50762dft.docx

7/15/2020

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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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
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
i

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
ii

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
Contains Nonbinding Recommendations

Draft — Not for Implementation

1

1 Pregnancy, Lactation, and Reproductive Potential: 

2 Labeling for Human Prescription Drug and Biological Products —

3 Content and Format

Guidance for Industry1 4

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

subsections of labeling for human prescription drug and biological products.

2 20 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 

POPULATIONS section.

3 23

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 

Labeling,” referred to as the pregnancy and lactation labeling rule (PLLR).4 27 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).
Contains Nonbinding Recommendations

Draft — Not for Implementation

2

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, FDA’s guidance documents do not establish legally enforceable responsibilities. 

52 Instead, guidances describe the Agency’s 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 

biological products.

5 69 

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.
Contains Nonbinding Recommendations

Draft — Not for Implementation

3

77

78 The PLLR revised the PLR content and format requirements for subsections 8.1 through 8.3 of 

the USE IN SPECIFIC POPULATIONS section of labeling as follows:6,7 79

80

81 8.1 Pregnancy

82

83 This subsection contains information on what is known about the drug’s 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).
Contains Nonbinding Recommendations

Draft — Not for Implementation

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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 

become inaccurate, false, or misleading.

8 121 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 

Potential subsection, applicants must continue to keep labeling up to date.9 131

132

133 B. Formatting

134

Subsection numbers and titles in the labeling must be bolded (e.g., 8.1 Pregnancy).

10 135 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

Cross-referencing follows the general principles of the PLR.11 148 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-fdaguidance-documents.
Contains Nonbinding Recommendations

Draft — Not for Implementation

5

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 

Pregnancy subsection for additional details.

12 157

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

otherwise required under the PLLR because it is clearly inapplicable or misleading.

13 167 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.
Contains Nonbinding Recommendations

Draft — Not for Implementation

6

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 

pregnancy registries that are consistent with FDA guidance.

14, 15 190 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 

statement must appear under the heading Pregnancy Exposure Registry:

16 195

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 

statement.17 202 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

subsection for the contact information for how to enroll.18 212

213

214 When a registry is closed or there are changes to the contact information of an existing registry, 

the labeling must be updated. 215 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 FDA’s 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. 
Contains Nonbinding Recommendations

Draft — Not for Implementation

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218 2. Risk Summary

219

220 The Risk Summary heading is required under the Pregnancy subsection because certain 

statements must be included even when no data are available.

20 221 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 drug’s 

pharmacology.

21 224 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 

risk.22 226

227

228 Adverse developmental outcomes include the following four groups of developmental 

toxicities:

23 229 

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 

following order: human, animal, and pharmacologic.

24 246 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).
Contains Nonbinding Recommendations

Draft — Not for Implementation

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251 When applicable, risk statements must include a cross-reference to additional details in the 

relevant labeling under the Data heading within the Pregnancy subsection.

25 252

253

254 When use of a drug is contraindicated during pregnancy, this information must be stated first 

under the Risk Summary heading.26 255 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 

population, regardless of drug exposure.

27 260 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 

Congenital Defects Program28 and the Texas Birth Defects Registry.

29 263 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 

Control and Prevention (CDC) reports a major birth defect rate of approximately 3 percent30 266

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 

occur in 15 to 20 percent of clinically recognized pregnancies.31 272 If information on birth defects 

273 and miscarriage is available for the approved patient population(s) for the drug, that information

also must be included.

32 274 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 

accurate.

33 276

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, 

1978–2005, MMWR Morb Mortal Wkly Rep, 57(01):1–5. 

29 See the Texas Birth Defects Epidemiology and Surveillance web page available at 

https://www.dshs.texas.gov/birthdefects/.

30 See the CDC’s 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).
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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 

statement:

34 280

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 

process that requires an assessment of the quality and quantity of available data.

35 297 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 

following information about the outcome(s):

36 311

312

• Its incidence37 313

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.
Contains Nonbinding Recommendations

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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 

at which the outcome occurs in the general population.

38 324

325

326 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 under the Risk Summary heading.39 327

328

For vaccines,40 329 the applicant should consider any risk to the fetus caused by the vaccine’s 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

risk for adverse developmental outcomes in humans and summarize the available data.

41 338 This 

statement must include the following:

42 339

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 

developmental toxicity studies or when there are no animal data.

43,44 347

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 

toxicity.

45 356

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 

potential associated risks.

46 362 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

The labeling under the Clinical Considerations heading47 372 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 

associated with the disease or condition for which the drug is indicated.

48 391 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 

Period subheading49 409 and should include appropriate cross-references to the specific dosage 

adjustments recommended in the DOSAGE AND ADMINISTRATION section50 410 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 

PHARMACOLOGY section.

51 412 

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 

or severity in pregnant women,

52 418 and should include appropriate cross-references to other 

sections of labeling (e.g., WARNINGS AND PRECAUTIONS,

53 ADVERSE REACTIONS54 419 )

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 

subheading of labeling55 422 (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 

of these adverse reaction(s) must be included.

56 424 

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 drug’s 

432 pharmacologic activity or placental transfer data), the labeling must describe the adverse 

reaction.

57 433 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 

neonate.

58 435 If known, the effect of dose, timing, and duration of exposure on the risk must be 

included.

59 436

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 drug’s effects on the mother and the 

fetus or neonate, and on the duration of labor and delivery.

60 446 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 

reactions.

61 449 

450

451 For drugs approved for use only during labor and delivery, this subheading (and the information 

required under this subheading) may be omitted.

62 452

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 

presented separately, and human data must be presented first.

63 460

461

462 a. Human Data

463

464 The labeling under the Human Data subheading must describe the data regarding adverse 

developmental outcomes, adverse reactions, and other adverse effects.

64 465 Both positive and 

negative study findings must be included.

65 466 Applicants should evaluate the quality and quantity 

of data available with respect to inclusion in labeling.

66, 67 467 

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).
Contains Nonbinding Recommendations

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469 To the extent applicable, the labeling under the Human Data subheading must include the 

following elements:

68 470

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 

not be included in this subsection.

69 486

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 

are based on animal data. This subheading must describe the following:

70 492 

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 

adverse developmental outcomes.

71 507 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 

equivalents and the basis for those calculations must be included.72 511

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 

by a positive signal.73 516 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 woman’s 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 

even when there are no data or information available.

74 536 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

effects of a drug and/or its active metabolite(s) on milk production.

75 539 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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17

the data are presented. 542 76 When human data are available, animal data must not be included 

unless the animal model is specifically known to be predictive for humans.

77 543 

544

545 When use of a drug is contraindicated during breastfeeding, this information must be stated first 

under the Risk Summary heading.78 546 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 

Risk Summary heading must contain only the following statement:

79 550

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

a. Presence of drug in human milk80 566

567

568 The labeling under the Risk Summary heading must state whether the drug and/or its active 

metabolite(s) are present in human milk.

81 569 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 

heading must state this.

82 571 

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 

assay(s).

83 575

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 

the actual or estimated infant daily dose.

84 579 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 

pediatric dose (if available) or the labeled maternal dose.

85 581 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 infant’s 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 child’s 

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 child’s gastrointestinal tract or not absorbed), the 

596 labeling under the Risk Summary heading must describe the disposition of the drug and/or its 

active metabolite(s).

86 597

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 

concentrations and actual or estimated infant daily drug dose that is reflected in the data.87 603

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 FDA’s current 

thinking on this topic. 
Contains Nonbinding Recommendations

Draft — Not for Implementation

19

and specify the animal species,

88 607 with a cross-reference to the Data heading within the Lactation

subsection.

89 608 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

metabolite(s) will be present in human milk.90 610

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 

(breast/nipple) skin (for topical products).

91 617 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.,

gastrointestinal tract) adverse reactions.

92 621 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 

breastfed child, the labeling under the Risk Summary heading must so state.

93 626

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 

active metabolite(s) on human milk production, if such data are available.

94 631 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) 

on milk production, the labeling under the Risk Summary heading must state this.

95 635

 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):736–744.

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 

benefit statement at the end of the labeling under the Risk Summary heading:

96 641 

642

643 “The developmental and health benefits of breastfeeding should be considered along with the 

644 mother’s 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 mother’s 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 

misleading;

97 657 if breastfeeding is not recommended (e.g., cytotoxic drugs), the risk and benefit 

statement must be omitted if including such a statement would be misleading.

98 658

659

660 2. Clinical Considerations

661

662 The labeling under the Clinical Considerations heading must contain the information described 

below to the extent that the information is available and relevant.

99 663 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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and imaging drugs, anesthetic drugs), or for short courses of therapy (e.g., some antibiotics).

100 672 

673 When applicable, labeling must also describe interventions to minimize a breastfeeding child’s 

oral intake of topical drugs applied to the breast or nipple area.101 674 

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 

the available clinical lactation study data are described in detail.

102 686 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 

be provided in the labeling under the Clinical Considerations subsection.103 699 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 

are based. 708 104 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 

for humans.

105 710 Applicants should evaluate the quality and quantity of data available with respect 

to what information warrants inclusion in labeling106, 107 711 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

and/or pre-implantation loss effects.

108 720 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 

headings, in the following order:

109 728

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 drug’s 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 FDA’s 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).
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739 1. Pregnancy Testing

740

When FDA has determined that pregnancy testing is required110 741 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 

information.

111 744 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 

recommended.

112 751 

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 

outcomes, the labeling under the Contraception heading must include this information.

113 757 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 

the Contraception heading.

114 763 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 FDA’s 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).
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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 

female fertility must be described under the Infertility heading.

115 788 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 cross794 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 

under the Infertility heading.

116 799 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 pre803 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.
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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 

comply with the PLR.

117 812 All NDAs, BLAs, and efficacy supplements approved on or after June 

30, 2001, are required to have labeling approved in PLR format.

118 813 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 

reports.

119 826 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 

categories must remain in the labeling.

120 828 

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).
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labeling content as a prior approval supplement.121 846 Applicants subject to PLR are required to 

convert their labeling to the new PLLR content and formatting requirements122 847 and should not 

848 remove the pregnancy letter categories before submitting revised labeling with the new PLLR 

849 content and format. To facilitate FDA’s 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 drug’s 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 applicant’s

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. 
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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

Applicants may request that FDA waive a labeling requirement under certain circumstances.123 892 

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).
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906 APPENDIX A: 

907 ORGANIZATION AND FORMAT FOR PREGNANCY, LACTATION, AND FEMALES 

AND MALES OF REPRODUCTIVE POTENTIAL SUBSECTIONS1 908

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.
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946 8.3 Females and Males of Reproductive Potential

947

948 Pregnancy Testing

949

950 Contraception

951

952 Infertility

953
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954 APPENDIX B: PREGNANCY AND LACTATION 

955 LABELING RULE (PLLR) IMPLEMENTATION PLAN

956

The tables below describe the pregnancy and lactation labeling rule (PLLR)1 957 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

Table 1: Applicationsa Required To Conform to PLLR Content and Formatb 962

963

Types of Applicationsa Applicationsa Required To Conform to 

PLLR Content and Format

Time by Which Labeling With 

PLLR Content and Format 

Must Be Submitted to FDA for 

Approval

New applications Initially submitted on or after 6/30/2015 At time of submission of new 

application*

Applications approved 

6/30/2001 through 6/30/2015 

or pending on 6/30/2015 

Approved 6/30/2001 through 6/29/2002

Approved 6/30/2005 through 6/29/2007 6/30/2018 

Approved 6/30/2007 through 6/30/2015 

6/30/2019c

Pending on 6/30/2015

Approved 6/30/2002 through 6/29/2005 6/30/2020

NDAs or BLAs approved 

before 6/30/2001 (with no ES

approved on or after 

6/30/2001)

Voluntary PLRd conversion originally 

submitted on or after 6/30/2015

At time of submission of 

voluntary PLR conversion 

labeling supplement

a 964 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). b 966 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. c 968 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). d 970 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).
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975 Table 2: Applications Required to Only Remove the Pregnancy Letter Category

976

Types of NDAs and 

BLAsa PLRb Conversions Recommendations Requirement

NDAs or BLAs 

approved before

6/30/2001 (with no 

ES approved on or 

after 6/30/2001) 

Voluntary PLR conversion 

originally submitted before 

6/30/2015c

Not required (but 

encouraged) to convert to 

PLLR format Must have 

removed

pregnancy 

category by 

6/29/2018d

Labeling is in non-PLR

formate and no voluntary 

PLR conversion was ever 

submitted

Not required (but 

encouraged) to convert to 

PLR and PLLR format

977 a NDA = new drug application; BLA = biologics license application; ES = efficacy supplement. b 978 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. c 983 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. e 988 See 21 CFR 201.56(e) and 201.80.

989