Pregnancy, Lactation, and 
Reproductive Potential:  
Labeling for Human Prescription 
Drug and Biological Products   
Content and Format 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https:///www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact the Division of Pediatric and Maternal 
Health (CDER) at 301-796-2200 or the Office of Communication, Outreach, and Development 
(CBER) at 240-402-8010. 
 
 
 
 
 
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) 
 
July 2020 
Labeling 
Revision 1 
50762dft.docx 
7/15/2020   
Pregnancy, Lactation, and 
Reproductive Potential:  
Labeling for Human Prescription 
Drug and Biological Products   
Content and Format 
Guidance for Industry 
 
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  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
 
 
 
 
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) 
 
July 2020 
Labeling 
Revision 1 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL PRINCIPLES ............................................................................................... 4 
A.  Revising Labeling ........................................................................................................................... 4 
B.  Formatting ...................................................................................................................................... 4 
C.  Cross-Referencing .......................................................................................................................... 4 
D.  Omitted Information ..................................................................................................................... 5 
IV.  SPECIFIC SUBSECTIONS ............................................................................................. 5 
A.  8.1 Pregnancy ................................................................................................................................. 5 
1. Pregnancy Exposure Registry .......................................................................................................... 6 
2. Risk Summary .................................................................................................................................. 7 
a.  Risk statement based on human data ......................................................................................... 9 
b.  Risk statement based on animal data ...................................................................................... 10 
c.  Risk statement based on pharmacology .................................................................................. 11 
3. Clinical Considerations ................................................................................................................. 11 
a.  Disease-Associated Maternal and/or Embryo/Fetal Risk ........................................................ 12 
b.  Dose Adjustments During Pregnancy and the Postpartum Period .......................................... 12 
c.  Maternal Adverse Reactions ................................................................................................... 13 
d.  Fetal/Neonatal Adverse Reactions .......................................................................................... 13 
e.  Labor or Delivery .................................................................................................................... 14 
4. Data ............................................................................................................................................... 14 
a.  Human Data ............................................................................................................................ 14 
b.  Animal Data ............................................................................................................................ 15 
B.  8.2 Lactation ................................................................................................................................. 16 
1. Risk Summary ................................................................................................................................ 16 
a.  Presence of drug in human milk .............................................................................................. 17 
b.  Effects of drug on the breastfed child ..................................................................................... 19 
c.  Effects of drug on milk production ......................................................................................... 19 
d.  Risk and benefit statement ...................................................................................................... 20 
2. Clinical Considerations ................................................................................................................. 20 
a.  Minimizing exposure .............................................................................................................. 20 
b.  Monitoring for adverse reactions ............................................................................................ 21 
3. Data ............................................................................................................................................... 21 
C.  8.3 Females and Males of Reproductive Potential .................................................................... 22 
1. Pregnancy Testing ......................................................................................................................... 23 
2. Contraception ................................................................................................................................ 23 
3. Infertility ........................................................................................................................................ 24 
V.  PROCEDURAL INFORMATION................................................................................ 25 
A.  Applications Covered by the Final Rule and Implementation ................................................. 25 
B.  Submitting Draft Labeling to FDA for Review ......................................................................... 25 
C.  Waivers and Extensions .............................................................................................................. 27 
i 
   
APPENDIX A:   ORGANIZATION AND FORMAT FOR PREGNANCY, LACTATION, 
AND FEMALES AND MALES OF REPRODUCTIVE POTENTIAL SUBSECTIONS ... 28 
APPENDIX B:  PREGNANCY AND LACTATION LABELING RULE (PLLR) 
IMPLEMENTATION PLAN .................................................................................................... 30 
 
ii 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Pregnancy, Lactation, and Reproductive Potential:  
2  Labeling for Human Prescription Drug and Biological Products  
3  Content and Format 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This guidance is intended to assist applicants in complying with the content and format 
19  requirements for the Pregnancy, Lactation, and Females and Males of Reproductive Potential 
20  subsections of labeling for human prescription drug and biological products.2  This guidance 
21  provides information and recommendations for preparing subsections 8.1 Pregnancy, 8.2 
22  Lactation, and 8.3 Females and Males of Reproductive Potential of the USE IN SPECIFIC 
23  POPULATIONS section.3   
24   
25  On December 4, 2014, we published the final rule Content and Format of Labeling for Human 
26  Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation 
27  Labeling, referred to as the pregnancy and lactation labeling rule (PLLR).4  This guidance 
28  provides recommendations on complying with the PLLR to applicants with new drug 
29  applications (NDAs), biologics license applications (BLAs) (for biological products that are 
30  regulated as drugs), and efficacy supplements to approved NDAs or BLAs, as described in 
31  greater detail in the final rule and this guidance.  This guidance also provides recommendations  
32  to applicants that have previously submitted NDAs, BLAs, and efficacy supplements to approved 
33  NDAs or BLAs during the time periods specified in the implementation plan in Appendix B.   
                                                 
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, in cooperation with the Center for Biologics Evaluation and Research, 
at the Food and Drug Administration. 
 
2 This guidance applies to drugs, including biological drug products, subject to the final rule Requirements on 
Content and Format of Labeling for Human Prescription Drug and Biological Products (71 FR 3922, January 24, 
2006) commonly referred to as the physician labeling rule (PLR).  For the purposes of this guidance, the term drug 
or drug product will be used to refer to human prescription drugs and biological products that are regulated as drugs. 
 
3 21 CFR 201.56(d)(1) and 201.57(c)(9)(i)(iii). 
 
4 21 CFR 201.57(c)(9).  See also the final rule Content and Format of Labeling for Human Prescription Drug and 
Biological Products; Requirements for Pregnancy and Lactation Labeling (79 FR 72064, December 4, 2014). 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34   
35  This guidance revises the draft guidance for industry of the same name issued in December 2014.  
36  Changes to this revised draft guidance from that draft guidance include the addition of the 
37  following: 
38   
39    Information on formatting, omitting information, and pregnancy registries, pertinent to 
40  PLLR labeling 
41   
42    Clarifying information related to the Risk Summary heading, risk statements, and human 
43  and animal data, pertinent to PLLR labeling 
44   
45    Information on labeling for subsection 8.3 Females and Males of Reproductive Potential, 
46  including information on pregnancy testing, contraception, and infertility 
47   
48    Procedural information on PLLR implementation and submission of draft labeling that 
49  complies with PLLR to the Agency for review 
50   
51  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
52  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
53  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
54  the word should in Agency guidances means that something is suggested or recommended, but 
55  not required.  
56   
57   
58  II.  BACKGROUND 
59   
60  Prescription drug labeling is a communication tool.  Its principal objective is to make available to 
61  health care providers the detailed prescribing information necessary for the safe and effective use 
62  of a drug, in a manner that is clear and useful to providers when prescribing for and counseling 
63  patients.  Prescribing decisions during pregnancy and lactation are highly individualized and 
64  involve complex maternal, fetal, and infant risk-benefit considerations.   
65   
66  The final rule Requirements on Content and Format of Labeling for Human Prescription Drug 
67  and Biological Products (physician labeling rule (PLR)) published January 24, 2006, and 
68  revised the requirements for content and format of labeling for human prescription drug and 
69  biological products.5   
70   
71  The PLLR revises the PLR requirements for subsections 8.1 and 8.2 of prescription drug labeling 
72  to provide a framework for clearly communicating information on the risks and benefits of using 
73  a drug during pregnancy and lactation to facilitate prescribing decisions.  The PLLR also updates 
74  the PLR requirements to include a new Females and Males of Reproductive Potential subsection 
75  to address issues in these populations.  The PLLR went into effect on June 30, 2015.   
76   
                                                 
5 21 CFR 201.56(d) and 201.57. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
77   
78  The PLLR revised the PLR content and format requirements for subsections 8.1 through 8.3 of 
79  the USE IN SPECIFIC POPULATIONS section of labeling as follows:6,7  
80   
81  8.1 Pregnancy 
82   
83  This subsection contains information on what is known about the drugs effect on pregnancy, 
84  including labor and/or delivery, and replaces the former Pregnancy and Labor and Delivery 
85  subsections. 
86   
87  The PLLR also removed the previously required pregnancy letter categories (A, B, C, D, and X), 
88  which FDA determined were often confusing and did not accurately or consistently communicate 
89  differences in degrees of fetal risk.  Because risk-benefit decisions regarding use of a drug during 
90  pregnancy are more complex than the category designations suggest, reliance on the categories 
91  by health care providers could result in inadequately informed clinical decision making.  Instead 
92  of pregnancy letter categories, under the PLLR, narrative summaries of the risks of a drug during 
93  pregnancy and discussions of the data supporting those summaries are required in labeling to 
94  provide more meaningful information for health care providers.  
95   
96  8.2 Lactation 
97   
98  This subsection contains the information that replaces the former subsection, Nursing Mothers.  
99   
100  8.3 Females and Males of Reproductive Potential 
101   
102  This new subsection provides information on pregnancy testing, contraception, and infertility. 
103   
104  Historically, information about contraception and pregnancy testing recommendations directed 
105  toward the care of females and males of reproductive potential might be found in the Pregnancy 
106  subsection or in the WARNINGS AND PRECAUTIONS section of labeling.  In contrast, 
107  clinical advice on infertility might be found with the animal data described in the 
108  NONCLINICAL TOXICOLOGY section, in the ADVERSE REACTIONS section, or in the 
109  WARNINGS AND PRECAUTIONS section.  This variability made it challenging for health 
110  care providers to locate and use the relevant and available information when prescribing for and 
111  counseling patients.  The new subsection created under the PLLR, Females and Males of 
112  Reproductive Potential, provides a dedicated subsection that discusses when pregnancy testing or 
113  contraception is required or recommended before, during, or after drug therapy, or when there 
114  are human and/or animal data that suggest drug-associated fertility effects.   
115   
                                                 
6 21 CFR 201.57(c)(9)(i)(iii). 
 
