Medication Guides — Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS)

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Guidance
Medication Guides —
Distribution Requirements and
Inclusion in Risk Evaluation
and Mitigation Strategies
(REMS)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2011
Drug Safety

Guidance
Medication Guides — Distribution
Requirements and
Inclusion in Risk Evaluation and
Mitigation Strategies (REMS)
Additional copies are available from:
Office of Communications
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Office of Communication, Outreach and Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
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ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
(Tel) 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
November 2011
Drug Safety

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
A. 	The Medication Guide Regulations .............................................................................................. 2
B. 	FDAAA Requirements for Medication Guides as Part of REMS ............................................. 3
III. 	DISCUSSION .................................................................................................................... 5
A. 	Distribution of Medication Guides in Certain Settings .............................................................. 5
1. Discussion........................................................................................................................................ 5
2. Distribution Requirements Under Part 208..................................................................................... 5
B. 	Medication Guides as Part of REMS ........................................................................................... 7
1. Policy ............................................................................................................................................... 7
2. Procedure for Requesting Removal of Medication Guides from REMS .......................................... 8

Contains Nonbinding Recommendations
Guidance1
Medication Guides — Distribution Requirements and
Inclusion in Risk Evaluation and Mitigation Strategies (REMS)
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I. 	INTRODUCTION2
This guidance provides information for industry, healthcare providers, and authorized dispensers
of prescription drug products. The guidance addresses two topics pertaining to Medication
Guides for drug and biological products:3
• 	When FDA intends to exercise enforcement discretion regarding when a Medication
Guide must be provided with a drug or biological product that is dispensed to a
healthcare professional for administration to a patient4 instead of being dispensed
directly to the patient for self-administration or to the patient’s caregiver for
administration to the patient.
• 	When a Medication Guide will be required as part of a risk evaluation and mitigation
strategy (REMS).
1 This guidance has been prepared by the Offices of Regulatory Policy, Medical Policy, Surveillance and
Epidemiology, New Drugs, Compliance, and Generic Drugs in the Center for Drug Evaluation and Research
(CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 This guidance does not apply to the distribution of Medication Guides to patients participating in clinical trials
conducted under an investigational new drug application (IND) because the specific information necessary for safe
use of the drug, which is comparable to that contained in a Medication Guide, is required to be made available to
study subjects in the informed consent forms and the investigators’ brochure. See 21 CFR 50.20 and 50.25; 21 CFR
312.23(a)(5) and 312.55.
3 When used in this guidance, the term drug includes biological drug products.
4 For purposes of this guidance, the terms administration or administer to a patient include both (1) when a
healthcare professional administers the drug to the patient (e.g., by injection or intravenously) and (2) when the
healthcare professional provides the drug to the patient to self-administer while under the healthcare professional’s
direct supervision (e.g., the healthcare professional hands the patient or the patient’s caregiver the drug for the
patient to take before leaving the healthcare professional’s office).
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Contains Nonbinding Recommendations
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
A. 	The Medication Guide Regulations
In 1998, FDA issued final regulations establishing requirements for the distribution of patient
labeling for certain prescription drug and biological products used primarily on an outpatient
basis without direct supervision by a healthcare professional (63 FR 66378, December 1, 1998).
These regulations, codified in 21 CFR part 208, apply to certain drug and biological products
that FDA determines pose a serious and significant public health concern requiring the
distribution of FDA-approved patient medication information that is necessary to patients’ safe
and effective use of the drug products (a Medication Guide). All Medication Guides are subject
to the standard in § 208.1 and the requirements of part 208.
Section 208.1(a) states that Medication Guides apply primarily to human prescription drug
products used on an outpatient basis without direct supervision by a healthcare professional and
are applicable to both new and refill prescriptions.
Section 208.1(c) authorizes FDA to require a Medication Guide if FDA determines one or more
of the following circumstances exist:
(1) The drug product is one for which patient labeling could help prevent serious
adverse effects.
(2) The drug product is one that has serious risk(s) (relative to benefits) of which
patients should be made aware because information concerning the risks could
affect patients’ decision to use, or continue to use, the product.
(3) The drug product is important to health and patient adherence to directions for
use is crucial to the drug’s effectiveness.
