl-.)'l-7.oxo-&.(2·p.'1en~etamido)-4-thia-1-az.abicyc­ COln!"'tible with mc1al ions and some rubber products. Its stabil-
ity may be affected by ionic aod 11011ionic sutfaccants, oxidising or where there is a serious risk of increased local dam-
lcl(3.2.0]hepuine-2~ic acid: (6R)-6-(2-Phen~e1an'li­
and reducing agcnu. alcohols, glycerol, glycols, IJl3crogols and age, such as with optic atrophy.
do)pervcillanic aod. other hydroxy compounds. some paraffins and bases. some prc- Hypersensitivity. The overall incidence of allergic re·
fieH31-W"teHMUMN•MH scr.·atives such as ehlorocrcsol or driomcrsal. carbohydrate Solu-
c,.H,1Nlo.s =334.4. tions in an alkaline pH, fat emulsions. blood and blood products, actions to penicillin has been reported to ~ from
CAS - 61-33·6. and viscosi1y modifiers. Bcntylpenicillin is incompatible with about 1 to I0% although some patients may have been
ATC - JOIC£01; SOl/.Al4. many ocitlic and basic drugs (sec Stabiliiy, below) and several incorrectly labelled 'allergic to penicill in'. Anaphylac-
ATC Vet- QJOICE.01; QJSl(E.01; QSOIAAl4 other anlimicrobials, including amphotcricin B, sornc ccpha- tic reactions occur in about 0.05% of patients, usually
UN/I - Q42T66VGOC losponns. and vancomycin. Bc11zylpenicillin and aminoglyco- after parcmeral use, but they have also been reported
sides are murually incompatible and injeelionsshould be given nt
separate sites. after taking oral penicillin.
Stability. Benzylpenicilhn t• hydrolysed in aqueous solu1ions Hypersensitivity to penicillin gives rise to immediate

OJ NJ=t
H
H H
: : S)<C H3
N-../ 'CH3
by degradation of die hcta-lactam ring and hydrolysis is aocelcr-
a1ed by increa~cd tempera11.-c or •lkaline condilions; inactiva·
tion also occurs under acid conditions. Degradation products in·
elude pcnillic, penicillenic, and penicilloic acids which lower the
reactions including anaphylaxis, angioedema, urticar·
ia, and some maculopapular rashes. Late reactions may
include serum sickness-like reactions and haemolytic
anaemia. Reactions are considered to be due mainly to
pH and cause• progressive increase in the ra1e of deterioration;
N-fonnylpcnicillarninc and vay small amounts of penicillamine breakdown products produced in virro before use or to
0 "COOH metabolites of pen icillin, and possibly penicillin itself.
have also been de1ee1ed. Oegr•dation is minimal ot about pH 6.8
and deterioration ofbtnzylpcnicillin in solution ruay be retarded 111csc act as haptens which, when combined witl1 pro·
Description. 111• ll~lllC bmzylpenicillin is commonly used to by using o citrnle buffer. Dilute solutions arc more scble than reins and other macromolecules, produce potential an-
describe either bcnzylpenicillin poUSSiwn or benzylpcnicillin cooccntratcd ones.
sodium as dltse ore the forms in which benzyli)cnicillin is used. tigens. As the hypenensitivi ty is related to tl1c basic
References.
In l>fanmdule. benzylpcnicillin means either 1he potassium or I. Lynn 0.. The s11bili1y ond 111dminlsu:uian of intmllCnous peni<:11·
penicillin structure, patients who are genuinely alletgjc
sodiun1 sail lins. BrJ lnlro~,, T'lttr 1981: l (Mat)'. 22-;9. to benzylpcnicillin must be assumed to be allergic to all
2. Oird AE.. ~tal N-fom1ylpcnicillaminc and pcnicilfamim: us dej· penicillins; sensitised patients may also react to the ce-
Be nz ylpenicil!in Potassium (B>.NM .e.'NM; ndalton pr0duct5 of penicillins in solu1ion.. J Phann PJu1n11ocol
phalosporins and other beta-lactam antibacterials.
19S6: 33: 91~11.
Bcncilpe,.;cil"a potisica: Bensytpenicillinkalivm; BentsyyfpenisilJ-
1nil-..ali11m: Benzipcniclfir.o kaloo druska: Benzlpenialin·loi.'Un: Tests for hypersensitivity may be used to dctcnnine
Benzylopenicylina potasowa; Benzy'.penicil1n draselN slt Ben- Un its those patients most likely to develop serious allergic
zy!pCniciline potassiqve: Benzyt;>enicil".-...m kalic:um: Ka6i Ben- The second International Standard Preparation (1952) reactions to penicillins. Skin tests are used to evaluate
zfpenicilinum. Pcnic:ilina G potisica: Pe><~"' G Potassium: Pe~~ of benzylpenicill in sodium contained 1670 units of the current risk of immediate or accelerated JgE-medi-
si1'~ G f'bt.\>)U'I' penicillin per mg but was withdrawn in 1968 since ated reactions, the most serious being anaphylaxis.
KaAM.A 6ewJt""'1CK"JJ~MtU•( penicillin can now be characterised completely by Both the major and minor detenninants of penicillin
C, 6 H 17 KN,0,S = 372.5. chemical tests. Despite this, doses of benzylpenicillin hypersensitivity should be used; the major detenninant
CAS -- I 13-98-~. are still expressed in units in some countries.
AJC -JO ICE.01 : SOIMl4 is available as penicilloyJ..polylysinc (p.2596) and a
ATC Ve1 - QJOICE.0 1: QSOIAAl4. Benzylpcnicillin potaSSium 600 mg or benzylpcnicil- minor-dctenninant mixture consisting of benzylpeni-
UNll - VL775ZTH4C. lin sodium 600 mg have generally been considered to cillin and its derivatives, including penicilloic acid and
Pharmacopoeias. Jn Chin., E11r. (sec p.vii), /nl.. Jpn, US, al>d be equivalentto about 1 million units (I mega unit). benzylpenici!loylamine, can be used, although if this is
Viet. not available a solution ofbenzylpenicillin may be sub-
Ph. Eur. 6.8 (Benzylpenidiin FblaSWm). The potassium sail ofa
substance produced by growing certain slrains ofPeni<:illh1m no-
Adverse Effects stiruted. Adrenaline should be available in case an an·
totum 01· related O<ganism• or obtuinc<l by any Olher mtans. A The most common adverse effects of benzylpenicillin aphylactic reaction develops. The results of skin tests
white or almOlit white crystalline powder. \.\:ry soluble in water; are hypersensitivity reactions, esp.:cially skin rashes; are unreliable if a significant lime has elapsed before
The symbol t denotes a preparation no longer actively morlc.etcd
232 Antibacterials
begiMing therapy. Several in-vitro tests including the Care is necessary if very high cfoses of penicillins are The following pathogenic organisms are usually sensi-
radioallergosorbent test (RAST) have been developed. given, especially if renal function is poor, because of tive lO benzylpenicillin:
Desensitisation may be attempted in patients allergic to the risk of neurotoxicity. The intrathecal route should • Gram-positive aerobes and anaerobes including Ba-
penicillin when treatment with penicillin is considered be avoided. Renal, hepatic. and haematological status cillus anthracis, Clostridit1111 pe1fringe11s, Cl. tetani,
essential. II involves very small doses of penicillin giv- should be monitored during prolonged and high-dose Corynebacterium diphtlieriae, Erysipelothrix rl111si-
en at relatively short intervals of 15 minutes or more, therapy. Because of the Jarisch-Herxheimer reaction, aparhiae, Listeria monocytogenes, Peptostreptococ-
and gradual ly increased to therapeutic concentrations. care is also nec:essaiy when treating patients with spi- cus spp., non-beta-lactamase-producing staphyloco-
However, desensitisation may be hazardous and rochaete infections, particularly syphilis. cci, and streptococci including Streptococcus
should only be carried out if the patient can be moni- Skin contact with penicillins should be avoided since ogalactiae (group B), Str: pneumoniae (pneumococ-
tored continuously and adrenaline and resuscitation sensitisation may occur. ci),Str. pyogenes (group A), and some viridans Strep-
equipment are immediately available. Desensitisation Penicillin therapy changes the normal bacterial flora lococei; enterococci are relatively insensitive.
should be regarded as temporary, and allergic reactions and can lead to superinfection with penicillin-resistant
may recur during the next exposure to penicillin. • Gram-negative cocci including Neisseria meningi·
organisms including Oostridium difficile or Candida, tidis (meningococci) and Neisseria gonorrhoeae
Neutropcnia. Neutropenia has been widely reported in particularly with prolonged use. (gonococci). although beta-lactamase-producing
patients given high doses of beta lactams and o.n inci- strains are common.
dence of 5 to more than 15% has been reported in pa- Penicillins may interfere with some diagnostic tests
tients treated for I0 days or more. Warning signs in- such as those for urinary glucose using copper sulfate, • Gram-negative bacilli includingPasteurella multoc-
clude fever, rash, and cosinophilia. Monitoring of the direct antiglobulin (Coombs') tests, and some les!S for ida, Streptobacillus i11oniliformis, and Spirillum mi-
leucocyte count is recommended during long-term urinary or serum proteins. Penicillins may interfere nus (or minor); most Gram-negative bacilli, includ-
treatment with high doses. Some have proposed a di- with tests that use bacteria, for example the Guthrie test ing Pseudomonas spp. and Enterobacteriaceae, arc
rect toxic effect whereas others have postulated an im- for phenylketonuria using Bacillus subtilis organisms. insensitive ald1ough some strains of Proteus mirabi-
mune mechanism. Potassium and sodium content. Each g ofbcmylpcnicillin lis and Escherichia coli may be inhibited by high
Electrolyte disturbances. Many penicillins have been or
potassium contains about 2.7 mmol potassium and each a of concentTations ofbenzylpenicillin.
bcmylpenicillin sodium contains about 2.8 mmol of sodium.
associated with electrolyte distwbances, particularly of care is neccssa1y if large doses of the potassium orsodiwn salts • Gram-negative anaerobes including Prevote//a
sodium and potassium. Benz:ylpenicillin potassium in are given to patients with reiaJ impairment or h...n failwe. High (non-fragilis Bacteroides) and Fusobacterium spp.
high doses may lead to hyperkalaemia, particularly in doses of benzylpenicillin potassium should also be used with
• Other organisms including Actinomyces and the spi-
those with renal impairmenL While hypematraemia caution in patients receiving potassium-eontaining drugs or po-
tassium-sparing diulctics. rochaew;,Borrelia, Leptospira, and Treponema spp.
can result from the high sodium loads associated with
the sodium salts of bcnzylpenicillin, c.arbenicillin, flu- • Mycobacteria, fungi, mycoplasmas, and rickcttsias
cloxacillin, and ticarcillin~ hypokalaemia may also re- In teractio ns are not sensitive.
sult from sodium-induced solute diuresis. In addition, Probenecid prolongs the half-life of benzylpcnicillin
by competing with it for renal tubular secretion and Activity with other antimicrobials. Benzylpenicillin
many semisynthetic penicillins (including caJbenicil- may exhibit synergy with other antimicrobials, partic.
lin, cloxacillin, mezlociUin, nafcillin, piperacillin, and may be used therapeutically for this purpose. Clinically
significant reductions in renal clearance have also been ularly the aminoglycosides, and such combinations
ticarcillin) can act as non-absorbable anions in the dis- have been used against enterococci and other relatively
tal tubule, resulting in urinary potassium loss and hy- noted for arnoxicillin, nafcillin, and ticarcillin. Ben-
zylpenicillin may also interact with bacteriostatic anti- insensitive bacteria. Its activity may be enhanced by
pokalaemia. This effect may be mediated by volume clavulanic acid and other beta-lactamasc inhibitors,
depletion, and has been seen mainly in severely ill pa· bacterials such as chloramphenicol and tetrncyclines
(see Antimicrobial Action, below), and may be incom- and both enhancement and antagonism have been
tienls. shown for bcta-lactarn combinations. Antagonism has
patible in vitro with other drugs, including some other
Elrect.s on the blood. Rercrcnccs 10 neutropenia associated antibacterials (see above). been reported 10 occur with some bacteriostatic drugs,
with penicillins. such as chlorarnphenicol or tetracyclines, that interfere
I. Anonymous.. Antibiotic-induced nc:utrcpcnia. lonc~t J9BS: U: The possibility of a prolonged bleeding time after oral with active bacterial growth necessary for benzylpeni-
814. treatment with a broad-spectrum drug like ampicillin
2. Nefie) KA, ti nl. Inhibition or granulopoiuis in vivo and in V•frO cillin to achieve its effecL
by ~-lactam on1ibiotic.. J ln/ect Dl1 198S: t5l: 90-8. should be borne in mind in patients receiving anticoag-
3. Ol:iison L. Alcsh& K. A pro.spec.live study or MUltopc11i3 in- ulants. For further details, and for the effect of other Resistance. Susceptible Gram-positive bacteria ac-
duced by hip doses or P-laclam antibiotics. J Ant(1n;~rob Chtm- penicillins on the activity ofwarfarin, see p.1566. quire resistance to beta lactams mainly through the in-
oth<r 1990; l5: 449-53. duction of bcta-lactamases, including penicillinases.
4. Peraha FG. ~' ol, lncidc:ncc of ncutropcnia duril'll trtatmcnt of Hormonal contraceptives. For the effect of penicillins oo
bonc·rclated infections with pipcrxil1in-taz.obac1am. Clin /nfeci These enzymes are liberated extracellularly and hydro-
Di12003;37: 1568-72. oral contraceptives, sec p.2272. lyse the bcta-laotam ring. This resistance is usually
S. Scheett MH. ct al. S)'Jlctn.U•C review of pipcradllin-induced Metnotrexate. for the e~t of penicillins on mdhOUeXllle,
ncu1ropcnio. Dnig Saf•ty 2007; 30: 295-306. plasmid-mediated and can be transferred from one bac-
sec p.820. terium to another. Gram-negative bacteria produce
Effects on the nervous system. References lo CNS effects
associated with penicillins. beta-lactamases within their cell membranes which
l. Schli1ttn$Cr SE. ~1 al. Neuroto~icity of ~-lacllm antibiotics: pre- A ntim icrobial Action may be chromosomally or plasmid-mediated; all
dispMing C1e1on and palhogcncsis. J AntlMS<tolt Che111other Benzylpenicillin is a beta-lactam antibacterial and has Gram-negative species probably contain small
t99t; 27: 40S-2S. a bactericidal action against Gram-positive bacteria, amou nts of beta-lactarnases. Resistance in Gram-neg-
Hypenensit lvity. Rcfcrcnecs to hypersensitivity reactions as- Gram-negative cocci, some other Gram-negative bac.. ative species may also be due to changes in d1cir outer
sncfatcd with penicillins. leria. spirochaetes, and actinomycctcs. membrane resull.ing in the failure of beta lactams to
I. Sullivan TJ, et al. Skin IHtina t.o dcrcct penicillin 11ler1r. J Al-
1'1JY CUn lnmwnol 1981; 68: 171-80. It exerts its kiUing action on growing and dividing bac. reach their target penicillin· binding proteins. Changes
2. BecleyL.Allergytopcnicillin 8MJ l984;m: Sll-l2. teria by inhibiting bacterial cell-wall synthesis, al- in the binding characteristics of penicillin-binding pro-
3. Holp1e ST. Penicillin allergy: how to diagnose and when to teins may also result in resistance in Gram-positive and
tn:•1. BUJ 1988; 296: 1213-14. though dle mechanisms involved are still not precisely
4. Anooymous.. Penicillin allergy in chUdhood. Lonee/ 1989; I: understood. Bacterial cell walls are held rigid and pro- Gram-negative bacteria.
420.
S. Surtecs SJ, 01 of. Allergy 10 penicillin: fable or (act? BMJ 1991; tected against osmotic rupture by peptidoglycan. Ben- Most strains of StaphylocaccztS aureus are now resist-
JOl: lOSt-2. Correspondence. ibid.: 1462-3. z:ylpenicillin inhibits the final cross-linkjng stage of ant to bcnzylpenicillin. Streptococcus pneumoniae
6. Ano<>ymous. Penicillin allergy. Drug TMr Bu/1 1996; 34: 87-8. peptidoglycan production by binding to and inaclival·
7. Salkind AR, et al. ls this patient allergic 10 pcniciUin7 An tvi- with reduced susceptibility or complete resistance lO
dcnce.,bascd anilrsls of 1ht likelihood of penicillin 1lh:r1y. ing transpeptidases, penicillin-binding proteins on the benzylpenicillin have increasingly been reported.
JAMA 2001 ; 185: 2498-2SOS. inner surface of the bacterial cell membrane. However, Strains of Neisseria meningitidis with reduced scnsi·
8. Park MA. Li JT. Di:tgnosil and manage1nent orpc:niciltin 1llCf'8Y· it is now realised that other earlier stages in cell-wall
Afa)'o Clin Prr;c 200S; 80: 405-10. tivity to benz:ylpenicillin have been identified. Penieil-
9. Yatt.s Al:S. Man.igcment of palients with a hi$10l)' of allcray 10 synthesis can also be inhibited. Other mechanisms in- linase-producing Neisseria go11orrhoeoe are wide-
bcto· .....m lll41biotics. AmJ Mtd2001; 121: Sn-6. volved include bacterial lysis by the inactivation of en- spread; reduced sensitivi ty of gonococci 10
dogenous inhibitors of bacterial autolysins. bcnzylpcnicillin may also result from alterations in
Precautions
Patients known to be hypersensitive lo penicillins lts action is inhibited by penicillinase and othcc beta· penicillin-binding proteins. Most strains of Haemo·
should be given an antibacterial of anotlier class; sensi- lac1amases that are pr<Xluced during the growth of cer- phi/us inj/uenzae and Moraxe/la cotarrhalis (Bronha-
tised patients may also react to the cephalosporins and tain micro-organisms. mella cotarrhnlis) are now resistant
other beta lactams (but see also Hypersensitivity, under Many Gram-negative organisms are intrinsically re- Some organisms, usually Gram-positive cocci such as
Cefalotin, p238). Desensitisation may be anempted if sistant by virtue of the inability of benzylpenicillin to staphylococci or ~"t.rcptococci, may develop tolerance
treatment with a penicillin is considered essential (see penetrate their outer membranes. Intrinsic resistance and are inhibited but not killed by benzylpcnicillin; in
Adverse Effects, above). Penicillins should be given can also be due to structural differences in the target such cases the minimum bactericidal concentration is
with caution to patients with a history of allergy, espe- penicillin-binding proteins. See under Resistance, be- much greater than the minimum inhibitory conccntra·
cially to drugs. low, for reference to acquired resistance. lion.
All cross-references refer 10 ~nlries in Volume A
 Benzylpenicillin 233
Pharmacokinetics zy lpenicillin (p.347) are prefen-ed; they 3re given Where mcnon~ilis. and <SJ>ecially mcningoccx:cal dis.:ose arc
Benzylpenicillin l'apidly appears in the blood after in- intramuscularly. Benzylpenicillin is sometimes given suspected. a single injection of benzylpenicillin is advised ur-
gently before uansfcr to hospital in the foll()wing d =
tramusculal' injection of water-soluble salts. and maxi- orally for .infections of moderate severity, but one of
• irtfanls under one year of age: 300 mg
mum concentrations are usually reached in 15 to 30 the acid-resistant penicillins such as phenoxymethyl-
• children I to 9 years of~: 600 m~
minutes; peak plasma concentrations of about penicillin (p.341) is preferable.
• children from I0 )-can of •11e: I.~ g
12 micrograms.lmL have been reported after single Bcnzylpenicillin is available as the potassium or sodi- In the USA. the American Academy of Pediacrics1susgats the
closes of 600 mg. um salL The dose of benzylpenicillin should be suffi- rotlowing doses given 1ntramuscul11rly or intravenously:
When given orally, benzylpenicillin is inactivated fair- cient to achieve an optimum bactericidal concentration • alt oeooates with a birth-weight less than 1.2 kg, a11d neonates
ly rapidly by gastric acid and only up to about 30% is in the blood as rapidly as possible; concentrations may less than t W<:ek old with a birth-weight of 1.2 10 2 kg: 15 lo
absorbed, mainly from !he duodenum; maximum plas- be increased by giving it with probenecid (p.608). In 30 "'"'leg (25 000 lo 50 000 unitsll;g) every 12 hours
some countries, doses are still expressed in units. Ben- • neon ales less than t week old with 3 birth-weight of men: than
ma-penici llin concentnllions usually occur in about l 2 kg. OJtd neonates t week of oge or older ,.;th a birlh-weight
hour. In order to attain plasma-penicillin concentra- zylpenicillin porassium 600 mg or bcnzylpenicillin so- of 1.2 to 2 kg: l S to 30 mi'kg (2S 000 to 50 000 units/kg) eve-
tions after oral use similar to those after intrdmuscular dium 600 mg have generally been considered to be ry 8 hours
inject.ion, up to 5 times as much benzylpenicillin may equivalent to ab nut I million units (I mega unit). • neonates 1 week of age or older "id1a birth-weight of more
be necessaiy. Absorption varies greatly in different in- For some infections, doses of0.6 to4.8 gofbenzylpen- dian 2 kg: 15 10 30 mg/I:& (25 000 lo 50 000 unilSlkg) every 6
dividuals and is belier in patients with reduced gastric icillin daily in 4 to 6 divided doses by intramuscular or hours
• children t month and older. in severe infection, do$es of I SO
acid production, inclllding neonates and the elderly. slow intravenous injection or intravenous infusion may IO ~40 mg'kg d•ily (25000010 400 000 units/kg) divided in 4
Food decreases !he absorption ofbenzylpenicillin. and be adequate, but higher doses given intravenously, of- 10 6 doses, to a maximuin of 14.4 g (24 million units) daily
oral doses are best given at least half an hour before or ten by infusion, are more usual for severe infections. maybe used
2 to 3 hours after a meal. For example, in endocarditis, benzylpcnicillin 7.2 g Dosing rccommendalions in $Ome neonatal populations have
daily (l .2 g every 4 hows) intravenously, usually with been suggested based on phannocok.inctic models. A study in 20
Benzylpenicillin is widely distributed. It appears in pretcttn neonates (less than 32 weeks gestational ager con·
pleural, pericardia!, peritoneal, and synovial fluids, but an aminoglycoside, is recommended; doses of up to
finned that a regimen of 30 mg/l:s (50 000 unrts/kg) cv<ry 12
in the absence of inflammation diffuses only to a small 18 g daily are not unusual for less sensitive streptococ- hours is adequate for empirical 111:/tUnent of common infeccions
extent into abscess cavities, avascular areas, the eye, ci and enterococci. ln meningococcal and pneumococ- on the third day oflift:; but for infections due to highly suscepd-
the middle ear, and tl1e CSF. Inflamed tissue is, howev- cal meningitis, benzylpenicillin 14.4 g daily (2.4 g eve- ble organisms, u 24-hour dosing interval is'likely sufft<:ient A
ry 4 hours) intravenously is recommended; up to I 8 g study in very tow bitth-wcigln neonates (less than 1.2 ka) with
er, more readily penetr4led and, for example, in menin- gestational age less than 28 weeJcsl SUiiested that, for that poJ>-
gitis higher concentrations ofbenzylpenicillin occur in daily has been recommended for meningococcal men- ulation, IS mg/kg (2S 000 uniwkg) c•CI)' 12 hours was suffi-
the CSF. Active transport out oflhe CSF is reduced by ingitis. High doses should be given slowly to avoid ir- cient to achieve effective dmg concenlntions in rhe serum and
pl'obenecid. Jn patients with uraemia, other organic ritation of the CNS and electrolyte imbalance, and a CSF for the tttatment of group B strcpeoooccal infections.
acids may accumulate in the CSF and compete with rate of not more than 300 mg/minute is recommended I. Amcncan Aca&:m)- of Pccfia1rics. 2no9 R¢ Boo!: Rep<>1·1 ofthtt
for intravenous doses above 1.2 g. High doses may Com111111u on /11ftt1io11J Dl.1<10s11. 281h ed. Enc: Grove Vill:ige.
benzylpenicillin for active transport; toxic concentra- llliuois, USA: Amcrian Ac,dtmy or Pcdiurics. 2009.
tions of benzylpenicillin sufficient to cause convul- need to be reduced in patients with rnnal impairment ?. Muller AE. ~ al. Pharm1cokinecic1 ar penicil!in 0 in in(tnts
(see below). with n Q"estnlion;il :11c of &cu lh:an 32 w~k.s. Anti1fli<:t0!1 Aiot.ts
sions can result. Cilemothu 2007: 51: 3720-S.
In patients with suspected meningococcal infection, 3. M~l$vtht T. ti ol. PhamwookillCtics of penicillin 0 in Vtf')'.. kJw..
Benzylpenicillin diffuses across the placenta into the benzylpenicillin 1.2 g by inb-avenous or intl'llmuscular birth-w~i&ln neonates. Anti111io-ob AgfmLT Chemotll'f!r 2001; 51:
feral circulatior., and small amounts appear in breast injection should be given before transfer to hospital. 199$-2000.
milk. Administration in "'"al impairment. Doses of parenteral
A dose for intrapartum prophylaxis against group B benzylpmicillin should be rodoo:d in pelients with renal impair-
The plasma half-life is about 30 minutes, although it streptococcal infection is benzylpenicillin 3 g intrave- ment, particularly when hig)Hlose regimens are being use<!. For
may be longer in neonates and the elderly because of nously initially, then 1.5 g every 4 hours until delivery. doses of0.610 1.2 g, UK licensed product infonnalion suggcSls
reduced renal function. In renal impairment the half- dosing int.en-ats no more lieq""nt than "'"Cr)' 8 hows. For high-
For details of doses in children, see below. dosc regimens used in the treatonent of serious infections, il rec-
life may be increased to about I 0 hours. AbOLtt 60% is
l'eported to be bound to plasma protein. Other routes. Benzylpenicillin eye drops and eye oint- ommends the following ~ based on crcatinine clearonee
ment are used in the treatment of susceptible eye infec- (CC):
Benzy!penicillin is metabolised to a limited extent and tions. For subconj unctival injection, 300 or 600 mg of • CCGOmVminule: l.2gevery4hours
the penicilloic acid derivative bas been recovered in the benzylpenicillin has been dissolved in 0.5 to 1.0 mL of • CC 40 mUminute: 900 mg every 4 hOurs
wine. Benzylpenicillin is rapidly e11creted in the urine, water, or another suitable solvent such as lidoca ine 2% • CC20mUminute: 600mge~ry4hours
pi1ncipally by tubular secretion, and about 20"/o of an with or witl1out adrenaline I in 200 000 or similar. • CC 10 mlfmL,ulc: 600 mg every 6 hours
oml dose appears wichanged in the urine; about 60 to Benzylpenicillin has also been given orally on an emp- • anuric: 300 mg every 6 hours or 600 mg every 8 hours
90% of a dose ofaqueous benzylpenicillin given intra- ty stomach in adult doses of 125to312 mg every 4 to Where ad'-anced liver disca~ is associated witb severe renal fail·
muscularly appears in the urine, mainly within the first ure. 1he reconnnendcd dose is 300 mg every 8 hours. Hacmodi-
6 hours. alysis patients sboutd be given an additional 300 mg el'ery 6
hour. Significant concentrations occur in bile, but in hours during 1he chatysis ntn.
patients witl111ormal renal function only small amounts lntrathecal injections are no longer recommended.