7 21 CFR 201.80 applies to drug products that are not required to convert their labeling to the PLR format.  Under 
the PLLR, drug products subject to 21 CFR 201.80 are only required to remove the pregnancy letter category from 
their labeling (e.g., Pregnancy Category C), but the standard statements that follow each of the pregnancy letter 
categories (21 CFR 201.80(f)(6)(i)(a-e)) must remain.  Accordingly, the PLLR also revised 21 CFR 201.80 by 
removing the references to the pregnancy letter categories in 21 CFR 201.80(f)(6)(i)(a)(e). 
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
116  III.  GENERAL PRINCIPLES 
117   
118  A.  Revising Labeling 
119   
120  Labeling must be updated when new information becomes available that causes the labeling to 
121  become inaccurate, false, or misleading.8  Consistent with this requirement, applicants should 
122  evaluate labeling content when revising existing labeling to comply with the PLLR to ensure that 
123  it accurately reflects current knowledge based on systematic review of available evidence.  In 
124  addition, applicants will typically need to include new content to comply with the PLLR, for 
125  example, adding the background rates of birth defects and miscarriage (see section IV. A., 8.1 
126  Pregnancy).  Applicants should also review and update other sections of labeling pertinent to the 
127  PLLR (e.g., WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY, PATIENT 
128  COUNSELING INFORMATION) as necessary when updating the labeling for the PLLR.  
129  Subsequent to the initial implementation of the pregnancy and lactation labeling changes 
130  required under the PLLR, including the requirements for the Females and Males of Reproductive 
131  Potential subsection, applicants must continue to keep labeling up to date.9 
132   
133  B.  Formatting 
134   
135  Subsection numbers and titles in the labeling must be bolded (e.g., 8.1 Pregnancy).10  In 
136  addition, unique to the PLLR is the requirement for the inclusion of specific headings (e.g., Risk 
137  Summary) and when applicable, specific subheadings under headings (e.g., Labor or Delivery 
138  under Clinical Considerations).  The formatting approach used to distinguish headings from 
139  subheadings within subsections (e.g., underlining for headings and italics for subheadings) 
140  should be consistently used throughout the labeling.  Occasionally, information may not fit in the 
141  existing headings or subheadings, and the addition of a heading and/or subheading other than 
142  those presented in Appendix A can be used to convey important information.  If a new heading 
143  or subheading is proposed, the applicant should provide justification for the proposed heading or 
144  subheading for Agency review.   
145   
146  C.  Cross-Referencing 
147   
148  Cross-referencing follows the general principles of the PLR.11  In most situations, the PLLR 
149  subsections of labeling will contain the detailed and most important information relevant to 
150  prescribing in the patient populations at issue.  Other sections of labeling (e.g., 
                                                 
8 21 CFR 201.56(a)(2). 
 
9 Ibid. 
 
10 21 CFR 201.57(d)(1) and 21 CFR 201.57(d)(7). 
 
11 For information about the recommended presentation of cross-references in the labeling, see the guidance for 
industry Labeling for Human Prescription Drug and Biological Products  Implementing the PLR Content and 
Format Requirements (February 2013).  We update guidances periodically.  To make sure you have the most recent 
version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents. 
 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
151  CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS) may briefly present a topic 
152  addressed in the PLLR subsections and will cross-reference the more detailed discussion(s) in 
153  the PLLR subsections.  For example, if a clinically significant drug-associated adverse 
154  developmental outcome warrants a contraindication in pregnancy, the CONTRAINDICATIONS 
155  section will include pregnancy as a contraindication with a brief description of the observed or 
156  anticipated consequences of using the drug during pregnancy and will cross-reference the 
157  Pregnancy subsection for additional details.12   
158   
159  Because the PLLR requires the inclusion of specific headings within subsections (e.g., Risk 
160  Summary), cross-referencing within a subsection is often necessary.  The recommended method 
161  of within-subsection cross-referencing is to present the title of the heading being referenced in 
162  parentheses and italics (e.g., (see Data)).   
163   
164  D.  Omitted Information 
165   
166  In some circumstances applicants must omit certain subsections or specific information 
167  otherwise required under the PLLR because it is clearly inapplicable or misleading.13  For 
168  example, if a drug is indicated for use only in neonates, an applicant must omit subsections 
169  Pregnancy and Lactation because this information is clearly inapplicable.  The applicant should 
170  provide to the Agency the rationale and justification for any proposed PLLR labeling omissions 
171  of subsections, headings, subheadings, or specific information required under the PLLR.  
172   
173   
174  IV.  SPECIFIC SUBSECTIONS 
175   
176  A.  8.1 Pregnancy 
177   
178  Information in the Pregnancy subsection of labeling is presented under the following headings, 
179  in the following order: 
180   
181    Pregnancy Exposure Registry  
182    Risk Summary  
183    Clinical Considerations  
184    Data  
185   
                                                 
12 For information on how to determine when information related to a PLLR subsection warrants inclusion in the 
major safety sections of labeling, see the guidance for industry Warnings and Precautions, Contraindications, and 
Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products  Content and Format 
(October 2011). 
 
13 Under 21 CFR 201.56(a)(2), labeling must be informative and accurate and neither promotional in tone nor false 
or misleading in any particular. Under 21 CFR 201.56(d)(4), any section, subsection, or specific information that 
is clearly inapplicable must be omitted from labeling. For additional information on omitting information in 
labeling, see the guidance for industry Labeling for Human Prescription Drug and Biological Products  
Implementing the PLR Content and Format Requirements. 
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
186  1.  Pregnancy Exposure Registry 
187   
188  The purpose of including information about a pregnancy exposure registry in the Pregnancy 
189  subsection is to inform health care providers of the availability of scientifically acceptable 
190  pregnancy registries that are consistent with FDA guidance.14, 15  FDA believes that including 
191  information about pregnancy exposure registries in prescription drug labeling will encourage 
192  discussions about and participation in registries, thereby improving their usefulness.   
193   
194  If there is a scientifically acceptable pregnancy exposure registry for the drug, the following 
195  statement must appear under the heading Pregnancy Exposure Registry:16  
196   
197  There is a pregnancy exposure registry that monitors pregnancy outcomes in women 
198  exposed to (name of drug) during pregnancy.   
199   
200  Contact information (e.g., a toll-free telephone number, website) for how to enroll in the registry 
201  or obtain information on the registry must also be included under this heading after the required 
202  statement.17  The information under this heading should also reference scientifically acceptable 
203  multidrug pregnancy exposure registries, if applicable.  A multidrug pregnancy exposure registry 
204  actively collects information on exposure to various drug therapies in specific diseases, such as 
205  human immunodeficiency virus, epilepsy, or asthma. 
206   
207  Applicants may also consider including the contact information for other pregnancy safety 
208  studies that are enrolling patients. 
209   
210  The labeling should also note in the PATIENT COUNSELING INFORMATION section the 
211  availability of a pregnancy exposure registry and include a cross-reference to the Pregnancy 
212  subsection for the contact information for how to enroll.18 
213   
214  When a registry is closed or there are changes to the contact information of an existing registry, 
215  the labeling must be updated.19  When there is no active, scientifically acceptable pregnancy 
216  exposure registry, the Pregnancy Exposure Registry heading should be omitted. 
217   
                                                 
14 Only registries that are actively enrolling patients should be included in the labeling. 
 
15 See the draft guidance for industry Postapproval Pregnancy Safety Studies (May 2019).  When final, this 
guidance will represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check 
the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
16 21 CFR 201.57(c)(9)(i)(A). 
 
17 Ibid.  
 
18 See the guidance for industry Patient Counseling Information Section of Labeling for Human Prescription Drug 
and Biological Products  Content and Format (December 2014). 
 
