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 
10903 New Hampshire Ave. 
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 
1401 Rockville Pike, Rockville, MD 20852-1448  
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 
 
1
Guidance  
 
Medication Guides  Distribution Requirements and 
Inclusion in Risk Evaluation and Mitigation Strategies (REMS) 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 patients 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 professionals 
direct supervision (e.g., the healthcare professional hands the patient or the patients caregiver the drug for the 
patient to take before leaving the healthcare professionals office).    
 
  1 Contains Nonbinding Recommendations 
 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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 drugs 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, 
  2 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 
patients 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 patients agent, or 
outside the licensed practitioners 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. 
   
  3 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 drugs 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 FDAs 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)  
  4 Contains Nonbinding Recommendations 
 
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 patients 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. 
  5 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 patients agent (i.e., FDA does not 
intend to exercise enforcement discretion) in the following situations: 
    
  When the patient or the patients 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.   
  6 Contains Nonbinding Recommendations 
 
  Table 1:  Medication Guide Enforcement Discretion Policy   
 
           
Setting  Patient or  Medication  Medication  Medication  Drug is subject 
Patients  Guide Provided  Guide Provided  Guide Provided  to an ETASU 
Agent  Each Time  At Time of First  When  REMS that 
Requests  Drug Dispensed  Dispensing  Medication  includes specific 
Medication  Guide Materially  requirements 
Guide  Changed  for providing 
and reviewing a 
Medication 
Guide 
Inpatient  Must  FDA intends to  FDA intends to  FDA intends to  Must provide 
provide  exercise  exercise  exercise  Medication 
Medication  enforcement  enforcement  enforcement  Guide as 
Guide  discretion;  discretion;  discretion;  specified in 
Medication  Medication  Medication Guide  REMS 
Guide need not  Guide need not  need not be 
be provided  be provided  provided 
Outpatient when  Must  FDA intends to  Must provide  Must provide  Must provide 
drug dispensed to  provide  exercise  Medication  Medication Guide  Medication 
healthcare  Medication  enforcement  Guide  Guide as 
professional for  Guide  discretion;  specified in 
administration to  Medication  REMS 
patient  Guide need not 
(e.g., clinic,  be provided 
infusion center, 
emergency 
department, 
outpatient 
surgery) 
Outpatient when  Must  Must provide  Must provide  Must provide  Must provide 
drug dispensed  provide  Medication  Medication  Medication Guide  Medication 
directly to patient  Medication  Guide  Guide  Guide as 
or caregiver (e.g.,  Guide  specified in 
retail pharmacy,  REMS 
hospital 
ambulatory  
pharmacy, 
patient samples)  
 
 
 
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 
  7 Contains Nonbinding Recommendations 
 
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. 
 
  8 Contains Nonbinding Recommendations 
 
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 FDAs Web page Postmarket Drug Safety Information for 
Patients and Providers at  
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm 
  9