Alternatively. some US experts recommend the following:
are excreted via the bile. Benzylpenicillin is removed Administration in ch~dren. Benzylpenicillin may be given
to neonates ond children for lhc lJCltmcnl of infections caused by • CC 10 10 SO mUtninute: 7S~~ oflhc total recomniendtd .me
by haemodialysis. • CC less thon 10 mL'minutc: 20 to SO'!. of the totol recom-
susceptible organisms by intTamuscular injection. or by slow in-
Renal tubular secretion is inhibited by probenecid b·avcnous injection or infusion; the intravenous route is f'Cl..."Orn- mended dose (\\'here haemoclialysis os required. doses should
(p.607). which is sometimes given to increase plasma- mcndcd for neonates and infunts. in the treatment ofcndocarditis be timed to be given ofter the diolysis run)
or meningitis, and in the treatment and prevention of neonatal
penicillin concentrations and prolong half-life. groop B streptococal infections.
Preparations
BP 2010: ~ilin lrjce\I""'
In the UK, the 8IVFC 1009 recommends the following doses:
Uses and Administration
Benzylpenicillin is used in the treatment of infections
For mild to moderate susceptible infections. includinc throot
infections, C>titis media, ~1onia, cellulitis, and t>eon:Jtal sep-
....
~~ :.~~<!"~ ~b."ci:J'S::~.!~~~:.,~
lion: Pe0<•lhn G ~Tablet~ Pcnlcolln G SO<fun lor~
:t:
due to susceptible organisms (see Antim icrobial Ac- sis: Proprietary Preparations (dc:lails are 1-iven lU Volume 8)
tion, above). They include abscess, actinomycosis, an- • p<ctenn neonates and those under 7 days of age: 25 mg/kg pt; Austro'-: Benpe_o: Broz.: AricW.:.: &:1"..n:<il~n:
Ari,: Pen1l'cdrin
Crist<lp\."1, Met'f""\1' Per.cl P: Con<>d.: (jy<'.op<n: Fin.: Geepei; Indio:
thrax, bites nnd stings, diphtheria, cndocardit\s, gas every 12 hours; dose doubled for severe infection ~'IX~ In.: ~Mex.: Oe<lt>: Fimlilbop; Pendi><n L-A
• neonates 7 to 28 days of age: 2S mg/kg every 8 hours; dose ~t: !'<mot Procos<>L Ptt.lOdnl. Scd'pcn. l.h>lcll 311; lhd 6:ll
gangrene, leptospirosis, Lyme disease, meningitis. Uncil Mega; NZ: B.?r.p<.". Ploilipp.: Crysucil; H.loblpen: f'enwv: S.A(r"
doubled for S<:vcrc infoction
meningococcal infections, necrotising enterocol itis, Bcnulte Bio-Pen: l~°""P""1· Spoio: ~bet Peni'evel: Sodlopen: U"oclo-
• children from 1 mond1 of age: 25 mg/l:g every 6 hours; in-
necl'otising fasciitis, neonatal conjunctivitis (if gono- creased to 50 mg/leg every 4 to 6 hours (rn:iximum 2.4 g every ~ ~~J;.I,tt!:;'IT,'3:6.~~:t~'s:; ~
cocci are sensitive), perinatal streptococcal infections 4 hours) for SCYere infection ciln: UK:~ USA: Pfo.<'f!W< Vener.: Pebencilt S.t:openj.
(intrapartum prophylll.llis against group S streptococ- For cndocordiru: Multi~nveditnt Aurtl'lo: For<CP<ot: Ophci1n Nf. Re'¥1*' compos>
ru<r< Broz.: 8enopen 8erxapen G: Cks;>ocilnl: ClnncM<1: E>q>eao<-act
ci), phaiyngitis (or tonsillitis), pneumonia, skin infec- • children from I month of age: 25 mg/kg every• hours; do.-;c Gin<J<QVKj. t..r/ocJr¢~..cf:Q1-.oc~:ot;l'ttld'l()(k~Wy­
tions, syphilis (neurosyphilis and congenital syphilis), may be doubled (maximum 2.4 g) if necessary C1llin; Chil•: l<Htll"'nf: " " ' - Forte: Fr.: 8icfnocJlnct: G..." l!ip><>-
sa•rt: l\olllollon ~ Hon1 Koni: P•o>-For\ Pro<-. Fl!<l,;111-> G
tetanus, toxic shock syndrome, and Whipple's disease. For tre•ttnent or prevention of neonatal &roup B streptococcal Proa•ne ror1.i(ed: Hun'.: Pn:m;t.cilin F01·tc; Indio: B.strepcte It.al.: Tri-
It is also used for surgical infection prophylaxis in first infection: Wyc•S:l\at ; Malaysia: Ptoc:.¥W! Ptn.c1lt1n: Mex.: AguipenUI: Ar"Qpe(lll
• pretenn ~onates and those utldc'f 7 days of age: 50 mg/l:g Benc<ln Comi,;,,.do: 8enz.ir.i Compuc<tol. ll<nzeoot Corr.oo.dcx l-ficl.
trimester abortion in women at high risk of pelvic in- Lu~ Mez>.;>e"I N:>rtd. ~'4>1: Pondben Compuo>toc Pe1it.t
fection. For details of these infections and their treat- .,.cry 12 hours -
Peripo< Per•>Odin~ ""'1ptocilN. l'roc#t Robcroxil: Sulpen: N oth.: Pe<»
• nconateS 7 to 28 days of•&•: SO mg/l:g every 8 hours 0-rol Olft Port.: Atralerlonaf. A~ Le.-rt.ocllln: P°"adut U3t:
ment, see under Choice of Antibacterial, p.170. ~ Rut.: llici lln·) (S....W-3); S.Afr" P..,llenle fcrt~ lJlln.
F'or meningitis: Cllin: Spain: Aqudini1 D At Bcn.-etad C~ C•podlona 63): Ne<>
Benzylpenicillin is usually given intramuscularly or in- - neonates: 7S rng,1\g every 8 hours penylj-: Ponie....i Rctrd: Turk: Pe!XMI l<: ~Venn.: ~z.,1tll 3·
trnvenously. Where a prolonged effect is needed ben- • children from I month of age: 50 inglkg ·~· 4 10 6 hours 3: s..u.tad 6-l·l: "'"'"•I"'"
zathine bcnzylpenicillin (p.230) or procaine ben- (maximwn 2.4 g every 4 hours)
The symbol t denotes a preparauon no longer actively marlr.eted
234 Antibacterials
Besifloxacin (tlNN) Biapenem (USAN.1Hm) infections, including amoebiasis, but less 1oxic drugs are pre-
Biapenem; Biaper>emcm; CL-186815: L-627: LJC- 10627. 6· ferred.
Befloxacine: BesiRoxacino: BesiOoxacirn.m. 7{(3R}-3·Ami·
noazepan-1-yf]-8-chloro--1-cydoproprl·6·fluoro-4·axo-1,1-dihy- {((4R55.65)-2-Catboxy-6-(( IR)· 1-hydroxyethyl]~-mcthyl - 7. P repa r a tions
droquinoline-3-carooxylic "id. oxo-1-a.zabicydo[3.2.o)hept-2-en-J.yf)'Jiio)-6.7-0liydro.5H- Proprietary Preparations (details arc given in \t>lumc B)
pyrazolo[ I.l-o]-s-1riuolA·i<ln hydroxide. inr.er sah. Fln.:St~.
&e3+oxcau•H
C 19H1 ,CIFN!O? 393.8.= &.ane..e1•
c ,sH, 9N,o,s = 350.4.
CAS- 141388-76-3. CAS - I 20410-24·4.
ATC - SOIAX23. ATC - )OIOHOS. Capreo m ycin Sulfate :tJSM( ,../NM)
UNI/ - 6FEZN6Z7NX ATC Ver - QJOIOHOS. 31977: Capreomycin s.Aphate (e.W\4); ~. Sulf.!te
UNll-YRSUJL9ZHI . de: CapreO!TljOOi Sulfas: Capromyon Sulphate: 5'llato de capre-
omicina.
~npeOMH:JHHa Cy~r
CAS - I 1003-38-6 (capreomycin): I 405-37-4 (copreo-
mycin sulfate).
ATC - )04A630.
ATC Vet - QJ04AB30.
UNI/ - 9HBD3j7V2 ! .

Profile
Biapenem is a c:arl>apcnem bcta-Jaetam antibacicrial similar lO
Besifloxacin H ydrochloride (US.W ttNNM) imipcncm (p.311), although ii is reponed to be: more stable IO
BCsifloxacine. Chlorf1)'drile de: BeSllloxacini HydrocNoridum: renal dehydropeptidasc I lhan imipencm.
BOL-303224-A; 1-fidrocbvo de be!llloxactt>: SS-731. (+)-7- OReviews.
((3R)-3-~IH-;aepio-l-)l}-S<tl«o-1-cydopro­ l. ~CM, lbbouon T. Biapene.m. Dn¢$ 2002: 62: 2221-~.
Pi'-6-llooro-4-oxo- 1.4-dhydroq.inoline·3-carbc:Jx)fic acid ry. 2. lb.... K, <I at Populaoon phannacokinctics and phannoc:ody·
drochloride. namics or bi.apcncm in pacdiarric patients. J Clin Phon11 TM'
2008; 33: 203-10.
6e•~cau.,.. r....,poXi'Opt<A 3. lhwa K. ~'al. Phannacokinetje-pliannaeodynamic ta1'et attain·
C19H2 1CIFN;03.HCI 430.3. = ment analysis of biapcncm in adult patients: a dosin& strategy.
Chtmotl1Uopy 2008: S4: 386-94. "
CAS - 405 I 65-61 -9. 4. lsobe V. •'al. Clinical and microbiologic.al elfccts orbiapcnem Gap<eomycin IA R • OH
ATC - SOIAX23 in rcbnlc nculropcnic patiems with hema1olog_k millignancics. Capteomycin tB R • H
.~011d J lnfoct Dis 2009; 41: 237-9.
UNll - 7506A6)57T.
(capreomycin)
Profile
Besifloxacin is a fluoroquinolone antib,ae1erial with propenics
$imilar to those ofeiprofloxacin. IL is used topically as lhe hydro-
Bro dimoprim (riNN)
Description. Capreomycin I oonsisrs of capreomyein IA
chloride in eye drops conlllinin& !he equivalent of 0.6% besi- Brodimopnma: Brodimoprime; Brodimoprimum: Ro- I 0-5970. (~ 1401 = 668.7) and C3preomycin IB
floxacin for 1he tn:atment nf conjunc1ivitis caused by s=ptible 2.4-Diamono-5·(4·bromo-3.5-dmethoxyt>el\l)'l)pyrimidine. (C,,H.,N,.O, = 652.7), which predominates. Caprcomycin U,
bacteria. "ttich makes up about 10'.4 of !he mi).iure, oonsisu of eapreo-
6po-">'MOOJ>"M
mycin llA and c:apn!'Omycin UB.
0 References. CnHosBrN,01 = 339.2.
CAS- 56518-41-3. Phannacopoeias. In Chin. and US.
I. Tepedino M£• ., al. Phase Ill efficacy and safely study of besi· US P 33 (Ca~ s.K.ate). The disulfatc ofcaprcomycin. a
floJC.1C'in ophthalmic suspension 0.6% in the lteattncnl or bxtc.·
ATC - JOIV.02.
rial conjWlcliviti.s. Curr Med Rts Op;,, 2009; 2.S: I IS9-69. ATC Vet - QJOI EM2. polypcp1idc mixrurc produced by the growth of Slt-qJ1omyces
UNll - VIYC7T6lll. capreclus. h contains not less than 90".4 of capreomycin I. A
2. K:,rpecki P, e1 al. Bc11flo.x1cin cphthalmic suspe.m,ion 0.6% in
pelicnu: wilh bacterial conjunc-tiv11i1: a mullkentet, prospec:tlve-, while lo practically while amorphous powdet. Freely soluble in
randomized, double·masked, vchicfe·controllrd, S..day efficacy water; practically insoluble in most organic solvcnrs. pH ofa 3%
and .. rc1p1udy. C/i11Thcr2009; 31: 514-26. solution in waler is between 4.5 and 7.5. Store in airtight contain-
3. McDonald MB, 111 ul. Efficxy and nrety of bcsiOoxacin oph· ers.
1h:ilmic suspension 0 .6% compared wi1h moxiOoxa.cin ophlhal·
mic solu1ion O.So/o for trcaling bacterfol conjunctivi1is:. Ophthal· Adve rse Effects and Treatme nt
mology2009; 116: 1615-1<>23.ol. The effects of caprcomycin on the kidney and cigh1h cranial
4. Haas w. er al. Bcs10oxocin. a no\•cl nuoroquinolonc. has broad· nerve arc similar lo those of aminoglycosidcs such as gen1amicin
.spectrum in ''itto activi1y ag.ainsc 1ct0bic and anaerobic bacteria. (p.306). Nitrogen retention, renal tubular dysfunc1ion, aud pro-
14"/imkrob Agents Clr('morhc-r 2009; 53: 3SS2~. gJCssivc renal damage may occur. H)')>Ol:alac.mia and othcrelec-
S. Caner NJ. Scon U. BcsiOoxacin ophthalmic .suspension 0.6%. 11oly1e abnormalities have botn rcponed. Vertigo, riMirus. and
°"'IP 201 O; 70: &3-97. hearing loss may also occur and are sometimes ilTe\lel$ible. Ab-
Pre parations Profile nonnalilics in liver function haYC been reponed when capreomy-
Brodimoprim os closely related strue111rally to uimc:lhoprim cin has been used wilb other anlituberculous clnigs. H~·
Proprietary Prep•r.itions (d<u1ls arc given in \t>lurne B) (p JBS} 111d has heal used in lhe treatment of infections of the tivity reaciions including urticaria, rnaculopapular rashes. and
USA:Bmnnte. respiralofy tract and car. sometimes fever have been reported. Leueocytosis and Jeuoope-
0 References. nia ha\'c also been obscrvod. Tioromboc:y1opct1ia bas been report-
I. Bn•unlltintr AR. Finsinger F. Srodimoprim: thenpeutice:mca- ed rarely. Eosinopbilia commonly occurs with c:apreomycin.
Betamipron (tlNN) cy lf'!d urc1y in lhc trea,ment of bacterial infee1ions. J Chemolh- Caprcomycin also has a neuromuscular blocking action. There
.,. 1993; 5: 507-11. may be pain, indlltation, and excessive bleeding at the sile ufin·
N-BeflZoyl-11-aJanjne: Be1amiprot1: Bewriprorn..m; CS-443. 3- rramuscular iojeclion; sterile abscesses may also fonn.
Benzamidop<opiolllc acid. Tcnnogenicity has been seen after high doses in rodcnrs.
6eTaM1i1 npow Broxyquinoline (1/NN') Trcatmcnl ofoverdose is generally supponive. Pa1ienrs with nor-
=
C, 0 H 11 NOJ 193.2. B<oksikinoliini: llroxicl\ino!inum; Broxikhoin; Broxiquinolina; mal renal function should be hydra1cd 10 maintain adequate urine
ouipul. Caprcomycin may be removed by hacmodialysis in pa·
CAS - 3440-28·6. Broxyqui'lolinum. 5.7-Dibromoquinolin-8-ol.
UNll - 3WOM24S736. tients with significant renal impairment.
6poKCHXl11 IOAH>I
C1Hs8r1NO 303.0.= Impurities. The manufacturer of a highly-purified capreorny-
ein product (C,,pocin; Cheilj~ng. Kar.) has claimed 1hat such
CAS - 521-74 ·4.
H ATC -A07AXOI; GOIAC06; POIAAOI. purilic:ation reduces the IOXicity and allcrs the phannaookineties
in animal studies, suggesting that some of the toxicity ofc:apreo-
0

6
N~O ATC Ver - QA07AXOI. QGOIAC06.
mycin is due 10 such impurities.1
UNll - UK4C6 I 8C8T.
I. Lee SH. a al. The impurities or c1prcomyc:1n make I diff'crenc:c:
~ OH in the pfrty and pharmacotinctic profiles. ln1 J Anlimiaoh

I~
OH Ag<nlS 21l03; ll: St-3.

erylyN~ Precautions
Capreomycin should be: given wilh care and in reduced dosage to
Profile
Betamipron is a renal protcelant u$Cd wi1h the carbapenem anli-
baclerial panipenem lo roducc its adverse renal effects.
tlyv
Br
patients with renal impairment. Care is also e~lial in patients
"ilh signs ofeig)llh cranial nerve damage. It is advisable lo mon-
itor renal and auditory fun<:lion and serum·polllssium oonecnua-
lions in patients before and during therapy. Periodic assessment
Preparat ions of hepatic function is also recommended.
Proprietary Preparations (details arc iiven in ~fume B) Profile Inter actions
Broxyquinolinc is a halogenated hydroxyquinoline thal has been Care should be taken when capreomycin is used wilh olher drugs
M ulti-ingredient: /pre
Cl1benin
used topically in vaginal infections. II was also formerly given lhal ha\'c neuromuscular blocl:ingadtivi1)'. h should no! be given
orally, with broxaldine. in !he treatment of intestinal procozoal with other drugs that are olotoxic or ntpluoloxic.
All cross-references refc.- lo entries in Volume A
 Besifloxacin/Carumonam Sodium 235
Antimicrobial Action Prohcntcid increases a11d prolon~ plasma conc:cntrncions of
Caprcomycin has activil)' againsl various 1nyoobac1cria. Rcsist- carbenicillill.
ana: develops readily if capreomycin ii: u~cd alone. It shows Carbcnicillin is rcmo"cd by hacmodialysis and, to some extent,
cross-resistance with kanamycin and ncomyci11. by pcrito11c31 dialysis.
0 References. Uses and Administration
I. Ha YU. ct ul~ ln..viuo :icti.,.itit11: 0(1m1nosl)'COSidc-aminocydit· Carbenicillin is a carboxypcnicillin Chat has been given by inJCC-
ols :i_pinn mycobatlcria. J Amlmlcrob CbeNOthc-r. 1997~ 40: tion as the disodium sal~ often with gentamicin, in the creatmcnt
27-32. of infcctioos due co Psm1dt>mo"m oeruginoso; ho"'Cver. other
~. M3u$ CE. Cl al Mol«ubr Mllly11is or cross·ruimncc to captc:· antipscudomonal penicillins such as ticarcillin (p.382) or pipcra-
omycin, kanamyc1n. omiktcin. :ind viamycin m Mycoti.c:tcnu01
cubcr-cul0$i5. Antimt~ A~m"' Chc.mmher 2005: .a9': 3192-7. cillin (p.342) arc now preferred. II has also been given to treat
(corbenici!linj serious infections due 10 non-penicillinasc-producing strains of
Phannacoldnetics Proteus spp.
Caprconiycin is poorly absort>cd from lhe gascroinlCSlinal tract.
Pharmacopoeias. In Pol. and US. Estco·s of ca1bcnicillin, such as carindacillin (p.235). ha\'t been
An intramuscular d~ of I g has been rcpo11cd to give a peak
USP ll (Carbenicifiin Dsodo.rn). A white co off-whi1e cl')'Sl3l- &ivcn orally in chc crcatmenl of urinary-tract infCClions.
scrum coneentration of about 30 miaogramslmL after I or 2
hours_ About 50% of a dose is o.crelcd unchanged in lhc wine linc powder. Freely soluble in waca; soluble in alcohol; practi- Preparations
by glomerular filtration within 12 hours. Capreomycin is re· cally insoluble in chlorofom1and in ocher. pH of a solution in,.•. USP 33: C.:bendin !or~'°"
moved by haemodialysis. tcr concaining die equivalent of catbcnicillin 1% is becwecn 6.S
and 8.0. Store in airtight containers.
Uses and Administration
Capreomycin is a second-line antimycobactcrial that may be Incompatibility. Carbenicillin sodium bas been reported to be Carindacillin Sodium (IWlll>\ tJNrlMj
used in the trcaunent of tuberculosis (p.212) as pal1 ofa multi- incompa1iblc with aminoglycosidcs, tecracyclines, and many
Carbc:r'cil.n lndan)'l Sodium (U$"'1}: Carindacilina s6dica: Carin-
dlug regimen when resistance to primul)' drugs has developed. other drugs including other antimicrobi3ls and ch~se drugs
should therefore be given separately. daciline Sodique; CP-1 5464-2: Natrii Unndacillimm. Sodium
Caprcomycin is given os the sulfacc by deep intnlmllSQllar injec- (6R)-6{2{ndan-S-yjoxycart>onyl)-2-phe<>y'.1Cetamido]peniciTia-
tion or by incravenous infusion. The usu3l dose is the equivalent Adverse Effects nate.
of I g ofcaprcomycin base (maximum 20 mg/kg) given daily for As for Benzylpcnicillin, p.231.
2 to 4 monchs. chen 2 or 3 times weekly for the remainder of HaTp•i'<Kl~
Hypersensitivity reactions have been rcpo1tcd 10 be Jess !Rquenc
thcn!py. c~ 6H,,N2 Nao,s = s 16.S
and less severe with cartcniClllin lhan with benzylpcnicilli.n. CA$ - 3553 1-88-S (cor111docillin): 26605-69·6 (coruldo·
For dclails of doses in children, sec below. Pain a1 the injecrion site and phlebitis may occ\11'. Electrolyte dis- cillir. sodium).
0 References. cwbanocs. particularly hypokalatmia or hypematraemia. moy ATC - jOICAOS.
I. Anonymous. CaptCOITI)'C'IH. Tt1bc:n:ufosis (£dinb) 2008: SS: follow large doses of carbenicillin sodium. ATC Vet - QJOICAOS.
89- 9 1. A dosc-dcpen~c ooagulncion defect has been reporled, espe- UNll -- 40UL8 I K2RT.
Administration in children. For the treatment of dnig-rcsist· cially in patitnts with renal impairment. Carbcnicillin appears to
ant ruberculosis in infants, children, and 3dolcsccnts the Ameri- interfere with platelet f'unccion tl>crcby prolonging"bleeding lime;
can Academy of Pediatrics' suggests un ininmuscular dose of puspura and hacmonbage from muoous membranes and else-
caprcomycin 15 co 30 mgllcg daily, lo a maximum dose of I g where may rcsulL
daily. Precautions
I. American Academy orPediatriC'S. 1009 Red Book: P.eporl 0/1/Ht As for Benzylpenicillin, p.232
Con1111i1'~~ 011 h!fec1iou1 Diftosn, 28th ed. Elk Grove Villaac.
Illinois. US.o.: American Acadenly o( Pediarrie!, 2009. Sodium content. Each g of car~n icillin soJium cotllJlillS
aboul 4.7 mmol of sodium. Carbenicillin sodium should tl>erc-
Administration in renal impainnent. As with amine>glyco- forc be given wiOi caucion lo paticncs on a restricted sodium diet.
sides, Uoe parenteral dose of caprcoinycin in pa1icnts with renal
impairment must be redur..ed based on crcalimnc cle-4ronc.:; Che Interactions
desired study-scace serum cap1·eomycin level is As for Benzylpenicillin, p.~32. Pharmacopoeias. In US.
10 mkrognunslmL Antimicrobial Action USP ll (Co-benialln lndanyl Sodo.m). A while to 011'-whicc
Prepilrations Carbcnicillin has a bactericidal mode of action similar to that of powder. Soluble in waler and in alcohol. pH of a I 0% solution in
USP 33: Ui>roomy::» for"""'°"' bcnzylpcnicillin, but with an extended spectrum of accivity
againsc Gram-neo,,;itivc ~ria.
w:ner is between 5.0 and &O. Score in oirtighc concaintl'S.
Profile
Proprietary Preparations (ck••ils ore given in Volume BJ
Aurttol.: Cap•rut Austria: CapHUtf: CL: Capart.r.t: Gr.: c..p..sw_ • It has ac1ivicy againsc Pse11domo11os uemgi11osa, allllou~1 Carindacillin is the indanyl eslcr ofcarbcnicillin (p.235) to which
Rtu~ Uj>as'.a< (KanacraTl. LY<OCJI\ (/\1-): Spafo: Capastat UK: C.· high conccntn11ions are imcrally 1J«CSSa1y. Activicy against it is hydrolysed after absorption from che gastrointestinal lract. !cs
p&st>t USA: up&R>t Ps. ""'""J:iMSCI n11d sonic Olher organisms can be enhanced by use h:is been rcslricted co Che treatment ofurin3ry·lract infections
gcntamicin and oOier ominoglycosidcs. due to Pseudomonas 5"1>· and other sensitive bac•cria inchxling
• ProlftJS, including indole-positi\'C spp. such as Pl: ndgoris aR Proteu• spp. .
Carbadox CW< thW pJNNj olso scnSJtive. Carin~cillin may Ix given orally as the SO<hum sail; 535 mg of
• A11ainst other Gram-negntive bacteria eccivity is similar co canndacilli11 sodium is equivalenc co aboul 38:! mg ofcarbenicil-
Carbadoxum: GS-6144. Metriyt 3-q•Jinoxa'n·2·ytme:hy{enecar-
nmpicillin. Scnsicivc organisms include some Enlcrobnccc- lin. Usual doses, expressed in tenns of carbenicillin, have bet:n
bazate l,4·oioxide. riaccoe, for example Eschel'ichit1 <'Oli and En1~111r spp.: 382 to 764 mg four times doily.
Kap6aAOKC Haemophilur influm:ott; ond Neisseria spp. Klebsiella spp.
Sodium conte nt. Each g of canndacillin sodium contuins
C11H 1oN 40, = 262.2 arc usually not suscxptiblc.
CAS - 6804-07-5. about 1.9 mmol of sodium.
le has less acri\•ity a1ai1lSI Gram-positive bectcria than ben-
UNI/ - M2X04R2E2Y. zylpenicillin. Preparations
• Anaerobic organisms are i:enerally suscepciblc but high con- USP 33' Ca~>eniallll lndlnf. Soc!u:r. Tab1.-,s
cencracioos are required for BocJeroidu fi·ogilis. Proprietary Preparations (~ifs •re given in \Illume BJ
USA: Geocilnt.
