NCSBN Practice Knowledge Network Call:

Off-Label Drug Use

1/10/2013

Margaret Leonard, MS, RN-BC, FNP

Sr. Vice President, Clinical Services
Hudson Health Plan
Anand Patel, RPh
Director, Pharmacy
Hudson Health Plan
Cathy Miller, MPH, BSN
Commander, U.S. Public Health Service
U. S. Food and Drug Administration
 Objectives

• Background on US FDA
• What constitutes Approved Indications
• Off-Label Drug use
1. Describe what off label use is and isn’t
2. Review how and when drugs are used off label
3. Discuss the role of the nurse when administering
drugs off label
4. Case example: off-label use of modafinil in patients
diagnosed with Steinert myotonic dystrophy
syndrome
5. Recommendations for practice
 US Food and Drug Administration

 The FDA is tasked with approving new drugs, medical

devices, vaccines, and biologics

 New drugs are approved for use for specific

indications and FDA approval of new indications for
existing drugs requires a supplemental NDA (New
Drug Application)

 FDA regulates approval, labeling, and marketing of

drugs. It has no bearing on how and for what uses,
physicians prescribe a drug.
What is an Approved Indication?
 To understand off-label use, it is important to understand
what an approved indication is.
 Approved Indication: The FDA defines Indication for use
as a general description of the disease or condition the
drug, device, or biologic will diagnose, treat, prevent,
cure, or mitigate, including a description of the patient
population for which the device is intended.
 Example - Metformin: As an adjunct to diet and exercise
to improve glycemic control in patients with type 2
diabetes. Metformin immediate-release tablets and
solution are indicated in patients 10 years of age and
older. Metformin extended-release (ER) tablets are
indicated in adults.
 Off-Label Drug Use

 Definition: The use of a medication in a manner different

from that approved by the FDA

 Prescribing and using medications for off-label is a legal

practice and not under the scrutiny or jurisdiction of the
FDA.

 However, FDA does not allow pharma to market drugs for

unapproved indications. There is plenty of controversy
surrounding this, and there are numerous lawsuits
alleging that the FDA is infringing on a salesperson’s right
to free speech under the First Amendment.
 Types of off-label use

The two major types of off-label use are:

a) Use of drugs for unapproved clinical

indications (ex. Avastin use for age related
macular degeneration or various macular
edema).
b) It can also constitute use in unapproved
patient populations(ex. Quetiapine use in
children under 10).
When are medications used Off-Label?
The following are situations that call for off-label use:
a) Disease state that affects a very small population for which
there are limited treatment options.
b) Off-label use may originate from a presumed drug class
effect, extension to milder forms of an approved indication,
extension to related conditions (the use of the antiasthmatic
montelukast [Singulair] for chronic obstructive pulmonary
disease).1
c) Expansion to distinct conditions sharing a physiological link
(the use of the antidiabetic drug metformin to treat polycystic
ovarian syndrome), or extension to conditions whose
symptoms overlap with those of an approved indication. 1
d) Selection of similar pharmacologic agents for unapproved use
when it is more cost-effective (use of Avastin instead of
Lucentis for AMD or macular edema - $50 vs. $2000 per
dose).
At what point in Tx to consider Off-Label use?

1. Guideline-recommended practice (aspirin in

diabetes for prophylaxis against
cardiovascular disease) as adjunct therapy1
2. Last-resort therapy (tacrolimus [Prograf] for
autoimmune diseases, in addition to
transplantation) 1
3. First-line therapy (gabapentin [Neurontin]
for painful diabetic neuropathy, in addition
to its use in herpes zoster) 1
 Prevalence of Off-Label use

 A 2003 report showed that for the 3 leading

drugs in each of the 15 leading drug classes,
off-label use accounted for approximately
21% of prescriptions.1

 The highest rates of off-label use were for

anticonvulsants (74%), antipsychotics
(60%),and antibiotics (41%).1
 Is Off-Label drug use safe?
It depends on who you ask:
1. Providers will suggest that there are no
studies suggesting that said drug is not safe
when being used for unapproved indications.

2. The FDA would refer you to the drug

approval process and urge that the said
drug has only been proven safe and
effective for the approved indication.
 Safety considerations
Caveats to consider for off-label use:
 Off-label uses have not been formally evaluated, and
evidence provided for one clinical situation may not
apply to others.1
 Regardless of the use, contraindications,
warnings/black box, dosing modifications for renal
impairment or liver disease, and drug interactions still
apply and should be considered before use.
 Side effects/Adverse events should be reported via
Medwatch.
http://www.fda.gov/Safety/MedWatch/default.htm
 Off-Label Use References
 Treatment guidelines published by various medical
organizations
 Well designed high quality published clinical trials
 US Drug Compendia references that recognize
clinically accepted off-label uses:
1) Pharmacology Online
http://www.clinicalpharmacology.com/
2) Micromedex 2.0 (Iphone/Ipad and Android apps
are free)
http://www.thomsonhc.com
3) NCCN Drugs and Biologics Compendium
http://www.nccn.org/professionals/drug_compendium
 Modafanil: An example of off label use

 Modafinil is analeptic drug FDA approved for treatment of

narcolepsy, obstructive sleep apnea, and shift-work
disorder.
 Off-Label uses include treatment of ADHD, medication
related somnolence, sleep deprivation, and Steinert
myotonic dystrophy syndrome.
 Patients diagnosed with ADHD have several FDA approved
safe and effective treatment options and use of modafinil
would not provide any other safety or efficacy benefit
over FDA approved Tx options.
 There is an opportunity for dosage adjustment, dosing
time adjustment, or medication selection opportunities to
alleviate medication related somnolence.
Modafanil: An example of off label use
 Sleep deprivation needs to be managed and treated as
opposed to using modafinil to treat residual effects
associated with sleep deprivation.
 Steinert myotonic dystrophy syndrome (MMD1) is a form
of muscular dystrophy that affects muscles and many
other organs in the body. The most common type of
myotonic muscular dystrophy, MMD1 is characterized by
muscle weakness and myotonia, an inability to relax the
muscles at will.2
 Daytime drowsiness is often associated with the subset of
MMD1 diagnosed patients experiencing weakness with
muscles integral to breathing and swallowing.
Modafanil: An example of off label use
 As yet, there’s no specific treatment that “gets at the
root” of myotonic muscular dystrophy (MMD).
Treatment is aimed at managing symptoms and
minimizing disability. 2 Treating daytime drowsiness
or fatigue with modafinil would be an acceptable off-
label use for MMD diagnosed patients.
 Serious side effects to consider would be
hypertension, hypersensitivity reactions, and mania.
 Other warnings include angioedema, increased risk of
cardiac events, mitral valve prolapse with CNS
stimulant use, and psychiatric adverse effects
 Practice Consideration
 Availability of drug references to identify clinically
accepted off-label use
 Electronic Prescription Order Entry Systems: Many
systems capture diagnoses specific to medications being
ordered, and if configured, this can be used to identify off-
label use.
 Electronic Health Records: Depending on the
configuration, an EHR system may or may not capture off-
label use.
 Any consideration for implementing systems to capture
off-label drug use must consider an integrated approach
where E-Rx and EHR systems both capture off-label drug
use with a bilateral flow of off-label use data
 Practice Consideration
 Manual workarounds in lieu of systems capabilities include:
1. Prescription orders, dosing charts, medication labels,
and other dosage administration documents include
‘off-label use’. Example:
Off-Label Use: Yes No
Medication Related Dx: ______________
2. Maintain an electronic list of all medications and the
specific off-label use commonly ordered at the practice
setting. Example:

Compendium
Drug Name Off-Label use
Supported
Metformin Polycystic ovary syndrome Micromedex 2.0
References:

1. Regulating Off-Label Drug Use – Rethinking the

Role of the FDA,
RS Stafford, NEJM 2008;358: 1427-1429

2. http://mda.org/disease/myotonic-muscular-
dystrophy/medical-management
 Drug Information Resources
 Drugs@FDA Database: provides information on FDA approved drug products
including proprietary name, active ingredient, approval date, manufacturer
name, drug label (PI), Medication Guide (if applicable), and other information on
the history of the drug such as labeling changes that have occurred over the life
cycle of the drug. The website link
is: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
 FDA MedWatch (Home Page): This is the main homepage which provides links
to recent Safety alerts for drugs, devices and other related products, information
on subscribing to receive regular FDA MedWatch safety alert information,
information on safety labeling changes for approved products and links to
reporting adverse events. The MedWatch Home Page link
is: http://www.fda.gov/Safety/MedWatch/default.htm
 FDA MedWatch Reporting Website link (Reporting Serious Problems to the
FDA): Provides a link for consumers, patients and healthcare professionals, to
complete a MedWatch Report and submit the report to the FDA. The link is:
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm

19
 Drug Information Resources
 FDA MedWatch Safety Alerts (By Year): Provides a listing of all published
MedWatch safety alerts by year for drug products, devices and nutritional and
cosmetic products, and undeclared ingredient safety information. The link
is: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanM
edicalProducts/default.htm
 FDA Drug Safety Labeling Changes (By Month): Provides a listing and summary
of all FDA approved products that have had safety labeling changes to the Boxed
Warning, Adverse Reactions, Contraindications, Warnings and Precautions and
Medication Guides section of the product label (monthly). The link
is: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-
RelatedDrugLabelingChanges/default.htm
 FDA Safety Alerts – Subscribe to receive alerts: When you subscribe to
received MedWatch Safety Alerts, you will receive an email when a MedWatch Alert
is published on a product. These alerts include new safety information, recalls, or
other safety related information on FDA regulated products. The link to subscribe to
MedWatch Alerts is: http://www.fda.gov/Safety/MedWatch/ucm228488.htm
 Drug Information Resources
 Patient Network News newsletter: Subscribe to receive twice monthly
newsletters containing FDA-related information on a variety of topics, including
new product approvals, significant labeling changes, safety warnings and
more. Subscribe at:
https://public.govdelivery.com/accounts/USFDA/subscriber/new?topic_id=USFDA
_203
 Health Professionals Updates newsletter: Subscribe to receive the twice
monthly newsletter on recent announcements, medical product approvals,
opportunities to comment on proposed rules, upcoming public meetings/advisory
committee meetings and other information of interest to health
professionals. Subscribe at:
https://public.govdelivery.com/accounts/USFDA/subscriber/new?topic_id=USFDA
_59
 FDA Office of Special Health Issues ‘For Health Professionals’
webpage: Information of interest to healthcare professionals including new
approvals, safety information, expert commentaries and FDA-Medscape
collaborations on FDA-related issues. The link to the ‘For Health Professionals’
page is: http://www.fda.gov/ForHealthProfessionals/default.htm
Questions?
 Contact Information

 Peggy Leonard
mleonard@hudsonhealthplan.org
 Anand Patel
apatel@hudsonhealthplan.org
 Cathy Miller
cathy.miller1@fda.hhs.gov