Pregnancy, Lactation, and 
Reproductive Potential:  
Labeling for Human Prescription 
Drug and Biological Products   
Content and Format 
 
  
Guidance for Industry 
 
 
 
(Small Entity Compliance Guide) 
 
 
 
 
 
 
 
 
 
 
 
   
 
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) 
 
June 2015 
Labeling 
   
Pregnancy, Lactation, and 
Reproductive Potential:  
Labeling for Human Prescription 
Drug and Biological Products   
Content and Format 
 
  
Guidance for Industry 
 
 
(Small Entity Compliance Guide) 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
or 
Office of Communication, Outreach and  
Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Rm. 3128 
Silver Spring, MD 20993  
Phone: 240-402-7800 or 800-335-4709 
ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm   
 
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) 
 
June 2015 
Labeling 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DESCRIPTION OF PLLR LABELING REQUIREMENTS....................................... 2 
A.  8.1 Pregnancy ................................................................................................................................. 3 
1.      Pregnancy Exposure Registry ..................................................................................................... 3 
2.      Risk Summary .............................................................................................................................. 3 
3.    Clinical Considerations ............................................................................................................... 6 
4.    Data ............................................................................................................................................. 7 
B.  8.2 Lactation ................................................................................................................................... 8 
1.    Risk Summary .............................................................................................................................. 9 
2.    Clinical Considerations ............................................................................................................. 11 
3.    Data ........................................................................................................................................... 12 
C.  8.3 Females and Males of Reproductive Potential .................................................................... 12 
IV.  QUESTIONS AND ANSWERS ..................................................................................... 13 
V.  ADDITIONAL LABELING GUIDANCES ................................................................. 16 
APPENDIX A:  ORGANIZATION AND FORMAT FOR PREGNANCY, LACTATION, 
AND FEMALES AND MALES OF REPRODUCTIVE POTENTIAL SUBSECTIONS ... 17 
i 
  Contains Nonbinding Recommendations 
Pregnancy, Lactation, and Reproductive Potential:  
Labeling for Human Prescription Drug and Biological Products  
Content and Format  
 
1
Guidance for Industry  
 
(Small Entity Compliance Guide) 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not create any rights for any person and is not binding on FDA or the public.  You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To 
discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title 
page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to help small businesses better understand and comply with the new 
content and format requirements of the Pregnancy, Lactation, and Females and Males of 
Reproductive Potential subsections of labeling for human prescription drug and biological 
products.2  On December 4, 2014, we published the final rule Content and Format of Labeling 
for Human Prescription Drug and Biological Products; Requirements for Pregnancy and 
Lactation Labeling, referred to as the Pregnancy and Lactation Labeling Rule (PLLR, or final 
rule, 79 FR 72064).3  The final rule requires that the former Pregnancy, Labor and delivery, 
and Nursing mothers subsections of the USE IN SPECIFIC POPULATIONS section of the 
                                                 
1 This guidance has been prepared by the Division of Pediatric and Maternal Health in the Office of New Drugs in 
the Center for Drug Evaluation and Research (CDER), in cooperation with the Center for Biologics Evaluation and 
Research (CBER) at the Food and Drug Administration. 
 
2 This guidance applies to drugs, including biological drug products.  For the purposes of the PLLR and this 
guidance, drug or drug product will be used to refer to human prescription drug and biological products that are 
regulated as drugs.  Because some drugs are prodrugs that are metabolized to an active form, it is assumed that 
human pregnancy data on any form of the drug (drug, prodrug, or active metabolite) are applicable in terms of 
developmental toxicity risk.   
 
3 In addition to reviewing the final rule, we recommend that small businesses review the draft guidance for industry 
we issued concurrently with the publication of the PLLR to help drug and biological product manufacturers comply 
with the new labeling content and format requirements:  Pregnancy, Lactation, and Reproductive Potential: 
Labeling for Human Prescription Drug and Biological Products.  When final, this guidance will represent the 
FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA Drugs guidance 
Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  1  Contains Nonbinding Recommendations 
labeling for human prescription drug and biological products be replaced by the three 
subsections entitled Pregnancy, Lactation, and Females and Males of Reproductive Potential.   
 
FDA has prepared this guidance in accordance with section 212 of the Small Business 
Regulatory Enforcement Fairness Act (Public Law 104-121). 
 
In general, FDAs guidance documents 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 
 
The requirements on content and format of labeling for human prescription drug and biological 
products were revised by the January 24, 2006, final rule,4 commonly referred to as the 
Physician Labeling Rule (PLR).5   
 
In the Federal Register of May 29, 2008 (73 FR 30831), we issued a proposed rule to amend the 
PLR content and format requirements of the Pregnancy, Labor and delivery, and Nursing 
mothers subsections of the USE IN SPECIFIC POPULATIONS section of labeling for human 
prescription drug and biological products, which appear in  201.57 (21 CFR 201.57).   
 