19 Labeling must be updated when new information becomes available that causes labeling to become inaccurate, 
false, or misleading (21 CFR  201.56(a)(2)); see also 21 CFR  314.70 and 601.12.   
 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
218  2.  Risk Summary 
219   
220  The Risk Summary heading is required under the Pregnancy subsection because certain 
221  statements must be included even when no data are available.20  The labeling under the Risk 
222  Summary heading provides risk statement(s) that describe, for the drug, the risk of adverse 
223  developmental outcomes based on all relevant human data, animal data, and/or the drugs 
224  pharmacology.21  Because some drugs are metabolized to toxic forms, data on any form of the 
225  drug (e.g., drug, prodrug active metabolite) can be applicable in terms of developmental toxicity 
226  risk.22 
227   
228  Adverse developmental outcomes include the following four groups of developmental 
229  toxicities:23   
230   
231    Structural abnormalities describes dysmorphology, which includes malformations, 
232  variations, deformations, and disruptions 
233   
234    Embryo-fetal and/or infant mortality describes developmental mortality, which 
235  includes miscarriage, stillbirth, and infant death (including neonatal death) 
236   
237    Functional impairment describes functional toxicity, which includes such outcomes as 
238  deafness, endocrinopathy, neurodevelopmental effects, and impairment of reproduction 
239   
240    Alterations to growth describes such outcomes as growth restriction, excessive growth, 
241  and delayed and early maturations  
242   
243  The labeling under the Risk Summary heading is an integrated summary, taking into account 
244  relevant information to inform decision-making, and not an individualized listing of available 
245  information.  When multiple data sources are available, risk statements must be presented in the 
246  following order:  human, animal, and pharmacologic.24  In some cases, multiple risk statements 
247  may be needed to address the risks for various outcomes.  If there is more than one risk based on 
248  human data, the information should be placed in the order of clinical importance.  The risk 
249  statement(s) based on animal data may differ from the risk statement(s) based on human data.  
250   
                                                 
20  21 CFR 201.57(c)(9)(i)(B). 
 
21 Ibid. 
 
22 See the guidance for industry Safety Testing of Drug Metabolites (November 2016). 
 
23 See the guidance for industry Reproductive and Developmental Toxicities  Integrating Study Results to Assess 
Concerns (September 2011). 
 
24 21 CFR 201.57(c)(9)(i)(B). 
 
 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
251  When applicable, risk statements must include a cross-reference to additional details in the 
252  relevant labeling under the Data heading within the Pregnancy subsection.25  
253   
254  When use of a drug is contraindicated during pregnancy, this information must be stated first 
255  under the Risk Summary heading.26  A brief description of the observed or anticipated 
256  consequences of the contraindicated use should also be included.  
257   
258  If a drug is systemically absorbed, the labeling under the Risk Summary heading must include 
259  information about the background risk of major birth defects and miscarriage in the U.S. general 
260  population, regardless of drug exposure.27  Because there is no single comprehensive birth defect 
261  surveillance program in the United States, various population-based data sources have been used 
262  to estimate the overall prevalence of major birth defects, including the Metropolitan Atlanta 
263  Congenital Defects Program28 and the Texas Birth Defects Registry.29  These programs vary in 
264  methods of ascertainment and goals and objectives.  Additional factors that may affect the birth 
265  defect rate include maternal age, race/ethnicity, and gestational age.  The Centers for Disease 
266  Control and Prevention (CDC) reports a major birth defect rate of approximately 3 percent30 
267  based on pooled data from state-based programs across the United States.  These data serve to 
268  estimate national rates, indicate regional variations, and describe the epidemiology of specific 
269  birth defects.  Because various factors may affect the overall major birth defect rate, FDA 
270  believes a range of 2 to 4 percent is a reasonable representation of the background major birth 
271  defect rate.  Miscarriage rates are also affected by factors such as age and have been reported to 
272  occur in 15 to 20 percent of clinically recognized pregnancies.31  If information on birth defects 
273  and miscarriage is available for the approved patient population(s) for the drug, that information 
274  also must be included.32  These numbers can change over time.  Applicants should periodically 
275  review the birth defects and miscarriage data to ensure that the information in the labeling is 
276  accurate.33  
277   
                                                 
25 Ibid. 
 
26 Ibid. 
 
27 21 CFR 201.57(c)(9)(i)(B). 
 
28 Rynn L, Cragan J, and Correa A, 2008, Update on Overall Prevalence of Major Birth Defects  Atlanta, Georgia, 
19782005, MMWR Morb Mortal Wkly Rep, 57(01):15.   
 
29 See the Texas Birth Defects Epidemiology and Surveillance web page available at 
https://www.dshs.texas.gov/birthdefects/. 
 
30 See the CDCs Birth Defects web page available at https://www.cdc.gov/ncbddd/birthdefects/data.html.  
 
31 See American College of Obstetricians and Gynecologists, 2018, Practice Bulletin Number 200:  Early Pregnancy 
Loss, 132(5): e197-207. 
 
32 21 CFR 201.57(c)(9)(i)(B). 
 
33 21 CFR 201.56(a)(2). 
 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
278  If data demonstrate that a drug is not systemically absorbed following a particular route of 
279  administration, the labeling under the Risk Summary heading must contain only the following 
280  statement:34 
281   
282  (Name of drug) is not absorbed systemically following (route of administration), and 
283  maternal use is not expected to result in fetal exposure to the drug. 
284   
285  For situations in which the drug is not absorbed systemically following one approved route of 
286  administration, but the drug is absorbed systemically following another route (or other routes) of 
287  administration, the above statement should be included for the route of administration resulting 
288  in no systemic exposure.  This would be in addition to any statements that are required under the 
289  Risk Summary heading based on data demonstrating that the drug is absorbed systemically 
290  following another route (or other routes) of administration. 
291   
292  The following discussion describes the requirements for the risk statements. 
293    
294  a.  Risk statement based on human data 
295   
296  Determining whether pregnancy exposure data establish a drug-associated risk is a complex 
297  process that requires an assessment of the quality and quantity of available data.35  Human data 
298  can come from any of the following sources:  
299   
300    Clinical trials 
301    Pregnancy exposure registries 
302    Other large-scale epidemiologic studies 
303   
304  A well-documented case series may also support a statement about fetal risk in particular 
305  situations, such as detection of a structural abnormality that is rare in the general population but 
306  occurs with relatively high frequency among exposed fetuses and infants. 
307   
308  When human data are available that establish the presence or absence of any adverse 
309  developmental outcome(s) associated with maternal use of the drug, a risk statement based on 
310  human data must summarize the specific developmental outcome(s) and must include the 
311  following information about the outcome(s):36  
312   
313    Its incidence37 
314    The effect of dose 
315    The effect of duration of exposure 
316    The effect of gestational timing of exposure  
                                                 
34 21 CFR 201.57(c)(9)(i)(B). 
 
35 See the reviewer guidance Evaluating the Risks of Drug Exposure in Human Pregnancies (April 2005). 
 
36 21 CFR 201.57(c)(9)(i)(B)(1). 
 
37 The FDA recognizes that some researchers use the term prevalence to reflect estimate of birth defect risk. 
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
317   
318  If human data indicate that there is an increased risk for a specific adverse developmental 
319  outcome in infants born to women exposed to the drug during pregnancy, this risk must be 
320  quantitatively compared to the risk for the same outcome in infants born to women who were not 
321  exposed to the drug, but who have the disease or condition for which the drug is indicated to be 
322  used.  When risk information is not available for women with these condition(s), the risk for the 
323  specific outcome in women exposed to the drug during pregnancy must be compared to the rate 
324  at which the outcome occurs in the general population.38  
325   
326  When there are no human data or the available human data do not establish the presence or 
327  absence of drug-associated risk, this must be stated under the Risk Summary heading.39 
328   
329  For vaccines,40 the applicant should consider any risk to the fetus caused by the vaccines active 
330  ingredient(s).  For example, for live attenuated viral vaccines it may not be known whether the 
331  attenuated vaccine virus causes fetal harm when administered to a pregnant woman.  However, if 
332  the naturally occurring viral infection in a pregnant woman can cause fetal harm, a live 
333  attenuated viral vaccine against that infection may be contraindicated for use during pregnancy.   
334   
335  b.  Risk statement based on animal data 
336   
337  When animal data are available, the risk statement based on such data must describe the potential 
338  risk for adverse developmental outcomes in humans and summarize the available data.41  This 
339  statement must include the following:42  
340   
341    The number and type(s) of species affected 
342    Timing of exposure  
343    Animal doses expressed in terms of human dose or exposure equivalents 
344    Outcomes for pregnant animals and offspring  
345   
                                                 
38 Ibid. 
 
39 Ibid. 
 
40 In this guidance, the term vaccine refers to vaccines for infectious disease indications. 
 
41 21 CFR 201.57(c)(9)(i)(B)(2). 
 
42 Ibid. 
 
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346  The risk statement must state when animal studies do not meet current standards for nonclinical 
347  developmental toxicity studies or when there are no animal data.43,44   
348   
349  Toxic drug exposure may be manifested as one type of developmental effect (e.g., 
350  embryolethality) in an animal species but a different type of developmental effect (e.g., structural 
351  abnormality) in humans.  Therefore, FDA does not believe it is possible to conclude that a drug 
352  causes an increased risk of a particular type of developmental effect based on animal data alone.  
353  There are multiple considerations when determining potential human risks from animal data, 
354  including whether an adverse developmental outcome occurs in more than one animal species, 
355  especially if the outcome is consistent across species or occurs in the absence of maternal 
356  toxicity.45 
357   
358  c.  Risk statement based on pharmacology 
359   
360  When the drug has a well-understood mechanism of action that may result in adverse 
361  developmental outcomes, the risk statement must explain the mechanism of action and the 
362  potential associated risks.46  Examples of well-characterized biochemical and physiologic 
363  mechanisms of action include cytotoxic drugs and drugs that inhibit normal sex hormone 
364  production.  For other drugs, the concern may be based on biologic plausibility or human 
365  experience (e.g., drugs that interfere with DNA replication, induce cell death, or alter 
366  transmission in major neurotransmitter systems).  If applicable, a cross-reference should be 
367  provided to the applicable subsection(s) of the CLINICAL PHARMACOLOGY section, where 
368  the pharmacologic data are more fully described.  
369   
370  3.  Clinical Considerations 
371   
372  The labeling under the Clinical Considerations heading47 provides information to further inform 
373  health care providers for prescribing and risk-benefit counseling.  Relevant information under the 
                                                 
43 For a description of current standards for nonclinical developmental toxicity studies, see the ICH guidances for 
industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization 
for Pharmaceuticals (January 2010), S5A Detection of Toxicity to Reproduction for Medicinal Products (September 
1994), and S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (May 2012).  See also 
the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
44 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
45 See the guidance for industry Reproductive and Developmental Toxicities  Integrating Study Results to Assess 
Concerns.  For vaccines, see the guidance for industry Considerations for Developmental Toxicity Studies for 
Preventive and Therapeutic Vaccines for Infectious Disease Indications (February 2006). 
 
46 21 CFR 201.57(c)(9)(i)(B)(3). 
 
47 21 CFR 201.57(c)(9)(i)(C). 
 
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374  Clinical Considerations heading is presented under the following five subheadings, to the extent 
375  information is available: 
376   
377    Disease-Associated Maternal and/or Embryo/Fetal Risk 
378    Dose Adjustments During Pregnancy and the Postpartum Period 
379    Maternal Adverse Reactions 
380    Fetal/Neonatal Adverse Reactions 
381    Labor or Delivery 
382   
383  Subheadings should be omitted if there are no data/information to inform them or the available 
384  data/information are not relevant.  The Clinical Considerations heading should be omitted in its 
385  entirety if all of the subheadings are omitted. 
386   
387  a.  Disease-Associated Maternal and/or Embryo/Fetal Risk 
388   
389  The labeling under the Disease-Associated Maternal and/or Embryo/Fetal Risk subheading must 
390  describe any serious known or potential risk to the pregnant woman and/or the embryo/fetus 
391  associated with the disease or condition for which the drug is indicated.48  This description is 
392  included to provide information on any serious risks of the untreated disease/condition in 
393  pregnancy, so that health care providers and patients may make informed decisions about 
394  treatment.   
395   
396  An example of a disease with serious risks to the pregnant woman and fetus is diabetes mellitus.  
397  Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic 
398  ketoacidosis, preeclampsia, and delivery complications caused by fetal macrosomia (e.g., 
399  perineal injury and lacerations, need for cesarean section, postpartum hemorrhage).  Poorly 
400  controlled diabetes mellitus increases the fetal risk for neural tube defects, cardiovascular 
401  malformations, oral clefts, stillbirth, macrosomia-related morbidity (e.g., brachial plexus injury, 
402  hypoxia), and neonatal hypoglycemia.   
403   
404  b.  Dose Adjustments During Pregnancy and the Postpartum Period 
405  Physiological changes associated with pregnancy may result in pharmacokinetic or other changes 
406  significant enough to warrant maternal dosage adjustments.  If pharmacokinetic data support 
407  dosage adjustment(s) during pregnancy and/or the postpartum period, the labeling must provide a 
408  summary of this information under the Dose Adjustments During Pregnancy and the Postpartum 
409  Period subheading49 and should include appropriate cross-references to the specific dosage 
410  adjustments recommended in the DOSAGE AND ADMINISTRATION section50 and to the 
                                                 
48 21 CFR 201.57(c)(9)(i)(C)(1). 
 
49 21 CFR 201.57(c)(9)(i)(C)(2). 
 
50 See the guidance for industry Dosage and Administration Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format (March 2010). 
 
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411  pharmacokinetic study data in the Pharmacokinetics subsection of the CLINICAL 
412  PHARMACOLOGY section.51   
413   
414  c.  Maternal Adverse Reactions 
415   
416  The labeling under the Maternal Adverse Reactions subheading must provide a summary of 
417  drug-associated adverse reactions that are unique to pregnancy or occur with increased frequency 
418  or severity in pregnant women,52 and should include appropriate cross-references to other 
419  sections of labeling (e.g., WARNINGS AND PRECAUTIONS,53 ADVERSE REACTIONS54) 
420  for additional information.  If clinical interventions are available to help monitor or mitigate 
421  drug-associated maternal adverse reactions, these interventions must be described under this 
422  subheading of labeling55 (e.g., monitoring blood glucose for a drug that causes hyperglycemia in 
423  pregnancy).  If known, the effect of dose, timing, and duration of exposure on the maternal risk 
424  of these adverse reaction(s) must be included.56   
425   
426  d.  Fetal/Neonatal Adverse Reactions 
427   
428  The labeling under the Fetal/Neonatal Adverse Reactions subheading describes fetal/neonatal 
429  adverse reactions that are not adverse developmental outcomes and that are not described under 
430  the Risk Summary heading.  If it is known or anticipated that maternal drug therapy increases or 
431  may increase the risk of an adverse reaction in the fetus or neonate (e.g., based on the drugs 
432  pharmacologic activity or placental transfer data), the labeling must describe the adverse 
433  reaction.57  The labeling must also describe the potential severity and reversibility of the adverse 
434  reaction and available intervention(s) for monitoring or mitigating the reaction in the fetus or 
435  neonate.58  If known, the effect of dose, timing, and duration of exposure on the risk must be 
436  included.59   
437   
                                                 
51 See the guidance for industry Clinical Pharmacology Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format (December 2016). 
 
52 21 CFR 201.57(c)(9)(i)(C)(3). 
 
53 See the guidance for industry Warnings and Precautions, Contraindications, and Boxed Warning Sections of 
Labeling for Human Prescription Drug and Biological Products  Content and Format. 
 
54 See the guidance for industry Adverse Reactions Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format (January 2006). 
 
55 21 CFR 201.57(c)(9)(i)(C)(3). 
 
56 Ibid. 
 
57 21 CFR 201.57(c)(9)(i)(C)(4). 
 
58 Ibid. 
 
59 Ibid. 
 
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438  For example, opioid analgesics administered during labor may cause reversible respiratory 
439  depression in the neonate.  Under the Fetal/Neonatal Adverse Reactions subheading, the opioid 
440  product labeling should describe this reaction and the appropriate intervention(s). 
441   
442  e.  Labor or Delivery 
443   
444  If the drug is expected to affect labor or delivery, the labeling under the Labor or Delivery 
445  subheading must provide available information about the drugs effects on the mother and the 
446  fetus or neonate, and on the duration of labor and delivery.60  The labeling under this subheading 
447  must describe any increased risk of adverse reactions, including their potential severity and 
448  reversibility, and available intervention(s) that can mitigate these effects and/or adverse 
449  reactions.61   
450   
451  For drugs approved for use only during labor and delivery, this subheading (and the information 
452  required under this subheading) may be omitted.62 
453   
454  4.  Data 
455   
456  Under the Data heading in the Pregnancy subsection, labeling must describe the data that 
457  provide the scientific basis for the information presented under the Risk Summary and Clinical 
458  Considerations headings.  The Data heading is required, as are the subheadings Human Data and 
459  Animal Data, to the extent information is available.  Human data and animal data must be 
460  presented separately, and human data must be presented first.63 
461   
462  a.  Human Data 
463   
464  The labeling under the Human Data subheading must describe the data regarding adverse 
465  developmental outcomes, adverse reactions, and other adverse effects.64  Both positive and 
466  negative study findings must be included.65  Applicants should evaluate the quality and quantity 
467  of data available with respect to inclusion in labeling.66, 67    
468   
                                                 
60 21 CFR 201.57(c)(9)(i)(C)(5). 
 
61 Ibid. 
 
62 Ibid. 
 
63 21 CFR 201.57(c)(9)(i)(D)(2). 
 
64 21 CFR 201.57(c)(9)(i)(D)(3). 
 
65 Ibid. 
 
66 See the reviewer guidance Evaluating the Risks of Drug Exposure in Human Pregnancies. 
 
67 21 CFR 201.56(a)(2). 
 
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469  To the extent applicable, the labeling under the Human Data subheading must include the 
470  following elements:68 
471   
472    Types of studies or reports (e.g., clinical trials, ongoing or completed pregnancy exposure 
473  registries, other epidemiological or surveillance studies, case series) 
474   
475    Number of subjects 
476   
477    Study duration 
478   
479    Exposure information (e.g., timing, duration, and dose of exposure) 
480   
481    Limitations of the data, including potential confounders and biases 
482   
483  Quantitative data from the comparator or control groups should be provided, as appropriate.   
484   
485  Individual case reports are rarely sufficient to characterize risk and therefore ordinarily should 
486  not be included in this subsection.69  
487   
488  b.  Animal Data 
489   
490  The labeling under the Animal Data subheading describes the nonclinical developmental toxicity 
491  studies that form the scientific basis for risk statement(s) under the Risk Summary heading that 
492  are based on animal data.  This subheading must describe the following:70   
493   
494    Types of studies 
495   
496    Animal species 
497   
498    Dose, duration, and timing of exposure 
499   
500    Study findings 
501   
502    Presence or absence of maternal toxicity 
503   
504    Limitations of the data 
505   
                                                 
68 21 CFR 201.57(c)(9)(i)(D)(3). 
 
69 See the guidance for industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment 
(March 2005). 
 
70 21 CFR 201.57(c)(9)(i)(D)(4). 
 
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506  Descriptions of maternal and offspring findings must include dose response and severity of 
507  adverse developmental outcomes.71  However, for certain drug products (e.g., vaccines), 
508  developmental toxicity studies do not include dose-response evaluations, and therefore, the 
509  descriptions of maternal and offspring outcomes will be different for such drug products.  In 
510  addition, animal doses or exposures must be described in terms of human dose or exposure 
511  equivalents and the basis for those calculations must be included.72 
512   
513  In evaluating and interpreting nonclinical data, various factors (e.g., presence or absence of 
514  maternal toxicity, relative animal-to-human exposure, multiplicity of effects, positive signals in 
515  other drugs in class, with the same mechanism of action) may affect the level of concern raised 
516  by a positive signal.73  The presence or absence of these factors can increase or decrease concern, 
517  and some factors can carry greater weight than others. 
518   
519  B.  8.2 Lactation 
520   
521  Information in the Lactation subsection of labeling, which replaces the Nursing Mothers 
522  subsection, is presented under the following headings: 
523   
524    Risk Summary 
525    Clinical Considerations 
526    Data 
527   
528  The PLLR uses the term lactation to refer to the biological state during which a womans body 
529  produces and excretes milk.  The PLLR uses the term breastfeeding to refer to all human milk 
530  feeding situations when an infant or child is fed with human milk whether the milk is received 
531  directly from the breast or as expressed milk. 
532   
533  1.  Risk Summary 
534   
535  The Risk Summary heading is required because certain statements are required to be included 
536  even when there are no data or information available.74  The labeling under the Risk Summary 
537  heading should summarize information on the presence of a drug and/or its active metabolite(s) 
538  in human milk, the effects of a drug and/or its active metabolite(s) on the breastfed child, and the 
539  effects of a drug and/or its active metabolite(s) on milk production.75  When relevant human 
540  and/or animal lactation data are available, the labeling under the Risk Summary heading must 
541  include a cross-reference to the Data heading within the Lactation subsection where the details of 
                                                 
71 Ibid. 
 
72 Ibid. 
 
73 For specific guidance on interpreting nonclinical developmental toxicity data, see the guidance for industry 
Reproductive and Developmental Toxicities  Integrating Study Results to Assess Concerns. 
 
74 21 CFR 201.57(c)(9)(ii)(A). 
 
75 21 CFR 201.57(c)(9)(ii)(A)(2)(i)(iii). 
 
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542  the data are presented.76  When human data are available, animal data must not be included 
543  unless the animal model is specifically known to be predictive for humans.77   
544   
545  When use of a drug is contraindicated during breastfeeding, this information must be stated first 
546  under the Risk Summary heading.78  This information should be followed by a brief description 
547  of the observed or anticipated consequences of the contraindicated use.   
548   
549  If data demonstrate that a drug is not systemically absorbed by the mother, the labeling under the 
550  Risk Summary heading must contain only the following statement:79 
551   
552  (Name of drug) is not absorbed systemically by the mother following (route of 
553  administration), and breastfeeding is not expected to result in exposure of the child to 
554  (name of drug).   
555   
556  For situations in which the drug is not absorbed systemically by the mother following one route 
557  of administration, but the drug is absorbed systemically by the mother following another route 
558  (or other routes) of administration, the above statement should be included for the route of 
559  administration resulting in no systemic exposure to the mother.  This would be in addition to any 
560  statements that are required under the Risk Summary heading based on data demonstrating that 
561  the drug is absorbed systemically following another route (or other routes) of administration.   
562   
563  The following discussion describes the requirements for the labeling under the Risk Summary 
564  heading if the drug is absorbed systemically by the mother.  
565   
566  a.  Presence of drug in human milk80 
567   
568  The labeling under the Risk Summary heading must state whether the drug and/or its active 
569  metabolite(s) are present in human milk.81  If there are no data to assess the presence or absence 
570  of a drug and/or its active metabolite(s) in human milk, the labeling under the Risk Summary 
571  heading must state this.82   
572   
                                                 
76  21 CFR 201.57(c)(9)(ii)(A). 
 
77 Ibid. 
 
78 Ibid. 
 
79 21 CFR 201.57(c)(9)(ii)(A)(1). 
 
80 The information on the drug and/or its active metabolite(s) in human milk should include the pharmacologically 
and/or toxicologically important forms of the drug (i.e., drug, prodrug, and metabolite(s) when relevant). 
 
81 21 CFR 201.57(c)(9)(ii)(A)(2)(i). 
 
82 Ibid. 
 
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573  If studies demonstrate that the drug and/or its active metabolite(s) are not detectable in human 
574  milk, the labeling under the Risk Summary heading must state the detection limits of the study 
575  assay(s).83 
576   
577  If studies demonstrate the presence of a drug and/or its active metabolite(s) in human milk, the 
578  labeling under the Risk Summary heading must include the concentrations in human milk and 
579  the actual or estimated infant daily dose.84  The actual or estimated infant daily dose must be 
580  calculated for an infant fed exclusively with human milk and compared to the labeled infant or 
581  pediatric dose (if available) or the labeled maternal dose.85  This comparison is especially 
582  important when there are safety concerns and the actual or estimated infant daily dose received 
583  through breastfeeding approaches the labeled infant or pediatric dose, or when there are concerns 
584  about the ability of a neonate or infant to adequately metabolize or eliminate the drug and/or its 
585  active metabolite(s) because of immature and developing drug metabolism and elimination 
586  pathways.  
587   
588  The labeled actual or estimated daily dose is based on an exclusively breastfed infants intake 
589  because it represents the highest potential exposure to the drug through breastfeeding.  The 
590  actual amount of the drug to which a breastfeeding child is exposed will vary based on a childs 
591  intake of other food (including infant formula).  
592   
593  If studies demonstrate the presence of a drug and/or its active metabolite(s) in human milk, but 
594  the drug and/or its active metabolite(s) are not expected to be systemically bioavailable to the 
595  breastfed child (e.g., drug is degraded in the childs gastrointestinal tract or not absorbed), the 
596  labeling under the Risk Summary heading must describe the disposition of the drug and/or its 
597  active metabolite(s).86 
598   
599  Lactation data may come from a clinical lactation study or studies or from other sources (e.g., 
600  published literature, lactation databases).  FDA recognizes that the number of women in a 
601  lactation study is usually small.  Given population variability in maternal drug exposure and 
602  resulting human milk drug concentrations, it is important to convey the range of human milk 
603  concentrations and actual or estimated infant daily drug dose that is reflected in the data.87  
604   
605  If only animal lactation data are available, the labeling under the Risk Summary heading must 
606  state only whether or not the drug and/or its active metabolite(s) were detected in animal milk 
                                                 
83 Ibid. 
 
84 Ibid. 
 
85 Ibid. 
 
86 Ibid. 
 
87 See the draft guidance for industry Clinical Lactation Studies  Study Design, Data Analysis, and 
Recommendations for Labeling (February 2005).  When final, this guidance will represent the FDAs current 
thinking on this topic.   
 
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607  and specify the animal species,88 with a cross-reference to the Data heading within the Lactation 
608  subsection.89  Drug levels from animal lactation data do not reliably predict levels in human 
609  milk; however, animal lactation data can be helpful in predicting whether a drug and/or its active 
610  metabolite(s) will be present in human milk.90  
611   
612  b.  Effects of drug on the breastfed child 
613   
614  The labeling under the Risk Summary heading must include available information on the 
615  likelihood and seriousness of known or predicted effects on the breastfed child from exposure to 
616  a drug and/or its active metabolite(s) through human milk and/or from contact with maternal 
617  (breast/nipple) skin (for topical products).91  Although drugs that are applied topically to the 
618  breast/nipple area may not result in maternal systemic absorption and excretion into human milk, 
619  a breastfed child may orally absorb drug from contact with maternal skin.  The labeling under the 
620  Risk Summary heading must include information on any systemic and/or local (e.g., 
621  gastrointestinal tract) adverse reactions.92  A summary of relevant pediatric data on absorption, 
622  distribution, and elimination (metabolism and excretion) that could affect safety in the breastfed 
623  child should also be included when available.   
624   
625  If there are no data to assess the effects of the drug and/or its active metabolite(s) on the 
626  breastfed child, the labeling under the Risk Summary heading must so state.93 
627   
628  c.  Effects of drug on milk production 
629   
630  The labeling under the Risk Summary heading must describe the effects of a drug and/or its 
631  active metabolite(s) on human milk production, if such data are available.94  The description can 
632  be based on data regarding the pharmacological action of a drug and/or its active metabolite(s) or 
633  on clinically relevant data.  The description should specify whether the effect is temporary or 
634  permanent.  If no data are available to assess the effects of a drug and/or its active metabolite(s) 
635  on milk production, the labeling under the Risk Summary heading must state this.95 
                                                 
88 21 CFR 201.57(c)(9)(ii)(A)(2)(i). 
 
89 21 CFR 201.57(c)(9)(ii)(A) and (C). 
 
90 Wang J, Johnson T, Sahin L, Tassinari MS, Anderson PO, Baker TE, Bucci-Rechtweg C, Burckart GJ, Chambers 
CD, Hale TW, Johnson-Lyles D, Nelson RM, Nguyen C, Pica-Branco D, Ren Z, Sachs H, Sauberan J, Zajicek A, Ito 
S, Yao LP, 2017, Evaluation of the Safety of Drugs and Biological Products Used During Lactation:  Workshop 
Summary, Clin Pharmacol Ther, 101(6):736744. 
 
91 21 CFR 201.57(c)(9)(ii)(A)(2)(ii). 
 
92 Ibid. 
 
93 Ibid. 
 
94 21 CFR 201.57(c)(9)(ii)(A)(2)(iii). 
 
95 Ibid. 
 
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636   
637  d.  Risk and benefit statement 
638   
639  For drugs absorbed systemically by the mother, unless breastfeeding is contraindicated during 
640  drug therapy, the labeling under the Risk Summary heading must include the following risk and 
641  benefit statement at the end of the labeling under the Risk Summary heading:96   
642   
643  The developmental and health benefits of breastfeeding should be considered along with the 
644  mothers clinical need for (name of drug) and any potential adverse effects on the breastfed 
645  child from (name of drug) or from the underlying maternal condition. 
646   
647  The risk and benefit statement provides a basic framework for health care providers and lactating 
648  women to use when considering the mothers need for treatment; the benefits of breastfeeding to 
649  the mother and to the child; and the potential risks to the child from exposure to a drug and/or its 
650  active metabolite(s) through human milk and/or contact with maternal skin during breastfeeding.   
651   
652  When the drug is not contraindicated for use in women who are breastfeeding, but breastfeeding 
653  is not recommended during drug use because of the potential risk to the breastfed child (e.g., 
654  cytotoxic drugs), the labeling should include a statement describing the reason(s) to avoid 
655  breastfeeding.  Additionally, as noted above, in some circumstances applicants must omit certain 
656  subsections or specific information otherwise required under the PLLR because it is 
657  misleading;97 if breastfeeding is not recommended (e.g., cytotoxic drugs), the risk and benefit 
658  statement must be omitted if including such a statement would be misleading.98 
659   
660  2.  Clinical Considerations 
661   
662  The labeling under the Clinical Considerations heading must contain the information described 
663  below to the extent that the information is available and relevant.99  If no data exist to inform this 
664  heading, the heading should be omitted. 
665   
666  a.  Minimizing exposure 
667   
668  Lactation information in labeling must describe ways to minimize exposure of the breastfed child 
669  through human milk if the drug and/or its active metabolite(s) (1) are present in human milk in 
670  clinically relevant concentrations; (2) do not have an established safety profile in infants; and (3) 
671  are used intermittently (e.g., acute migraine therapies), in single doses (e.g., radiopharmaceutical 
                                                 
96 21 CFR 201.57(c)(9)(ii)(A)(3). 
 
97 Under 21 CFR 201.56(a)(2), labeling must be informative and accurate and neither promotional in tone nor false 
or misleading in any particular. For additional information on omitting information in labeling, see the guidance for 
industry Labeling for Human Prescription Drug and Biological Products  Implementing the PLR Content and 
Format Requirements. 
 
98 See 21 CFR 201.56(a)(2). For more on omitted information, see section III., D., Omitted Information. 
 
99 21 CFR 201.57(c)(9)(ii)(B). 
 
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672  and imaging drugs, anesthetic drugs), or for short courses of therapy (e.g., some antibiotics).100  
673  When applicable, labeling must also describe interventions to minimize a breastfeeding childs 
674  oral intake of topical drugs applied to the breast or nipple area.101   
675   
676  The labeling should describe, when applicable, interventions that are intended to minimize 
677  exposure of the breastfed child to a drug and/or its active metabolite(s), such as timing the 
678  administration of the drug relative to feedings at the breast, pumping sessions, and/or expressing 
679  milk to discard it (pump and dump) for a specified time period.  The specified period should be 
680  determined based on available data or on a multiple of the half-life of a drug and/or its active 
681  metabolite(s).   
682   
683  A summary of data from clinical lactation studies and/or pharmacokinetic studies can be used to 
684  inform the labeling under the Clinical Considerations heading in the Lactation subsection.  A 
685  cross-reference should be provided to the Data heading within the Lactation subsection, where 
686  the available clinical lactation study data are described in detail.102  If applicable, for 
687  pharmacokinetic studies, a cross-reference can also be provided to the Pharmacokinetics 
688  subsection of the CLINICAL PHARMACOLOGY section, where available pharmacokinetic 
689  data are fully described. 
690   
691  In general, FDA does not recommend describing ways to minimize exposure of the breastfed 
692  child to drugs used chronically by lactating women because it is typically not possible to 
693  minimize exposure when the maternal drug and/or its active metabolite(s) are at steady state.   
694   
695  b.  Monitoring for adverse reactions 
696   
697  A description of available interventions for monitoring and mitigating drug adverse reactions in 
698  the breastfed child, which were described in the labeling under the Risk Summary heading, must 
699  be provided in the labeling under the Clinical Considerations subsection.103  This information is 
700  important for health care providers who are counseling lactating women taking drugs about the 
701  relative risks and benefits of breastfeeding to the mother and to the child and about how to 
702  monitor for clinically significant adverse drug reactions in the breastfed child. 
703   
704  3.  Data 
705   
706  Under the Data heading in the Lactation subsection, the labeling must describe the human and/or 
707  animal data on which the labeling under the Risk Summary and Clinical Considerations headings 
708  are based.104  When the labeling under the Risk Summary heading is based on human data, 
                                                 
100 21 CFR 201.57(c)(9)(ii)(B)(1). 
 
101 Ibid. 
 
102 21 CFR 201.57(c)(9)(ii)(C). 
 
103 21 CFR 201.57(c)(9)(ii)(B)(2). 
 
104 21 CFR 201.57(c)(9)(ii)(C). 
 
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709  animal data must not be included unless the animal model is specifically known to be predictive 
710  for humans.105  Applicants should evaluate the quality and quantity of data available with respect 
711  to what information warrants inclusion in labeling106, 107 If there are no data, the Data heading 
712  under the Lactation subsection should be omitted.  
713   
714  C.  8.3 Females and Males of Reproductive Potential 
715   
716  The PLLR established the Females and Males of Reproductive Potential subsection of labeling 
717  and requires information for these populations when (1) there are recommendations or 
718  requirements for pregnancy testing and/or contraception before, during, or after drug therapy, 
719  and/or (2) there are human and/or animal data suggesting drug-associated effects on fertility 
720  and/or pre-implantation loss effects.108  The recommendations and/or requirements for 
721  pregnancy testing and/or contraception may be based on concerns for potential or demonstrated 
722  adverse developmental outcomes associated with drug exposure during pregnancy.  Below is a 
723  further description of the appropriate format and content for the Females and Males of 
724  Reproductive Potential subsection.  Circumstances in which pregnancy testing and contraception 
725  are required fall under risk evaluation and mitigation strategies.  
726   
727  As applicable, the information required under this subsection must appear under the following 
728  headings, in the following order:109 
729   
730    Pregnancy Testing 
731    Contraception 
732    Infertility 
733   
734  A heading should be omitted if there are no recommendations or requirements for pregnancy 
735  testing and/or contraception or no clinically relevant data on a drugs effects on human fertility.  
736  The Females and Males of Reproductive Potential subsection should be omitted entirely if all of 
737  the headings are inapplicable.   
738   
                                                 
 
105 21 CFR 201.57(c)(9)(ii)(A). 
 
106 See the draft guidance for industry Clinical Lactation Studies  Study Design, Data Analysis, and 
Recommendations for Labeling.  When final, this guidance will represent the FDAs current thinking on this topic.   
 
107 21 CFR 201.56(a)(2). 
 
108 21 CFR 201.57(c)(9)(iii). 
 
109 21 CFR 201.57(c)(9)(iii). 
 
  22  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
739  1.  Pregnancy Testing 
740   
741  When FDA has determined that pregnancy testing is required110 or recommended before, during, 
742  or after drug therapy for the appropriate use of a drug with potential risk of adverse 
743  developmental outcomes, the labeling under the Pregnancy Testing heading must include this 
744  information.111  When pregnancy testing is recommended, consider including a statement that 
745  clarifies to the health care provider that the timing and frequency of pregnancy testing and the 
746  type of pregnancy test used should be individualized to the patient and is dependent on the 
747  chosen contraceptive method. 
748   
749  A statement regarding pregnancy testing should also be added to other sections of labeling, as 
750  applicable (e.g., DOSAGE AND ADMINISTRATION) if pregnancy testing is required or 
751  recommended.112   
752   
753  2.  Contraception 
754   
755  When FDA has determined that contraception is required or recommended before, during, or 
756  after drug therapy for the appropriate use of a drug with potential risk of adverse developmental 
757  outcomes, the labeling under the Contraception heading must include this information.113  This 
758  information should also be included in other sections of labeling (e.g., PATIENT 
759  COUNSELING INFORMATION).   
760   
761  If data from nonclinical studies or information based on the mechanism of action raise concerns 
762  about mutagenesis, a summary of this information and its clinical implications must appear under 
763  the Contraception heading.114  A cross-reference to the Carcinogenesis, Mutagenesis, 
764  Impairment of Fertility subsection of the NONCLINICAL TOXICOLOGY section, when 
765  pertinent for a detailed discussion of the nonclinical studies, should be included.  If data from the 
766  nonclinical studies do not raise concern with respect to mutagenesis, then that information should 
767  be described only in the Carcinogenesis, Mutagenesis, Impairment of Fertility subsection.   
768   
769  If there are pharmacokinetic studies of semen that inform contraception recommendations, a 
770  summary statement of pertinent findings and recommendations should be included under the 
                                                 
110 Section 505-1 of the Federal Food, Drug, and Cosmetic Act establishes FDAs risk evaluation and mitigation 
strategy (REMS) authority.  A REMS is a required risk management strategy that can include one or more elements 
to ensure that the benefits of a drug outweigh its risks.  If FDA determines that a REMS is necessary, the Agency 
may require one or more REMS elements, which could include elements to assure safe use (ETASU).  ETASU may 
include, among other things, a requirement that the drug be dispensed to patients with evidence or other 
documentation of safe use conditions, such as a negative pregnancy test. 
 
111 Ibid. 
 
112 See the guidance for industry Dosage and Administration Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format. 
 
113 21 CFR 201.57(c)(9)(iii). 
 
114 21 CFR 201.57(c)(9)(iii). 
  23  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
771  Contraception heading, followed by a cross-reference to the Pharmacokinetics subsection of the 
772  CLINICAL PHARMACOLOGY section for a more detailed study description.   
773   
774  In addition, there may be instances in which drug use information pertinent to females or males 
775  of reproductive potential that is not necessarily related to adverse developmental outcomes or 
776  infertility may be considered for inclusion in this subsection.  For example, if there is a 
777  demonstrated interaction between the drug and hormonal contraception, additional information 
778  about contraception should be considered for inclusion.  Information for consideration could 
779  include, for example, a summary statement concerning the interaction and any pertinent clinical 
780  recommendation to use a nonhormonal or additional method of contraception.  In such cases, the 
781  information should appear under the Contraception heading, followed by a cross-reference to the 
782  DRUG INTERACTIONS section for a more detailed description of the interaction and, if 
783  applicable, to other relevant sections of labeling.  
784   
785  3.  Infertility 
786   
787  The availability of  human data that demonstrate adverse effects of drug exposure on male or 
788  female fertility must be described under the Infertility heading.115  Determining whether 
789  available human data can establish a drug-associated risk is a complex process that requires an 
790  assessment of the quality and quantity of the data.  The Infertility heading also should include a 
791  description of what is known about the potential reversibility of the adverse effect(s).  Human 
792  studies conducted to address potential fertility concerns that do not demonstrate detrimental 
793  implications for human fertility should be summarized under the Infertility heading and cross-
794  referenced to the section of the labeling where the detailed study description is provided.   
795   
796  If data from animal studies or information based on the mechanism of action raise concerns 
797  about impairment of human fertility, including mutagenesis, and/or pre-implantation loss effects 
798  in females or males, a summary of this information and its clinical implications must appear 
799  under the Infertility heading.116  A cross-reference to the Carcinogenesis, Mutagenesis, 
800  Impairment of Fertility subsection of the NONCLINICAL TOXICOLOGY section, when 
801  pertinent for a detailed discussion of the animal studies, should be included.  If data from the 
802  animal studies do not raise concern with respect to impairment of human fertility and/or pre-
803  implantation loss effects, then that information should be described only in the Carcinogenesis, 
804  Mutagenesis, Impairment of Fertility subsection.   
805   
806   
                                                 
115 21 CFR 201.57(c)(9)(iii). 
 
116 Ibid. 
 
  24  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
807  V.  PROCEDURAL INFORMATION 
808   
809  A.  Applications Covered by the Final Rule and Implementation 
810   
811  The content and format requirements of the PLLR apply to applications that are required to 
812  comply with the PLR.117  All NDAs, BLAs, and efficacy supplements approved on or after June 
813  30, 2001, are required to have labeling approved in PLR format.118  Failure to submit labeling in 
814  PLR/PLLR format with an application may be a consideration when deciding whether to refuse 
815  to file an application. 
816   
817  The required timelines for submitting proposed labeling in the PLLR content and format are 
818  included in Table 1 in Appendix B.  The types of applications that are only required to remove 
819  the pregnancy letter category in their labeling, and the deadline for doing so, are addressed in 
820  Table 2 in Appendix B: Pregnancy and Lactation Labeling Rule (PLLR) Implementation Plan. 
821   
822  Holders of applications approved before June 30, 2001, and for which no efficacy supplements 
823  have been approved on or after June 30, 2001 (i.e., applications not subject to PLR ), were 
824  required to remove the pregnancy category from their labeling within 3 years after the effective 
825  date of the PLLR (i.e., by June 30, 2018) and to report the labeling change in their annual 
826  reports.119  Although the pregnancy letter categories were required to be removed from the 
827  labeling, the required pre-PLLR standard statements that follow each of the pregnancy letter 
828  categories must remain in the labeling.120   
829   
830  Applicants not subject to PLR but that submitted a labeling supplement to voluntarily convert to 
831  PLR before June 30, 2015 (PLLR effective date), must have removed the pregnancy letter 
832  category by June 30, 2018.  FDA encourages these applicants to submit proposed labeling to 
833  comply with the content and format of PLLR.  Applicants not subject to PLR but that have 
834  submitted an application to voluntarily convert to PLR on or after June 30, 2015 (PLLR effective 
835  date), are required to comply with all content and format requirements of PLR/ PLLR.    
836   
837  FDA encourages holders of applications whose labeling is not subject to PLR to voluntarily 
838  convert their labeling to comply with PLR/PLLR.  Although FDA recognizes the effort involved 
839  in revising labeling, FDA strongly believes that PLR/PLLR is an important advance in 
840  communicating drug information.   
841   
842  B.  Submitting Draft Labeling to FDA for Review 
843   
844  Holders of applications subject to the PLLR content and formatting requirements and applicants 
845  submitting voluntary PLR/PLLR labeling conversions are required to submit the proposed 
                                                 
117 21 CFR 201.56(b)(1) and (c). 
 
118 Ibid. 
 
119 See 21 CFR 314.70(d)(2) and 601.12(f)(3) about changes requiring submission in an annual report. 
 
120 21 CFR 201.80(f)(6)(i). 
 
  25  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
846  labeling content as a prior approval supplement.121  Applicants subject to PLR are required to 
847  convert their labeling to the new PLLR content and formatting requirements122 and should not 
848  remove the pregnancy letter categories before submitting revised labeling with the new PLLR 
849  content and format.  To facilitate FDAs review of labeling, we recommend that the following 
850  versions of labeling be submitted (in Microsoft Word file format), as appropriate: 
851   
852    Last approved labeling  
853   
854    A clean version containing the proposed changes (i.e., no redline/strikeout) 
855   
856    A marked-up version that includes proposed changes to the last approved prescribing 
857  information (e.g., changes that comply with the PLR/PLLR content and format 
858  requirements) as tracked changes 
859   
860    An annotated version of the prescribing information that includes annotations that 
861  support all proposed revisions, including annual reportable changes (Microsoft Word or 
862  Adobe PDF file format)  
863   
864  Applicants should explain significant or notable changes in wording or content, relocation of 
865  information to a different section or subsection, and how the decisions to make those changes 
866  were made.   
867   
868  The submission should include the following: 
869   
870    A review and summary of the available published literature regarding the drugs use in 
871  pregnant and lactating women and the effects of the drug on male and female fertility 
872  (include search parameters and a copy of each reference publication)  
873   
874    A cumulative review and summary of relevant cases reported in the applicants 
875  pharmacovigilance database (from the time of drug product development to present)  
876   
877    A summary of drug utilization rates among females of reproductive potential (e.g., aged 
878  15 to 44 years) calculated cumulatively since initial approval (if applicable)  
879   
880    An interim report of an ongoing pregnancy registry or a final report on a closed 
881  pregnancy registry (if applicable) or other study   
882   
883  If applicants believe the information is not applicable, they should provide justification.  
884  Otherwise, this information should be located in Module 1 of the eCTD.   
885   
                                                 
121 See 21 CFR 314.70(b)(2)(v) and 601.12(f)(1). 
 
122 79 FR 72064 at 72095-96.  
  26  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
886  To facilitate identification of the type of submission for the Agency, the applicant should mark 
887  clearly on the cover letter, Pregnancy and Lactation Labeling/PLLR Conversion and locate 
888  the labeling and review of current available evidence in Module 1. 
889   
890  C.  Waivers and Extensions 
891   
892  Applicants may request that FDA waive a labeling requirement under certain circumstances.123  
893  The Agency also may consider, on a case-by-case basis, requests for an extension of the required 
894  submission date of proposed labeling that complies with PLLR format and content.  Applicants 
895  should submit a formal waiver or extension request, with a clear rationale, to their marketing 
896  applications or supplements and clearly identify the request for a PLLR waiver or extension in 
897  the cover letter.     
898   
899  FDA anticipates that waivers, if any, from the PLLR requirements will be granted only in rare 
900  circumstances and/or for a limited duration.  In addition, FDA anticipates that extensions of the 
901  required submission date will be granted only under extenuating circumstances (e.g., completion 
902  of a pregnancy registry for which the report will be finalized within 6 months) and for a limited 
903  duration.  Consistent with this, in general, FDA does not intend to grant such extension requests 
904  in situations where a marketing of a drug product has been discontinued and an applicant is 
905  seeking an extension until such time as the applicant begins remarketing the drug product. 
                                                 
123 See 21 CFR 201.58 (providing for waivers of labeling requirements with respect to content and format of 
labeling for human prescription drug and biological products described in 21 CFR 201.56(b)(1)); see also 21 CFR 
314.90(a) (providing for waivers of the NDA requirements under 21 CFR 314.50 through 314.81). 
  27  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
906  APPENDIX A:   
907  ORGANIZATION AND FORMAT FOR PREGNANCY, LACTATION, AND FEMALES 
908  AND MALES OF REPRODUCTIVE POTENTIAL SUBSECTIONS1 
909   
910  The following information outlines the headings and subheadings (as applicable) for subsections 
911  8.1 through 8.3 of the USE IN SPECIFIC POPULATIONS section of labeling as stated in the 
912  pregnancy and lactation labeling rule (PLLR).  
913   
914  8.1  Pregnancy 
915   
916  Pregnancy Exposure Registry  
917   
918  Risk Summary  
919   
920  Clinical Considerations  
921   
922  Disease-Associated Maternal and/or Embryo/Fetal Risk  
923   
924  Dose Adjustments During Pregnancy and the Postpartum Period  
925   
926  Maternal Adverse Reactions  
927   
928  Fetal/Neonatal Adverse Reactions  
929   
930  Labor or Delivery  
931   
932  Data 
933   
934  Human Data  
935   
936  Animal Data  
937   
938  8.2  Lactation 
939   
940  Risk Summary  
941   
942  Clinical Considerations  
943   
944  Data  
945   
                                                 
1 There may be circumstances in which certain subsections, headings, subheadings, or specific information 
otherwise required under the final rule Content and Format of Labeling for Human Prescription Drug and 
Biological Products; Requirements for Pregnancy and Lactation Labeling, (pregnancy and lactation labeling rule or 
PLLR) is omitted because this information is clearly inapplicable or misleading, or informative data are not 
available.  For more on omitted information, refer to section III., D., of this guidance. 
 
  28  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
946  8.3  Females and Males of Reproductive Potential  
947   
948  Pregnancy Testing  
949   
950  Contraception  
951   
952  Infertility  
953   
  29  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
954  APPENDIX B:  PREGNANCY AND LACTATION  
955  LABELING RULE (PLLR) IMPLEMENTATION PLAN 
956   
957  The tables below describe the pregnancy and lactation labeling rule (PLLR)1 implementation 
958  plan and timelines for the types of applications required to conform to PLLR content and format 
959  requirements (see Table 1) and the types of applications only required to remove the pregnancy 
960  letter category (see Table 2). 
961   
962  Table 1:  Applicationsa Required To Conform to PLLR Content and Formatb 
963   
Time by Which Labeling With 
Applicationsa Required To Conform to  PLLR Content and Format 
Types of Applicationsa 
PLLR Content and Format  Must Be Submitted to FDA for 
Approval 
At time of submission of new 
New applications   Initially submitted on or after 6/30/2015 
application* 
Approved 6/30/2001 through 6/29/2002 
6/30/2018  
Approved 6/30/2005 through 6/29/2007 
Applications approved 
Approved 6/30/2007 through 6/30/2015  
6/30/2001 through 6/30/2015 
6/30/2019c  
or pending on 6/30/2015   Pending on 6/30/2015 
Approved 6/30/2002 through 6/29/2005  6/30/2020 
NDAs or BLAs approved 
At time of submission of 
before 6/30/2001 (with no ES  Voluntary PLRd conversion originally 
voluntary PLR conversion 
approved on or after  submitted on or after 6/30/2015  
labeling supplement 
6/30/2001) 
964 a The term applications includes 505(b)(1) and 505(b)(2) new drug applications (NDAs), 351(a) and 351(k) biologics license 
965  applications (BLAs), and efficacy supplements (ESes).  
966 b See the final rule Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for 
967  Pregnancy and Lactation Labeling, (PLLR) published December 4, 2014, for all the PLLR content and format requirements. 
968 c For NDAs, BLAs, or ESs pending on 6/30/2015, the required submission date for PLLR format and content is 6/30/2019 or at the 
969  time of approval (whichever is later). 
970 d The final rule Requirements on Content and Format of Labeling for Human Prescription Drug Biological Products (physician 
971  labeling rule (PLR)) published January 24, 2006 (21 CFR 201.56, 201.57, and 201.80) describes the scope of applications subject to 
972  the requirements (see 21 CFR 201.56(d)).  The Agency encourages applicants with applications not otherwise subject to the PLR 
973  requirements to voluntarily convert their labeling to the PLR content and format. 
974   
                                                 
1 The final rule Content and Format of Labeling for Human Prescription Drug and Biological Products; 
Requirements for Pregnancy and Lactation Labeling, (commonly known as PLLR) published December 4, 2014.  
The PLLR requirements are found in 21 CFR 201.57(c)(9). 
  30  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
975  Table 2:  Applications Required to Only Remove the Pregnancy Letter Category 
976   
Types of NDAs and 
PLRb Conversions  Recommendations  Requirement 
BLAsa 
Voluntary PLR conversion  Not required (but 
originally submitted before  encouraged) to convert to 
NDAs or BLAs  Must have 
6/30/2015c   PLLR format 
approved before  removed 
6/30/2001 (with no  pregnancy 
Labeling is in non-PLR 
ES approved on or  Not required (but  category by 
formate and no voluntary 
after 6/30/2001)   encouraged) to convert to  6/29/2018d 
PLR conversion was ever 
PLR and PLLR format 
submitted 
977  a NDA = new drug application; BLA = biologics license application; ES = efficacy supplement. 
978  b The final rule Requirements on Content and Format of Labeling for Human Prescription Drug Biological Products 
979  (physician labeling rule (PLR)) published January 24, 2006 (21 CFR 201.56, 201.57, and 201.80) describes the 
980  scope of applications subject to the requirements (see 21 CFR 201.56(d)).  The Agency encourages applicants with 
981  applications not otherwise subject to the PLR requirements to voluntarily convert their labeling to the PLR content 
982  and format. 
983  c Effective date for the PLLR. 
984  d Although the pregnancy letter categories must be removed from the labeling, the standard statements required by 21 
985  CFR 201.80(f)(6) that follow each of the pregnancy letter categories must remain in the labeling.  Applicants must 
986  include removal of the pregnancy letter categories in the annual report.  See 21 CFR 314.70(d)(2) and 601.12(f)(3) 
987  about changes requiring submission in an annual report. 
988  e See 21 CFR 201.56(e) and 201.80. 
989   
  31