Resisrantt. Carbcnicillin is inactivated by penicillinases and
(TI 0 some other bcta-loctamases, although it i$ more stable to the

YN'II
, N"' N,
0
)l0 ,.CH3
chromOS<'mally mediated bcca-l3ctamascs produced by some
Gram·negati\'c organisms. induding Ps. oeruginoso and some
P..oteus spp. Resistance co c.'IJ'bcnicillin may de\'elop i11 Ps. uer·
Carumonam Sodium ~~~ dNNM)
AMA-1080 (cuumonam): Car'UJTl0<\2<11 s6dico: Cai·urnomm
0 ~ N uginoso during tre:auntnr with carbcnlcillin or olht:r beta Sodiq~ CRMN; Navi Ca1"mona~ Ro-17-130 I (car\liTion-
H lactams. This resistance moy be intrinsic where lhcrcarechaw~es am): Ro-17-2301/006 (carumonam sodU:n). {Z)-(2-Amnothia-
in cell wall pcrmc:<1bility or penicillin-binding pro<eins, or it may zol-4-yQ([(25.3S)-2-wi>amoyfoxymethyl-'1-oxo·l-suiphoazeti-
Profile be due co plasmid•mcdiated belll-lactamase produccion chac may
di1-J-yl)ca1t>a~ino-0><yacet1c acid. cisodium
Carbadox is an oncibacterial that has been used in veterinary be transferred co and !Tom certain sinins ofEncerobactcriaceae.
salt
praccicc for treacing swine d)•stnlery and entcricis and for pro- There niay be cross-resistance between carbenicillin and other
anlipscudomooal penicillins. Hnp.1,::; KapyMOHa..
motins growth. However, its use has been prohibited in 1he EU
ond some other counlrics after reporlS ofcaicinogenicity. Outbtcaks of pseudoinona.l o'Csistance co carbctlicillin have been C 1 :H 1 ~N 0Na~0 10S2 = ~10.4
associated with C.'ttcnsivc use in, for cxampl~, hospital bums CAS - 87638-04-8 (corumonom); 86832· 68·0 (<oru-
unils. monam sodium).
UNI/ - B4}4M4939D.
Carbenicillin Sodium (8ANl/i. rlNM''~ Pharmacokinetics
Carbcnicillin is nol absorbed from the giistrointcslinal tract and
BRL-2064; Carben:cilina s60cl: Cubenic1llin Oisodium llMN}'. has therefore been &ivcn either intramuscularly or intn1ve11ously.
Carbenidline sodiquc: Carbenicilir't.rn natncum; n-Carbox)'bef\- The half-life of carbcnicillin is repo11ed to be about l to 1.5
zy!;Jenic Nin Sodium; CP-lS-6;9-2; GS-3159 (carbenicimn potas- hours; ic is increased in pinienrs with renal impairment, ~1-
sr.im): Karbcnic1llrn-Ntritr.1; K.arbenocyfr.a sodowa: Matrii Cari:>e- ly if there is also hepatic impaim~nL and also in neonates. Half-
nioftlR<.fn: NSC-11 ! 071. The di sodium salt of (6R)-6-(2-carboxy- lives of I 0 co 18 hc>urs have been repo11cd in renal impairment.
2·phcn)4acewnido)penicllanic acid . Ocarance is enhanced in patients with cystic fibrc>sis. Carbc.ni-
H;;T"""1~H cillin is about 50% bound co plasma proteins. Dislribution of
C,,H,.N 2Na10 6S 422.4. = carbcnicillin in the body is similar to \hat of other penicillins.
Small amouncs have been detected in breast milk. Thero is little
CAS - 4697-36-3 (corbcmc111in); 4800·9{-6 (corbcnJC1ltin
disodium); f 7230-86 -3 (corbenicillin pocossium) diffusion into the CSF except when the meninges are inflamed.
ATC - JOICA03. Relatively high concentro.cions have been reported in bile, but (~orumonam)
ATC Vet - QJOICA03. carbcnicillin is cxae~d principally by re11ol tubular secretion
UNll - 9TS483H261 . and glomcnilnr filcration. Pharmacopoeias. In Jpti.
The symbol t denotes a preparation no longer actively marketed
236 Antibacterials
Profile against Hoemophilus injluenzoe. It is active against ~->< Kauncl: Malcov.it'< l"oedolox; P.>ncJor. ~b't>e Streptocol-R:
Carumonam is a monobeciam amibacterial with a specuum of U~ Honi Kon1: Camlf; Ceclor; Celiloct. Clortr"1: Me<ioclor:
some beta-lactamase-producing strains of H. injluen- Phoclcr: Quali<eclor: Q.loliphor; So6dor: Syn!aclor: Vorce(: Vid<clor:
antimicrobial action in virro similar to that of 1121JCOn8m (p.227).
II is given by intramuscular or intravenous injedion as the sodi·
zoe. lt may be less resistanttostaphylococcal pcnicillin- Hone-: Ccctor. C.Clore"a: ll<t<tlt. Indio: Habctf. Keflor: In don.: Cai>o-
batic: Ceclc><t: Clo<>cel: Espedorf: fcrilek; Medikonceft. Soder. lrl.; Cef-
wn salt and doses are expressed in terms of carumonam; 1.09 g ase lhan cefalexin or cefradine and a marked inoculum . , , 0.'1a<IO<': K.rt;d: Pnactor. luaok Celalor: ltol.: Allodor: Bxtccf.
of carumonam sodium is equivalent to about l g of carumon.am. effect has been reported in vitro. Bact1gram: CcilAtonf: Oond: Clcl'Uer: Dorff Euroccf.xt: GenclcY;
The usual dose is 1 to 2 g daily in two divided doses. l<Jo.Kct lafardo,-, Ma."""°" Nedorn Omasp;rt; (.hl(f:f P.wccf; Pcrbm-
er. SeMclor: T•ke<et Tblor. Vale<lor: M olaylio: Oislador: Cfxb-: Si-
Sodium content~ Each g of carumonnm sodium contains Pharmacokinetics faclor: Sofo<lor: ~et Mex~ Atcefal: Ccc: Ccclot: ~ ~ Fasi·
about 3.92 mmol ofsodium. clor: Fermed. Jlandor: S..Vdor: Tecnoclor; T - Neth.: C«Jor: NZ:
Cefaclor is well absorbed from the gastrointestinal Ctorotl1: PhfGpp.: Aactxi: B<elO>t: Cec:lobod Cedor: CFC: Oor-cef.
Preparations tract. Oral doses of250 mg, 500 mg, and I g produce Cloroti'f: EplYcrc l.crcef. A<medlor; St.M'ccct ~ ~ v.rut Xe-
le"t: XeZlrOl\t: 'l\i<rcx Zcdor; Zynolcx Zl"'C•f. Pol,, Co:1o<: Cd¢ KJora.
Proprietary Preparations (details are given ln ~ume 8) peak plasma concentrations of about 7, 13, and ceff; Pando<:~: Ve«c~ P<>«.: Cedor: Rus.: Ccdor(U...-.ip): Ya-·
Jpn: ArnostAn 23 micrograms/mL respectively after 0.5 IO l hour. cef ~lt S.Afr.: Ceq: Ceci<tj; Ve<tet Sln1apore: Clcancel:
Oimdcrf; ~br; Vcrccf: Spain: Cect><. Swiu..: Cedor: Tho/.; Cctco.
The presence of food may delay the absorption of ce- Oorcnr. Oisuclor: Sil>clor: lltt<et Tur"-' C«lor; Kelsid. Lose<ar: S.nocet
faclor, but the total amount absort>ed is unchanged. A UAE: Recocet UK: Bac:bt.lor; D-lor. Keltid: USA: Ceclor; llorctor;
Cefador (MN. LtWJ. p1NN) plasma half-life of 0.5 to I hour has been reported; it Ve.nee Ceder:
Huld·in.gredient: Mtx.; Cecbcbc.
Cifaclor; Cefador<MTI: Cefadon..rn Monohydricum: Cefakl6r; may be slightly prolonged in patients with renal im-
Cefaldor: Cef.iklor monohydr.it; Cefaidoras; Compound 99638: pairment. About 25% is bound to plasma proteins.
Kefa!doori: Scfaldor. (7R)·3.chlor<>-7-(Cl·O-phenylglycylamino}3- Cefaclor appears to be widely distributed in the body;
cephem-4-carb0><)"•C acid rncnohydrate. it crosses the placenta. and low concentrations have Cefadroxil (BAN. uSAN. pJNN)
UE$1Mop been detected in breast milk. lt is rapidly excreted by BL-5578; C~ilis monohidratas: Ccr.droksyt jed~
C 15 H 11CIN~0,5.H20 = 385.8. !he kidneys; up to 85% of a dose appears unchanged in Ceractuxil: Cefad-o>ol monoh)'drat Cefddroxil monohydrit":
CAS - 53994-73-3 (anhydrous ce(oclor); 70356-03-5 the urine within 8 hours, the greater part within 2 hours. Cefad-oxilmonoh)'drat Cefadroxikx Cefadrox~um: Cefaaox-
(ce{oclor monol>ydrotc). ik.m monoliydricum: CcphadrQ>Ol; Kefadroksnl~ Kefadrol<si>-
ATC - JOIDC04.
High concentrations of ccfaclor occur in the urine mono>iydraani: MJF-11567-3; Seladrol<sil. (7R)-7·{Cl-0-4-Hy-
ATC Vet - QJOIDC0 4. within 8 hours of a dose; peak concentrations of 600, drox)'phcnylglycylamino)-J..meth)'l-'.kephem-4-cart>oxylic aOd
UN/I - 69K7K I 9H4L (ce(oclor); 3Z6FS31KOK (anhydrous 900, and I 900 micrograms/mL have been reported af- monohydr.te.
ce(o<lor). ter doses of 0.25, 0.5, and I g respectively. Probenecid l.1e4>u.pOKCM/\
delays excretion. Some cefaclor is removed by baemo- C 16H11N10sS.H10 =381.4.
dialysis. CAS - 50370-12-2 (anhydrous cefodroxi/); 119922-85-9
(ce(odroxil hemihydroce); 66592-87-8 (ce(odroxil monohy-

: ~~0s
0 References.
I. Wise R. The plwmacokfnt1ies of 1he oral ccph,al0$pCWins-e re .. droce).
view. J Antimicrob Chemollrcr t 990; 26 C.•ppl E): t:>--20. ATC - JOIDB05.
2. Sourg.cn.s H. ~'al Phannacokinctic profite of cefaclor. /nt J Clln ATC Vet - QJO!D805.
PhnlWfO<OI Tli<r 1997; 35: 374-80. UN/I- Q525PA81JB (anhydrous ce(odroxil); 28011IGI60
NH 2 _j--N,.&
o Cl
Uses and Administration
(ce(odroxi/ monohydrote);j9CMF646/M (cefodroxil hemt·
hydrate)
COOH Ccfaclor is a cephalosporin antibacterial given orally in
the treatment of susceptible Gram-positive and Gram-
Pharmacopoeias. Jn Chi11., Ev• (see p.vii). and US. Jp11 in-
cludes the anhydrous substance. negative bacterial infections including upper and lower
HOWtO
Ph. Eur. 6.8 (Cefaclor). A white or slighlly yellow powder. respiratory-tract infections, skin infections, and uri- I H H

~+-(0s
Slightly soluble in water; p<aetically insoluble in dichloromcd>- nary-tract infections. Some classify cefuclor as a sec-
ane and in methyl alcohol. A 2.5% suspension in water has a pH ond-generation cephalosporin and its greater ~ctivity .& :
of3.0 to 4.5.
USP 33 (Cebclor). A white to off-white cryslalline powder.
against Haemophilus inj/uenzoe makes it more suitable NH2 _j--N,.&
than cefalexin for the treatment of infections such as 0 CH3
Slightly soluble in watet; practically insoluble in chloroform, in
methyl alcohol, and in benzene. pH ofa 2.5% S11$pcnsion in wa- otilis media. For details of these infections and their COOH
ter is belwccn 3.0 and 4.5. Store in airtight containers. · lreatment, see under Choice of Antibacterial, p.170.
Pharmacopoeias. In Chin.• Eur. (sec p.vii), and US. Jpn in-
Cefaclor is given as the monohydrate. Doses are ex- cludes the anhydrous substance.
Adverse Effects and Precautions pressed in tenns of the equivalent amount ofanhydrous Ph. Eur. 6.8 (Cef~roool Monol'.yd·ate). A white or almost white
As for Cefalexin, p.237. cefaclor; I .05 g of cefaclor monohydrate is equivalent powder. Slighlly..wluble in waler; very slightly soluble in alco-
Hypersensitivity. Serum-siclmess-like reactions may be more to about I g of anhydrous cefaclor. The usual adu lt hol. A 5% suspension in wn1cr has a pH of 4.0 to 6.0. Protect
common with ccraelor than several other oral antibactcrials1 cs· dose is250 to 500 mg every 8 hours; upto4 gdailyhas from lighL
pccially in roung childrcn,2.l and typically after SC\'Cflll courses US P 33 (Celad:oxi~. A white to off-white crystalline powder.
ofcefaclor; features include skin reactions and anhralgia. A rel-
been given. Slightly soluble in water; practically iMOluble in alcohol, in chlo-
atively high incidence of maphylactic reactions has been report- For details of doses in children, see below. roform, •nd in ether. pH of a 5% SU$p<11Sion in water is between
ed from Ja1»n.• Modified-release fonnulations of cefaclor arc availa- 4.0 and 6.0. Store in airtig)lt conuiincrs.
There has been a repon ofmyncarditisthatde\'Clopcdas a hyper· ble in some countries.
sensitivity reaction to ccfaclor in a 12-ycar-old child.~ Adverse Effects and Precautions
I, McCuc JO. Delayed dctec1ion of krum sicknes.s caused b)' onl Administration in children. Cc&clor may be given orally to As for Cefalexin, p.237.
anumicrobials. Adv Therapy 1990; 7: 22·7. children for the treatment of infections caused by susceptible
2. Vial T, C'I al. ceraclor·associ1tcd s.tNm sicknC$$·likc discaK.: Gram-positive and Gram·ne&alive bocteria, including Hotmo- Breast feeding. Although higher concentrations of c:cfadroxil
ciJht cases and review of lhc literature. A1m Phormocothtr 1992: phl/us i11/fuer1zoe. A suggested dose for children O\fer I month or were reported in breast milk compared with ccfalcxin, cefalotin,
26: 910-14.
3. King BA, Gcclhoed GC. Advttse skin and joinl rcac1ions U50- age is 20 mg/kg daily in 2 to 3 divided doses. For more serious cefapirin, and ccfotaxime, 1 no dcteCl3blc c:cfadroxil would bccx·
ciated with 01'111 antibiotics in d\ildrcn: 1hc role of «factor in infections, such as oti1is media, and for infect.ions caused by less pected io breast-fed infants and no advcnc elfeels have been
scrum sickness.. like rn.c1ions. J Po1dio1r Cltl/d llttilth 2003; J9: susceptible batleria the dose should be incteascd to 40 mg/kg seen in infants whose mothers were receiving c:cfadroxil. Ac-
611-81. daily, to a maximum total daily doscof7SO mg to l.S g. An al- cordingly, the American Academy of Pediatrics considers' that
4. H4:una R. Mori K. lfi&h inc-ideflcc of soapJ,yh.ctic rc-acttons 10 temati'-e dose regimen recommended by the BNFC 2010111 is: ccllldroxil is usually compaliblc with breut feeding.
ccfaclor. Lancu 1988; l: 133 I. I. Kafeuis DA. ~' of. Passage or ccphalosporin~ and amoxicillin
S. Bcgheui M. rl al. Hyperscnsi1ivity myoe:udi1is caused by an a l ~ • children I month to I year of ~e; 62.5 mg 3 timcs daily
inro !he br<on milk. Ac10 Pocawtr Scood 1981; 70: 2SS-8.
lergic reaclicn 10 cefaclor. J Ptdlo" 1998; 132: I n-3. • childn:n I to S years of age: 125 mg 3 timcs daily 2. American Academy of Pediatrics. The transrcr ofdr~gs 2nd OCh·
• c,hildren over 5 years ofai:e'. 250 mg 3 limes daily er chemicals into hulftan milk. PedifJtrics 2001; 108: 17649.
Interactions ~s may be doubled for severe infections. [Rc1in:d May 20101 Conution. Ibid.; 1029. Also ....il•bl• 11:
hl t p://a appo Iicy. 1appubl i cot ions. org/cg i/cont cntlfult/
As for Ccfalexin, p.237. For osymptomatic carriage of II. i11j/11enzoe or mild e.taccrba- pediatrics%3b108/3/l76 (•cctsscd 25/0S/04)
tions in cystic fibrosis the BNFC 2010111 recommends the fol- ·
A nticoagulants. UK licensed product infonnation recom-
mends that moniloting of prothrombin time should be consid- lowing oral doses: Interactions
ered in patients reo:iving ccfoclor and wo1forin after rate rcpor1S • children I month to I year ofage: 125 uig every 8 hours As for Ccfalexin, p.237.
of increased prothrombin times. ll is nol kn0\\11 whether this in· • those •gcd I to 1 years: 250 mg 3 times daily
lcraction is related to the vilamin K-rclated hypoprochrombinae- • lbosc more than 7 years of age: 500 mg3 timcs daily Antimicrobial Action
mia seen with some ccphal<lolporins (see Adverse Efl'eclS ofCe-
famandole, p.240), but cefaclor does not conlain the side-chain Preparations As for Cefalexin, p.237.
usually in1plicated in this reaction. =-T~lor Capo\Ae• Cellclor Or.If~ Probogod·rdcasc
USP Jl: Cer2ClorC•psulos: Cof>dcr Che-Nll>le T•bl<t<; Cclldc>' E>clenO-
Pharma.cokinetics
Antimicrobial Action ~Tablets: Cef•clor b-Or.i ~ Cefadroxil is almost completely absorbed from the
Cefaclor is bactericidal and has antimicrobial activity Proprietary Prepa.rations (delllils are given in Volume B) gastrointestinal tract. After oral doses of 500 mg and
similar to that of ccfalexin (p.237) but is reported to be Arr.: Cefal<lcnt: Cefr.it: Auruvl.: Ador: Cector. Cc:ll<.ort Kotlor; Keib-: I g, peak plasma concentrations of about 16 and
Ozcef. Aunrlo: C.C: t:<dol': Cefast>d; Ccf&><; 8el1.: Cedc<f; Ooccefaclo:
more active against Gram-negative bacteria including Bra;r.: Ce(fO<: Celodorett Corm-Ped: Faclort: l'ta:ort: llef»q: Conod.: 30 microgr.uns/mL respectively occur after I .5 to 2
Escherichia coli, Klebsiello pneumonioe, Nelsseria C•clor; Cz.: Cect: Cectort: Se""'1or: Verul; Fin.: l<dolor: Fr,, Alfa~I: hours. Although peak concenlralions are similar to
H.oor.t Ge..: Cec: Ceclotbou: Ccf-D;olan; Hd>cbrf: lnfectoCel. Pononlf:
gonorrhoeae, and Proteus mirobilis, and especially Sigacefalt Gr~ AleruJn; Brandt><: c.mro.: Cede><: CfQ(loril: fred,...n; those ofcefalexin, plasma concentrations are more sus-
All CrOS$-rcfcrenccs refer to entries in Volume A
 Cefaclor/Cefalexin 237
tained. Dosage with food d(~ nm appear 10 affect 1he C:ef.Uexin (6AN. p1NNJ inpalicnts taking broad-spectnom an11bac1erials, see under Hor-
absorption of cefadroxil. Abou1 200/o of cefadroxil is monal Contraceptives, p.2272.
66873: Ceralcks1nas monohidntas: Cela eks)'r.a; Cefalexin I. Frlcdman M. (!( al. Ccph1ltx1n l\nd Micr~Q_ynon-30 do not ~
reported to be bound to plasma proteins. The plasma monon)'drit: Cefalexina: Ceiale>Me; Cefalexine monohydratee: wcll lOMClhcr.J Obmt G,o·na•<:ol 1 98~: l : 19$-6.
half-life of cefadroxil is about 1.5 hours and is pro· CefalexinmO<\Ohydrat Cefalexinum: Cefalexiovm mooohydr;.
longed in patients with renal impairment. cum; Cephalexin (USAN); Kefaleksiini: Kefaleksiinimo:iohydraani: Ant imicrobial Action
Cefadroxil is widely distributed to body 1issucs and flu- Sefaleksin. (7Rl·3-Methyl·7-(o.·D-phenylg'.ycylamino)-3·cephem- As for Cefalotin Sodium, p.239, although ccfalexin is
ids. I! crosses the placenta and appears in breast milk. 1-carboxyl1c acid monohydrate. generally less potent. Some strains of Gram-negative
tje~<CMH bacteria may be inhibited only by the high concentra-
More than 90% of a dose ofcefadroxil may be excreted C,6H17N304S,H10 = 365.4. tions achievable in the urinary tract. Haemophi/11s in-
unchanged in the urine within 24 hours by glomerular CA5 - f 5686· 71-2 (onllyd1ous ce(olexin); 23325-78-2 j111em:ae is moderately resistant to cefalexin.
filtration and tubular secretion; peak urinary concentra- (ce(olex1n mononydro(e).
tions of I .8 mglmL have been reported after a dose of ATC-)010801. Pharm a co kine tics
500 mg. Cefadroxil is removed by hacmodialysis. ATC Vtt - QJOID801: Qj51DAOI.
Cefalexin is almosl comple1cly absorbed from the gas-
UN/I - 08N7UDS42Y (ce(olexin): 5SFF!W6677 (anhy-
(t RererellC"s. drous cefolexlll).
trointestinal 1ract and a peak plasma concentration of
I. Tanri:scvcr 8. Santella PJ. Ccfadro>.il: a rt\iCW of its 1nt1blc,cri· about 18 microgramsfmL occurs I hour after a 500-mg
a1, pharmacokinct1c and therapeutic propertif:s in compan.son oral dO!iC. If cefalexin is tak.en wi1h food, absorption
withccphalcxinandccphndinc.Drugs 1986;31(suppl3): 1-16.
may be delayed, but the IOtal amoum absorbed is not
2. \Vise R. 'The pharmaco.kin-:1ics of 1hc oral ccphtlospor1ns-1 rt·
>i<w.JAmimic>'Ob Ch""°'~' 1990: 26 (suppl E): l:l--20. H H appreciably altered. Up to 15% of a dose is bound to

: ~+(~s
3. Oarrigues TM~~' ol. Dosc-dependem absorption and clinh.na11on plasma proteins. The plasma half-life is 11bout 1 hour;
of ccfadro>.il in man. Eur JC/in Pltor•IOCOl 1991: •1· 179-83. it ina-eases with reduced renal function.
NH2_)-N, .&- Cefalexin is widely distributed in the body but does not
Uses and Administration 0 CH3
enter the CSF in significant quantities. It crosses the
Cefadroxil is a first-generation ccpbalospo1in an1ibac- COOH placenta and small quantities are folUld in breast milk.
terial that is the para-hydroxy deriva1ive of cefalexin Cefalexin is not metabolised. About 800/o or more of a
(p.237), and is used similarly in die treatment of mild Phanna.copoeias. In Chin.. Ettr. (see p.vii),Jpn. US, and ~iet. dose is excreted w1changed in the urine in the first 6
to moderate susceptible Gram-p05i1ive and Gram-neg- Ph. Eur. 6.8 (Cefalexin Mor.ohydme). A white oc almost white
Ct)'Slallinc powder. Sparingly soluble in waler; practically insoJ· hours by glomeru lar filtration and tubular secretion;
alive baclcrial infections. II is given orally, and doses uble in alcohol. A O.S% solution in water has a pH of 4.0 to 5.S. urinary concentrations greater than I mg/mL have
are expressed in terms of the anhydrous subslancc; Protect from light been achieved after a dose of 500 mg. Probenecid de-
1.04 g of cefadroxil. monohydrate is equivalent to USP 33 (Cephalexi'o). A white to off-white crystalline powder. lays urinary excretion. Therapeutically effective con-
about I g of anhydrous cefadroxil. The usual dose is 1 Slightly soluble in water; practically insoluble in alcohol, in chlo- centrations may be found in lhe bile and some may be
to 2 g daily as a single dose or in two divided doses. rofonn, aod in crhor. pH of a 5% suspension in water is between
3.0 and 5.5. Store in airtight containers. excreted by this route.
The dose of cefadroxil may need lo be reduCed in renal Ccfalexin is removed by haemodialysis and peritoneal
impainnent, see below. Sec also below for details of Cefalexin Hydrochloride (BANM piNNM) dialysis.
doses in children. CCfalexine, Chlorhydrote de; Cefalexini Hydrochloridum; Ce- 0 References.
Cefadroxil has also been used as lhe lysine derivative. phalexin Hydrochlooide (USANJ: Hid.-odoruro de cefalexina; LY. I. Wisc R. The ph&ml:lcOkinctics of the oral ccphalospo1ins-a re-
OS I 188. view. J A1ui111icrob ChdmoJlu:r 1990; 26 (suppl E): 13-20.
Administration in children. Cefudroxil may be given or~lly Ue4il,c•<c•110 r""P'""'op""'
to children for the lrcatmcm of mild 10 mocleraie infections
caused by susceptible Gram-posi1ivc and Gram-ncgarivc bactc·
C 16 H 17 Nl0,S,HCl.H20 =401 .9. Uses and Administ ration
Cefalexin is a first-generation oral cephalosporin anti-
CAS - 105879·42·3.
lia. UK licensed producl infonnation (BoxOll) recommend~ 1he ATC- )OIDBOf. bacterial for the treatment of infections caused by sus-
follo,.ing dose for children weighing less than 40 kg: ATC Vtt - QJ0/0601. ceptible Gram-positive and Gram-negative bacteria in-
• children less than I year of ago: 25 mll/ka daily in divided UNI/ - 6V)£5G3D98.
cluding infections of1hc rcspiralol)' and genito-urimu-y
doses Phannacopoeias. Jn US. 1racts, bones, and skin. For details of these infections
• dlOSC ag<' J 10 6 ycors: 250 mg. twice daily USP 33 (Cepha!exin H)d-ochloride). A white to off-white crys-
talline powder. SoJ\lble I in JOO in waler. in acetone, in ace- and their 1reatment, sec under Choice of Antibacterial,
• diose moo-c ~ion 6 years of age: 500 mg rwicc d3ily tonirrilc, in alcohol, in dimcthylfonn:imide, and in methyl alco- p. 170.
Alternatively. 1hc American A~demy of Pediatrics' sugscsts a hol; prac1ically insoluble in chlorofonn, in ethc:t, in ethyl acetate, Cefalexin is usually given as the monohydrate al-
d:!ily dose of 30 mg/kg in 2 divided doses, too ma•imum dose a.'ld in isopropyl alcohol. pH ofa I% solution in water is between though the hydrochloride is sometimes used. Doses are
oClgcbily. 1.5 and 3.0. St0tt in airtigb: containers.
expressed in lerms of lhc equivalent amount of anhy-
I. A1nerican A~rny or Pc-d1amcs. 1009 Rtd B«M Rc-pon of1hc-
C01ttr:.ut1r~ on lufec'1k111~ DlscttM1. 231b ('cf Elk Cirovc ViU11r. Adverse Effects and Precautions drous ccfalcxin; 1.05 g of cefalexin monohydrate and
Illinois. USA: American Academy of Pcd1aincJ. l009.
As for Ccfalotin Sodium, p238. 1. 16 g of ccfalexin hydrochloride arc each equivalent
Administration in renal impairment. Followir-a an initial to about I g of anhydrous cefalexin.
The most common adverse effects of ccfalexin and
loading dose or I g, Ollll doses of ccfadroxil should be adjUSlc:d
other oral cephalosporins are generally gaslroinleslinal II is given in doses r.mging from I to 4 g daily in divid-
in patients wilh renal impainnall aceo.-diria lo crea1inine clear- ed doses; 250 to 500 mg every 6 to 8 hours is typical.
ance (CC'): dislurbances and hypersensitivity reactions. Pseu-
domembranous colitis has been reported. For skin and soft tissue infections, streptococcal phar-
• CC 26 to 50 mUminutc per 1.73 on2: SOO n1g.'i:Vl!I)' 12 hours yngitis, and uncomplicated urinal)'-tract infections a
• CC II to25 mUminutc per 1.73 nr: SOOmacvcry24 hours 0 References. dose of 250 mg every 6 hours or 500 mg every 12
I. Da,·c J. ~'al. ~.:Jlexin induced toxic epidt<mil nccrol)'$iJ, J
• CC IOmUminutepcr 1.73 rn2orlcss:S001ngc:very36hours. AmimicrobChemOlh" 1991; 18: 477~ . hours may be given. If daily doses greater than 4 g are
'2. Baran R. Perrin C. Fix~d-<lrug CJVptton pre~rt1in1 as :Jin Mule needed, parenleral cephalosporins should be consid-
Preparations paronycbia. /JrJ Dcrm(ltol l991: 125: 59:?- S.
ered.
) . Clartt RF. Crys:tallurla following ctphalexin overdose. Ptdi'ot·
BP 2010: C.<adro>o1c.p..;1es:c.r.do·o... 0.'1I Suip..-.i<n
USP 33: CeCacro>cil CopUes: Cefadro><I for Oral S..spernoon: Ccf•dro>OI
ria 1992; 89: 672-4. For the prophylaxis ofrecurrent w-inary-lract infection,
4, Murray KM, Camp MS. Ccphakxin·inducc."(j Scevcns·Joh1ison
To1>1cu. syndrome.Am1Pharmaco1hct· l992: 16: 1230 ~ 3.
cefalexin 01ay be given in a dose of 125 mg at night
Prop rietary Preparations (dttails arc gh1en in Volume B) S. Cz~ch owicz. RT, e10J. Bullous pemphigoid induced by ctph:iltN- For details of doses in children, see below.
Arg.: Cclatar: C.f•dina; Ccladro>e Cclamor: Cef•sint. Ce<•l•nl< Dmxilt in. A1MtrtdllS J D~nnotof200J ; 42: 132-S.
6. Longs1rcth KL. ct ol. Ccpl u1lc~i11· indueed 11cu1e tubular n-.-cru$i:t. The dose of cefalexin may need to be reduced in renal
IW>dkit'< l<lcnc!o-mol: V""':rtic: A ustria: 8iodroJ<lt: Ovra<ef: Sele.: Durocef,
Mo>OKeft: Bn>L: C•d""'* c.rado'OXOI\ Cei.mox: Cdo<on'1: Cctoxint Pho,.mocorlrerop,1' 200~ ~ 24: $08-l I. impainnent, see below.
Oo'()(axilt Nco Cefadtit Can ad.: Ovo'Kcl: Chile: Adroxcf: Ccfamox: 7. Skoog SM. c1 ul. Cepha1e:tin·induced cholcsratic hepatitis. J
s.tiafetj: s.rade.: Cr.: Biodroool: Cedro><t: Ccfadro><t: Dvoxtf. Fin.: D<J. Clin GnstrO.!nlerol 2004 ~ 3~ : 833. Cefalexin sodium or cefalexin lysine have been used
r.<ef: f r.: 0.lCcfat Gft.: Cod""'t: GrU<1<cf. Gr.: Bilroxet..-c Cefalorrc Cy· S. ChM AL, ttl al. Fatal Dnaphylnctic reaction to intravcnou* \:C• parcntcra lly.
dcmy<ioe·I<: l<leotrot: Mcd·L..-.1: Moxocc:! Ncf1lox: Ultrocof: Honr Kani: phalexin. C/i,, Dn1g /11w:11200S; 25: 675- 8.
Amberl: AndrO><Ylt, lliod"1001t, Ou<oo:•lt. Q.rolodr<»c Hung.: Biocfn»Olt: 9. PenltiUl J, e1 al. Oelirium in an :adoJcsccnf patient during treat- Administration in children. C~litlexin may be given orally to
Duracef: Indio: 'cef•<lrox: Cdadur: L1<1ocef. L)'(lrooat Odox~: 1'$1dro>c: nic:nt w irh ..:ephi!lcxin. J Ado/ts~ Htolr/1 2006~ 39: 782-3. children for the treannem of infeclions caused by susceptible
V.;wi: v,sudfcoc /ndon• Al><i: Ancer.. Bodiceft: lliodro><H: Cera~ Dt><acef: Gram.positive and Gram-negative bac1cria. The usual recom-
Dcxor: Doovax: Droxal: Do"""t.. Dwice??v£.,,to1dro>c: Ethlcef. Kelfex: 1..ap. Porphyria. Ccfalexin is considered to be unsafe in patients with
o..c1rox: •f. Q C..l Qidrox ~·istit'<
ice(: Libro<cft. L.ooa<cf. ep;cer: poo-phyria ~hhough lhcn: is conflicting experimental evidence of mended dose is 25 10 50 mg/kg daily in 2 or 3 divided doses. In
Roksiup: Sedrcfen: St;ilocio: To,.cet Voe o: W'odrox; Yaricef: /r/.: Ult~ceft: porphyrinogenicity. severe infections the dose may be doubled and foe otilis media a
broe~ Bioclroxil: ltol.: Cef•drot C.,pho<t, Foxitt, 0-.<lo'ooct M oloysio: Ce· dose of7S to 100 mg/kg daily in 4 divided closes is rttamonend-
f>dl•·: K - Solid.'COC Mu .: Cd'amox: Cepo<e<: D\Jr><<f: lntcfot. Kt· ed.
ba; T.........._ Pl>ilipl'·' Dmo>e 0...:od. Le>Opid: Pol: 8ioc!ro>Ot C>..-acef. Interactions Allen>ative doses recommended by lhc BNFC 2010//J aie:
Tadfoxi: Pon.:~ Ce!acole: Cefont Ce<rot. S.Afr.: Qpoc1r: 0.cel: The renal excretion of cefalexin, and many other ce-
D.roceft: Singopon: Dv>etlt, Sdodrox: Spain: O..occf. Swod.! C«•· • children over I ononth of age: 12.5 mgll;g iwi"" daily; dose
mox. Turk.: Cefradur; Ou<1cef. UK: S.><1nt: Ukr.: Cedn>hex•I phalosporins, is delayed by probenecid. should be doubled in sc''CfC infection (lo a maximum dose of
(~r<><(W. USk 0...:eft. V•roa.! &dro>cyl C~ ~ I g 4 times daily) or
to(-\ Cc!onai< Droccf. °"*"-'< c:.-v-t ~ H ormonal contraceptives. The<e ha~ been isollltc:d rcpMS
ofcefalexin decreasing the efficacy ofocs1rogcn-conta1ning oral • childml I month to I yurofage: 12Smg!WM:edaily-
Multi-insredie<>c AtJ.: Y'OC>t.'11 ~M••~ Dln«CE>cp«. • children I 10 5 years of.age: 125 mg 3 times daily
contraceptives.' For • disrussion or decreased effocacy of oral
cootraccptn-es and the need for addilional ~ptivc methods • cliildrcn more than 5 )'C31SOfagc: 2..'\0mg 3 times daily
Tioc symbol t denote> a prcp.;nition no longer actively marketed
238 Antibacterials
A llh ou gh nol licensed in lbc UK for neona1 es, lh e Cefalo tin Sodium (BA.NM. ptNNMJ Acute intersti tial nephritis is also a possibility as a
BNFC 2010/JJ suggesL• a dose of25 mG!l<g (lo a maximum of manifestation of hypersensitivity.
125 mg) may be given twice daily for ncooa1es less lhan 7 days 38253; Ccfalotin sodiU sUI: Cefalotina sodica: Cc!falotine soci·
old, 3 times daily for lh= aged 7 to 21 days, and 4 times daily que: Cefalotimatrium: Cefalotin-n3trium: Cefalotino natno drus· Transient increases in liver enzyme values have been
for lh= aged 21 to 28 days. l<a: Ccfalotim.rn r.atric1rn: Ccfalotyna sodowa: Ceptlalothin Sodi· reported. Hepatitis and cholestalic jaundice have oc-
for lhe prophylaxis of recwrcnl urinary-tracl infec1ion lhe um (USil"'.): Ke<a'oliininatrium: N..uii Cdalolrum: Sodium Ce- curred rarely with some cephalosporins.
BNFC 1010/JJ recommends lhal ch1lclrcn over 1 month of age phalothin. Sodoum (7/l)-7-{2-(2-lhien)'l)acetamido)cephalospo- Convulsions and other signs ofCNS toxicity have been
be given 12.S mg/kg orally a1 night (10 a maximum dose of ~: Sodium (7R)·3-aceto><:-meth)4-7-{2-(2·1hienyf}acetimt- associated with high doses, especially in patients with
125 mg). do)-3-aphem-+catbox)'la1e.
severe renal impairment
Administration in renal impairment. Oral doses of ce- H;npi<M ~'TMH
Gastrointestinal adverse effects such as nausea, vomit-
falexin may need to be reduced in patients wilh renal impair· C,.H ,sN2Na06$i = 418.4.
menl. The BNF 59 rec()mrncnds lhc following maximum daily CAS - 153·61 · 7 (ce(aloun); 58-71-9 (<e(olotin sodium).
ing, and diarrhoea have been reported rarely. Pro-
doses aceonling lo crea1inine clearance (CC): ATC - }010803.
longed use may result in overgrowth of non-suscepti·
• CC 40 lo SO mLJminulc per I. 73 m1: maximum 3 g daily ATC Vet - QJO I 0803. ble organisms and, as with other broad-spectrum
• CC JO to40mUminu1cper 1.73 ml: ma.,imum l.5gdaily UNll - C22G6E.YP88. antibacterials, pseudomembranous colitis may develop
(see also below).
• CC less than JO mL/minute per 1.73 ml: maximum 750 mg
daily There may be pain at the inject.ion site after intramus-
cular use, and thrombophlebitis has occurred on intra-
Preparations venous infusion of cephalosporins. Cefalo1in appears
BP 20 I 0: Cefalexin Capwles: Ceraltxln Oral Su!per>lior( C..1ai.M Tablets: to be more likely to cause such local reactions than oth-
USP 3 3: Cephaleocin C.psul<>: ~em br Oral Su_..;o,,: Cephalex·
la°"''
... Tabictl; C<J>halcx"1 Tableu SuipensOO. er cephalosporins.
Proprietary Preparadons (detoils ate gi\•en in \lolu~ B) Antibiotic-associated colitis. Pscudomcmhranous colitis has
Arf.: ~~cm.:~ Ylapo<enf;c.&molt: Cef~.a: Ce- OCClned wilh many anlibactcrials, including broad"5pOCUUm oe-
fo5ponn ~ Fabat~ Krinl ur..ina: 1.rs: wn Lc'1lice1a>c phalosporins.1-1In1991 the UKCSM warned' of the dangers of
No.olexinf; l'emMWt s.noc..c: ~ T""'1a: Tri>ic:Veleocm: Au,_ pscudomcrnbnnous colitis wilh the newer, as well as the oklcr,
tra/.: Olex Wei< tiilox ~ Roin{ ~ Aunria: c-mt: (ce(olotin)
~ ~ 0spon SaN>drc Bt/£: Cepo<1'Xj: K<font Braz.: cnl cephalosporins. Jn addition to 33 reports of psaidomcmbra-
Betocefl: Ce~t: Celaget Cefapt: C:efavanc Ce!anat Ce~ nous colitis associated wilh cefalexin, ccfradine, cefadroxil, and
Cef.,..... CeoexirJt; Cetenc Ctl--c Ctf-t: F-t: ~>ITTj: Keib». PhannacopO<!ia.s. lnChin., Eur. (seep.vii),Jpn. and US. cefaclor, 6 of which proved fatal, they had received 12 rcpo11s of
nat: Keflex Keloritt: IGl!o-t; Lem LilUlonf: Neo Celle>c; Neace~ Ph. Eur. 6.8 (Ccf.ilotin Sodiun). A white or almosl white pow- probable or confumed cases with ccfuroxime axctil and 15 wi1h
Primacef Pmr.,...., Todec"'t: Wllclc C..nod.: Apo.~ KeflO>C: der. Frcc:ly soluble in waler; slightly soluble in dchydraled alco-
Na..o.LexO; Nu-Cophale>c; C.., Celadonf: Orac<ft: Osee*'t Sporide>cf: cefixime, one of them fa laI. In clinical sl\ldics of cefuroximc a.~­
hol. A I0'.4 solution in water has a pH of 4.S to 7.0. Pro1ce1 from ctil and cefiximc, diatrhoea and pscudomcmbnlnous coli1is ap-
~~,::~~~~~K~~~~J~~n~=:.~ lighl. - peared 10 be dose-related and therefore the CSM recommended
Medalex;ne: Nept<*>: Nyi;chlor: Sln1hoc111on( Tricytatril: Zabytrex; H ong US P 33 (Ceph;llothin Socium). A white to oft:white, prac1ically lhat higher doses should be reserved for severe infections. In any
Kong: An><Crt: Apo·C""'1•1« Celocap.id!t Ctfat<t C..facuret, Cephalexyt odourless, Clj!St.:lllinc powder. Freely soluble in water. in sodium
C<:ph;.,; Ceporuq: f•lcxin: Medoia><irc o....e; °""""1: Solle>< Sollkxint: event they advised Uiat 1rcahncnt should be Slopped if symptoms
Syntolexn: Hunf" Keflext: l'y.u111t S.,,..;,porf: Indio: AJe>m: 8e01SpOre: chloride 0.9%, and in glucose <olutions; insoluble in mi-.;1 organ· suggestive of pseudomembranous coli Iis arose.
Cefmi>: Cepllade>c C..~ Nvfex: ~ llolex: Sepexir< Spaide?< In- ic solvents. pH ofa 25% solution in waler is between 4.5 and 7.0. For li.lrthcr discussion of the management of lhis condition, see
don" Celabiotic: Made,.;,;~ Pr•bont: Sol"'°" T<'J>'xirt Theraiex· Slorc in ai11ight conlaineIS. p.182.
"1t: lrl.: l<Elexnt; K<ile>< lsroo~ Celai.rrt: Celor>t Cef<Mt ltol.: Ceporex:
l<ciont L.a!arinc Jpn: Lar'°" Moloyf/o: Cde>int: C~ f e)e>;r< Incompatibility and stability. Cefalotin sodium h>S been rc- I. de ti Ha F. e1 al. Third gencn1ion ccphaJosporins IS a nsk raclor
Modolexii: ~ Solllex Sporidcx Upllo'<>c" Mox.: Aaant: Ancetov. pol1ed to be incomp1tiblc wilh aminoglyoosides and wilh many ror Clos1ridium difficile-associated disease:• fou,...yc:..r survey
N'"'°"' ~ ~: Ceporex: Factllt Fale>cdj: flexinW>t; Aexmo1: inagencnlhospita1.JAn1imkrobCl~;1tOlht'r 1989: ll: 623-31 .
other drugs. Precipitalion may occur in solu1ions wilh 1 pH of
Ken..: Nabcil; Naxlelr. Noda(.C: ~ P..'<nOn; ~ 2. Gollod&• CL. ., ol. Exlcoded speclrvm cepllalo'flOrins and
5.n.icd SponcoZ Nedi.: k8oral; Norw.! ~ NZ: KeC0oq: PluUpp.: less than S. Clostridium difficile. J Anti1nictob ChcllfOtlt~r 1989; 23:
Anx; l!a.cile:>cil; 6ai>dix: ~ 8lctec; ~Ce*< Cendolex: C<p- 929-31.
orex CfI'<. CN>ltx Oop'W\ °'llec E~ Eliphcrn E>d F.Jib: fa.ltlc;
f.iteN: forexin<: ~ In'-': ~ KoGn: ~ U!:>a.m<
Adverse Effects l. Freiman JP. e1 of. Pscudomcmbranous coti1is USOC'ile4 •ith sin-
aJc-dosc c:eph31osporin prophylixis. JAMA 1919: 262: 902.
Lonanl{: L)'Cq>lx: Madeocr< Modlt.rc Mtdcocile: Mon-nit>¢ Nefoclonc The adverse effects associated with cefalotin and other 44. CSM. Pseudomembnnws (antibio1ic·1.1societc:d) coli1is and di-
NecleaO\: NttDlex: Oneftex; Ptdllooc: ~ ~t s.Nsport:So<lvc: ccphalosporins are broadly similar to those described anhot:a with cephalosporins. CurtTnl hobltt,,,1 J1 1991.
Spondext: Xeface: Xinlle>c Zopl>er,t Zeporin: Zepocex; Ze>Cifltit z;nace:
Zuc:ott.Jrinf; Pol.: K.cllcx: Pori.: C.ila><I: ~xf; Kd'""¢ S.Afr" K,c. for penicillins (see Benzylpenicillin, p.231 ). The most Efl'ects on the blood. Refe,.,nccs.
R:x-t: L8l0Cefj: Ranctplt S/n,.poro: ee1..,n: Cet:Nlenc Cep/l2'Ynydn: common arc hypersensitivity reactions, including skin I. Lipsky JJ. Antibiotic-associated hypoprOlhrombinacmia. J Anli-
c..,orext, Ospexr1: SoNex: Spondex: Upholexin: Spain: Cefalexgobens: microb Oicmot/Jer 1988; 21: 281-300.
Kellorici'ia: Loxinc•f. Sulquipont: Torla>porirc Swed.: Kefiex: Thai.: Aox· rashes, urticaria, eosinophilia, fever, reactions 'rescin· 2. Shearer MJ, d al. Mcc:hJnism of «pNlosporin-induc.cd hypo-
ert eer.,.;,,t: C..lex: Celex;rc Cepl>al°")'\ Cepllirt Ceporext: Farm>lex: bling scrum sickness, and anaphylaxis. prothrombinemfa: relation to c:ephl\losporin side chain, vi1nmin
fele.>Ott lbilex: Kenex: Mycer: Neolcxin: PondOKeft: Sofas""< Sialexin: K metabolism, and vi1amin K Slfltus .•/ Clin Phorm(Jeol I988: 28:
Sporic;of: Sporidext; SPQ<1d•n: ~x: Tollcx: Ulr.ex: Val!Ceplt Zeplcx; There may be a posilive response to the Coombs' lest SS-95.
Turi<.: M.>kslpor; Sef. U,4£; Cefnn: UK: Cep0rex: Ke~ex: Ukr.: Ospex"1 3. Wclagc LS. ct al. Comparu1ivc cvaluo1ion of the pharm~cokirM:t­
(OcneKCt<\H): USA: Bioceff: O:f.-.e:>c: K.eAtx: Vtnez..: Bidcxef. Ce(atogat allhough haemolytic anaemia rarely occurs. Neutrope-
ics of N-mc1hyhhi0tc:tratolc followin3 id ministration of cefop-
KefcntStncer. nia and thrombocytopenia have occasionally been re- erazone, ccfotctao. and ccfmctazole. AnllmfC'rob Agt.111s Chen,.
Multi-ingredieni: Indio: Cace11; Cephldtx Ul: Mex" Al"..,.,,., 8; Celal» ported. Agranulocytosis has been associated rarely othe,- 1990; 34: 2369-74.
roJC1t Cepobrom: Mutocof. Rcml>oo< with some cephalosporins. Bleeding complications re- Effects on the kidneys. References.
lated to hypoprothrombinaemia and/or platelet dys· I. ZMm:J GG. Ccpb.alosporil"l-inducod ncphto1oxici1y: docs ii cx-
iSI? DJCP A>1n PhormOt:t>llwr 1990: 14: 262- S.
function have occurred especially with cephalosporins 2. Tune BM. Ncphroto.•iciry of bctt·lact>m ant1boo11cs; mccha-
Ce falonium ~ plNN) and cephamycins having an N-methylthiotetrazole nDms md s1t1U:gjcs for prcYt..."YUion. Ptt/iorrN~plH"Ol l991; IJ:
7~72.
11071: Carba~cefaloridine: Ccfalonocx C.Cfalonio..rn: CephaJo. side-chain, including
nUT\ (7R)·J..(4-Carbarrooyj.l·P'fl'•dmiomethyl)-7-[2-(2-ttie")l)- • cefamandole Hypenensitivity. Hypcrscnsiliviry reactions, up IO and includ-
acetamido}-3<ei:Mm-4~ate.
ing rare reports of anaphylaxis, arc "'cogniscd adverse effects of
• ccfbupera7.onc ccphalosporins. However, !here is some dcbale about the risks of
U~HH • ccfmenoxime cross·sensitivity between cephalosporins and penicillins, Md be·
C20H11N,OsS, 458.5 . = • ccfmetazole
rwccn ccphalosporins of diffcrcnl classcs. •J
A srudy in patients with documcn1ed penicillin allergy fouod tha1
CAS - 5575-21-3.
ATC Vet - QJ510A90. • cefonicid 14 of 128 had positive skin-t.est results lo one or more of ocfalo-
• cefoperazone cin, cefamandole, cefuroximc, ccftaz.idine, ceftriaxonc, or cefo-
taximc.' Of 101 patienlS with nega1ive skin·ICSI rcsuhs 10 lhc lal·
• ceforanidc ter 4 drugs, all tolerated subsequenl Lest dOSCS Of cefuroxime
• cef0tct.an axctil and cefiriaxone. However, the 11% ero~reactiviry rale
was considered to suppo11 lheavoidancc ofccphalOSpOrins in pa-
• cefpiramide licnts wilh positive resullS to penicillin skin tests.
• latamoxef. lo contrast, a review2 qucsrioned the C\~dcncc lhar cross-sensitiv-
ity ralcs between penicillins and cephalosporins arc as high as the
The presence ofa methylthiodiazolethio/ side-chain, as otien-<:ited rates of 8 to I8".. It considcnd lhal lhe immunc re-
in ccfazolin, or an N-methy/thiotriazine ring, as in spon.<e to ccphalosporins is highly dcpendcnl on their side-cllain
cdbia.xone, might also be associated with such bleed· SUUCIUJe, which more closely rc.scmblcs penicillins in some than
Pharmacopoeias. BP(Vtt) includa lhe dihydrate. ing disorders. Hypoprothrombinaemia which is usual- in others. ll was suggested tha1
BP(Vet) 20 I 0 (Ce!a!onium). The dihydralc is a white or almosl • ifa patient hod a his1ory consis1enl with a severe, lgE-medial·
white crysmlline powder. Very slightly soluble in water and in
ly reversible with vitamin K, was once thought to be
cd reaction IO a penicillin lheo ccphalosporins such as ocfulo-
methyl alcohol; insoluble in alcohol, in dichloromelhane, and in due to an alteration in intestinal flora but interference 1in and cefoxitin, wilh a similnr 7-posilion side-chain on the
clher; soluble in dimethyl sulfoxide. ll dissolves in dilute acids witl1prothrombin synthesis now seems more likely. bcta-lactam ring, should be used with caUlion
and in allcaline solutions. S1ore Al lcinpcrarurc not exceeding 30°. Nephrotoxici ty has been reported with cefalotin al· • if lhe reaction followed use uf ampicillin or amoxicillin Uie
Protect from light ocphalosporins wilh a similar side-chain (ccfalexin. ccfradine,
though it is less toxic than cefaloridine. Acute renal tu-
Profile ocfat1faine, eefadtoxil, cefacfor, and ccfpro<il) should be used
bular necrosis has followed excessive dosage and has wilhcaution
Cefalooium is a cephalooporin antibaelerial used in veterinary also been associated with its use in older patients or
practice. • palienlS who have had a non-lgE-1ncdiated reaction 10 a peni-
those with pre-existing renal impairment, or when used cillin, cephalosporins may be used (in unccruin cases, elec-
with ncphrotoxic drugs such as aminoglycosides. tive penicillin skin testing is advisable)
All cross-references refer 10 entries in Volume A
 . Cefalon1um/Cefamandole 239
The incidence of cross-rcaetiviiy in penicillin-allergic patienu it is also active against Mormel/a catmrhalis (Bra- The dose of cefalotin may need to be reduced in renal
appears to \1ary with the gener::ation of the c.cphalosporin, being nhamella catarrha/is) aod Neisseria spp., though impairment, sec below.
hig}lcsl with the first-generation dnigs (considered lo be about
0.4%) and •irtually absent for dn•ss such as ccfuroximc. ccfpo-
Haemophilus i1if/uenzoe is moderately resistant. For details of doses in children, see below.
doxime. and cefdioir. Patients who have had a type-I reaction to Buctl!l-oides fi-agilis and Pseudomonas aeruginosa Cefalorin sodium may be added to dialysis solutions or
a specific ccphalosporin should probably n<.-vcr be sivcn lhal are not sensitive. Mycobacteria, myc-0plasma, and saline and given intraperitoneally.
drui ogoin, but the risk of cross·scnsitivicy lo ~nothcr ccpha- fungi are resistant.
lo.\porin appears to be low if the side-chains of die drugs arc not Administration in children. Ccfaloiio may be given 10 chil-
similar. Resistance of bacteria to ccfalotin may be due to sever-. dren for the treatment of infections caused by susceptible Gram·
Rom:no A, et o/, Crcm-rC:Aaivity and colenibility of ctph•· al mechanisms: the drug may be prevented from reach- positive and Gram-ncgath-e bacteria. It is given parcnterally by
tosporins in ~\ien1s with immediate hype™nsith-ity co pcnjciJ.. ing its site of action, for example in some Gram-nega- deep intramuscular injection, by slow intravenous injcctioo, or
hns..Amtlnt~ni Mcd2004; 141: 16-2:. by intennittenc or continuous intravenous infusion. l11C usual
2. Pichtchcro ME. A review or cvidenec sllprpOFting tht: A111tdcan
tive organisms the cell wall may be a potential barrier; recommended dose is 80 to 160 mglkg daily in divided doses.
Atadcmy of Pedialrics fecommendatiol'> (or prescribinJ ceph:.• rhe target pen icillin-binding proteins may be altered so For su.sicaJ infection prophylaxis, children may be given 20 to
losporin anlibtotics for ~nicillin·nllcrgit patients. PNhorrlts that cefalotin cannot bind with these proteiJlS; or, most 30 mglkgin thesamedo.singschedulcas foradults(see Uses and
200~: 115: 1048-S7.
importantly, the organism may produce bet.a-lactama- Administration, •bove).