Part 208 specifies the content and format of Medication Guides and manufacturer requirements
to provide Medication Guides for distribution. Manufacturers of drug products for which a
Medication Guide is required must:
• 	obtain FDA approval of the Medication Guide before the Medication Guide is
provided, and
• 	ensure that Medication Guides are provided in sufficient numbers, or provide the
means to produce Medication Guides in sufficient numbers, to distributors, packers,
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Contains Nonbinding Recommendations
and authorized dispensers to permit the authorized dispenser to provide a Medication
Guide to each patient receiving a prescription for the drug product.5
Part 208 also specifies the requirements for distribution of Medication Guides:
• 	Distributors and packers who receive the Medication Guides, or the means to produce
Medication Guides, must provide the Medication Guides or the means to provide
them to authorized dispensers.6
• 	Each authorized dispenser of a prescription drug product for which a Medication
Guide is required must provide the Medication Guide directly to each patient or each
patient’s agent when the product is dispensed, unless an exemption applies.7
Section 208.3(a) and (b) contain the following definitions:
Authorized dispenser is “an individual licensed, registered, or otherwise permitted by the
jurisdiction in which the individual practices to provide drug products on prescription in
the course of professional practice.”
Dispense to patients means the “act of delivering a prescription drug to a patient or an
agent of the patient either:
(1) By a licensed practitioner or an agent of a licensed practitioner, either directly
or indirectly, for self-administration by the patient, or the patient’s agent, or
outside the licensed practitioner’s direct supervision; or
(2) By an authorized dispenser or an agent of an authorized dispenser under a
lawful prescription of a licensed practitioner.”
B. 	FDAAA Requirements for Medication Guides as Part of REMS
The Food and Drug Administration Amendments Act of 2007 (FDAAA)8 created new section
505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355-1), which
authorizes FDA to require a risk evaluation and mitigation strategy (REMS) when necessary to
ensure that the benefits of a drug outweigh the risks. Under section 505-1(e), FDA may require
that a REMS for a drug include one or more of the elements described in the subsection,
5 21 CFR 208.24(a) and (b).
6 21 CFR 208.24(c).
7 21 CFR 208.24(e).
8 Public Law 110-85, September 27, 2007.
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Contains Nonbinding Recommendations
including when the criteria in 21 CFR part 208 are met, the requirement for an applicant9 to
develop a Medication Guide for distribution to each patient when the drug is dispensed.
Under part 208, Medication Guides may be safety-related, addressing serious risk(s) (relative to
benefits) of which patients should be made aware, and/or efficacy-related, when patient
adherence to directions for use is crucial to the drug’s effectiveness.10 Since the enactment of
FDAAA, FDA has considered any new Medication Guide (or safety-related changes to an
existing Medication Guide) to be part of a REMS. However, the Agency has the authority to
determine, based on the risks of a drug and public health concern, whether a Medication Guide
should be required as part of a REMS when the standard in part 208 is met, and may decide the
Medication Guide should be required as labeling but not part of a REMS if FDA determines that
a REMS is not necessary to ensure the benefits of the drug outweigh its risks.
Between March 25, 2008, when the REMS provisions of FDAAA took effect and January 1,
2011, FDA has approved over 150 Medication Guides for products approved under new drug
applications (NDAs) and biologic license applications (BLAs) as part of a REMS. One hundred
and eight of these REMS included only a Medication Guide and a timetable for submission of
assessments of the REMS. In some cases, Medication Guides have been approved as part of
REMS for drugs that are often provided in inpatient settings or in outpatient settings where the
drug is dispensed to a healthcare professional who then administers the drug to the patient.
Questions have arisen concerning FDA’s policy on whether the Medication Guide must be
provided every time the drug is dispensed because part 208 states that the regulations are
intended to apply primarily in the outpatient setting.11
FDA can require the development of — or safety-related changes to — a Medication Guide and
can require these to be completed quickly, whether or not a Medication Guide is part of a
REMS. Medication Guides are part of labeling (21 CFR 201.57(c)) and are subject to the safety
labeling change provisions of section 505(o)(4) of the FD&C Act, added by FDAAA. Under
these provisions, FDA can require the development of a Medication Guide (or safety-related
changes to an existing Medication Guide) based on new safety information of which FDA
becomes aware after approval of the product. Section 505(o)(4) includes tight timeframes for
applicant submission of a supplement containing the labeling changes or a statement detailing
the reasons why such a change is not warranted, as well as authority for FDA to order the
labeling changes if agreement is not reached within the statutorily specified timeframes.
9 The Medication Guide regulations refer to manufacturers. For purposes of this guidance discussing Medication
Guides in the context of the FD&C Act as amended by the FDAAA, we use the term applicant to include “holder of
an approved covered application” in section 505-1 of the FD&C Act and “responsible person” in section 505(o)(4)
of the FD&C Act (21 U.S.C. 355(o)(4)).