In the Federal Register of December 4, 2014 (79 FR 72064), we published a final rule (PLLR) 
that amended our regulations governing the content and format of the Pregnancy, Labor and 
delivery, and Nursing mothers subsections of the USE IN SPECIFIC POPULATIONS 
section of labeling for human prescription drug and biological products.   
  The PLLR requires the removal of the pregnancy categories A, B, C, D, and X from all 
human prescription drug and biological product labeling.   
  The PLLR also revises the PLR content and format requirements for subsections 8.1 
through 8.3 (now Pregnancy, Lactation, and Females and Males of Reproductive 
Potential) of section 8 USE IN SPECIFIC POPULATIONS of the full prescribing 
information (FPI) (21 CFR 201.57(c)(9)(i) through (c)(9)(iii)).   
The final rule is effective on June 30, 2015.  The citations to the Code of Federal Regulations 
(CFR) in this guidance refer to the CFR as amended by the PLLR. 
 
III.  DESCRIPTION OF PLLR LABELING REQUIREMENTS 
 
Appendix A of this guidance provides an outline of the organization and format for the 
Pregnancy, Lactation, and Females and Males of Reproductive Potential subsections of the 
                                                 
4 See the final rule, Requirements on Content and Format of Labeling for Human Prescription Drug and Biological 
Products, published in the Federal Register (71 FR 3922, January 24, 2006). 
 
5 PLR labeling requirements are described in 21 CFR 201.56 and 201.57.   
 
  2  Contains Nonbinding Recommendations 
PLLR labeling.  Below, we describe in more detail the content requirements for these labeling 
subsections.   
 
A.  8.1 Pregnancy 
 
Information in the Pregnancy subsection of labeling is presented under the following 
subheadings: 
 
  Pregnancy Exposure Registry  
  Risk Summary  
  Clinical Considerations  
  Data  
 
1.  Pregnancy Exposure Registry  
 
If there is a scientifically acceptable pregnancy exposure registry for the drug,6 the following 
statement must appear under the subheading Pregnancy Exposure Registry 
( 201.57(c)(9)(i)(A)):  
 
There is a pregnancy exposure registry that monitors pregnancy outcomes in 
women exposed to (name of drug) during pregnancy.   
 
This statement must be followed by contact information (e.g., a toll-free telephone number, Web 
site) needed to enroll in or to obtain information about the registry ( 201.57(c)(9)(i)(A)).   
 
When there is no pregnancy exposure registry, this subheading should be omitted.  
 
The availability of a pregnancy exposure registry should be noted in the PATIENT 
COUNSELING INFORMATION section, and a cross-reference to 8.1 Pregnancy should be 
included for the contact information necessary to enroll. 
 
2.  Risk Summary 
 
The Risk Summary subheading is always required because certain statements are required to be 
included even when there are no data or information available.  The Risk Summary provides 
risk statement(s) that describe for the drug, the risk of adverse developmental outcomes based 
on all relevant human data, animal data, and the drugs pharmacology ( 201.57(c)(9)(i)(B)).   
 
When multiple data sources are available, risk statements must be presented in the following 
order:  human, animal, and pharmacologic ( 201.57(c)(9)(i)(B)).  The Risk Summary should be 
presented as an integrated summary and not as an individualized listing of information.  If there 
is more than one risk based on human data, the information should be placed in the order of 
clinical importance.     
                                                 
6 The Agency considers a pregnancy exposure registry scientifically acceptable when it is consistent with FDA 
guidance.  See FDAs guidance for industry, Establishing Pregnancy Exposure Registries. 
  3  Contains Nonbinding Recommendations 
 
When applicable, risk statements must include a cross-reference to additional details in the 
relevant portion of the Data subheading in the Pregnancy subsection ( 201.57(c)(9)(i)(B)).  
 
If a drug is systemically absorbed, the Risk Summary must include information about the 
background risk of major birth defects and miscarriage in the U.S. general population, regardless 
of drug exposure ( 201.57(c)(9)(i)(B)), in order to establish a basis for comparison.  If 
information on birth defects and miscarriage is available for the patient population for whom the 
drug is labeled, the information also must be included ( 201.57(c)(9)(i)(B)).  Applicants should 
periodically review the birth defects and miscarriage data to ensure that the information in 
labeling is accurate (see  201.56(a)(2)).  
 
When use of a drug is contraindicated during pregnancy, this information must be stated first in 
the Risk Summary ( 201.57(c)(9)(i)(B)).   
 
If data demonstrate that a drug is not systemically absorbed following a particular route of 
administration, the Risk Summary must contain only the following statement 
( 201.57(c)(9)(i)(B)): 
 
(Name of drug) is not absorbed systemically following (route of administration), 
and maternal use is not expected to result in fetal exposure to the drug. 
 
For situations in which the drug is not absorbed systemically following one route of 
administration, but the drug is absorbed systemically following another route (or other routes) of 
administration, the above statement should be included for the route of administration resulting 
in no systemic exposure.  This would be in addition to any statements that are required in the 
Risk Summary based on data demonstrating that the drug is absorbed systemically following 
another route (or other routes) of administration. 
 
