Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products — Content and Format Guidance for Industry (Small Entity Compliance Guide)

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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., 4 th 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
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Development
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Food and Drug Administration
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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

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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

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Pregnancy, Lactation, and Reproductive Potential:
Labeling for Human Prescription Drug and Biological Products —
Content and Format
Guidance for Industry1
(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
FDA’s 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.

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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, FDA’s 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.

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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 drug’s 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 FDA’s guidance for industry, Establishing Pregnancy Exposure Registries.

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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

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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 FDA’s guidance for industry, Reproductive and Developmental Toxicities — Integrating Study Results to
Assess Concerns. For vaccines, see FDA’s 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 FDA’s 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.

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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 drug’s pharmacologic activity, or other data, the labeling must describe the

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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 drug’s 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 FDA’s reviewer guidance, Evaluating the Risks of Drug Exposure in Human Pregnancies.

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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 FDA’s
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 woman’s 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

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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.

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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)).

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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 mother’s 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 child’s 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

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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 FDA’s draft guidance, Clinical Lactation Studies – Study Design, Data Analysis, and Recommendations for
Labeling.

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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).

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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.

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Implementation Plan
Applications Required To Conform to New
Pregnancy/Lactation Content Requirements
Time by Which Labeling With New
Pregnancy/Lactation Content Must
Be Submitted to FDA for Approval
New or Pending Applications:*
● Applications submitted on or after the effective
date of the final rule
Time of submission
● Applications pending on the effective date of the
final rule
4 years after the June 30, 2015,
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,
2001, up to and including June 29, 2002, and from
June 30, 2005, up to and including June 29, 2007
3 years after the effective date of the
final rule
● Applications approved any time from June 30,
2007, up to and including the effective date of the
final rule
4 years after the effective date of the
final rule
● Applications approved from June 30, 2002, up to
and including June 29, 2005
5 years after the effective date of the
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 FDA’s 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

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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.

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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)