10 21 CFR 208.1(b) and (c).
11 21 CFR 208.1(a)
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III. 	DISCUSSION AND POLICY
A. 	Distribution of Medication Guides in Certain Settings
1. 	Discussion
Questions have arisen concerning the requirements for providing a Medication Guide when a
drug is not dispensed directly to a patient for self-administration or to the patient’s caregiver, as
anticipated in § 208.1(a), but rather is dispensed or distributed to a healthcare professional who
then administers the drug to the patient. For example, in an inpatient setting such as a hospital or
nursing home, drugs are dispensed by the hospital pharmacist and then administered by hospital
staff to patients. Similarly, in an outpatient setting such as a clinic or infusion center, drugs are
dispensed or distributed to a healthcare professional who then administers the drug to the patient,
sometimes without the involvement of a dispensing pharmacy or pharmacist. In some cases,
these drugs are administered to a patient several times a day or several times a week.
One goal of this guidance is to articulate the circumstances under which FDA intends to exercise
enforcement discretion regarding the requirement to provide Medication Guides in certain
settings, such as when a drug is dispensed to a healthcare professional for administration to a
patient in an inpatient setting. We believe that this exercise of enforcement discretion will allow
patients to receive important information about the drugs they will be taking without burdening
the healthcare system to provide repetitive information when no material changes have been
made.
2. 	Distribution Requirements Under Part 208
Medication Guides must be provided according to the requirements in 21 CFR part 208. See
section II.A.
a. 	Circumstances under which FDA intends to exercise enforcement
discretion regarding Medication Guide distribution
A Medication Guide need not be provided (i.e., FDA intends to exercise enforcement discretion
concerning distribution of a Medication Guide to a patient) when a drug is dispensed under the
following circumstances:
• 	When the drug is dispensed to a healthcare professional for administration to a patient in
an inpatient setting, except as provided in b. below.
• 	When the drug is dispensed to a healthcare professional for administration to a patient in
an outpatient setting, such as in a clinic or dialysis or infusion center, except as provided
in b. below.
In these settings, the drug will be administered to a patient by a healthcare professional who
should provide the patient instructions on appropriate use of the drug, including what potential
side effects may occur or follow-up that may be required as appropriate, and answer any
questions the patient may have.
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Contains Nonbinding Recommendations
b. 	Circumstances under which FDA will not exercise enforcement
discretion and a Medication Guide must be provided to a patient in
inpatient and outpatient settings
A Medication Guide must be provided to the patient or the patient’s agent (i.e., FDA does not
intend to exercise enforcement discretion) in the following situations:
• 	When the patient or the patient’s agent requests a Medication Guide.
• 	When a drug is dispensed in an outpatient setting (e.g., retail pharmacy, hospital
ambulatory care pharmacy) and the product will then be used by the patient without
direct supervision by a healthcare professional.
• 	The first time a drug is dispensed to a healthcare professional for administration to a
patient in an outpatient setting, such as in a clinic or dialysis or infusion center.
• 	The first time a drug is dispensed in an outpatient setting of any kind, after a Medication
Guide is materially changed (e.g., after addition of a new indication, new safety
information). FDA plans to specify in the letter approving a revised Medication Guide
when a change is considered to be a material change, and applicants will be directed to
notify healthcare professionals that a material change was made (i.e., a new indication,
new safety information).
• 	When a drug is subject to a REMS that includes specific requirements for reviewing or
providing a Medication Guide as part of an element to assure safe use (possibly in
conjunction with distribution), the Medication Guide must be provided in accordance
with the terms of the REMS, as when healthcare providers are required to review the
Medication Guide with patients before patients are enrolled in a REMS program.
The Medication Guide must be provided in outpatient settings, even when the drug is dispensed
to a healthcare professional for administration to the patient, the first time the drug is dispensed,
and if the Medication Guide is materially changed. In these instances, we would expect the
Medication Guide to assist the healthcare professional in communicating important information
about the drug to the patient.
FDA intends to exercise enforcement discretion with regard to providing Medication Guides in
certain circumstances as described above. The following table reflects those circumstances, in
accordance with the above-described policy.