Precautions ses (ccphalosporinases). Ccfalotin is relatively resist- Administration in renal impair~nt Reduced doses are
Licensed product information states that cefalotin ant to hydrolysis by st.aphylococc.al beta-lactamase, but recommended if cefalotin is given to pntieols with renal nnpair·
is inactivated by a variety ofbeta-lactamases produced ment. Aflcr an intravenous loading dose oft to 2 g patients may
should not be given to patients who are hypersensitive be given die following maximum doses according to theor mal-
to it ortoother cephalosporins (but see also above). Im- by Gram-negative organisms; resistance of Gram-neg- ininc clearance (CC):
munological srudies have suggested that up to 20% of . alive organisms often depends on more than one factor. • CC 50 to 80 1nUminutc: 2 g every 6 hours
penicillin-sensitive patients may also be allergic to ct> Resistance can be chromosomally or plasmid-medial· • CC25to50ml./minute: l.5gcveiy6hours
phalosporins although clinical srudies indicate a lower ed and may sometimes be inducible by ccphalosporins. • CC 10 to 25 ml/minute: t g cvciy 6 hootS
frequency and the true incidence is uncertam; great Ccnain strains of bacteria may be inhibited but not • CC 2 to 10 ml/minute: 500mgevciy 6hours
care should be taken if ccfalotin is to be given to such killed by ccphalosporins 01· penicillins and in such cas- • CC less than 2 ml/minute: 500 ma every 8 hows
patients. Care is also necessary in patients with a histo- es the minimum bactericidal concentration is much Preparations
ry of allergy. greater than the minimum inhibito1y concentration; USP 33: Ce~rc.on lo< "io<t.ott ~11\in lrjoction.
this is known as tolerance. Proprietary P;eparatlons (detoils are given in Volume B)
Cefalotin should be given with caution 10 patients with
As well as with other cephalosporins, some cross-rc-
renal impairment; dosage reducti~n may be necessary.
sistance may occur between cefalotin and the penicilli-
~..Ar~:~w::li~~r~.;,_"'~~~~~~Y~
Renal and haematological starus should be monitored irt Oonm" Kelinf; Gr" Pnctogen: lndon.: Ceptiouont. &<'IOl'C Mora><ine;
nase-rcsistalll penjcillins. · l<al.: Ketl<rt, Mu.: Ct<olet>: Cefliiaf: falol; Kellr< 1Ce"'6t Urol<rn t l.oril<·
especially during prolonged and high-dose therapy. en: Lotin: ieq>!>ltA; N•<"-: Ke;lin: Norw" Kellon: Phlr>f>P.: Fettfj: S.Afr.:
Cefalotin and some other cephalosporins and ce- K<fl;r.t; Sinropore: CeM<t Venez.: Ccfacochnlf; Ceftto: ~t.
Pharmacokinetics
phamycins (ccforanide, cefotetan, cefoxitiJ1, and ccf-
Cefalotin is poorly absorbed from the gastrointestinal
pirome) may interfere with the Jaffe method of. meas-
tract After intramuscular mieciion peak plasma con-
uring crcatinine concentrations and may produce
centrations of about 10 and 20 micrograms/mL occur Cefamandole <MN. USAN. nNN)
falsely high values; this should be borne in mind when 83405: Cefamandol; C~ramandole: Cefama>dolum: Cepllaman-
measuring renal function. Positive results to the direct within 30 minutes of doses of 500 mg and I g, 1-espec-
tively. A concentration of30 micrograms/mL has been dole: Compoo.nd 83405: Kefamand<». (7R)-7-c-Mandelamido·
Coombs' test have been found during lreatmenl with 3-( l·melhy!-IH-ICllW-5-ytthiomelh:,.1)·3-cephem-4-olboxyl·
cefalotiu and these can interfere with blood cross- reponed 15 miltutes after the intravenous injection ofa
k ac;d, {6R-[6c.71l(R")])-7-[(hydroxyphenyiamyf)aminoJ·3·{[( I·
I-g dose; a rdnge of 14 to 20 microgramslmL has been medl)'l-1 H-~e~-azol·>>i)thio]me\hyl}·8·oxo·5·thia- l-azabicyc·
matcbing. The urine of patients being treated with ce-
falotin may give false-positive reactions for glucose achieved by the continuous intravenous infusion of lo{4.2.0)0<t·?-cne-2-carl>axy!ic <.cid.
500 mg/hour. Ueta...a~OA
using copper-reduction reactions.
Cefalotin is widely distributed in body tissues and flu- C, 1H, 1 N,OsS 2 = 462 .S.
Por phyria. Ccphalosporins are considered 10 be unsafe in pa- ids except the bl-ain and CSF where the concentrations CAS - 34444-01 -4.
tients with porphyria although there is conflicting e:q>crimental
evidence of porphyrinogcnicity.
achieved arc low and unpredictable. It crosses the pla- ATC - JOIDCOJ.
centa and low concentrations have been detected in ATC Ver - Q)OIDC03
Sodium content Eacii E of ocfalOlin sodium contoin• '1bout breast milk. The plasma half-life varies from about 30 UNll - 5CKP8C1W
2.39 nunol of sodium. '
to 50 minutes, but may be longer in patients with renal
Interactions impairrnem, especially that of the metabolite. About
The use of nephrotoxic dn1gs such as the aminoglyco- 70% of ccfalocin is bound to plasma proteins.
sides gentamicin and tobramycin may increase the risk Abati! 20 to 300/o of cefalotin is rapidly dcacetylated in
of kidney damage with ccfalotin. There is also some the liver and about 60 to 70% of a dose is excreted in
evidence for enhanced nephrotoxicity with the loop di- the urine by the renal rubules within 6 hours as cefalo-
uretic furosemide, but this is less certain than for furo- tin and the less active metabolite, desacetylcefalotin.
sernide with ccfaloridine. As with pen icillins, the renal High urine concentrations of &00 microgramsfmL and
excretion of cefalotin and many other cephalosporins 2.5 mgimL have been seen after intram uscular doses of
is inhibited by probenecid. TI1ere may be all!agonism 500 mg and I g, respectively. l'robeneeid blocks the re- Cefamandole Nafate (8/ol'I. US~N tlNNM)
between cefalotin and bacteriostatic antibacterials. nal excretion of cefalotin. A very small amount is ex-
106223: Cefamandole Formate SoOurrc ceramzndole, nafate
creted in bile.
de: Cefamandolc Nafate Sodt.rn: Cefamandoli nafas: Cefaman·
Antimicrobial Action doli Nofatum; Cefamandolio nafatas: Cefamlndolnaf<t Cefa.
Cefalotin is a bela-lactam antibacteria l. Tl is bactericid- Uses and Administr ation mandol·nafat Cefarnandolu nafan: Cefinandoli Nafas: Ccpha-
al and acts similarly to benzylpenicillin (p.232) by in- Cefalotin is a first-generation parenteral ccphalosporin mandole Na fate; l:ef.rnandoliNfaatti: N<fato de cefamandol So-
hibiting synthesis of the bacterial cell wall. It is most antibacterial that has been used in the treatment of in- dium (7R)-7·[(2R) 2 formyloxy-2-phenylacet~rr-Odo}-3{1-me­
active against Gram-positive cocci, and has moderate fections due to susceptible bacteria, and for surgical in- thyl-IH-tetmol·5·yltn:omethyl)-3-cep.'wn·1·cal'boxylate.
fection prophylaxis, but has generally been replaced by Ue+aMa>IAOlla Ha4>a··
activity agains1 some Gram-negative bacilli.
newer ccphalosporins. It has higher activity against c,<H 17 N,Nao.si =s12.s.
• Sensitive Gram-positive cocci include both penicil- Gram-positive than Gram-negative bacteria. CAS - 42540-40-9.
linase- and non-penicillinase-producing staphyloco- ATC - )OIDCOJ.
Cefalotin is given as the sodium sa.lt by slow intrave- ATC Ver - QJOIDCOJ.
cci, although meticillin-resistant staphyloC-OCCi are nous injection over 3 to 5 minutes or by intem1inent or UNll - SHOO 794 I DO.
resist.ant: most streptococci are also sensitive, but not continuous infusion. It may be given intramuscularly Pharmacopoeias. lu Eur. (~ p. vii) and US.
penicillin-resistant Streptococcus pneumoniae: cnle· but this route is painful. Doses are expressed in terms Ph. Eur. 6.8 (Cefamandole Nafate). A white, or almost white
rococci are usually resistant. of the equivalent amount of cefalotin; 1.06 g of cefalo- powder. freely soluble in water. sparingly soluble in medl)1 al-
Some Gram-positive anaerobes are also susceptible. cohol. A l~osolution in wa1crhasa pH, measoredafler30min-
tin sodium i$ equivalc1ll to about I g of ccfalotin. 111e utcs. of 6.0 to 8.0. Slorc in airtight con1.1.iners. PIOlcct from light.
Ccfalotin is usually inactive against Listeria mo110- usual dose is 0.5 to I g of ccfalotin every 4 to 6 hours; USP 33 (C~e Nafare). A white, odourless, cryslalline
c:y1ogenes. up to 12 g daily has been given in severe infections. solid. Soluble in water and in melhyl alcohol; practically insolu-
• Among Gram-negative bacteria cefalotin has acti~i­ For surgical infection prophylaxis. a dose of2 g is giv- ble in chloroform. in cydohe.one, in ether, and in ben2enc. pH
of a I O"/o solution in water is between 3.5 and 7.0. Store in air-
ly against some Enlerobacteriaccac including srrains en intravenously 30 to 60 minutes before the operation, tight containers.
of Escherichia coli, Klebsiella pireumoniae, Proteus followed by 2 g during surgery; 2 g is given every 6
Incompatibility a nd stability. Ccfamandole nafatc bas beell
mirabilis, Salmonella, and Shigella spp., but not hours postoperatively for 24 hours. For patients under- rq><>rted to be incompalibl~ ,.;th aminoglycosides and with met-
against EmerobacJer, indolc-positive Proteus, or going heart valve replacement or arthroplasty, cefalotin ronidazolc. formulations of ccfamandole n1fcre available for in-
Se1ralia spp. should be continued for up to 72 hours. jection contain sodium carbonate and arc incompatible with so-
1lic symbol t denotes a preparariol\ no longer actively marketed
240 Antibacterials
lutions containina calcium or magnesium salts. When proteins. The plasma half-life varies from about 0.5 to
rc.:onstitllted ,.;lh Wiler the sodium carbonate rapidly hydrolys- 1.2 hours depending on the route of injection; it is pro-
es about 30"/o oflhe ester to eefamandole sodium; during storage
of the reconstituted solution at room tempc:mwc carbon dioxide loogcd in patients with reaal impairment.
is produced. Cefamandole is widely distributed in body tissues and
Refen:nces. fluids including bone, joint fluid, and pleural fluid; it
L frabJt' RA. r1 al. S1ability of cefam:tndok nJ(1lc- i.njcction wjth diffuses into the CSF when the meninges are inflamed, Cefa pir in Sodium {BANM. plNNM)
parenitri• solutions and addirives. Am J Hosp Pharm 198?; J9: Bl-P-1322; Cefapinn sodna sUI: Cefapima s6dia: G!fapirinc
622-7. Corrcc1ion. ;o;d.; 1479. but concentrations are unpredictable. Cefamandole has
also been detected in breast milk. It is rapidly excreted sodiquc: Celop;nma:riu:n; Cefapirin·nWium: CefaprV\o natrio
unchanged by glomerular filtration and renal tubular drusi<a; Ce~ natricum; Ccphapitin Sod.,m (USAr~: Kcfa-
Cefamandole Sodium (SIJ>IM. rWNM) pirill'linatri..,,: Natrii Ccfapirinum. SodUm (7R)-7·[2-(4-pyri-
Cefamaodol sOdico: C~Wnir>dole Sodique; Cephamanclc* So- secretion; about 80"/o of a dose is excreted within 6 dytthio)acet.Vnido)ccphalosporanate; Sodium (711)-3-ace-
dium: Natrii Cefarnandol\Jm. hours and high urinary concentrations are achieved. toxyrneth)ol-7-{2-(4-pyridyfthio~}-3-cephcm·4-carbox­
Harp11~ l.Je:l>a"'3><A0.'
Probenecid e-0mpetes for renal tubular secretion with )late
C11H11N,NaOsS2 484.5. = cefamandole resulting in higher and prolonged plasma HaTpH14 UC<j>anvpMH
concentrations of cefamandole. lbcrapeutic concen-
CAS - 30034-03-8
ATC - JOIDC03. trations of cefamaodole arc achieved in bile.
=
C 11H 14 NlNa0 5S2 445.4
CAS - 21593-23-7 (cefcpirin): 24356-60-3 (cefapirin so-
ATC Vet - QJOIDC03. Cefamandole is removed by haemodialysis to some dium).
UNll - IY623400VR. ATC-)010808.
extent.
ATC Vet - QJ01 0808.
Adverse Effects and P recautions UNll - 431lFF717J.
As for Cefalotin Sodium, p.238. Uses and Administration
Cefamandole is a second-generation cephalosporin an-
As mentioned under Cefalotin, ccphalosporins with an
tibacterial used in the treatment of infections due to 0
N-methylthiotet:razole side-chain such as cefamandole II H H
susceptible Gram-positive and Gram-negative bacteria
(and possibly those with mcthylthiadiazolethiol or N-
(including infections of the respiratory and genito-wi- i(Ys~ +-Ys'j
methylthiotriazine side-chains as well) may produce
bleeding disorders associated with hypoprotluombi-
nary tractS, bones and joints, and of the skin and skin
structure) and for surgical infection prophylaxis. For
N~ ~i~-N~ol(cH3
naemia and/or platelet disorders.
details of these infections and their treatment, see under COOH 0
Sodium content. I.OS g of ccfamandole sodium and I.I lg of Choice of J\Jltibactcrial, p. J70.
ccfamandolc nafatc each COlltaU1about2.2 mmol of sodium. (cefapirm)
Cefamandolc is given principally as cefamandolc na-
Inte ractions fatc (the sodium salt of cefamandole fonnyl ester). Pharmacopoeias. In Eur. (seep.vii), Jpn. aod US.
A disulfiram-like interaction with alcohol may occur Doses are expressed in tcnns of the equivalent amount US also includes Ccphapirin Bcnz.athine for veterinary use.
and has been attributed to the N-mcthylthiotctrazole of ccfamandole; I .05 g of ccfamandole sodium and Ph. Eur. 6.8 {Cefapirin Sodi<rn). A white or pale yellow powder.
side-chain of cefamandole; patientS should avoid alco- LI I g of cefamandole nafate arc each equivalent to Soh1ble in water, practically in.<0luble in dichloromethane. A 1%
about I g of ccfamandole. It is given by deep intramus- solutioo in water has a pH of 6.S to 8.S. Protect from. lighL
hol during, and for at least several days after, cefaman- USP 33 (Cephapirin Scxilrn). A white to off.white crystalline
dole treannent. Interactions are also possible with prci>- cular injection, by slow intravenous injection over 3 to powder, odourless or having a slight odour. Very soluble in wa-
arations containing significant amounts of alcohol. 5 minutes, or by intermittent or continuous infusion in ter; insoluble in most Of!!anic solvents. pH ofa solulion in water
doses of0.5 to 2 g every 4 to 8 hours depending on the con1ainingthc equivalent ofcefapirio 1% is between 6.S and 8.5.
Cefamandole, and other ccphalosporins with on N-
severity ofthe infea ion. If cefamandole is used with an Store in airtight containers.
mcthylthiotetrazole side-chain, may enhance the hypo-
aminoglycoside, the drugs should be given separalely. Profile
prothrombinaemic response to anticoagulants as dis-
For surgical infection prophylaxis, a dose of I or 2 g Cefapirin is a first-generation eephalosporin antibacterial with
cussed under Warfarin (p.1566). actions and uses ,.ery similar tO those of ccfalolin (p.238). Doses
intravenously or intramuscularly 30 to 60 minutes be-
Probenccid reduces the renal clearance ofcefamandole have been expressed as cilhcr lhc sodium sail or as the base
fore surgical incision, followed by I or 2 g every 6 I.OS g ofccfitpirin sodium is equivalcntto •bout I & ofccfapirin.
and many other cephalosporins.
hours for 24 to 48 hours, is recommended. For patienlS Usual dose.' ofO.S to I g ba,·e been given every 4 to 6 hoon by
0 References. undergoing procedures involving implantation of pros- intramuscular injection or intravenously. In severe infc<:tioos up
I. PortiC'r H,,, ol. lnlcr3cl1on bcl\"t~n etphalOS(lorins and alcohol. thetic devices, cefamandole should be continued for up to 12 g daily has been used.
Lont:<I t980: II: 263.
l . Drummer S. Cf of. An1abuK·fil.C' .:fi'C\·t ~(p- lac.(am antibioliC$. N to 72 hours. Administration in renal impairment. Reduced parenteral
En11J M•d 1980: 303: 1417-18. dose.~ of ccfapirin sodium may be n=ssary in patients with rc-
The dose of cefamandolc may need to be reduced in
na I impainment. One regimen, based on crc.atinine clear~nce
patients with renal impairment, see below. (CC), !hat has been suggc<ted is:
Antimicrobial Action
Ccfamandolc is bactericidal and acts similarly to cefal- For details of doses in children, see below. • CC S lO 20 mVminutc: I g every 12 hours
otin, but has a broader spectrum of activity. It generally Admlnistradon in children. Ce!ilmandolc m.ay be g,ivcn to • CC less than 5 mUminutc; I g every 24 hoUIS
has similar or less activity against Gram-positive sta- children for the trcalmcnt of infections caused by susceptible Paticnts uodergoing hacmodialysis niay receive 7.5 to 15 mg/kg
phylococci and streptococci, but is resistant to some Gram-positive ond Gram·negative bacteria and for sw-gical in- after each dialysis.
fection prophyloxis. It is given pasa11crally by deep imramuscu-
beta-lactamascs produced by Gram-negative bacteria. lar injection, by slow intnven<ltl$ iJJjection over 3 to S minules. Sodium content. Each g of cefapirin sodium. contains ahout
It is more active than cefalotin against many of the En- oc by intermittent or continuca.i5 in fusion. 2.2 mmol of sodium.
tcrobacteriaceae including some strains of Entero- For trcatm.ent, children over 1 month of age m.ay be given SO to Preparat ions
bocte1; Escherichia coli, K/ebsiello, Salmonella, and 100 mg/kg daily in divided doles every 4 to 8 hours; 150 mg/Ilg USP 33: Cephapi'in for Injection
some P1'0tl!us spp. However, resistance to cefamandole daily may be given io severe infections, but this dose should not
ProprieRry Preparations (dtcails arc &ivcn in Volume B)
and other beta lactams has emerged in some species, exceed the =ximum adult dose (sec Uses and Administration, Cz.: Cer.tt~: F<: Cclaloject Gr.:
Cel1treoc Spain: Br;,i:':not.
above).
notably Enteroboc1er, during treatment with cefaman-
For surgical inl<ction prophylaxis, children over 3 months ofage
dole. Cefamandole is very active in vitro against Hae· may be i;ivcn ccfamandolc in a similar schedule to adults (see
mophilus influenzoe although an inoculum effect has aboYC); 50 to too mglk11 is given daily in equally divided doses. Cefatrizin e (SAN. USMt f>INNJ
been reported for bcta-lactamase-producing strains. Administration in ,...nal impairment. Parenteral doses of BL-56'10: Cefatri21r11: Cifatnzinc: Cefatrizinutr< SXF-60n I: S-
Like cefalotin, most strains of BoCJeroides fragilis arc ccfamandole should be reduced for patients with renal impair- 640?. (7R)-7-{a-04·~glycylamino)-3-( IH-1.2.3-tri-
resistant to cefamandolc, as are Pse11domonas spp. ment After an initial dose of I to 2 g the following maintenance azol-4-ylthiometll)'I)-3-ccp...,.m-1-carboxyfoc acid.
0 References. dose< have been recoinmcndcd based on crc.'llinioe cle>rance
(CC): U~p"3HH
I. Sabath l ~D . Rcappr.aisaJ of lhe antistaphylococc1.l arli'vities of
• CC SO to80m.l/minute pcr1.73 m2:0.7S to2 gevery6hours C 11H ,,N,OsS, = 462.5.
fi~·stn~nttion (nurrow-.-.pc:ctrum) 3nd sccond-ac~ralion (cx-
p11ndcd-spectrum) cephalosporins. Antimicrob Ag(!~,,, Ch""1th- CAS - 5 1627-14-6.
• CC2StoSOmUminutc per 1.73 m2:0.7Sto2 gcvcry8 hoUIS
er 1989; )3: 407- 11. ATC - )0 10807.
• CC JO to 2S mUminute per 1.73 m2: O.S to l.2S g e"cry 8 ATC Vet - QJ0/0807.
hours
Pharmacokinet ics UNI/ - BP4W949T8K.
• CC2 lo JOmUminutcpcr 1.73 m2: 0.Sto I gcvcry 12 hours
Cefamandole is poorly absorbed from the ga!>'tToimes-
tinal tract. Lt is given intramuscularly or intravenously, • CC less lhan 2 mUminute per 1.73 m7: 250 to ?SO mg every
12 hours
usually as the nafate which is rapidly hydrolysed to re-
lease cefamandole in vivo. Peak plasma concentrations Preparat ions
for cefamandolc of about 13 and 25 microgranlS!mL - USP 33: C•f•m.nclole N.r.te for lrjccl>on.
have occurred 0.5 to 2 hours after intramuscular doses Proprietary Prttpara.tions (details arc given in Volume 8)
of 500 mg and I g respectively; ~oncentrations are ~nral;.~~M~=~f~ ~;~=M~'.
very low after 6 hours. About 70% ts bound to plasma dck'clf. Indon.: Oordolceft: DolKef: ''•'" Cciont <:"""""' Lompom,.,.
All cross-references refer to entries in Volume A
 Cefapirin Sodium/Cefazolin 241
Cefatrizine Propylene Glycol (Bl<NM. t!N'MJ Incompatibility and stability. Ccfuzolin sodium has been re- tions of the biliary, respiratory, and genit0-urinary
Cefatriz11>a propi!engticol, Cdatr~ p•opiiengli'<olos; Cera:ri2ine ported 10 be i11compatiblc wilh aminoglycosidc:s and n>any other tracts, bones and joints, and of the skin and skin struc-
drugs. When the rH ofa solUtion exceed~ R.5 there may he hy-
propy.enegtycol; Cefatmin-propile~il-.ol: Cefa1ri?inpropyleng-
drolysis and \\~1cn it is below 4.S insoluble cc(a1.0lin may be pre-
ntre) and for surgical infection prophylaxis. For details
lj'l:ot C.efatrizin-prop-1iengiykol: Cefatronum p.-op)'ien gl)'Colt.m: cipitated. of these infections and their treatment, see under
Celawin.im ?ropy!cngfycolum: Ke'atnt$1nopro;i)1ieeniglykoli. References. Choice of Antibacterial, p.170.
(7R)- 7.;.,.o-4-Hydroxypher.y(glycytamino)-3-(I H- I.2.3-mazoi- I. N1hau MC. Ah ah PA. Sn~bi ! 11y ofccfuolir'I $Odium in peritoneal
1-y:thoome1hyl}-3-c~m+carboxylat~ prcpy'.ene *'ol. Cefazolin is given as the sodium salt by deep intramu.¥
di~lysi s solu1ioo.s Am J Ho.,p P/1&,.,,, 1991: 48: 191-2.
1. Wu C.C.. e1 of. Stabilh~· or ccraiolin in hcpariniud and non· cular injection, by slow intravenous injection over 3 to
U<$1TP""'"" n~'"''"°" heparinlu-d pcr1tonet1I diolysis solutH>ns. A•J J Heoltl1·S,1·s1 5 minutes, or by intennittent or continuous intravenous
C, 8 H , 8NPsS~. (C3H10,),,. PJwn., l00l 059: ISJ7-&.
CA5 - 64 217-62-5. 3. Lin Y·F. t i nl ~abilily I)( tcfa1.olin sodium 1n 1codu 1rin·eon~ infusion. Doses are expressed in tenns of the equiva-
ATC - }Oi 0807. Lainin¥, pc:n1onc1I d~1Jysis solUlic>n. Am J Ha,.'th·S.,.,-1 Phorm lent amount of cefazolin; 1.05 g of oefaz.olin sodium is
A7C Vet - QJ0/0807. ~002: 5?: 2362. 2364.
equivalent to about I g of cefazolin. 11le usual dose is
UNI/ - 37311A5Gl9. the equivalent of0.25 to I g of cefazolin every 6, 8, or
Pharmacopoeias. Jn Eur. (seep.vii) and Jpn. Adverse Effects and Precautions
As for Cefalotin Sodium, p.238. Stevens-Johnson syn- 12 hours. In severe, life-threatening infections I to
Ph. Eur. 6.8 (Cefatrizine Prop)'iene Q)<ol). A whito or almOSt
white pO\\-der. Slightly soluble in "'l'llet; pr3ctically insoluble in drome has occurred. 1.5 g every 6 hours may be given; up to 12 g daily has
alcohol and in dicbloromethnnc. been used.
Like cephalospotins with an N-methyltl1iotetrazole
Profile side-chain, cefazolin has been associated with hypo- For the prophylaxis of infection during surgery, a 1-g
Cefatriune is a fom-genenition cephalosporin anubactcrial with dose is given half to one hour before the operation, fol-
protllfombinaemia.
actions and uses similar to lhosc of cefalexin (p.237), ahhough it lowed by 0.5 to 1 g during surgery for lengthy proce-
might be more active ;,, vitro. h is given orally as the base or, Brea.st fecdin&· In a srudy 1 of20 women receiving cef~lin, dures. A dose of 0.5 to I g is given every 6 to 8 hours
more often, tlS a compound with propylene glycol, in usual doses lhe amomll ofcefazolin in breast milk was found to be extremely
equival<'lll to 500 mg !\\-ice daily of ecfatrizine. small (equivalent IO lt$S than 0.o75% of the dose). No adverse postoperatively for 24 hours, or up tO 5 days in certain
effects have been sec:o in brclst·fed infants \\1lOSC mochcrs were cases.
Preparations =eiving ccfaiolin, and the American Academy of Pediatrics
Proprietary Preparations {detail( are given 1n Volume B)
The dose of cefazolin may need to be modified in pa-
considers2 that it is therefore usually compatible with breast feed-
s.i,.: Celaperosj: F•.: Cerapero1t: Gr"~"""'"""'
Ce~m Cctrilr.: Ocmio: Foa·F: GC<10l'Y/(ir< lwVi: Ktluce~
e,,,,,,,,,...,, ing,
tients with renal impairment, sec below. See also below
Kie....... U·
I. Yoshioka H, ll ul. Transrerorcda2.0lin into human mifk.J Ptdi·
for details of doses in children, including dose modifi-
am,or< tilerost: ~ M.... n: Noboan: NorViroo: l'hacobiotic Re~
otr t919; 9~: ISl-2. cation for those with renal impainnent.
~~~,~~~.t:.1t.''~~~~.:::t.~; 2. American Academy or Pcdi:uric$. ~ traruJer or druss and oth-
Other routes used for cefazolin sodium include intra-
Micrcpe:i: ~~e~ er c-ht:mk.als 1nlo hum~n milk. Pediofl-ics 2001; lnM: 776-89.
IRC1ircd May 20101 Correction. ib;d.~ 1029. Al.so av:1il:Jblc zi; peritOneal use in peritoneal dialysis solutions, and in-
hup:J/GAppo11cy ~pp ublic-31ions.o rs/cgl/conten'11\ilVped i,atrics tra-ocular injection.
'lo)b 108/Jn76 (><tt<s<d 25'05104)
In some countries a modified-release intramuscular
Cefazolin (BAN. pH-O Effects on the nervous system. References.
fonnulation of cefazolin sodium with the less soluble
I. Manzella JP. e1al. CNS to:cicily usochucd wirh inuaven:aricular
Cel:izoLna: Cefazol;,e: Ccfazolnurrc Cc:phazol1n; Kefatrol ini: Se- 111jce1ion or cduolin: .-cpoct o( three c;1sc~. J N~mT>stn'f 198Si dibenzylaminc salt of cefazolin, in 'the ratio of I:4, has
fuolin 3-((5-Methyl-I.M-th adim:»-2-)'i)thiomethyl)-7-{tcin- 63: 970-1.
been used.
2 Manin ES. '1t nl. Sdwres 1fta 1n1ravtnlricul;ir c~fozol in admln·
2ol- I ·ylacEtamdo)·3-<ephem·4·cartx»cyic acid i5l.ra1ion. Cli11 Plro,.m 1992; 11: 104-S.
3. Arbravichi-(n W. 11 ol. Ccfu.olin induced s.ei:tutes in hcinodial~
Administration In children. Cefazolin may be giYCn to chil·
U$30N1H
C,.H ,.N,O,S1 = ~5·1.S.
ys;. pa1ic11U. J Mad Amx: Thai 2006; 89: 1981- J. drcn for the treatment of infections caused by susceptible Gram-
positive and Gram-negative bacteria. It is 11ivcn parenterally by
(AS - 25953-1 9-9. Sodium content. Each g of cefa7,0lin sodiun:o contains abolll clccp intr:linuscular injection, by slow intravenous injection OYCr
ATC - }010801. 2. 1 mmol ofM>C!ium. 3 to Sininu1cs, or by intenninen1 or conunuous intravenous info·
AT( Vet - QJOIC604; QJS I OA01. s1on. Olildren O"er I month of age may be given 25 to 50 mg/kg
UNll - IHS69LOY4T. inte ractions daily in 3 or 4 divided doocs. increased in scYCn: infections to a
Cefazolin contains a methyllhiadiazolethiol side- maximum of 100 mgllcg daily.
chain; like cephalosporins containing the related N- The dose of celilz.olin should be modified in children with rc1ial
methylthiotetrazole side-chain (see Cefamandole, impairment. Aft<r a loading dose the following doses b~ on
crcatininc clearance {CC) h3ve bceo suggested:
p.240), it may have the potential to cause a disulfiram-
• CC 4-0 to 70 mUminute: 60% of the normal daily dosc in 2
like reaction with alcohol, and enhance the effects of divided do.cs
warfarin. • CC 20 to 40 mVminutc: 2S% of the no1mul daily dose in 2
Tiie renal excretion of cefazolin and many other cepha- divided doses
losporins is delayed by probenecid. • CC S to20 ml/minute: 10'!.ofthenonnaldailydosccvcry 24
hours -
Antimicrobial Action Administration in renal impairment. Pattntenil dOS3gc of
As for Cefalotin Sodium, p.239, although cefazolin is ccfazolin should be reduced in patients "ilh renal impairment
Pharmacopoeias. Ill US. and various modifications have been recommend.:<!. ARcr a
USP 33 (Cefazoli1). A white to slightly ofl~whilc, odourlc$.s more sensitive to staphylococcal beta-lactamase.
loading dose lhe licensed product inf<>nn:ltion SUJl&C$tS the fol·
crystalline powder. Sli&htly soluble in water. in alcohol, and in lowing doses bescd on crcatininc clearance (CC):
methyl alcohol: sparingly soluble in acetone; prnctically insolu- Phanna.cokinetics • CC 55 mL or mm per minute: usual doses
ble in chlorofonn, in dichloromcthanc, in ether, and in benune; Cefazolin is poorly absorbed from the gastrointestinal • CC 35 to 54 mUminute: usual doses bot at intervals ofat least
soluble in d11ncthylfom1amide and in pyridine, very slightly sol- tract and is given by the intramuscular or intravenous
uble in elhyl >eerate, in isopropyl alcohol, and m methyl isobutyl 8 hours
ketone. Storr in aittight containers.
routes. After a 500-mg dose given intramuscularly, • CC 11 to34 mUmi11111e: half the usual dose every 12 hours
peak plasma concentrations of 30 micrograms or more • CC 10 mL or less per minme: half the usual dose every 18 to
Cefazolin Sodium ~~ USAN. p/NNM) per mL occur after I hour. About 85% of cefaz.olin is 24 hotrs
bound to plasma proteins. The plasma half-life of ce- One report' indicated thnt, for patients on long-term hacmodial-
46083; Celazolin SO<i'l.i slA; Cefuclina S6dica; Cefazolne sodl- ysis,an inlr.lvcnous dose of20 mg/kg given 3 times w..:klyaflcr
we; Celazolinnauium: CeWi:>..,-na:nvm: Cefazolino na1n0 fozolin is about 1.8 hours, and is increased in patients
dialysis maintained thernpeutic cefazolin concentrations.
d"'1Sl<a; Cefazcl1nu1n ncrti itL1n: Cephzzolin Sodium: Kclatso!in· with renal impainnent Cefazoli n diffuses intO bone I. Ahc:tn J W. ~' ol. C~r:n.olin dosjns protocol for patients recci vin~
r.atriurr< Natrii C~fazol11'olir'I'~ Sef<2ofin Sodyo.im; SKF-41 SSa and in10 ~~cilic, pleural, and synovial tluid but not ap- long·1ct1n henl0di3lysis. Am J H~olth-S.~t Phom• 2003: 60:
Ha-rpv.V. U.30AMH preciably into the CSF. It crosses the placenta; only low 17&-81.
C 14 H 1jN1NaO, S3 :: 176.5. concentrations are detected in breast milk. Preparations
CAS - 17164-46-1 Cefazolin is excreted unchanged in the urine, mainly BP 101q, Cof«cl;n 'niectOn:
ATC - }010604 USP 33: Cofuolin ru lnjKOOn: Cc'aoln triec:.on: Cduolin Qi>itNmoc
ATC Vet - Qj01v80< by glomerolar filtration with some renal tubular secre- Scluuon.
UNI/ - P380M04547. tion, at least 80"/o of a dose given intramuscularly being Proprietary Preparations (details arc givtn in Volume B)
excreted within 24 hours. Peak Utine concentrations of At;.: Cefilom<N. c.r.mczin: Austral.: Ke<zo\ A.is<ria: 1Ct'1.et Sorvazo·
Pharmacopoeias. In CT1itt, E11r. (sec p.vii), Jpn, and US. lint Zokefl; Stiz" Ccra:i:lolt; l<elwt _a,..,_, C.1-nt: ~~l.Cf'.l>t: ~ocet
Jpn also includes lhc pcntabydrate. more than 2 and 4 mglmL have been reponcd after in- Faiolon: t<e<azcl; l''*'t CL: Ke!,olf: 0-ozolooi: v..r..o ... Fr•• Cofoclclalt.
Ph. Eur. 6.8 (Cefazoin Sod.rn). A wh!te or almost white. vay tramuscular doses of0.5 and I g respectivcly. Probene- Ge •. : &soc.!. Elzo(rimt: G'" llc>zolin: Kelal'lft Kefzot Tr-on: Vor.iotn
hygroseopic powder. It exhibits polyrnoqihism. Freely soluble in Honz Konz: C.r.ineJri; Hung" To<>cdt: /ndl~: A:din: Rellirc Zol'"'f:
cid delays excretion. Cefazolin is removed to some ex- lndon.: ~iozol"f: Cdallot fvairc IJ¥ael: Ce~ t:ef.uin: tc.fzdf: TOl.l·
water, very slightly soluble in alcohol. A 10% solution in water cclj, lt<>l.1 Ace~ Cefaboz,mf: C.W-....zon: Ceiuil Cromem: NcW<it Re-
has a pH of 4.0 to 6.0. Store in airtight containers. Protect from
lenl hy haemudialysis. ul; Sic:•ft: Tot""'ft: /pn: ~-°""~" Cczt. Neth.: Ccfocidolt: Ca·
High biliary concentrations have been reported, al-
~t~ ~~~~'1.".::~:?~~~i~~
light. 1
USP 33 (Cefarolin Sodium). A while to o ff-white, po':lctically thougll the amount excreted by this route is small. Ktt Nor.iet Oryont: P1czor..: S.0-0.~ SUncot Zalulin: Zoladc!x ~
odourle~s. Cl)'Slalline powder, or o white 10 off-white solid. Free· Pol" Sdiroin: T•nwin: Port.: <:cf.,,,.."< t:.Jrg•n: Rus.: CclamtZ#I
ly soluble in water, in sodiwn chloride 0.9%, and in glucose so- Uses and Administration (Ll<>jooMe:s.o•~ lizol ~"'°")t. Inv~ (lwpa30,....): Kcfl.CI (~>oA~
lutions; '"'-.Y slighdy soluble in alcohol; practically insoluble in Ly>aln {/looc>Mot) Nacol (Hau.+).~ i°""""""l· ~llin (P*-lf:
Cefazolin is a first-generation cephalosporin antibacte- l'ot>ef(TOT.....t,Zolin(~•),S.Afr" ~ lac~:Ke/zol!R.an­
chlorofonn and in clhcr. pH ofa solution in waler containing the
equivalent ofcefazolin IO'A. is between 4.0 and 6.0. Store in air- rial used to treat infections due to susceptible Gram- ><>l: Spoin:""""'*" 6ri1.C'ir.et: C..-i<cfj: ~ f.,cplttj: lntr>zol>
no: Ktfolt: l<ul'p'C 1loqx 7edarolina: Zoli""t Switc Kcflc>t Th<>i.: Cci•l;rc
tight conwiners. positive and Gram-negative bacteria (including infec- Ceramezin: Ctluli>; Ccfazd: Cefzo!in: Fl20lon: Ze'1. Zcpi'c:>t. Zo0cel.
TI1e symbol t denotes a preparation no longer actively marketed
242 Antibacteria.ls
Zo!ime<t Turk.: CeCametin; Cefo3" Cete>t EqiJitol1n; lespor; MaksipO!"in: Cefdinir (8AN. USAN. rlNN) impa irme nt whose c rea1inine c leara nce is less tha n
ReOOs;n: SofaNW<: SeWot V• n•L: C•f..:i:l•I: C•Jarizoo: CeloMa: Kefzolt. 30 "!Uminute.
Cerdinirom: 0·983: FK-482; Kcrcliniiri. (-)-(6R,7R)-7-{2-(2-Arru·
no-4 ·thiazolyl)gl)oxylamidoJ-8-oxo- 3-vinyl-S-thia· I·azabicyc- The dose oforal ocfdinir should be reduced in children wirh renal
Jo(4.2.0]oct-2-cne-2-carboxy1ic aciG. 72-(Z)-oxime: 7·{(2-hn•· impairment (crea1inine clearance less than 30 mUminute) 10
Cefbup e razone (U)AN. rlNN) no- I .3·thiuol·~-yl}-2·[(Z)·h)'droxyirr<no]acetamido)-3-viiyl· 7 mg/kg given once daily, up to a maximum dose of300 mg.
BMY-25182; Cefbuperazona; Cefbo.4>erazone; CeibuperazOl'lJm; cephem-4-wboxylic aicod. Cefdinir is removed by haemodiolysis; therefore parienlS on
T-1982 7-((2R.3S)-2-(1~2.~I-~
chronic baemodialysisshould initially be given adoscof300 mg
~.6"'*'!> (or 7 mgikg)everyahem;iteday. A do5eof300 mg(or7 mg/leg)
do)-~}7~-3-(1-meth)l-IH-te!ra·
C ,.H11NsOsS1 = 395.1. should be gi\"'1 at the conclusion of each haernodialysis session.
zci.S-yttNome:hyt)-3-<~-arboo<yk acid. Subsequent doses arc then given every 1ltcma1e day.
CAS - 91831-40-5
U~palOH ATC-)010015. Preparations
C22H29N,o,s, : 627.7. ATC Ver - Q)OIOOl5.
USP33:Cddni'~·cs.
CAS - 76610-84-9. UNll - CIOFA063WC.
UNll - T0785]3X40.
Proprietary Preparations (details are given in Volume B)
~!: ~~~~~h~lf~~Ce~~~~~t.~~~1;;~;:~~~
0 1

r«ef. S•mnk: Tur k.: Cefcinex USA: Omrice(

C e fd ito re n Pivoxil (rlNNM)

Ccfdtorene, Pivo>OI de; Cefditoreni Pivoxi: Celdrtoreno pivoxilo;
ME-1207: ME-1206 (celditoren~ Pivaloyloxymethyl (+)-(6R.7R)-
7-{2-(2-Arl'W>o-4-thiazol)of)g~}3·[(Z)·2{4-melhyl-S­
Pharmacopoeias. In Clun, Jpn. and US. thazol~o-S-:hia-1-azabicydo{1.2.0)oct-2-ene-2-c.ar-

Cefbuperazon e Sodium 1~
Cc~ ~sodc. C~ Sodique: N..-.tiCehJ.
perazorun
USP 33 (Cefdrir). A white to light yellow crystalline powder.
Practically insoluble in walef, in alcohol, and in ether. Store in
ainighl ccruainers. Protecc from light.
Adverse Effects and Precautions
~ope... n--
boxytic acid 72.(Z)-(O.~).

C1sH21N60,S1 = 620.7.
CA5 - 104145-95·1 (cefdirorM}; 117467-28-4 (cefdi-
Harp~,;, U~epalOti
As for Cefalotin Sodium, p.238. There have been repons of red- toren ptvoxol).
C22H,.N,NaO,s, ; 619.6. dish stools in petienlS given cefdinir ,.;th iron supplcmcnlS (see ATC- )010016.
UNll - I VX59V9685. also lmerac1ions, below). ATC Vee - QJOIODl6.
Pharmacopoeias. In Jpn. Inte ractions UNll - 78THA2 I 20H.
Profile Absorption of cefdinir is decreased by antacids or iron supple-
Celbuperazone is a cephamycin antibaclcrial •imilar 10 cefoxitin ments and doses should be separated by an interval of al least 2
(p.249) but wilh an N"mc1hyllhiote1nZOlc sidc..:hain like cefa- hours. Probenecid reduces !he renal excretion of cefdinir.
mandole (p.239). II is given by injection as lhc sodium salt TIS Iron. A rcpon1 of red stools in an infant given ccfdinir while
spectrum ofactivity includes E111eroboctcriaceae, but more espe· being fed wilh an infant formula containingsupplemenlal iron. It
cially anaerobic bacteria such as Boctt!IOides frogilis. Cclbuper- was considered imporun110 be aware oflbe interaction because
azone does not appear to be active npinsl cefoxitin-resistanl of the risk !hat it m1gh1 be mistaken for a sign of ga$trGintC$1inal
sttains of B. frogilis. bleeding.
Preparations I. lanc.as1er J. no/, Nonbloody. red stools from coadministrtltOfl
or cefdanjr and 1ronasuppkmc:ntcd ir.fan1 (onnulas. Phorm«O• (cefd•toren)
Proprietary Preparadons (details arc given in Volu~ B) 1/lcropy 2008; 21: 67&-a I.
Jpn: Kl'r-'!xnn Antimicrobial Action Pharmacopoeias. In Jpn.
As forCcfixime, p.244. However, cefdinir is reported to be much
more active In vlrro than ccfiximc against Staplry/oeo<cuJ ou· Ad verse Effects and P recautions
Ce fcape ne Pivoxil H ydrochlo ride (rlNNMJ reus, bu! nol me1icillin-resislanl strains, and it is less active As for Ccfalotin, p.238.
against some Enlerobocteriaceae. The most frequently rcponed adverse cO-cCIS of ccfditoren are
Cerc;ip~c Pivoxil, Chl0<hychtc de: Cefcapeoi Pivoxili 1-!yd<o-
Pharmacokln etics gastrointestinal <listmbances, especially diarrhoea.
chlorid<Kll; Hidrocloruro de ccfcapeno pivo>Olo; S-1108: S· 1006
(ccfcapeoe). Pivaloyloxymctnyl (+)-(6R.7R)-7-[(Z)-2-(2-aminc>- Ccfdiniris ahd>ortcd from the gastroin1es1inal tract and Jl(ak plas- For reference 10 camiline deficiency with some pivaloyloxymc-
ma concentrations occur 2 to 4 hours after an oral dose. Oral bl· 1hyl esters, sec Pivampicillin, p.344.
4-lhiazol)of)-2-p<!ntenamidoJ-3- (h)'dnoxymethyQ-8·oxo-S-thia- I-
azabicydo[4.2.0]oct-2·cne· 2·carboxy1ic: acid C41bamate mono·
oavailability hos been c.~imatcd 10 range from 16 10 2S%. It is Interactions
widely distributed into tis<ues and;. 60 10 70'/o bnund 10 pl11$ma
hydrochloride monoh)'drate. proteins. Cefdinir is 001 appreciably metabolised and is exacted Absorption ofccfditoren alter oral doses is decreased by antacids
or hisrarninc Hrrea:J>lor antagonists. J>robenecid reduces 1hc rc-
U~ flMBOKCIW r ~XAOpMA in !he wine with an elimination half-life of 1.7 hours.
n.al excretion of cefditorcn.
C23H29Ns01S,.HC1.H,o =622.l Cefdinir is removed by dialysis.
Antimicrobial Action
CA5 - 135889-00-8 (ce{copMe): 105889-45-0 (cefcop- Uses and Administration
Me pswml): 147816-23-7 (onhydrous cefcopene pivoxil As for Ccfoxime, p.244. Cefdicoren also has activity agains1 Sta-
hydrochloride): 14 7816-24·8 (cefcopMe pivoxff hrdrochlo-
Cefdinir is a lhird-gcncra1ion oral ccphalosporin antibaclenal phylococcus OllTe:JS.
rlde):. used to tral infections due 10 susceptible Gram-positive and
Gtam-neiative bacteria, including infections of !he respiratory Pharmacokinetics
ATC - )010017. Ccfdiloren pivoxil is absorbed from !he pstroinlcstinal trace and
tract and ofchc skin and skin s1rucrures. For details ofinfcctioM
ATC Vee - QJOIOOl 7. and their 1reatmcn1, sec under Choice of Anribacierfal, p.170. is hydrolysed co cefdi1oren by cstcrascs 10 release active cefdi-
O:fdinir is given orally in a usual dose of 600 mg daily as a sin- loren in the bloodstream. Peak plasma coneentralions average
J.8 micrograms/mL in fasting subjects l.S 10 3 homs after a 200-
gle dose or in two divided doses. Twice daily dosing should be mg dose. Bioavailability-is about 14% in fasting subjects and is
used for pneumonia and skin infections. increased when cefditoren pivox il is given wilh a high·fal meal.
The dose of ccfdinir may need lo be reduced in patients wilh re- Plasma protein binding is reported to be 88%. The plasrna balf-
nal impairment, sec below. See also below for details of doses in life is about 1.6 hours and is prolonged in patie111s wilh renal im-
children. paim1C111.
ORevicws. Ccfdi1oren is not appreciably metllboliscd 3nd is excreted mainly
I. Guay DRP. Cofdinir: an e>panded-speetrum oral cepholosporin. in !he urine by glomerulor fil1r.>1ion nnd 1ubulor secretion. It is
AnnPharlnO<Olh.r2000;34: 146~77. removed by bacmodialysis.
2 Guay OR. #I ttl Ccfdinir: an adV3nttd-gcnera1ion. twnad..~­
cnun 01al cq>hllosporin. Clin 1Mr JOO?; 2A: 473-89. Uses and Administration
). Petty CM. Scou u . Cerdinir. a review or its USC iJ'I lhc manac.e.-
Ccfdilorcn is a third.generation oral c:q>halosporin antibactc:rial
(cefcopene) ~4e;t;[.~ild-to-modcraLt bacterial infections. DrvgJ 2o<M; 6.1: used lo IJCaC infections due to susocp1ible Graon·posilive and
Gram-negative bacteria. including infections of the rcspilalory
4. Sader HS. Jor.u RN. Ccfdinir: :m o:-al cephalosp0rin f« the traci and of the skin and skin struc:lwa. For details of infectioos
Pharmacopoeias. In Jpn. treaiment of respiral°')' Intel infcct~ns :md skin 1nd Min SINC• and lh.U treatment, see under Choice of Anlibac1erial, p.170.
lure inrcctions. £.t.~1·1 R~ Anti 111/ttt Thtr2007; S~ 29-43. Cor-
P rofile rccoion. Ibid.: 754. (dO$C error) Ccfdilorcn is given orally as the pivaloyloxymclhyl ester; cefdi·
Cefcapenc is an oral cephalosporin •nlibaccerial given orally as Coren pivoxil, but doses are expressed in terms of ccfdiloren;
the ph-aloyloxymelhyl ester, cefcapene pivoxil hydrochloride. Administration in children. Ccfdinir may be given orally 10 245 mg of cefditoren pivoxil is equivalent to about 200 mg of
For refe<cncc to cami1inc deficiency occurring with some pival- children for the treatment of infections caused by susceptible ccfditorcn. A usual dose is 200 10 400 mg given '"ice daily.
oyloxymethyl esters, sec Pivampicillin, p.344. Gram-positive •nd Gram-negative bacteria. Children from 6 For details of reduced doses to be used in patients with moderate
mon~1s of age may be given 14 mg/kg daily as a single dose or
10 S<:vere renal jmpainncnl, see below.
Preparatio ns in cwo divided~ (lo a maximum daily dose of 600 ong).
Proprietary Preparadons (de11ils 1re given in Volume Bl For details ofdoses in ebildrcn with renal impaiiment sec bdow. OReviews.
/pn: Flcmcx. L Wclliniton K. Curran MP. Ccfditorcn ph'oxil: a rc,··iew of ils u~c
Administration In renal impairment. Oral dosesofocfdinir in the trcatmc.nl of buttri'1l infec1ion1. Drugi 2004: 6..-:
should be reduced 10 300 mg once daily in patients with renal 2S97·2618.

All cross-references refer to entries in Volume A

 Cefbuperazone/Cefepime Hydrochloride 243
!. Hcm8ndtz~M1nm J. ~; nl Ctfdilarcn pi\·oxilo;.un.=- noc\'a ctfa- 4. FDA. ~rly c01nttu,mkation about ;m ongoina sa(el)' review: Uses and Administrat ion
lo$p\lrina oniJ p11ni 1n(cc:cioncs de vi3s rc.spinuorias y de ptd 'I cef(pin1e (morketed as Maxiriinc) (issued 14th t-ovcmbcr
tej;dos blanduL R<i· EJp fl><imioru 2()Q/j: 19: 231~. 2007). Available at: hup:t/www. fd a.~ov/Dru1$10ru_g5afcty/ Cefepime is a fourth-generation parentera l cepha-
;. BicdcntHlch OJ, Jones RN. Upcbtc of c:cfdi1oren acth•ity tested Posun:ukc1DrusS1fetylnformationfotP:i1ient11ndPro,·iders! losporin antibacterial used in the treatment of infec-
api11s1 com1nunily-:icquired p.athog:tns associated with inft.t- Otu£,S. rel)' In ror mat ion for H c 111 he. rep C('I f css 1On<! Is/
llons of the rdpiralory 1rac1 and skin and skin struccures. includ- ucm070496.htm(accessed 20/07/10) tions due to susceptible Grom-positive and Gram-neg-
mg rtttnl phannocodynamic con1ider11ions. Diagn Microbiol S. rDA. lnfonnation fo1 healtb~c p<oft:ssionafs: ccJe-pimc (mar· ative bacteria, including those of the abdomen, urinary
lnftct Dis 2009; 64: 202-12. keted u Maxir;me): (is<ued 17th Jv.. 2009). lra<:t, respiratory tract, and skin and skin structwes. It is
Avail1blt a t: http :/fo1 ~·v.· fd1. go\•/Drugs/Dru3Saftty/
Administration in renal Impairment. Oral doses of cefdi- Postmart:.etOrua:Safc1ylnform11io.nforPatitnl$.andProvidcrs/ effective against Pscudomonas ae11Jgi11osa and may be
toren pivoxil should be reduced in patienls with moderale to se- DrugS::fcty Infor m o1ion fa rH eathcarc r ro re u i ona Ist given empirically for febrile neutropenia. For details of
vere renal impairment :><:cording to creatinine clcaranoe (CC): uc•n 16725".bim (ocoeuod 19/06109)
lhese infections and their treaanent, see under Choice
• CC 30 to 49 ml..bnintnc: !he dose should not t>.'Cted 200 mg Effects on the nervous syste m . Refcrcoces lO neurotoxici·
twiocdaily of Antibacterial, p.170.
1y,1->• sometimes manifesting as nonoonvulsive status epil<:pti-
• CC less lhlln 30 mUminute: the dose should be 200 rng once cus, associaled with use ofcefcpime (particularly but not exclu- Cefepime is given as the hydrochloride by deep intra-
daily. sively in palicnts with impaired renal funclion). muscular injection, or intrave nously by infusion over
Prepa..ations I. Chow KM. et al. Rcll'OSpCdirt review of rieurotoxicity induced at least 30 minutes. Doses are expressed in tenns of the
by cefepimc and ccftazidime PhortntJcotherap.v 2003: 13:
Proprietary Preparat;ons (details are given in Volume 8) 369-73. equivalent amount ofcefepime; 1.19 g of cefepime hy-
Gr.: Specvotet Indio: Cefdnr.n: Ind.,.: l1eoaa: Ital: G.sio<>: Jpn: Me1- 2. Ferrara N. er al. NcuroloXteity induced by ccfcpimc in a \Cf)' drochloride is equivalent to about I g of cefepime. The
•ct Mu.: ~ Port.: Moi>n: ~pe<1r.ac<f. SpoM: Moixt; Specvacot. old bcmod;•lysis p>licnl. Clin Ntplwl 2003; 59: 388-90.
Telo; Thcri" ~ Turi<.: Mti;ic• Sp.ktrocef: USA: Spear>cel: 3. Dakdouki GK. Al·Aw~t ON. Cefepi_mie...iodY<'.ed cnccph.ilop., usual dose is I to 2 g daily in 2 divided doses for mild
1hy. /111 J l•fe<r Dlt 2004; 8 : S9~1. to moderate infections, increased to 4 g daily in 2 di-
4. Alpay H. tt o/. Cc(epimc-inJuccd non-<Xltl•ndsivc status cpilcp- vided doses in severe infections, although up to 6 g dai-
ticus in 1 pcri1oneal dialysis. patient. Pediotr H#pltrol 200-4; 19:
44S-7. ly in 3 divided doses has been given for febrile neutro-
Cefepim e Hydrochloride S. Ab:m1da S. d al. Reversible eoma scoondlt)' 10 ufcpime ncu- penia.
(BANM USAN. rlNNM) ro1oxici1y. A,,n Pltarr11oco1hcr 2004: 38: 606--8.
6. Coppun 11i FJ, d ol. Cefc-pime· and ccflx ime~induce-d c:ncepha-
4
The dose of cefepimc may need to be reduced in pa-
BMY-28142 (cefepime): G!fepime. Chlomydrate de: Cefepime, lopa1hy In a. parient wi1h nofmal renal r\lnction. N~urology200$;
65: 1840. tients with renal impainnent, see below_See also below
~e de; Cerepimi dohydro<hlotidum; Cefepimi H)d'o-
1. Maganti R, el al. Nonconvulai~ sl:itus cpilepticus due lO for details of doses in children, including dose recom-
cl>loricbr< Hidrodoruro de cC!fepima: Sefepin Hidroldoriio: {6R- cdepime in a patient with normal renal function. Epilr.p.t)l 8•
[6o..7P(Z)]}- I -{(J-{((2-An1t>o-1-thiaioly!Hme-Jlox)1mino)- "°" 2006; 8: 312-4. mendations for those with renal impairment.
acctyf)amino)-2-urt>oxy-8-oxo-5·th.;- 1-uabicydo{1.2.0)oct-2- 8. !::Ji~~~l:~i~~~~i~~!:":;,e~~=:~~~f:!,,r1i::,•,,~::;: ORcvicws.
en-3-yf}methyl)- 1-methylpyrrohdinium ctilonde monohydro- ''""""2006:24: 1169-74. I. Variou5.. Cdcpime: a p-lactama.se-slablc: c.xtcndcd·spcclru:rn « ·
chloride monohydra-.e: 7-((2-Amino- l,3-ttiazol-'l·yf}-2-[(Z)- 9. Sol'K:k J. a ol. The ncuroto:dcity ind s.arct)' o.f ucatmcnt wi1h phalospurin. J ll111imicrob Chuiorl1<r 1993: 32 (Suppl 8):
mcthoxyirnno)acetamido)·3-( I -methylpyrrol1d~3-ce­ ~~et~: i=~tS wifh renal failurt. N•phrol Dini Troruplanl 1-114
phem-1-carbcocylate ~e. 2. Oa!Tldctl LO. Bryson HM. Ccfcpime: 1 review of its a.nlibac1t-
10. Oarccs EO. ct al. Rmal failure ii. 11 ri~ f111:tor for ttftpimc- ri1I 1c.th'ity, pharmscokinetic propenies and therapcu1j: us~ .
U~1<Ma r"'APOl<JIOPl<A induced cncepl\alopalhy. J Nophml 2008; 21: S'.!6-34. ,,,..., , 1994: 41: 471-505.
C 19HuCIN•OsS2.HC1.H,O 571.5. = Antimicrobial Action
3. Ok1mo10 MP. e1 ol. Cefe pime: a new fourth· gcncration ccph;i-
lo.sporin. Am J H0tq1 Phan•t 1994; SJ; 463-77.
CAS - 88040-23-7 (ce(ep1me); 123171-59-5 (ce{Epime
hydrochloride monohydrote) Cefepime is a fourth-generation cephalosporin and is 4. Wynd MA, Pal.achno JA. Ccfepimc: a fo1o1.nh1tnent1on
p:ucntcral ccphalosporin. Ann Phormaco1he1- 1996: 30:
ATC - JOIOE.01. active against many Gram-positive and Gram-negative 1414-24.
ATC Vet - QJOIDE.01 . aerobic organisms. Against Gram-positive cocci, its s. Wong-Bcringet A. Truring .K'fious i11r..:1r..1ioiu1: fucus on
UNI/ - 18XI00607P. activity is similar to that of cefotaxime (p.247) and in- e<rep;mc: Pharmocorheropy 2004: 24: 216S-23S.
cludes staphylococci (but not meticillin-resistant S1a- 6. RoXns JA, rt ul. Ccfepilnc rtrSUS cet\uidim~: con.sidcrations
f«cmpirical uu in critically ill pa.1ient1./ut J .4illfmicrobAgents
p/1ylocooc11s aureus) and streptococci. Against Entero- 2007; 19: 117-28.
bacteriaceae., it has a broader spectrum of activity than Administration in children. Ccfepime may be given 10 chil·
o ther oephalosporins, including activity against organ- dren for the treatment of infec1io11s caused by su;ccptible Gr~m­
isms producing cltro1noi;omally mediated bela-lacta- positive and Gram-ncgati"c bacteria. Cefepime is g;,..., by deep
mases such as Enterobacter spp. and Proteus vulgalis. intrllmuscular injection, or inCravenously by infusion over at least
Against Pseudomonas aeruginosa, ii has similar o r 30 minules. Children aged over 2 mooths and weiglting up lo
40 kg muy be given 50 mg/kg twice daily; this dose should be
slightly less acrivity than cefiazidime (p.254), although givm 3 limes daily for febrile nculropenia.
Pharmacopoeias. In Ew: (seep.vii), lf"•, and US. it may be active against some strains resistant to
Ph. Eur. 6.8 (Ce~me Dih~ Monoll)O'ate). A white US licensed product iufonnatinn reaim1nend ~ tha1 for children
or almosl while, aystalline po-..'der. freely soluble in water and ceftazidime. with renal inipainnent these dn.<es of cefcpime should be re-
in melhyl alcohol; practically insoluble in diehloromethane. Pro- duced by similar proportions to~iotl$ io adults (<ee below).
tect from light. · Pharmacokinetics Administn.tion in renal impalnnent. Parenteral dosage of
USP 33 (Cefepime HydrocNonde). A white 10 off-white, non· Cefcpime is given by injection as the hydrochloride. It cefepitne sh<lUld be modified in renal impainnent After a nor-
hygr0'1icopic, crystalline powder. freely soluble in waler. S1ore in is rapidly and almost completely absortxxl on intra- mal firat dose the maintenance doS3gc should be adjllSlcd oc-
airtight oonrainers. Protecl from light muscular iitjection and mean peak plasma concentra- cording to Ute patient's crc.:itinine clear.ince (CC) and !he severi-
Incompatibility and stability. References. tions of about 14 and 30 micrograms/mL occur about ty of the infection:
I. SlC"-'lfl Ji, .t ti/. Sl ~1bil i1y i>r~fqHfnC' hydrochloride injC(.tion in 1-5 ho~ after doses of 500 mg and I g respectively. • CC 3010 60 mUnunute: 0.5 to 2g cvety 24 hours (2gevery
polypropylene •Yringes •t - 2o•c, 4-C, and 22-24•C. Am J 12 hours for febrile ncull'openia)
H<olr"-Sy<I Ph<>ni1 1999: 56: 4;7- 9. ... Within 30 minutes of similar intravenous doses, peak
2. Stcwan JT.~n/. Stabili1yofccfopintt hydrochkwidc in polypro- plasma concentrations are 40 a nd 80 microgramslmL • CC 11 to 29 mLlminutc: 0.5 to 1 g every 24 hours (2 g every
pylene syrins,cs.. 401 J H~ulth-Sy.vt Pltunu 1999; S': 1134.
respectively. TI1e plasma half-life of cefepime is about
2• hours for febrile nculrOpCllil)
or
3. W1llianlSOn JC.. 11 al. Stability ccrc1>imc in peri1oncal di;alysis • CC IOmUminuleor less: 250 to 500n1gc•·ery 24 hou1~(I g
solution. Am1 Pharmacothcr 1999: 33: 906...9, 2 hours and is prolonged in patients with renal impair-
<""')' ~4 hours for febrile ncuaopcnia)
4, Oaririan N. ~t al. S&abilicy and comp:nibility study of c..-fcpimc ment. About 20"/o of cefepime is bow1d to plasma pro-
in comp.uiscn with crt\aZJd1mc ror potenti:1:I administration ~Y PatienlS undergoing haemodialysis should be given o dose of I g
cot1tinuous iorusion under conditions pertinenl io ;irnbt.itak>l'y teins. on the fora day of1rt11incn1, followed by 500 mg doily; !he dose
Cr~tmcnc of cystic Cibrosi1 ~tic:nlS :ind to 3dminis1r.uion m in·
lens.i'·~ c:irc u11hll J A"timlcrob Chauother 2003~ ~ 1 : 6Sl-8.
Cefepime is widely distributed in body tissues and flu- should begi••en after haemodiolysison lhoscdays. A dose of I g
5. Tri-SKI Lo\. Xu OA. Stability of cefepimc hyctrochlnridc in Au- ids. High concentrations OCC\tr in bile. Low concentra- doily should be used for febrile neutropenia. PalienlS undetgoing
toOosc inrusion sys1c01 b:!l,g.s. ..t11n Pko1'1HO~o1h11 · 2003; 37: tions have been detected in bceast milk. continuous nnibulatcxy peritoneal dialysis should ttcei•'C notmal
804-7 recommended doses at int.Cl'11is of48 bOllrs. A do6e of2 g every
Cefepime is eliminated principally by the kidneys and 48 how-sis used for febrile neutropenio.
Adverse Effects and Precautions about 85% of a dose is recovered unchanged in the
u1ine. Cefepime is substantially removed by haemodi- Pre parations
As for Cefalotin Sodium, p.238.
alysis. USP 33: Cei.p;m. fa< lnjootoon.
0 The safety ofcefepime has been ncviewcd. 1-3 A meta-analysis2 Propn..tary Preparations (deia;ls are given in l.\>lun>c B)
of srudies .invol•ing cefepime suggested that there mighl be an 0 Refcncnccs. Arc.: U,-,..-1(; Max<of. FJ\oep;me; Austral, ~ Austrfo: Max:p-
increased risk of all-coUS< mortoliiy compared with other bc<a- L Okamoto MP.~ nl Cefcpinie clinici\I pharm1cok1M1ics.. Clin ;me: B•li.: ~ Bren.: Celcpenf: Cemi>cf; Octtt Moxee( Max'.I [;
bctams. ·nic FDA subsequernly annou11ccd lhol ii would review Pliormacokir,.r 1993; JS: 88-102, Canod.: ~ Chile: M>~ ~ C...: M»op;me: Oenm.:
safety data to further evaluate !he risk of death associated with 2. Ryb:ik M. The pl\:lhnacokinc:tic profile u( u new ttcn~lKlin of Maxiprncf: fl°" Mio<'(limc fr" ~ Ger.: ~ Gr.: An!i<epOn;
ccfepimc use.' In June 2009. after this analysis, tile fDA issued p•ronmol ceph1losporin. ,,., J M<d 19?6: 100 (ouppl 6A): G<n<cf. Maje« 11a,;pm.; ~;me: Z<~ Hattf Koni; ~
39S-44S. Hutti.: Moxpme: lttdlo: 8iopme: Cekacl FO<Ptr: lndon.: Mx<:/; Ce-
a sia1anen1 that no stotisiically significant increase in monalily lom< Exepimo; lnlesJ>int Hoed M.,OCef. M~l&nc M>Ximer, ~:
for ceftpimc-1rea1ed palients oompa~ 10 comparator-treated l . Reed MO. tt al. rh:a.l'rnacokinttk.' of in1ra\'c11ously al"td intra·
muKulatly itdmiuisten:d ce(cpimc 1n inf•nt$11nd childr~n. An1i- Proc.p;m: Rapmo: Rima><~ Sop;me: V1pome: ltf" Ma:>QPrret. itol"
pa1icn1.s was nOled and that oefepime ranains an appropriate mkrobAgcnt.i Chemothc.t' 1991; 4J: 17~7. Ce;>m: CejWnex: Ma~ MoJoyr;o: t',..;p;me: Megppime: Mu.: Max·
therapy for its approved indic.'llions.S et'"· 6, ~ NZ: M - • . Pt>Uif>P.: c~_HapOn<JC ~ Sv>
p#ne; Zep1m; Pol.:~•me: Port.: t1axap1mc; Ru.s.: Max.pme
4. AUaoudticht' B, Phann1cokinetics ofttfCpimc: during con·
I. Neu HC. Sa(ctyof cercpime: I\ new cx1endcd-spcc1rum pgr(nler- tinuous vcnovcnou~ he1nodiR'1ttra1ton. Antimicrob Agc,,11 ~): Maxyuf (M•<e,.>Ot~ S.Afr, t1a>iptne: Singapore.: M»C'!>
al ccphalOSpOo;n.A.,J M.td 1996; 100 (suppl6AY. 68S 7SS ci,,,•..,,,.., 1m; 41 : 2424-7. me SpGW.: ~:Swed.:~ Swill.: Ma>Opimet: Thal.: Max-
2. Yalwv D. "' ol EO-tcat)' Jnd safe:1y of cefcpimc: a sya.tematic 5. Blumer JL. a ol. Review of the pha1maeok:tnc:1it.s of ccfcpi1nc in j>1n0; Otpitr.e: ,..,..,., Sefpime: Tori<.: ~ Ho>JPme: Urlsel: Ulu.: Ef.p
review ;ind mc1a-:in1tyus. Loncl'l ln.fec1 Dis 2007; 7: 338-&8. children. P«/ioJr lefttt 0;1 J200J; 20: l37~2. me~~ VSA: Ma>Op;!Jl<: Venez.: M.,.;pine
3. Or-ago L, l)c Vecchi E. n.e
$Jifcty of ce:tCpi1nc in the ttt1tmitnl 6. Cappartt1i E. ti ol Popu13tion pharmacoklnctks of cercpimc in
of;nfc<tion. E.rp.n Op/ni>rwg S<Jf•I'!' 2008; 7: 377- 17. lhc nCOO:\tC. Antl11tlcrob A~uls Chemothtr 2005; 49: 2760-6.

The symbol t denotes a preparation no loni;cr acti\'ely marketed

244 Antibacterials
Cefetamet rJSAN, rlNN) soluble in 70% soroitol and in octanol. pH of a solution in water infections and their treatment, see under Choice of An-
containing tllc equivalent of cefixime 0.07% is between 2.6 and tibacterial, p.170.
Cefetamet: Cefetamet..,m; LY.097964; Ro-15-8074. (Z)-7-(2-(2-
4.). Store in airtight containers.
Nninothiazol-4-yf)-2-methoxyim:noaceta<nido}-3-me!Jiyl-3-ce- Cefixime is available as the trihydrate and doses are
phem-4-carboX)'lic acid. expressed in tenns of anhydrous cefixime; 1.12 g of
Adverse Effect s and Precautions
Ue<j>eTaMeT
As for Cefalotin Sodium, p.238. cefixime trihydrate is equivalenl to about 1 g of anhy·
=
C,.H, 51\J 50 5S2 397.4.
. The most frequently reported adverse effects of cefixi- drous cefixime. It is given orally in doses of 200 to
CAS - 65052-63-3 (ce{etornel}.
ATC-JOIDDIO. me are gastrointestinal disturbances, especially diar- 400 mg daily as a single dose or in two divided doses;
ATC Ver - QJOIDDIO. the higher dose is recommended in the USA. A single
rhoea. Ceftxime should be stopped if diantioea is se-
UNll - 4R5TV783X3. 400-mg dose is given for uncomplicated gonorrhoea.
vere.
The dose of cefixime may need to be reduced in pa-
Although ceftxime does not have the N-methylthio-
tetrazole side-chain usually associated with hypopro- tients with renal impainnent, see below. See also below
thrombinaemia increases in prothrombin times have for doses in ch ildren.
occurred in a few patients. 0 General references.
I. Lcg.g,eu NJ, el al. Ccfixime. DJCP Ann Phormocother 1990; 24:
Antibiotic-associated colitis. For reports of diarrhoea and 489-95.
pseudomembranous colitis associated with eefixime, see Cefalo- 2. Adam D. \Vallace RJ, eds. Symposium on ctfixime. Drugs 1991 ~
tin, p.238. 42 (suppl 4): 1-32.
3. Markham A, Brogden RN. Cdiximt: a rt"vic\"' of il$ lhmpcutic
efficacy in lower rcspicitory trocl infections: Dnrgs 1995; 49:
Interaction s 1007-22.
Care should be exercised in patients receiving antico- 4 . Hamilton~Millcr JM. Overview of oefixiine use in community~
acquirtd inftctions. Clin Microbiol !11fm 2000; 6 (suppl 3);
agulants and cefixime due to the possibility that cefix- 79-8 1.
Cefetamet Pivoxi l Hydrochloride (rtNNM) ime may increase prothrombin times (see above). S. Ve.rhoef J. Gillis.sen A. Rc:sislanl Hsemophilus influenzae in
communi[y•acquired respiratory tract inCc:ctioi:i-s: a role for cefix~
CCfetamet Pivoxil. Oilomydratc de; Cefetameti PM>xili Hydro- ime. Int J An1im1'crob Agent.t 2003~ 21: 501-9.
chloridum; Cefetametpivoxilhydro~Jorid; Cefetametum Pivoxili Ant imicrobial Action
Administration in child•en. Cefixime may be given orally to
Hydrochlorid<NTI; Hidrodoruro de cefetamet pivoxilo: Kefeta- Cefixime is bactericidal and is stable to hydrolysis by children for lhe treatment of infections caused by susceptible
meettipi>10ksiilihydrokloridi; Ro-I 5-8075 (cefetamet pivoxil). manv beta-lactamases. It has a mode of action and Gram-posilive and Gram-negative bacteria. Children over 6
Cefetamet pivaloyloxymethyl hydrcchloride. spectrum of activity similar to those of the third-gener- months and Wldcr SO kg may be given 8 mg/kg daily as a single
Ue<j>eTaMeTa n..eOKC'1Aa r"1Ajl0XllDP'1A ation cephalosporin cefotaxime (p.247), but some dose or in two divided doses.
=
C 20 H2sNs01S 2 .HCI 548.0. Enterobacteriaceae are less susceptible to cefixime. Administ ration in ren aJ impairment. Oral doses of cef1xi-
CAS - 65243-33·6 (ce(etomet pivoxil): I 11696-23-2 Haemophilus injluenzoe, Moraxello caton-halis (Bran- me should be reduced in patients with moderate to severe renal
(ce(etomet pivoxil hydrochloride). impairment according to creatinine clearan:e (CC). UK licensed
ATC - JOIDD/0. hamel/a catan-ha/is), and Neisseria gonorrhoeae are
product information recommends that a dose of 200 mg daily
ATC Vet - QJOIDDIO. sensitive, including penicillinase-producing strains. Of should not be exceeded in patients with a CC less than
Profile the Gram-positive bacteria, streptococci are sensitive 20 mUminute, as well as those on continuous ambulatory peri-
Cefetamet is a third-generation eephalosporin ontibaclerial simi- to cefixime but most strains of staphylococci, entero- toneal dialysis or hoemodialysis. In lhe USA licensed product
lar to cctiximc (below). It has been given orally as the hydrochlo- cocci, and Listeria spp. are not. information recommends doses adjusted as follows:
ride of the pivaloyloxymethyl ester, cefetamet pivoxil hydro- • CC 60 mlJminuteor more: lhc usual dose of4-00 mg daily
chloride, which is hydrolysed to cefetamct in viW>. The usual Enterobacter spp., Pseudomonas aeruginosa, and
• CC 21 to 59 mUminute or those on haemodialysis: 300 mg
dose is 500 mg twice daily. Bactel'Oides spp. are resistant to ceftxime. · daily ·
for reference to camitine deficiency occurring with some pival- • CC less lhan 20 mVminute or those on continuou.<ambula!o-
oyloxymetllyl esters. see Pivampicillin, p.344. Pharm acokine tics ry peritoneal dialysis: 200 mg daily
OReviews. Only 40 to 50% of an oral dose of ceftxime is absorbed
Prepara tio n s
I. Bryson HM. B;ogden 'RN. Ccfotam:t pivoxil: a review of its an· from the gastrointestinal tract, whether taken before or
tibactcrial aclivily, phannacokinetic properlic:s and therapcutjc USP 33: Cefodme for Oral Suspension; Cefixime labteu.
use. Dnrgs 1993; 45: 589-62 l.
after meals, although the rate of absorption may be de- Proprietary PrepMations (details are given in Volume B)
2. Blouin RA. Stoeckel K. Cef'ctamet pivoxiJ clinical pharm:tc::oki- creased in the presence of food. Cefixime is better ab- Arg.: Novacef; V1><cet Austria: Mto<et Ei\zinet: Exdolt: Tncct Xefot;tt;
netics. Clin Phamu1cokinel I 993; 25: 172-88. sorbed from oral suspension than from tablets. Absorp- Xetinolt: Bra<-: Cefnaxt. Neo Cefo<. Canad.: Suprax Chile: Tncet Uro-
tricet Cz.: Supra><; Fr.: Oroken: Ger.: Cef'ocdurat: Cephora~ lnfectoOp-
Preparations tion is fairly slow; peak plasma concentrations of2 to ticet Suprax LY.c>-Cepl>O<al: Gr.: Ce~oral: Covocef-N; Hung.: St.-proc In-
Proprietary Preparations: (details are given in Volume B) 3 micrograms/mL and 3.7 to 4.6 micrograms/mL have dio: Biotax.O: C.efoc. Cefocef'·lS: Fi>;X; Si·f-ixim; Xi1' Zip<a.x; lndon.: An!DC
Gr.: Globoccf; Pol~ TafCev;st Port.: G:oboceft. • Cefaro>e Ccfilo; Cefspa.o; Cept;k; Comspor;n: Ethfi><: FOGJcep; r...._,, Hxef.
been reported between 2 and 6 hour.; after single doses foopt:ar: Ynfac: Maxpro; Nucet Op(>c.ime: Simcef; Sofix SpNl<eft; Spaxim:
of200 and 400 mg, respectively. The plasma half-life SporcLik; Starter; Taxime: Tocef. Trb<im: Urticef; Yafx: /ti.: S~ Israel:
~ ltol.: Cefoxorat St.v>x; UnOcime: Jpn: C•fsp<>r>: Molaysla: Cefo.;
is usually about 3 to 4 hours and may be prolonged Cefb<}'Cin: b<ime; Minixime: fh..x.: Dcn11ar: Nerh.: fiximf: Philipj>.: Axetef:
C efix ime (BAN. USAN. rlNN) when there is renal impainnent. About 65% of cefix- C-Tax P: Cefix""'in; Fix-A: FOO:ef. Ref><;me: S."<Cef; Sept;p.rc Taxocef;
Tergecef; Ultraxime: Zefral; Port.: Bonocef: Cef.mix; Cefrton: Ccfizel: Ne-
Cef1ksimas; Ce,xim: Cefixim trihydrat; Cefocima; Cefixime; Cefix- ime is bound to plasma proteins. ocef: Tricef. Rus.: P•n;:ef (lla1tt~); S.,,,,-"" (CJ'l'lP'«); S.Afr" POOmet.
Spain: Denvar: Necoper< Sw;tL: Cep!>orol: Thor.: Ccfspan; Turk.: Cc-
irrum: Cefocimum Trih)'drirum; CL-28%35; FK-027; FR-17027: Infonnation on the distribution ofceftxime in body tis- !*'>< Fix<f: S.ncefoc: Suf"O>< Z-.mal:s: UK: Su~rax Ufu.: Cefix (Ue$,.c):
Kcfiksiimi; Se~ksim. (Z)-7-(2-(2-Amnothiaiol-4-yl)-2-(car- sues and fluids is limited. It crosses the placenta. Rela- Max;bat (M;o<CH6aT); USA: Supnx: Venn.: long;icel
boxymethoxyirrino)acetamidoJ-3-,inyl-3·cephem-4-carboxylic tively high concentrations may occur in bile and urine. Mu lti-ingred~t Indio: Ceb LB.
acid trihydratc. About 20% of an oral dose (or 50% of an absorbed
Ue<j>MKC'1M dose) is excreted unchanged in the urine within 24
C,.H,5Ns01S2.3H20 = 507.S. hours. Up to 60% may be eliminated by nonrenal Cefm e noxi me Hyd roch loride (U5AN. rJNNM)
CAS - 79350-37. L Abbott-50192; Cefmenoxime. Chlorti)'dr<te de; Cefmenoximc
mechanisms; there is no evidence of metabolism but
ATC - jOIDDiJ8. Hemihydrochloride; Cefmenoximi Hydrochbidurn; Hidro-
ATC Vet - QJO f 0008.
some is probably excreted inlo the faeces from bi le. It
doruro de cefmenoxima; SCE-1365 (cefmenol<ime). (Z)-(7R)·7 •
UNll - 9711 C92E55.
is not substantially removed by dialysis. (2-(2-Amir.othiazol-4-yl)-2-methoxyiminoacetamido}3-(( I·me-
0 References. thyl- IH-tetrazol-S-yl)thiomethyfj-3-ccphem-4-carooxylic icid
I. Britt~in DC, ct ol. The phannac:.okinctic and bactericidal charac- hydrochloride.
1eristics of oral cefixime. Clin Pltarmacol Thdr J98>: 38: 59~.
2 . Guay ORP, et al. Pharmat:-0kineli(.'$ of cdiximt (CL·2S4,63S; r
Ue$.'leMOKC1"M3 »APOXAOP"'A
FK027) in hc.,hhy subjccls and patients with renal insufficiency. (C,.H11N905S 3),.HCI 1059.6.=
Anthnicrob Agents Chemothcr 1986; JO: 4S5--90. CAS - 65085-01-0 (ce(menox1mc); 75 738-58-8 (ce(-
3. Faulkner RD, et al. Pharmacokinc1ics of cc(lximc in the: young menoxime rydrochloride).
a.nd elderJy. J An1imlcrob Chcmorht.r 1988; lJ: 787-94. ATC - JOIDD05.
4. Stone JW. ct al. Ccfixime, in-vitro activity, ph3nn3cokinctics
:ind tissue pen~tration. J An1imicrob Clttin:other 1989; :?l:
ATC Ver - QJOIDDOS.
221-8.
UNlf- NON736D32W.
5. Wcs1phal Jf, et cl. Biliary excretion of ccfi.ximc: assessment in
p.atients prO\·ided with f·lube drainage. Antimicr()b Agents
Chcmother t993; 37: 1488-91.
P hannacopoeias. In.Eur. (seep.vii) and US. Jpn includes lhe 6. Somekh E, ti al. Penelratjon and bactericidal activity orcefiximc
llllhydrous $\!bstMce. in synovial fluid. A,,,timicrob Ascnts Chemothcr 1996; 40:
Ph. Eur. 6.8 (Celixime). A white or almost white, slightly hy· 1198-1200.
groscopic, powder. Slightly solubleio water, sparingly soluble in
dehydrated alcohol; practically insoluble in etl1yl acetate; freely Uses and Administration
soluble in methyl alcohol. A 5% su;pension in water has a pH of Cefixime is generally classified as a third-generation
2.6 to 4.1. Store in airtight containm. Protect from light cephalosporin antibacterial and is given orally to treat
USP 33 (Ceiixirre). A while to light yellow crystalline powder.
Practically insoluble in water, in ether, in ethyl acetate, and in
infections due to susceptible Gram-positive and Gram-
hexane; slightly soluble in alcohol, in acetone, and in glycerol; negative bacteria, including gonorrhoea and infections
soluble in methyl alcohol and in propylene glycol; very slightly of the respiratory and urinary tracts. For details of these (ce{menoxime)

All cross-references refer to entries in Volume A

 Cefetamet/Cefodizime Sodium 245
Phannacopoelas. lnJpnand US. Ii fc ofabout I . I to 1.5 hours hos been reported; it is prolonged in S odium content. Each g of cefmioox sodium con1ains about
USP 33 (Cefmen<»ome ~:le). While to light orange. patienls with renal impairment Small amounts hi\.., been dc1cc1- 1.84 m1110J of sodium.
yellow crysculs or cryst~lline powder. Very slighlly soluble in cd in breast milk. Rclaiively high concentrations have been Preparations
water: practically insoluble in dehydrated alcohol and in ether, achieved in bile. ·
freely soluble in f0tmamidc; slightly soluble in mechyl alcohol. Proprietary Preparations (detail• •r• given in 'W>lume B)
The majocity of a dose is excreted unchanged in the urine result- Jpn: Mtotthn: Port.: Ten:e( Sj>Gin: Tencel: ThoL: Moicefl..,_
Store in aillisht containers. •n& in high concentrations: up 10 85% of a dose has been recov-
Profile ered within 12 hours. Ccfiuetazole is partly excreted by renal tu-
Cc/incnoximc is a lhird"ga1cra1ion ccphalosp<lrin antibacterial bular secrc1ion and probenccid prolon@S elimination.
Ccfinelalole is removed 10 some c>.1cnt by haemodialysL~. Cefodizime Sodium /W'l'-t tN'IM)
with actions and uses similar to chose of ccfotaxime (p.247). le
has been given as the hydrochloride by intramuscular injection, Cefodi:ima s6dica; Cefodiz.me ~ HR- 221: Natrl Cefodiz.
Uses and Administration imtrn: S.771221B: Sefodzim Di500y\>m! THR-22 1; TRH-221.
or intravenously by injection or infusion in the trealmenl of sus- Cefm~laz.ole is a ccphamycin antibacterial generally classiCicd
ceplible infections. with the sccond-gi:ncntioo cepllalosporins and used similarly to (Z)-7·[2·(2-ArninothiazoH-yf)-2-me~ceramido]-3-
Like cefamandole (p.239). ccfinenoximc Im an N..ftlcthyld1io- cefoxilin (p.250) in the treatment and prophylaxis of anaerobic (5-cai~1-methylthiazol-2-ylthoornet/1yl)· l·cEphem-1-
te1n12X>lc side·chnin and ooagulopathy and ~..disul(iram-like in- and mixed bacterial infections, especially inlra·•bdominal and <•rboxy!ic acid. disoc!i.m ..11.
tcnction wi1h alcohol have~ reponed rarely.
Cefmenoxime hydrochloride is also giYCD as eye drops for the
pelvic infections. It may also be used in the treatment of gonor·
rhoca. For details of chcse inli:ctioos and dicir treanncnt, see un-
HaTpMi< U*'"""'.. =
C,~H 1eN•Na201S• 628.6.
truttnent of eye infections. der Choice of Antibacterial, p.170. CAS - 69739-16·8 (<efodizime): 86329-79-S (ctfodiz·
ORcvicws. Cefinctaz.ole is given intravenously as !be sodium salt by infu· ime sodivm).
I. C:Jmpoli-·Ri-chatds DM. Todd PA. Ccf1nenoxi~c: a review of ils sion over 10 to 60 minulcs or by slow injection over 3 to S min· ATC - JOI0009.
:111tilnc1crial activity. pharmacokinctic properties and thtrapeu.. utes. Cefinctazole sodium is also used intramuscularly in some ATC Ve; - QJO I 0009.
lie use. Dnrgs 19!7; 34: 188-221. countries. Doses arc expressed in lctmsoftlte equi\lllk:nl amount UNll - HCIT5 1593A.
Preparations of ccfmeta:.Ole; I.OS g of cefine!azole sodium rs equivalent to
about I gofcefmcwolc.
USP 33: Ct"""'Ol<ime for rr;.a;on.

""l,Jl J±'1
Proprietary Preparations (details art give11 in Volume B) The U9ual dose is0.5 to I g intramuscularly or intravenously C\-C-
<K.: Tocet Jpn: 8estcaJI: SeS"JOO. ry 12 hours. For severe infections the dose may be increased to 3
to 4 gdaily, given in divided do= every 6, 8. or 12 hows.

Cefmetazole (\MN, rtNN)

For details of reduoed dosage ofccfinetazolc in patients "'th re·
nal impairment, sec below. ~,N
s....!\
: N~S'<SffCOOH
COOH N-!\
Cefmetazol; Ceimeta.tole: CefmetazoUn: U-7279 1. (6R.7S)·7· O Rcfercnocs.
t. Fincb R. ti of• .:ds. Cefmcc.az.ole: • clioical apprtisJI. J Antlml· NM, CH,
{2{(Cyanomethyf)thio)acetamido)-7-rnelhoo<)'.-3-1(( 1-memyl-
crobO.-ltor 198'): 13 (SupPI 0): 1-1~2.
rH·tetrazol·S·yl)thio)nethyl)-8-oxo-5-lhia· l·azabicydo{4.l0} (ce{odi21mt)
oa-2-ene-2<•rbcx)'ic .od. Administradon In renal impairment. Pventcral doses of
ccfmetazole should be reduced in patient$ with renal impair-
Ll~TA,OA Pharmacopoefas. In Jpn.
ment. It has been suggest•d lhat the interval between doses
C,sH11N10sS) = 47 i.5. should be 12, 16, or 24 hours in paiients with mild, moderate, or Adverse Effects and Precautions
CAS - 56 796-10-4.
severe renal impairment, respectively; patients "ith virtually no As for Cefotaxime, p.247.
ATC - JO I OC09.
ATC Vtt - QJOIDC09. renal function might be given cefineta:wlc every 48 hows, after Sodium content. Eich &ofcefodizimc sodium CMtains ahou1
UN/I - 3J'f62UjT8H. hacmo<!i.lysis. 3.2 mmol of sodium.
Prepar ations Interactions
USP 33: C..fmeta:ole r... 1nj«t""1; Ce~ lrjcct.On. Probcnccid reduces 1he reillll clearance of ccfooizitne.
Proprietary Preparation• (details are gi\'Cft in Volume B) Antimicrobial Action
lndon" QlllOl /tol.: Meurar: Met.,.; Jpn: Cern<won. USA: Z~-fawoiet.
Cefodiiime has similar antimicrobial ICti~ity to tha1of cefotaxi-
mc (p.247) although cefodizimc has no active metabolite. It has
variable activity against Cirrobacterspp.. and Pseudomona:s ner·
Cefminox Sodium (:>/NNM) 11gl1>0So and lkH:teroidts frog I/ls arc generally resistant
Cefminox s6dico: ~lmi-oxSodique: MT-14 1; Natiii~ltlOX­ Pharmacokinetics
um. Sodium 7-(2·((S)·2-anino-2·carboX)ethyl)thioace!MTido}- Cefodizimc is gi~i by injection as 1he sodiwn salt lntramuscu·
Pharmacopoeias. In l.iS. 7-mcthoxy-3-( I-methyl- IH-:etrazd-S-y.'thiomelh~)-3<ephem- lar injcclion of I & cefodizime produces peak pl8Sllll concentra-
USP 33 (Ce"'1etazole). Store in airtight containers. 4-arboxylatc. tions of about 60 to 75 mic:rogramslmL at about I ID 1.5 bows.
HaTpMi; U+,~HOKC Immediately aftcrintra"cnousdoscsof I or 2 gccfodizimemean
peak plasma conccntrarioos of215 and 394 mlcrograms/mL rc-
Cefmetazole Sodium (UY.N 41'1NM} c ,.H;of'l;NaO,s) = 54 1.6. spc<ti\'ely, have been acl1ieYed. Cefodizime is about 80"tf. bound
Cefmetazol s6doco: Ce'memole Sodique: Cefme-.azolnatrium: O,S - 75481-73-1 (cefminc•) to plasma proteins and is widely distributed into body 1issues and
Cefnietazolum NiMrum; CS- I 170; Kcfmetatsoloiatrixn; Natrii UNll - YNM406)3N8. Ouids. It cros.<es the placenl8 and small amounts have been de·
Cefmet.azolum: SKF-83088; U..7279 1A. 1ecred in breast milk. Plasma elimination is reported to be rripha-
Hnp~;. Ue~•-<eTa30I\ sic with a tenninal eliminalion half-life of about 4 houri. The
C 15 H,.N 7 N•Os5; 193.S.= half-life is prolonged by renal impairment.
CAS - 56196·39-5. Tiie majority of• dose is excreted unchanged in lhe urine; up 10
ATC - JO I OCO'i. 80% of a dose has been rccovtrcd within 24 houtS. Cefodizimc
ATC Vet - QJOIOC09. is mainly excreted by glorncrular (ihra1ion wilh sonic rubular SC·
UNll - 37Y9VR4W7A. eretion. Prohenccid delays excretion. Ccfodizin1e is removed by
Pharmacopoeias. In Jpn and US. • d13lysis.
USP 33 (Cefmet.azole Sodum). A "ltilc solid. \by soluble in Uses and Administration
wn1er and in methyl alcohol; soluble in M:CIOnc; pnctically insol· (ce(mrnOJ<)
Cefodizime is a lhird·gen~lion cephalosporin antibacterial
ublc in chloroform. pH ofa IO'A. solu1ion in water is bdwccn 4.2 with uses simil•r to those of cefotaximc (p.248).
ind 6.2. Store in ainight containers. Pha"""copoeias. Jpn includes the heptahydrate.
Ccfodizime is given as 1he disodium sa.11 by intramuscular injec-
Adverse Effects and Precautions Profile tion or intravenously by ittjcction or infusion in the trealmcnt of
A5 for Ccfalotin Sodium, p.238. Ccfu1inox sodium is 1 cq>l1amycin antibacterial w~h properties susccpcible infec1ions. Do5es are expressed in tcmis ofrhe equiv·
Ccfmeta:tole comains an .V-meOtylthiotetrazole side-chain and similar to lhosc of cefoxitin (p.249) but with an N-methyllhi- alent amount of ccfodizimc; 1.08 g of ccfodizimc sodium i•
h2S the potcntial 10 cause hypoprolhrombiMemia and bleeding. otetrazole siJe<hain hke ccfamandolc (p.239). ll is used in the cquivale11110 about I g of ccfodizimc. Adults are usually given
ireatmcut of anaerobic aod mixed baclcrial infections, especially I gcvc1y 12 or24 hours furlowerrespiralory·traa iofedions and
Effects on the blood. Rcfen:nccs. I or 2 a every 24 hour.; for tlppcr and lower urinary-Inlet infec-
intr•-abdon1inal and pelvic infections. lt is given intrav•nously
I. Breen GA. SC Pe-1cr WL. Hypoprothrombincmi.a ;"iSCM.:iat<"d with
«fn,e1az.olc. Amr/'hormoco1her 1997;31: 180-C. as the sodium sail but doses aJC ex~d in tem1s ofcefminox; tions. Totnl daily doses of np to 6 g 1nay b..l given for severe in·
1.04 & of cefininox sodium is cquivalen1 to about I g of cefini- fection. In women with uncomplicoted lower urinary-lract infoc·
Sodium content Each g of cefine1azole sodiun1 contains nox. A usual dose is 2 to 4 g daily gi\'cn in di•idcd doses. 1ions a single dose of I to 2 8 may be sufficient. for gonorrltOel
about 2 mmol ofsodium. a single dose onso 10 500 mg may be gi\'Cn. Doses m•y need to
0 References.
Interactions he reduced in patienls wi1h renal impairmen1 {sec below).
or
I. Wa1:mabe S. Omoto S. Pharmacology ccfmioox. a new lx\cte·
As for Cefamandole. p..24-0. ricidal ttphamyc.1n Dr1111 E.vp CUn Res 1990; 16: 4'61- 7. 0 References.
Antimicrobial Action ::?. Sori:lno f, ti ul. Comparative s.usceptibility ofcicfm1nox and ce- ~ds. Cdodizime: ;i thud ac:ncr:uion ctpha-
I. Finc:h RG. rt ol,
Cefmctazolc is a cephamycin antibacterial with a similar spec- fo.si1 in lo P·lacumases of 8Jcteroides spp. J Antimlaob CMm- losporin wi1h 1mmunomodulating properties. J Anlimicrob
01/ir,. 1991: 28: 55-60. Cl1•mml1t1 1990. 16 ("'Pill q , 1- 1)4.
trum of antihacle1ial activity to that of cefo•itin (p.250). inducl- 3. AJuil~r L. ti al. C~fminox: com:larian between in-vitrQsu.sc:ep- 2. Barr1dcll LB. Brog.den RN. Cefodizimc: a review of its anribgc.
ing the anaerobe Boc1a1oides fragilis. cib1lity and pharmt11c-0kinctics aruJ ~rum b;ictcricid111 activity in tc:ri11I oc11vit}', pha~inctic propcnics and 1herapeU1i.c use.
htlhhy \'Oluntet-rs. J Anlimkrob CM1,,othtr 1994; 33: 91-101. DntgJ 1992; 44: SOO-SJ.4.
() References.
4 M1ya1na T. ct ol. Postmar'.tetin~ a.rvc11Jance on side-cffcctt of 3. Thalha miner F, rt al. Sin~dosc C\..-i'odiiimt: l\5 infcc1ion proph-
I. Comidc NA~ t!I "'· Activity of ee(n-.eiazok opinst :a.n::ierobic cefcninox sociium (Meicel;n). Im J Clm Phorrnacol Ther 1995: yb."<i.'\ in ahd<>minal surgery: ' prospttth'c multiceincr $\Udy. /n-
bac.1cria. Attri111it:robAgt!.lu.1Chtmo1h~r 1 987; 31: 20l0- 12. 33: 1•9-SS. f«non 1998: 26: 136-8.
Pharmacokinetics S. Hocl1m:m DB.. et ol. Jn vitro ci1:ti\>ities ofocfminox 1g1insl anacr· 4. Matsumoco T, ct of. SiniJc do$f' o( ccfodirimit complcldy end·
After ccfmetazole sodium 2 g inlr•vcnously e"cty 6 hours, peak obic.bae:teria c:ompared v.ilh those o(nine«htrcompownds. An· ica1cd multidrua·rtsi313nt $tram ofNcis.:scria 1onOC'rh oc~c in urc·
timiCrO!> •.fft'nlJ CMMOlll~r l 998: 42: 49S-SOI. 1hriti$and uknne cc:rvici1is. J lnfrcr C~MOthl,. 2006; 12: 97-9.
and irougb plasma conccntralions of 138 and 6 microgrlms/mL <i. Torres AJ. a ul. Cefmiuo.x versus rnc:tronidatolc plus 1cnt1micin S. Macsumoc.o T. tt ol. Multiple dostJ of ccfocHtime are ncc<.ssary
ha'-e been achieved. Celinctazole is 65 to 85% bound ID pl3Sma in intra-abdominal infections: a pro5pccrivc nindomrud control- for 1hc 1tc1tment ofNcisseria gononhoccac pha.tyngeal infcelion.
proteins. depending on the plasma concentracion. A plasma half- led clinic•l 1ri1I. /11f«tion 2000; 28: 318-22. Jhofct:•C:~-M.-2006; 12: 145- 7.
llie symbol t denotes a preparation no longer actively martcted
246 Antibacteria ls
Administration in renal impairme nt. Although the lirsi For surgical infeclioo prophylaxis, a single dose of I g given l 6. Scott SM. Incompatibil ity of ccfoperuonc ind promcthuinc..
dose is the same as for those with normal renal function (see hour hefore surl)ical incision is usually sufficient, but may be An1 J Hosp Phann 1990; 47: 51 9.
above), subsequent parenteral doses of cefodi2imc should be ad- given daily for a funher 2 days in prosthc1ic anbroplasty oropen- 7. Trinel LA~ er ol. Compitibili1y or rcmifcnaanil hydrochloride
justed in patients ,,..;th renal impairment according to creatinine hcar1 surgery. with selected drugs during simulated Y·sile admlninrarion. Am J
HMllh·SJ>t /'harm 1997; 54 : 2 192-6.
clearance (CC): 0 References.
• CC I0 10 30 mUminute: I lo 2 g daily
• CC less than 10 mVminute: O.S 10 I g daily
I. Saltiel E. Broaden R."'l. Cefonkkl: a review of il.S antib1ctcri11 Ad verse Effects and Precautio ns
ac1ivity. phamt1CC'lloaical properties and thenpeutic use. Dn111
As for Cefalotin Sodium, p.238.
Jn patients undergoing dial1•s1s, O.S 10 l g daily is given after di- 1986; 32: 222-59.
alysis. Administration In renal impainnent. For patients with re- Like cefo1axime (p.247), cefoperazone has the poten-
Preparations nal impainncnt a loading dose equivalent to cefonicid 7.5 mg/kg tial for promoting colonisation and superinfection with
Proprietary Prepuadons (details are given in Volume 8) is recommended, followed by reduced maintenance doses ac.. resistant organisms. Changes in bowel flora may be
Aunria: T"""'<J: Ital" Ooezr>e: MocMct Timecef: Jpn: K.encet NZ: cording lo the crcarinine clearance and the SC\ICrity of the infcc- more marked than with cefotaxime because of the
Timc:cef: Port.: Mo6-nd Turk.: ModMd. lioo. A dose supplement is not required after dialysis.
greater biliary excretion of cefoperazone; diarrhoea
Preparations may occur more often.
USP 33: Cefon<id (or Injection.
Cefonicid Sodium (BANM. USA~ t!NNM) Cefoperazone contains an N-me1hylthiotettazole side-
Proprietary Preparations (details are given in Volume 8)
Cefonicid s6dico: Cefonicide 50diriue: Cefonicide Sodique: Cefo- Israel: Monocof. Ital.: Abiocclt Bacidt. eioolf: Bio1icc Ceroboclett, Ce- chain, a siructure associated with hypoprothrombinae-
nicidum natricvm; Natrii Cefonicidvm: SKF-D-75073-Z1: 5KF-D- lo<ie: Cerci<f: Celoplus; Oler: Dayce(; Diesport: Emi<.lo>irl: Epocefj: Foni· mia. Hypoprothrombinaemia has been reported in pa-
75073·Z (~efonicid monosodium). 7 [(R)-Mandelamido)-J.Cl - c.id; Framcccft. lpaclctt: Krucel; l~cxefj: Li<at: Maxid. Mlcrocidl.
tients treated with cefoperazone and has r.i.rely been as-
sutJhome thyl-IH-tetnzo~S-ylthiomethyl)-3-cephem- 4 -cart>ox­
Modiceft. Mochm: Monobiost. Mooobbtic Monocidf: NeOO; NolOdt.
P....odf; Pro\icel: Raikoc:el: ROOc!f; Si'-cclj: Sint:xef. Solircicl \k>itidt, sociated with bleeding episodes. Prothrombin time
)'1ic acid. disodium salt V<lt0<1 Port.: Mor><Xid; Spoin: Monocid: Unidio.
should be monitored in patients at risk of hypopro-
1-!alpH::i U'*""'Ul<A thrombinaemia and vitamin K used if necessary.
C 18 HisN,Na 20 1S1 =586.5.
CAS - 6 I 270-58-4 (ce jon1C1d): 6 I 270-78-8 (ce(onicid Sodium content. Each g of ccfopcnzone sodium contains
disodium): 7 1420-79-6 (ce(onic1d monosodium). Cefoperazone Sodium about 1.5 mmol ofsodium.
ATC - JOI DC06. (8ANM USAN. rlNNM)
ATC Vet - QJOI DC06
UNll - F74MFl 78A I (ce(onicld sodium): QD9G66C5Ur Cefoperuon sodN sU: Cefoperazon sodowy. Cefoperazona Interactions
(ce(onicid monosodium) sOcjc~ Ccfophuone sodq.oe: Cefoperazomatriurrc Cefopera- As for Cefamandole, p.240.
20<>-<\itrium; Ce(operazono natrio drusl<a; Cefoperuonum na· Unlike many other cephalosporins, the renal clearance
tricum; CP·S2610-2: CP-52640 (anhydrous cc(Opetuone); CP- of cefoperazone is not affected by probenecid.

00:.;_;,~s
52640-3 (cefoperazone dihydrate): Kefoperatsonc~atrii.in: Na:trii
Cefopera:zonum; Sefoperazon Sodyum: T-1551 (<efoperazone
A ntimicrobial Action
H03s l or cefoperazone sodium). Sodium (7R)-7-[(R)-2-(4-ethyf-2,3·di·
Cefoperazone has anti microbial activity similar to that
_;-N, OH ..&- s .........,,N,
oxopiperazin· 1-ylcartx>xamido)· 2-(4-hydroxyphenyl}aceuimi·
do}3-[( 1-mcthyt-II l·tctrazol.S.yf)thiomethyQ-3·ccphcm-4-car· of cefta7idime (p.254), although it is slightly less active
against some Enterob~cteriaceae. It has good activity
0 \\ ,,N boxylate.
COOH N-N HaT))H~L!~ against Pseudomonas aeniginoso, but is less active
(ce(on1c1d) CisHuN,Na0aS2 = 667.6. than ceftazidime.
CAS - 628 93-1 9-0 (ce(operozone): 62893-20-3 (ce(op- Cefoperazone is more susceptible than cefotaxime to
Phumacopoeias. In US. erozone sOdium). hydrolysis by certain bela-lactainases.
USP 33 (eeroncid Sodun). A white lo off-white solid. Frccly ATC - }CI DDI 2.
soluble in waler, in sodium chloride 0.9°/o, and in glucose >"•; Activity, particularly against Eoterobacteriaceae and
ATC Vet - QJOI OO I 2.
'ttf'J slightly soluble in dchydnted alcohol; soluble in methyl al- BacJeroides spp. has been enhanced in the presence of
UNll - 5FQG977~WD.
cohol. pH ofa S% solution in watcr is betwc:ai 3.5 and 6.S. St°"' the beta-lactamase inhibitor sulbactam; resistant Ps.
in air1igh1conc iners. oeruginosa are not sensitive 10 the combination.
Adverse Effects and Precautions 0 References.
As for Cefalotin Sodium, p.238.
I. Fan RJ. et al. In vicro ac1ivilics or cefopcruone and suJbactam
Cefonicid contains a substiNled N-melhyllhiolelrazole side- sina.ly and in combinalion against ceroper11onc·rcsis1an1 mem-
chain, a structure associated with hypoprolhrombinacmia. bers orthe family Entcrobactc-riaccac and Mllfenncntcrs. An1i-
Effects on the blood. References. mlcrob Agcms Ch•mo1her 1990; 34 : 2256-9.
l . Clark RB. et al. Mulliccntrc sludy on anllbiotic susetptibili1jcs
J. Riancho JA. 1:i of. Lifc..1hrc:ucning bleeding in 11 )Nlticn1 trcalcd
with ccfonie-id. Ann b111m }.fed 1995; IU: 472-3.
oranaerobic bacteria 10 cefoperatonc-su1bac11m and other M li·
microbial agents. J Amirnkrob Chtmothtr 1992; 29: S?-61.
Effects on the liver. Rcfcn:nce.•.
1. Famubro Q et o/, E.osinophili< htpa1ilis usoci11cd with e:cfoni· Phannacokinetics
cid thcr2py. A1:11 P/KJnnae01lotr 2001 ; JS: 1669-71 .
Cefoperazone is given parenterally as the sodium salt.
Sodium content. Each g of ccfonicid sodium contains about With intramuscular doses equivalent to cefoperaz.one I
3.4 nunol of sodium. (ce(operozone)
or 2 g, peak plasma concentrations of 65 and
Interactions 97 micrograms/mL have been reported after 1 to 2
As for Ccfamandole, p.240. Phumacopoelas. In Chin.. Eur: (see p.,ii). Jpn. and US. hours. The plasma half-life of cefoperazone is about 2
Ant im icrobial Action Ph. Eur. 6.8 (Cef~azone Sodium). A "flite or slightly ycl·
Cefonicid sodiwn has an antimicrobial aclion and panem of re- low, hygr=or ic, powder. lf crystalline it exhibits polymor· hours, but may be prolonged in neonates and in pa·
sistance similar to lhosc of ccf3mandole (p.240), although ii is phism. Freely soluble in water; slightly soluble in alcohol; solu- tients with hepatic or biliary-tract disease. Cefopera-
generally less active against Gram-positive cocci. ble in methyl alcohol. A 25% solution in water bas• pl I of 4.S 10 1..one is 82 to 93% bound lo plasma proteins, depending
Pharmacokinet ics 6.S. Slorc in airtight containers at a temperature of2" 10 8°. Pro- on the concentration.
Ccfonicid is ghoen parenlerally as lhc sodium salt Peak plasma tect liom light
USP 33 (Cefoperazone Sodium). A while 10 pale buff crystal· Cefoperawne is widely distributed in body tissues and
concentrations ranging from 67 to 126 microgrnms/mL have fluids, although penetration into tl1e CSF is geoerally
been achieved I to 2 hours after a J.g intramuscular dose. Cefo- line powder. Freely soluble in waler and in methyl alcohol;
nicid is more than 900/o bound to plastna proieins.11 has a plasma slightly soluble in dehydrated alcohol; insoluble in acetone, in poor. It crosses the placenta, and low concentrations
h31f-life of about 4.5 hours, which is prolonged in patients with ether, and in ethyl 3CCtalc. pH of a 25% solution in water is be- have been detected in breast milk
renal impairment. tween 4.S and 6.5. Store in airtight containers.
Cefoperazone is excreted mainly in the bile where it
Therapeutic concentrations of ccfonieid ha\'c been reported in lncompadbility. As with moSI bela lacwns, admixture of cef-
maoy body tissues and Ruids. opcruzone sodiwn with aminoglycosidcs is not recommended rapidly achieves high concentrations. Urinary excre-
Up 10 99% of a dose of cefonicid os excreted unchanged in lhc bec3usc ofthe potential for inactivation ofeither drug. tion is primarily by glomerular filtration. Up to 30"/o of
urine within 24 hours. Probcnecid re4u<ies excretion of ccfoni· There have been rcpons of inCOOlpatibility ...;th other dnl&S on- a dose is excreted unchanged in the wine within 12 to
cid. cluding dihiazem, 1doxorubicin.' pcntamidinc,1 pctphcnazine,4 24 hours; this proportion may be increased in patients
Uses and Administration pcthidinc,s promethazine,' and remifentaniJ.l with hepatic or biliary disease. Ccfoperazone A, a deg-
Cefonicid is a sccond-~ncratioo ccphalosporin antibactuial t. Ga)'e.d AA. t1 ol. V1su.al compatibilit) ofdiltjaze.m i.njcc.tion wi1h radation product less active than cefopcrazone, has
used similarly 10 cefamandole (p.240) in the treallll<nl of suscq>- v.tnou's diluents and medications during ljmulated Y-~1te injet·
tion. Am J llta/1h-S)•J1 Phorm 1995: Sl: 516-20.