The following discussion describes the requirements for the risk statements. 
  
a.   Risk statement based on human data 
 
When human data are available that establish the presence or absence of any adverse 
developmental outcome(s) associated with maternal use of the drug, a risk statement based on 
human data must summarize the specific developmental outcome(s), and include the following 
information ( 201.57(c)(9)(i)(B)(1)): 
 
 Its incidence 
 The effect of dose 
 The effect of duration of exposure 
 The effect of gestational timing of exposure  
 
If human data indicate that there is an increased risk for a specific adverse developmental 
outcome in infants born to women exposed to the drug during pregnancy, this risk must be 
quantitatively compared to the risk for the same outcome in infants born to women who were not 
  4  Contains Nonbinding Recommendations 
exposed to the drug, but who have the disease or condition for which the drug is indicated to be 
used ( 201.57(c)(9)(i)(B)(1)).  When risk information is not available for women with these 
condition(s), the risk for the specific outcome in women exposed to the drug during pregnancy 
must be compared to the rate at which the outcome occurs in the general population 
( 201.57(c)(9)(i)(B)(1)).   
 
When there are no human data or the available human data do not establish the presence or 
absence of drug-associated risk, this must be stated in the Risk Summary 
( 201.57(c)(9)(i)(B)(1)).   
 
b.   Risk statement based on animal data 
 
When animal data are available, the risk statement based on such data must describe the potential 
risk for adverse developmental outcomes in humans and summarize the available data 
( 201.57(c)(9)(i)(B)(2)).7  This statement must include ( 201.57(c)(9)(i)(B)(2)):  
 
 The number and type(s) of species affected 
  Timing of exposure 
  Animal doses expressed in terms of human dose or exposure equivalents 
  Outcomes for pregnant animals and offspring  
 
The risk statement must state when animal studies do not meet current standards8 for nonclinical 
developmental toxicity studies, or when there are no animal data ( 201.57(c)(9)(i)(B)(2)).   
 
c.   Risk statement based on pharmacology 
 
When the drug has a well-understood pharmacologic mechanism of action that may result in 
adverse developmental outcomes, the Risk Summary must explain the mechanism of action and 
the potential associated risks ( 201.57(c)(9)(i)(B)(3)).  In addition, the Risk Summary should 
explain the mechanism of action and the potential associated risks when there is a well-
understood pharmacologic mechanism of action that may result in drug class-associated adverse 
developmental outcomes.  A cross-reference should be provided to CLINICAL 
PHARMACOLOGY, where the pharmacologic data on which this Risk Summary is based are 
more fully described. 
 
                                                 
7 See FDAs guidance for industry, Reproductive and Developmental Toxicities  Integrating Study Results to 
Assess Concerns.  For vaccines, see FDAs guidance for industry, Considerations for Developmental Toxicity 
Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications. 
 
8 For a description of current standards for nonclinical developmental toxicity studies, see FDAs guidance for 
industry, M3 (R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization 
for Pharmaceuticals and the International Conference on Harmonisation S5 (R2) Guideline:  Detection of Toxicity 
to Reproduction for Medicinal Products and Toxicity to Male Fertility.  
 
 
  5  Contains Nonbinding Recommendations 
3.    Clinical Considerations 
 
Relevant information under the Clinical Considerations subheading ( 201.57(c)(9)(i)(C)) is 
presented under the following five headings, to the extent information is available: 
 
  Disease-associated maternal and/or embryo/fetal risk 
  Dose adjustments during pregnancy and the postpartum period 
  Maternal adverse reactions 
  Fetal/Neonatal adverse reactions 
  Labor or delivery 
 
A heading should be omitted if there is no information on the heading topic or the available data 
are not informative.  The Clinical Considerations subheading should be omitted in its entirety if 
all of the headings are omitted. 
 
a.   Disease-associated maternal and/or embryo/fetal risk 
 
When relevant data are available, this portion of labeling must describe any serious known or 
potential risk to the pregnant woman and/or the embryo/fetus associated with the disease or 
condition for which the drug is indicated ( 201.57(c)(9)(i)(C)(1)).  This description is included 
to provide information on any serious risks of the untreated disease/condition in pregnancy, so 
that health care providers and patients may make informed decisions about treatment.   
 
b.   Dose adjustments during pregnancy and the postpartum period 
 
If there are pharmacokinetic data that support dose adjustment(s) during pregnancy and the 
postpartum period, a summary of this information must be provided ( 201.57(c)(9)(i)(C)(2)).  
As appropriate, additional information elsewhere in the labeling (e.g., CLINICAL 
PHARMACOLOGY and DOSAGE AND ADMINISTRATION) should be cross-referenced.   
 
c.   Maternal adverse reactions 
 
Labeling must describe drug-associated adverse reactions that are unique to pregnancy or occur 
with increased frequency or severity in pregnant women ( 201.57(c)(9)(i)(C)(3)).  If clinical 
interventions are available to help monitor or mitigate drug-associated maternal adverse 
reactions, these interventions must be described in this portion of labeling 
( 201.57(c)(9)(i)(C)(3)) (e.g., monitoring blood glucose for a drug that causes hyperglycemia in 
pregnancy).  If known, the effect of dose, timing, and duration of exposure on the maternal risk 
of these adverse reaction(s) must be included ( 201.57(c)(9)(i)(C)(3)).   
 
d.   Fetal/Neonatal adverse reactions  
 
This heading describes fetal/neonatal adverse reactions that are not adverse developmental 
outcomes and that are not described in the Risk Summary.  If it is known or anticipated that 
maternal drug therapy increases or may increase the risk of an adverse reaction in the fetus or 
neonate, based on the drugs pharmacologic activity, or other data, the labeling must describe the 
  6  Contains Nonbinding Recommendations 
adverse reaction ( 201.57(c)(9)(i)(C)(4)).  The labeling must also describe the potential severity 
and reversibility of the adverse reaction and available intervention(s) for monitoring or 
mitigating the reaction in the fetus or neonate ( 201.57(c)(9)(i)(C)(4)).  If known, the effect of 
dose, timing, and duration of exposure on the risk must be included ( 201.57(c)(9)(i)(C)(4)).   
 
e.   Labor or delivery 
 
If the drug is expected to affect labor or delivery, the labeling must provide available information 
about the drugs effects on the mother, the fetus or neonate, and the duration of labor and 
delivery ( 201.57(c)(9)(i)(C)(5)).  The labeling must describe any increased risk of adverse 
reactions, including their potential severity and reversibility, and available intervention(s) that 
can mitigate these effects and/or adverse reactions ( 201.57(c)(9)(i)(C)(5)).   
 
For drugs approved for use only during labor and delivery, this heading (and the information 
required under this heading) may be omitted ( 201.57(c)(9)(i)(C)(5)). 
 
4.    Data 
 
Under the subheading Data, labeling must describe the data that provide the scientific basis for 
the information presented in the Risk Summary and Clinical Considerations 
( 201.57(c)(9)(i)(D)(1)).  This subheading is required, as are the headings Human Data and 
Animal Data, to the extent information is available.  Human data and animal data must be 
presented separately, and human data must be presented first ( 201.57(c)(9)(i)(D)(2)).   
 
a.   Human data 
 
This portion of labeling describes the data supporting any risk statement(s) in the Risk Summary 
and the information under Clinical Considerations that is based on human data.  Both positive 
and negative study findings must be included ( 201.57(c)(9)(i)(D)(3)).  Applicants must update 
labeling as new data become available ( 201.56(a)(2)).  Applicants should evaluate the quality 
and quantity of data available with respect to what information warrants inclusion in labeling.9  
This portion of labeling must describe the data regarding adverse developmental outcomes, 
adverse reactions, and other adverse effects, and, to the extent available, must include the 
following elements: 
 
  Data source (e.g., controlled clinical trials, ongoing or completed pregnancy exposure 
registries, other epidemiological or surveillance studies, case series) 
  Number of subjects 
  Study duration 
  Exposure information (timing, duration, and dose of exposure) 
  Limitations of the data, including potential confounders and biases, if known 
                                                 
9 See FDAs reviewer guidance, Evaluating the Risks of Drug Exposure in Human Pregnancies.   
  7  Contains Nonbinding Recommendations 
 
Individual case reports are rarely sufficient to characterize risk and therefore ordinarily should 
not be included in this section.  
 
If available, data from the comparator or control group and data confidence intervals and power 
calculations should also be included. 
 
b.   Animal data 
 
This portion of labeling describes the nonclinical developmental toxicity studies that form the 
scientific basis for any risk statement(s) in the Risk Summary that are based on animal data.  The 
labeling must describe the following ( 201.57(c)(9)(i)(D)(4)):   
 
  Types of studies 
  Animal species 
  Animal doses or exposures described in terms of human dose or exposure equivalents and 
the basis for those calculations 
  Duration and timing of exposure 
  Study findings 
  Presence or absence of maternal toxicity 
  Limitations of the data 
 
Descriptions of maternal and offspring findings must include dose-response and severity of 
adverse developmental outcomes ( 201.57(c)(9)(i)(D)(4)).  
 
For specific guidance on how to interpret nonclinical developmental toxicity data, see FDAs 
guidance for industry, Reproductive and Developmental Toxicities  Integrating Study Results 
to Assess Concerns. 
 
B.  8.2 Lactation 
 
Information in the Lactation subsection of labeling, which replaces the Nursing mothers 
subsection, is presented under the following subheadings: 
 
  Risk Summary 
  Clinical Considerations 
  Data 
 
The PLLR uses the term lactation to refer to the biological state during which a womans body 
produces and excretes milk.  The PLLR uses the term breastfeeding to refer to all human milk 
feeding situations when an infant or child is fed with human milk whether the milk is received 
  8  Contains Nonbinding Recommendations 
directly from the breast or as expressed milk.10  It is assumed that drug levels in human breast 
milk will be collected on the drug, prodrug, and active metabolite(s). 
 
1.    Risk Summary 
 
The Risk Summary subheading is always required because certain statements are required to be 
included even when there are no data or information available ( 201.57(c)(9)(ii)(A)).  The Risk 
Summary subheading should summarize information on the presence of a drug and/or its active 
metabolite(s) in human milk, the effects of a drug and/or its active metabolite(s) on the breastfed 
child, and the effects of a drug and/or its active metabolite(s) on milk production 
( 201.57(c)(9)(ii)(A)(2)(i)-(iii)).  When relevant human and/or animal lactation data are 
available, the Risk Summary must include a cross-reference to the Data portion of the Lactation 
subsection where the details of the data are presented ( 201.57(c)(9)(ii)(A)).  When human data 
are available, animal data must not be included unless the animal model is specifically known to 
be predictive for humans ( 201.57(c)(9)(ii)(A)).   
 
When use of a drug is contraindicated during breastfeeding (e.g., radioactive iodine-containing 
imaging and therapeutic products), this information must be stated first in the Risk Summary 
( 201.57(c)(9)(ii)(A)).  This information should be followed by a brief explanation of the risk.   
 
If data demonstrate that a drug is not systemically absorbed by the mother, the Risk Summary 
must contain only the following statement ( 201.57(c)(9)(ii)(A)(1)): 
 
(Name of drug) is not absorbed systemically by the mother following (route of 
administration), and breastfeeding is not expected to result in exposure of the 
child to (name of drug).   
 
For situations in which the drug is not absorbed systemically by the mother following one route 
of administration, but the drug is absorbed systemically by the mother following another route 
(or other routes) of administration, the above statement should be included for the route of 
administration resulting in no systemic exposure to the mother.  This statement would be in 
addition to any statements that are required in the Risk Summary based on data demonstrating 
that the drug is absorbed systemically following another route (or other routes) of administration. 
 
The following discussion describes the requirements for the Risk Summary if the drug is 
absorbed systemically by the mother. 
  
a.   Presence of drug in human milk 
 
The Risk Summary must state whether the drug and/or its active metabolite(s) are present in 
human milk ( 201.57(c)(9)(ii)(A)(2)(i)) and should include a brief description of the available 
                                                 
10 American Academy of Pediatrics Policy Statement.  Breastfeeding and the use of human milk. Pediatrics. 2012; 
129(3):e827-41. 
 
  9  Contains Nonbinding Recommendations 
data.  If there are no data to assess the presence or absence of a drug and/or its active 
metabolite(s) in human milk, the Risk Summary must so state ( 201.57(c)(9)(ii)(A)(2)(i)).   
 
If studies demonstrate that the drug and/or its active metabolite(s) are not detectable in human 
milk, the Risk Summary must state the detection limits of the study assay 
( 201.57(c)(9)(ii)(A)(2)(i)). 
 
If studies demonstrate the presence of a drug and/or its active metabolite(s) in human milk, the 
Risk Summary must include the concentrations in human milk and the actual or estimated infant 
daily dose ( 201.57(c)(9)(ii)(A)(2)(i)).  The actual or estimated infant daily dose must be 
calculated for an infant fed exclusively with human milk and compared to the labeled infant or 
pediatric dose (if available) or the labeled maternal dose ( 201.57(c)(9)(ii)(A)(2)(i)).  
 
If studies demonstrate the presence of a drug and/or its active metabolite(s) in human milk but 
the drug and/or its active metabolite(s) are not expected to be systemically bioavailable to the 
breastfed child (e.g., drug is degraded in the gastrointestinal tract or not absorbed), the Risk 
Summary must describe the disposition of the drug and/or its active metabolite(s) 
( 201.57(c)(9)(ii)(A)(2)(i)). 
 
If only animal lactation data are available, the Risk Summary must state only whether or not the 
drug and/or its active metabolite(s) were detected in animal milk and specify the animal species 
( 201.57(c)(9)(ii)(A)(2)(i)), with a cross-reference to the Data portion of the Lactation 
subsection ( 201.57(c)(9)(ii)(A)), where the data are fully described ( 201.57(c)(9)(ii)(C)).   
 
b.   Effects of drug on the breastfed child 
 
The Risk Summary must include available information on the likelihood and seriousness of 
known or predicted effects on the breastfed child from exposure to a drug and/or its active 
metabolite(s) through human milk and/or from contact with maternal (breast/nipple) skin (for 
topical products) ( 201.57(c)(9)(ii)(A)(2)(ii)).  The Risk Summary must include information on 
any systemic and/or local (e.g., gastrointestinal tract) adverse reactions 
( 201.57(c)(9)(ii)(A)(2)(ii)).   
 
If there are no data to assess the effects of the drug and/or its active metabolite(s) on the 
breastfed child, the Risk Summary must so state ( 201.57(c)(9)(ii)(A)(2)(ii)). 
 
c.   Effects of drug on milk production/excretion 
 
The Risk Summary must describe the effects of a drug and/or its active metabolite(s) on human 
milk production/excretion, if such data are available ( 201.57(c)(9)(ii)(A)(2)(iii)).  The 
description can be based on data regarding the pharmacological action of a drug and/or its active 
metabolite(s) or on clinically relevant data and should specify whether the effect is temporary or 
permanent.  The Risk Summary must state if no data are available to assess the effects of a drug 
and/or its active metabolite(s) on milk production/excretion ( 201.57(c)(9)(ii)(A)(2)(iii)). 
 
  10  Contains Nonbinding Recommendations 
d.   Risk and benefit statement 
 
For drugs absorbed systemically by the mother, unless breastfeeding is contraindicated during 
drug therapy, the Risk Summary must include the following risk and benefit statement at the end 
of the Risk Summary ( 201.57(c)(9)(ii)(A)(3)):   
 
The developmental and health benefits of breastfeeding should be 
considered along with the mothers clinical need for (name of drug) and 
any potential adverse effects on the breastfed child from (name of drug) 
or from the underlying maternal condition. 
 
2.    Clinical Considerations 
 
The Clinical Considerations subheading must contain the information described below to the 
extent that the information is available and relevant ( 201.57(c)(9)(ii)(B)).  If there are no data 
to inform this subheading, it should be omitted. 
 
a.   Minimizing exposure 
 
Lactation labeling must describe ways to minimize exposure to the breastfed child through 
human milk and/or contact with maternal skin during breastfeeding if the drug and/or its active 
metabolite(s): (1) are present in human milk in clinically relevant concentrations, (2) do not have 
an established safety profile in infants, and (3) are used either intermittently (e.g., acute migraine 
therapies), in single doses (e.g., radio-imaging drugs, anesthetic agents), or for short courses of 
therapy (e.g., some antibiotics) ( 201.57(c)(9)(ii)(B)(1)).  When applicable, labeling must also 
describe interventions to minimize a breastfeeding childs oral intake of topical drugs applied to 
the breast or nipple skin ( 201.57(c)(9)(ii)(B)(1)).   
 
Interventions that are intended to minimize exposure of the breastfed child to a drug and/or its 
active metabolite(s), such as timing the administration of the drug relative to feedings at the 
breast, pumping sessions, and/or expressing milk in order to discard it (pump and dump) for a 
specified time period, should be described when applicable.  The specified period should be 
determined based on available data or on a multiple of the half-life of a drug and/or its active 
metabolite(s).   
 
A summary of data from clinical lactation studies and/or pharmacokinetic studies can be used to 
inform this portion of lactation labeling.  A cross-reference should be provided to the Data 
portion of the Lactation subsection, where the available clinical lactation study data are 
described in detail ( 201.57(c)(9)(ii)(C)).  If applicable, a cross-reference can also be provided 
to CLINICAL PHARMACOLOGY, where available pharmacokinetic data are fully described. 
 
 
b.  Monitoring for adverse reactions 
 
A description of available interventions for monitoring and mitigating drug adverse reactions in 
the breastfed child that were described in the Risk Summary must be provided in this portion of 
lactation labeling ( 201.57(c)(9)(ii)(B)(2)).  This information is important for health care 
  11  Contains Nonbinding Recommendations 
providers who are counseling lactating women taking drugs about the relative risks and benefits 
of breastfeeding to the mother and to the child and about how to monitor for clinically significant 
drug adverse reactions in the breastfed child. 
 
3.    Data 
 
The Data subheading must describe the data on which the Risk Summary and Clinical 
Considerations are based ( 201.57(c)(9)(ii)(C)).  Applicants must update labeling as new data 
become available ( 201.56(a)(2)).  Applicants should evaluate the quality and quantity of data 
available with respect to what information warrants inclusion in labeling.11  If there are no data, 
this subheading should be omitted. 
 
C.  8.3 Females and Males of Reproductive Potential 
 
The final rule establishes subsection 8.3 Females and Males of Reproductive Potential to require 
information for these populations when (1) there are recommendations or requirements for 
pregnancy testing and/or contraception before, during, or after drug therapy, and/or (2) there are 
human and/or animal data suggesting drug-associated effects on fertility and/or pre-implantation 
loss effects ( 201.57(c)(9)(iii)).  The recommendations and/or requirements for pregnancy 
testing and/or contraception may be based on concerns for potential or demonstrated adverse 
developmental outcomes associated with drug exposure during pregnancy.  As applicable, the 
information required under this subsection must appear under the following subheadings, in the 
following order: 
 
  Pregnancy Testing 
  Contraception 
  Infertility  
 
If data suggest no adverse effects on fertility, this information should be presented under 
Infertility.   
 
If data from animal studies raise concerns about mutagenesis or impairment of human fertility in 
females or males, a summary of this information and its clinical implications must appear under 
Females and Males of Reproductive Potential.  A cross-reference to NONCLINICAL 
TOXICOLOGY, for a detailed discussion of the animal studies, should be included.   
 
A subheading should be omitted if not applicable.  Subsection 8.3 should be omitted if none of 
the subheadings are applicable.  
 
                                                 
11 See FDAs draft guidance, Clinical Lactation Studies  Study Design, Data Analysis, and Recommendations for 
Labeling.   
 
  12  Contains Nonbinding Recommendations 
IV.  QUESTIONS AND ANSWERS 
 
Question 1:  How has the formatting for subsections 8.1 through 8.3 changed under the 
PLLR? 
 
The PLLR merges the former 8.1 Pregnancy subsection and 8.2 Labor and delivery subsection 
into a single 8.1 Pregnancy subsection, which will now include information about labor and 
delivery. 
 
Under the PLLR, the former subsection 8.3 Nursing mothers is replaced by subsection 8.2 
Lactation.    
 
Under the PLLR, there also is a new subsection 8.3 Females and Males of Reproductive 
Potential, which provides information on pregnancy testing, contraception, and infertility. 
 
Subsection numbers and titles in the FPI must be bolded (e.g., 8.1 Pregnancy) ( 201.57(d)(7)).  
In addition, as outlined in Appendix A to this guidance, there is a requirement under the PLLR 
for the inclusion of specific subheadings and headings under subheadings within subsections 
(e.g., Risk Summary).  Additional subdivisions of information other than those presented in 
Appendix A are not recommended.  
 
Because the PLLR requires the inclusion of specific subheadings within subsections (e.g., Risk 
Summary), cross-referencing within a subsection is often necessary.  The recommended method 
of within-subsection cross-referencing is to present the title of the subheading being referenced 
in parentheses and italics (e.g., (see Data)).   
 
Question 2:   How has the content for these subsections changed? 
 
The final rule requires the removal of the pregnancy categories  A, B, C, D, and X  from all 
human prescription drug and biological product labeling.12 
 
The final rule replaces the pregnancy letter categories with three subsections that provide details 
about use of the drug in the Pregnancy, Lactation, and Females and Males of Reproductive 
Potential (if applicable) subsections.  
 
The Pregnancy subsection requires information about a pregnancy exposure registry, if one 
exists.  It also must include a summary of the risks of using a drug during pregnancy and relevant 
                                                 
12 Section 201.80 (21 CFR 201.80) applies to products that are not required to convert their labeling to the PLR 
format.  Under the final rule, products subject to  201.80 only are required to remove the pregnancy letter category 
from their labeling (e.g., Pregnancy Category C), and not the standard statements that follow each of the 
pregnancy letter categories (e.g., (Name of drug) has been shown to be teratogenic (or to have an embryocidal 
effect or other adverse effect) in (name(s) of species) when given in doses (x) times the human dose.  There are no 
adequate and well-controlled studies in pregnant women. (Name of drug) should be used during pregnancy only if 
the potential benefit justifies the potential risk to the fetus(21 CFR 201.80(f)(6)(i)(c)).  Accordingly, the final rule 
also revises  201.80 by removing the references to the pregnancy letter categories in  201.80(f)(6)(i)(a)-(e). 
 
  13  Contains Nonbinding Recommendations 
information, if it is available, to help health care providers make prescribing decisions and 
counsel women about the use of the drug during pregnancy.  
 
The Lactation subsection must provide information about using the drug while breastfeeding, 
such as the amount of the drug in breast milk and potential effects on the breastfed infant. 
 
The Females and Males of Reproductive Potential subsection is a new subsection in labeling and 
must include, when applicable, information about the need for pregnancy testing, contraception 
recommendations, and information about drug-associated fertility effects.   
 
In addition, the Pregnancy and Lactation subsections will include three subheadings:  Risk 
Summary, Clinical Considerations and Data.  The subheadings are intended to describe, for 
example, human, animal, and pharmacologic data on use of the drug in these populations, 
specific adverse reactions in these populations, and information about dose adjustments during 
the pregnancy and postpartum periods.   
 
Question 3:  Who must comply with the final rule? 
 
All holders of applications (NDA, BLA, or efficacy supplement), including those approved prior 
to June 30, 2001 (i.e., applications not subject to PLR), are required to remove the pregnancy 
categories from their labeling. 
 
The new content and formatting requirements of the final rule apply to any NDA, BLA, or 
efficacy supplement that is required to comply with the PLR.  As stated in  201.56(b)(1), this 
includes:  
  prescription drug products for which an NDA, BLA, or efficacy supplement was 
approved between June 30, 2001, and June 30, 2006,  
  prescription drug products for which an NDA, BLA, or efficacy supplement was pending 
on June 30, 2006, or 
  prescription drug products for which an NDA, BLA, or efficacy supplement was or is 
submitted anytime on or after June 30, 2006. 
 
Question 4:  When must holders of applications comply with the PLLR requirements? 
 
The final rule is effective June 30, 2015.  There is a phase-in period for holders of applications to 
comply with the new labeling requirements.  The required timelines for submitting labeling in 
the new format are based on the implementation schedule in the preamble of the PLLR and is set 
forth below.  NDAs submitted on or after the June 30, 2015, effective date must use the new 
format upon submission.  NDAs, BLAs, or efficacy supplements that are pending with the 
Agency on the June 30, 2015, effective date must comply within 4 years of the effective date, or 
at the time of approval, whichever is later.  Previously approved NDAs, BLAs, or efficacy 
supplements that were approved on or after June 30, 2001, have a phased-in implementation 
schedule from 3 to 5 years.   
 
Holders of applications approved before June 30, 2001, are required to remove the pregnancy 
category from their labeling within 3 years after the June 30, 2015, effective date.   
  14  Contains Nonbinding Recommendations 
Implementation Plan 
 
Applications Required To Conform to New  Time by Which Labeling With New 
Pregnancy/Lactation Content Requirements  Pregnancy/Lactation Content Must 
Be Submitted to FDA for Approval 
New or Pending Applications:* 
  Applications submitted on or after the effective  Time of submission 
date of the final rule 
  Applications pending on the effective date of the  4 years after the June 30, 2015, 
final rule  effective date or at time of approval, 
whichever is later 
Approved Applications Subject to the Physician Labeling Rule: 
  Applications approved any time from June 30,  3 years after the effective date of the 
2001, up to and including June 29, 2002, and from  final rule 
June 30, 2005, up to and including June 29, 2007 
  Applications approved any time from June 30,  4 years after the effective date of the 
2007, up to and including the effective date of the  final rule 
final rule 
  Applications approved from June 30, 2002, up to  5 years after the effective date of the 
and including June 29, 2005  final rule 
 
*Applications are NDAs, BLAs, and efficacy supplements. 
 
Question 5:  How should draft labeling be submitted to FDA for review? 
 
Holders of applications subject to the new content and formatting requirements in the final rule 
are required to submit the new labeling content in the new format as a prior approval labeling 
supplement.  To facilitate FDAs review of labeling, we recommend that the following versions 
of labeling be submitted as appropriate:  
 
  Labeling in the old format 
  A clean version (i.e., no redline/strikeout) that complies with the PLLR content and 
format requirements 
  A marked-up version that complies with the PLLR content and format requirements 
(in redline/strikeout or as tracked changes) 
  Microsoft Word versions of all the above 
 
Applicants should explain significant or notable changes in wording or content, or relocation of 
information to a different section, and how the decisions to make those changes were made.  To 
facilitate identification of the type of submission for the Agency, the applicant should mark 
clearly on the cover letter, Pregnancy and Lactation Labeling/PLLR Conversion. 
If the labeling for applications approved before June 30, 2001 (i.e., applications not subject to 
PLR) contains a pregnancy category, the application holders are required to remove the 
  15  Contains Nonbinding Recommendations 
pregnancy category by 3 years after the effective date of the final rule and to report the labeling 
change in their annual reports.13   
 
Question 6:  How does this rule apply to generic drugs? 
 
The labeling for a product approved under an abbreviated new drug application (ANDA) must be 
the same as the labeling approved for the reference listed drug (RLD) (with limited exceptions).  
As a result, if the labeling of an RLD is updated as a result of the final rule, the ANDA labeling 
must also be revised. 
 
Question 7:  Can applicants request a waiver of the labeling requirements? 
 
Applicants may request that FDA waive a labeling requirement under 21 CFR 314.90(a) or 21 
CFR 201.58.  Applicants should clearly identify the submission as a request for a waiver.   
 
 
V.  ADDITIONAL LABELING GUIDANCES 
 
FDA has issued several additional guidances for industry on prescription drug labeling.  These 
guidances include, but are not limited to, the following: 
 
  Clinical Studies Section of Labeling for Human Prescription Drug and Biological 
Products  Content and Format 
  Content and Format of the Dosage and Administration Section of Labeling for Human 
Prescription Drug and Biological Products 
  Labeling for Human Prescription Drug and Biological Products  Implementing the PLR 
Content and Format Requirements 
  Warning and Precautions, Contraindications, and Boxed Warning Sections of Labeling 
Human Prescription Drug and Biological Products  Content and Format 
 
Agency guidances can be found at the Web site listed below.  This Web site is updated regularly 
as new or revised guidances are published. 
 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/default.htm    
 
 
                                                 
13 See  314.70(d) and 601.12(f)(3) about changes requiring submission in an annual report. 
 
  16  Contains Nonbinding Recommendations 
 
APPENDIX A:  ORGANIZATION AND FORMAT FOR PREGNANCY, LACTATION, 
AND FEMALES AND MALES OF REPRODUCTIVE POTENTIAL SUBSECTIONS 
 
  8.1  Pregnancy 
 
Pregnancy Exposure Registry (omit if not applicable) 
 
Risk Summary (required subheading) 
 
Clinical Considerations (omit if none of the headings are applicable) 
    
     Disease-associated maternal and/or embryo/fetal risk (omit if not applicable) 
 
     Dose adjustments during pregnancy and the postpartum period (omit if not applicable) 
 
     Maternal adverse reactions (omit if not applicable) 
 
     Fetal/Neonatal adverse reactions (omit if not applicable) 
 
     Labor or delivery (omit if not applicable) 
 
Data (omit if none of the headings are applicable) 
     
     Human Data (omit if not applicable) 
 
    Animal Data (omit if not applicable) 
 
 
  8.2  Lactation 
 
Risk Summary (required subheading) 
   
      Clinical Considerations (omit if not applicable) 
 
      Data (omit if not applicable) 
 
 
  8.3  Females and Males of Reproductive Potential (omit if none of the subheadings are  
applicable) 
 
Pregnancy Testing (omit if not applicable) 
 
Contraception (omit if not applicable) 
 
Infertility (omit if not applicable) 
  17