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Table 1: Medication Guide Enforcement Discretion Policy
Setting 	Patient or
Patient’s
Agent
Requests
Medication
Guide
Medication
Guide Provided
Each Time
Drug Dispensed
Medication
Guide Provided
At Time of First
Dispensing
Medication
Guide Provided
When
Medication
Guide Materially
Changed
Drug is subject
to an ETASU
REMS that
includes specific
requirements
for providing
and reviewing a
Medication
Guide
Inpatient 	Must
provide
Medication
Guide
FDA intends to
exercise
enforcement
discretion;
Medication
Guide need not
be provided
FDA intends to
exercise
enforcement
discretion;
Medication
Guide need not
be provided
FDA intends to
exercise
enforcement
discretion;
Medication Guide
need not be
provided
Must provide
Medication
Guide as
specified in
REMS
Outpatient when
drug dispensed to
healthcare
professional for
administration to
patient
(e.g., clinic,
infusion center,
emergency
department,
outpatient
surgery)
Must
provide
Medication
Guide
FDA intends to
exercise
enforcement
discretion;
Medication
Guide need not
be provided
Must provide
Medication
Guide
Must provide
Medication Guide
Must provide
Medication
Guide as
specified in
REMS
Outpatient when
drug dispensed
directly to patient
or caregiver (e.g.,
retail pharmacy,
hospital
ambulatory
pharmacy,
patient samples)
Must
provide
Medication
Guide
Must provide
Medication
Guide
Must provide
Medication
Guide
Must provide
Medication Guide
Must provide
Medication
Guide as
specified in
REMS
B. 	Medication Guides as Part of REMS
1. 	Policy
While all Medication Guides must meet the standard and requirements in part 208, not every
newly required Medication Guide will be an element of a REMS. A REMS is a strategy for
managing the risks associated with a drug and a Medication Guide can be one part of that
strategy. As the risks associated with the use of a drug increase, the tools needed to ensure safe
use of a drug also increase. Depending on the risks involved, FDA may approve a Medication
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Guide under part 208 without requiring a REMS when that alone is adequate to address the
serious and significant public health concern and meets the standard in § 208.1. In other cases,
FDA may determine that a Medication Guide and other elements of a REMS, such as elements to
assure safe use, are necessary to ensure that the benefits of a drug outweigh the risks. In most
cases, FDA expects to include a Medication Guide as part of a REMS only when the REMS
includes elements to assure safe use. However, FDA will include a Medication Guide in a
REMS that does not include elements to ensure safe use if we determine that having the
Medication Guide without a REMS will not be sufficient to ensure that the benefits of the drug
outweigh the risks.
Medication Guides that are required as part of REMS under section 505-1 are subject to the
assessment and modification provisions of section 505-1(g) and (h) of the FD&C Act.
2. 	Procedure for Requesting Removal of Medication Guides from REMS
Applicants who currently have a REMS that includes only a Medication Guide and a timetable
for submission of assessments may submit a prior approval supplement that proposes a REMS
modification to eliminate the REMS if they do not believe that the REMS is necessary to ensure
that the benefits of the drug outweigh the risks. Applicants with a REMS that includes a
Medication Guide, a communication plan, and a timetable for assessment also may submit a
prior approval supplement that proposes a REMS modification to remove the Medication Guide
from the REMS, if they do not believe that a Medication Guide that is a part of the REMS is
necessary to ensure that the benefits of the drug outweigh the risks. FDA will review any such
supplements and determine whether the Medication Guide is necessary to ensure that the benefits
of the drug outweigh the risks of the drug, as a tool of a REMS under section 505-1.
The proposed REMS modification must be accompanied by a REMS assessment.
• 	If the REMS has been assessed in the past 18 months, the assessment may consist of a
statement to that effect.
• 	If the REMS has not been assessed in the past 18 months, including a REMS for which
the first assessment has not been submitted, the assessment may consist of an update on
the status of any postapproval study or clinical trial required under section 505(o) or
otherwise undertaken by the responsible person to investigate a safety issue, including
the information required under section 505-1(g)(3)(B) and (C) of the FD&C Act. If the
REMS is not eliminated (e.g., the Medication Guide is removed from the REMS but the
approved modified REMS still includes a communication plan and timetable for
submission of assessments), this assessment to support the REMS modification will not
replace any assessments required by the timetable for submission of assessments in the
approved REMS.
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9
When the requirement for a REMS that includes only a Medication Guide for a reference listed
drug has been removed,12 generic drug applicants may submit a changes being effected (CBE)
supplement that proposes a REMS modification to eliminate the REMS (21 CFR 314.70(c)(6)).
Even if the Medication Guide is removed from the REMS or the requirement for the REMS is
removed, the Medication Guide will continue to be part of the approved labeling in accordance
with part 208, unless the FDA approves a supplement removing the Medication Guide from the
approved labeling.
12 Information about approved REMS is available at FDA’s Web page “Postmarket Drug Safety Information for
Patients and Providers” at
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm