Guidance for Industry 

Clinical Lactation Studies – Study 

Design, Data Analysis, and 

Recommendations for Labeling 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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 comments to the Division of Dockets Management (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 (CDER) Kathleen Uhl 301-443-5157, or 

(CBER) Toni M. Stifano at 301-827-6190. 

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) 

February 2005 

Clinical Pharmacology 
Guidance for Industry 

Clinical Lactation Studies – Study 

Design, Data Analysis, and 

Recommendations for Labeling 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

http://www.fda.gov/cder/guidance/index.htm 

or 

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike 

Rockville, MD 20852-1448 

(Tel) 800-835-4709 or 301-827-1800

http://www.fda.gov/cber/guidelines.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

February 2005 

Clinical Pharmacology
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................1

II. BACKGROUND ..............................................................................................................2

III. CONSIDERATIONS FOR WHEN TO CONDUCT A CLINICAL LACTATION 

STUDY..............................................................................................................................4

IV. STUDY DESIGN CONSIDERATIONS ........................................................................5

A. Mother-Infant Pair Design.......................................................................................................... 5

B. Lactating Women Only Designs ................................................................................................. 6

1. Lactating Women (Plasma and Milk) ............................................................................................ 6

2 Lactating Women (Milk Only) ....................................................................................................... 7

C. Other Design Considerations ...................................................................................................... 7

1. Longitudinal Design ...................................................................................................................... 7

2. Multiple Arm Design...................................................................................................................... 8

3. Study Participants.......................................................................................................................... 8

4. Controls ......................................................................................................................................... 8

5. Sample Size .................................................................................................................................... 9

6. Sample Collection and Analysis..................................................................................................... 9

7. Population PK Studies................................................................................................................. 10

8. Pharmacodynamic Assessments................................................................................................... 10

V. DATA ANALYSIS .........................................................................................................11

A. Parameter Estimation................................................................................................................ 11

B. Development of Dosing Recommendations for Lactating Women........................................ 13

C. Development of Recommendations to Minimize Infant Drug Exposure from Breast Milk 14

VI. LABELING ....................................................................................................................15

A. Clinical Pharmacology............................................................................................................... 15

1. Pharmacokinetics Subsection ...................................................................................................... 15

2. Special Populations Subsection ................................................................................................... 15

B. Precautions/Nursing Mothers ................................................................................................... 16

C. Dosage and Administration....................................................................................................... 17

VII. CONSIDERATIONS FOR FUTURE RESEARCH ...................................................17

BIBLIOGRAPHY......................................................................................................................18
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Guidance for Industry1 1 

2 Clinical Lactation Studies: Study Design, Data Analysis, and 

3 Recommendations for Labeling 

4 

5 

6 

7 

8 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

9 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

10 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

11 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

12 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

13 the appropriate number listed on the title page of this guidance. 

14 

15 

16 

17 

18 I. INTRODUCTION 

19 

20 This guidance provides recommendations for how and when to conduct clinical lactation studies 

and how to assess the influence of drugs or biologic products2 21 on lactation. The goals of this 

22 guidance are to (1) provide the basic framework for designing, conducting, and analyzing 

23 clinical lactation studies and (2) stimulate further study and research to assist in rational 

24 therapeutics for lactating patients. 

25 

26 Clinical lactation studies can be designed to assess: 

27 

28 • The influence of lactation on maternal pharmacokinetics (PK), and where appropriate 

29 pharmacodynamics (PD) 

30 • The extent of drug transfer into breast milk 

31 • The effects of drugs on milk production and composition 

• The extent and consequent effects on breast-fed infants3 32 of exposure to drugs in breast 

33 milk 

34 

 

1

 This guidance has been prepared by the PK in Pregnancy Working Group of the Pregnancy Labeling Task Force, 

Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and 

Research (CBER) at the Food and Drug Administration. 

2

 Throughout this document, the term medical product or drug means drug and biological products and their 

metabolites, including vaccines. 

3

 The terms child(ren) and infant(s) are used interchangeably in this guidance to refer to human breast-feeding 

offspring of any age. 
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35 This guidance will be most helpful when used in conjunction with other pharmacological and 

36 clinical literature on the design, conduct, and interpretation of PK studies. Because studies in 

37 lactating patients and their breast-fed children require specialized knowledge in a variety of 

38 areas, the investigators preparing to design and conduct such studies are encouraged to obtain 

39 advice from experts in specific fields (e.g., pediatrics, obstetrics, pharmacology, clinical 

40 pharmacology, pharmacometrics, statistics). 

41 

42 FDA’s guidance documents, including this guidance, do not establish legally enforceable 

43 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

44 be viewed only as recommendations, unless specific regulatory or statutory requirements are 

45 cited. The use of the word should in Agency guidances means that something is suggested or 

46 recommended, but not required. 

47 

48 

49 II. BACKGROUND 

50 

51 Breast milk is widely acknowledged to be the most complete form of nutrition for infants and to 

52 include a range of health benefits for breast-feeding women and infants. Accumulated data 

53 support the benefits of breast milk for infants including growth, immunity, and development. 

54 Specific data show decreased incidence and severity of diarrhea, respiratory infections, and ear 

55 infections. Maternal benefits of breast-feeding include reduction in postpartum bleeding, earlier 

56 return to prepregnancy weight, reduced risk of premenopausal breast cancer, and reduced risk of 

57 osteoporosis (U.S. Department of Health and Human Services (DHHS) 2000). The DHHS 

58 sponsored Healthy People 2010 Initiative targets to increase the percentage of mothers who 

59 breast-feed from the current rate to 75 percent in the early postpartum period, 50 percent at 6 

60 months, and 15 percent at 1 year (DHHS Services 2000). The American Academy of Pediatrics 

61 (AAP) recommends that all new mothers who are able should breast-feed until the child reaches 

62 1 year of age. A recent survey reports that 69.5 percent of women in the United States initiate 

63 breast-feeding and 32.5 percent continue to breast-feed their infants to 6 months of age, 

64 reflecting the highest percentage in recent history of women in the United States choosing to 

65 breast-feed (Ryan 2002). The AAP considers breast-feeding to be the ideal method of feeding 

66 and nurturing infants (AAP Work Group on Breastfeeding 1997). 

67 

68 It is highly likely that a woman will need and take medications while she is breast-feeding, 

69 potentially exposing her child to the effects of these medications. Surveys in various countries 

70 indicate that 90-99 percent of nursing mothers receive a medication during the first week 

71 postpartum, 17-25 percent of nursing mothers will take medication by 4 months postpartum and 

72 5 percent of nursing mothers receive long-term drug therapy (Bennett 1988). 

73 

74 The presence of a drug in breast milk does not necessarily indicate a health risk for the breast-fed 

75 child. Detecting the presence or absence of the drug in milk is only the first step in determining 

76 risk. For most drugs, little scientific information is available about the extent of their passage 

77 into breast milk, their effects on milk production, their effects on the breast-fed infant, or 

78 whether a dose adjustment is needed to treat a lactating woman. Therefore, breast-feeding 

79 women and their health care providers must make decisions regarding treatment of maternal 
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80 medical conditions in the absence of data. In some cases, this can result in a decision to stop 

81 breast-feeding to take needed drug therapy, unnecessarily eliminating the benefits of breast82 feeding for mothers and their infants. The AAP has tried to fill the information void regarding 

83 infant safety by issuing consensus documents on the use of drugs in lactation or breast-feeding 

84 women (AAP 1989, 1994; AAP Committee on Drugs 2001), but data upon which to make these 

85 assessments is sparse. Clinical lactation studies would provide much needed additional data on 

86 which to base treatment decisions. 

87 

88 Since data on dosing lactating women are rarely available, most clinicians treat lactating women 

89 with the dose studied in and recommended for nonpregnant adults. This practice disregards the 

90 impact of the physiologic changes that occur during lactation and the effects of additional breast 

91 and milk compartments. A variety of potential differences in PK might be important in the 

92 postpartum and lactating periods, including differences caused by endogenous hormonal 

93 changes, altered body fat proportion, and changes in weight or muscle mass. 

94 

95 Most studies of drugs and breast-feeding focus on health risks for the nursing infant, not the 

96 mother. Even when studies collect drug concentrations in maternal serum and breast milk, 

97 individual PK is not often characterized, and customary PK parameters (e.g., clearance, half-life) 

98 are not reported. Some studies focus on the detection of drug in infant serum compared with 

99 maternal serum or milk at a single point in time, but they rarely include comparisons to the non100 lactating state or control groups. Most studies do not account for changes in serum protein 

101 concentrations and unbound drug in serum, as well as other physiological changes in the early 

102 postpartum period, that can affect maternal PK and contribute to variability among data from 

103 lactating women (Fleishaker 1989). 

104 

105 Many studies of drugs in breast milk are performed only during the first few postnatal days, or 

106 they fail to define when samples were obtained or whether milk samples were drawn from 

107 foremilk, milk obtained at the onset of feeding or manual expression, or hindmilk, milk obtained 

108 at the end of feeding or expression. Human milk fat and protein content change dramatically in 

109 the first several weeks postpartum (Hibberd 1982). Breast milk is high in lipid and has a pH that 

110 is more acidic than plasma and varies in content by stage of lactation, the time of expression, and 

111 diurnally (Neville 2001). Colostrum has a lower fat content and smaller volume relative to 

112 mature milk. Foremilk is more aqueous with a lower fat content relative to hindmilk. Because 

113 of these variations and their potential to alter the effects of drugs during lactation, it is 

114 recommended that studies be designed and conducted to capture data that takes these variations 

115 into account. 

116 

117 Experts in environmental health have substantial experience in assessing chemical exposures 

118 through breast milk. The World Health Organization (WHO) European Centre for Environment 

119 and Health has been involved with monitoring environmental exposures via studies on levels of 

120 chemicals in human milk, particularly polychlorinated biphenyls (PCBs), polychlorinated 

121 dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) (WHO 1989). A 

122 WHO Working Group has also published guidelines for studies on the passage of drugs into 

123 breast milk (Bennett 1988, 1996). A 2001 Expert Panel Workshop on Breast Milk Monitoring 

124 for Environmental Chemicals in the United States sponsored by the Milton S. Hershey Medical 
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125 Center made recommendations on the methods for obtaining human milk, detecting chemicals in 

126 those samples, and interpreting and communicating the results of such surveillance and research

127 (Berlin 2002). Some of these methodologies used by the environmental health community are 

128 applicable to assessing exposures to pharmaceuticals in breast milk. The environmental health 

129 model can also be useful when designing clinical lactation studies. 

130 

131 The consistent application of adequate study designs as described in this guidance would 

132 improve the quality and quantity of data available regarding lactation and assist patients and 

133 health care providers in making decisions about the use of drugs in lactating women. 

134 

135 

136 III. CONSIDERATIONS FOR WHEN TO CONDUCT A CLINICAL LACTATION 

137 STUDY 

138 

139 Circumstances for which the Agency recommends clinical studies in lactating women be done 

140 include: 

141 

142 • A drug under review for approval is expected to be used by women of reproductive age 

143 • After approval, use of a drug in lactating women becomes evident (e.g., via reports in the 

144 medical literature or lay press) 

145 • A new indication is being sought for an approved drug and there is evidence of use or 

146 anticipated use of the drug by lactating women 

147 • Marketed medications that are commonly used by women of reproductive age (e.g., 

148 antidepressants, antihypertensives, anti-infectives, diabetic and pain medications) 

149 

150 If a drug is not used in lactating women or women of reproductive age, then clinical studies in 

151 lactation are usually not needed. 

152 

153 Information on experiences and exposure in lactating women will emerge after approval during 

154 marketing for virtually all drug products, and sponsors should send information about such 

155 experience to the FDA on a routine basis. The International Conference on Harmonisation 

156 guidance for industry E2C Clinical Safety Data Management: Periodic Safety Update Reports 

157 for Marketed Drugs lists “positive or negative experiences during pregnancy or lactation” as one 

158 safety issue to be explicitly addressed in the Overall Safety Evaluation section of the Periodic 

159 Safety Update Report. 

160 

161 Other sources of information that can help determine whether to conduct clinical lactation 

162 studies or which study design to use include (1) publications of safety or efficacy data in 

163 lactating women or safety in breast-fed children via exposure to drugs in breast milk, including 

164 case reports describing use of a drug in this population, (2) publications on the effects in breast165 fed children of maternal ingestion of a drug, and (3) information from medical specialty groups 

166 (e.g., consensus documents or opinion papers). Even when use is expected to be rare (e.g., with 

167 rare diseases such as multiple sclerosis or infrequent use such as vaccines or radioimaging 

168 agents), it is advisable to conduct lactation studies if there is concern that the consequences of 

169 uninformed dosages are potentially great. 
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170 

171 The applicability and predictability of nonclinical models (e.g., predictions of drug transfer or 

172 milk/plasma (M/P) ratios using physicochemical properties of the drug) are still under 

173 consideration, but these models do not help in deciding whether to conduct a study in lactating 

174 women. 

175 

176 

177 IV. STUDY DESIGN CONSIDERATIONS 

178 

179 The clinical question at hand will determine whether a study of breast milk only, breast milk and 

180 maternal PK, or these components plus the infant are warranted. The latter, mother-infant pair 

181 studies (1) characterize the PK of the drug in lactating women, (2) measure the amount of parent 

182 compound and metabolites transferred into breast milk over the dosing interval, and (3) assess 

183 drug exposure in the breast-fed child via breast milk. In addition, depending on the study’s 

184 primary objective: 

185 

186 • A study of lactating women (plasma and milk) or lactating women (milk only) would be 

187 performed before a mother-infant pair study. 

188 • Data from studies in lactating women coupled with what is known about a drug in the 

189 pediatric population can supplant the need for further lactation studies in the breast-fed 

190 child. 

191 • Any of these strategies could potentially provide data on the extent of drug transfer into 

192 breast milk, effect on milk production, and milk composition (e.g., volume, fat, protein, 

193 immunologic characteristics). 

194 

195 Regardless of the design chosen, for drugs that are used chronically, the Agency recommends 

196 that subjects be studied at steady state. However, for drugs that do not accumulate with chronic 

197 dosing, a single-dose study might be sufficient. For drugs that are used to treat acute medical 

198 conditions, a single-dose study might be sufficient. 

199 

200 It is possible to nest clinical lactation studies within a larger clinical study on safety or efficacy 

201 outcomes or in combination with the postpartum assessment of the effects of pregnancy on the 

202 PK and/or PD of a drug. Data obtained from single-dose studies are useful and might be 

203 considered more acceptable to volunteers and aid in recruitment. Ultimately, standard 

204 therapeutic practice (e.g., dose, frequency, and route of administration) is an important 

205 consideration in deciding which study design is rational for the drug in question. 

206 

207 A. Mother-Infant Pair Design 

208 

209 The mother-infant pair design allows for data collection in one study to potentially: 

210 

211 • Determine the PK of the drug in lactating women 

212 • Determine the amount of drug transferred into breast milk 

213 • Show effects of drug on milk production and composition 

214 • Assess drug exposure and PD in the breast-fed child 
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215 

216 Such a study usually enrolls mother-infant pairs who are planning to or are currently receiving 

217 study medication. Its hallmark is the frequent collection of corresponding maternal blood and 

218 milk samples as well as sampling of infant blood and/or urine. Infant sampling provides 

219 information regarding the fraction of drug that is systemically available to the breast-fed child. 

220 Total clearance of the drug or metabolite by the breast-fed child can be estimated as well. 

221 

222 If possible, the Agency encourages PD endpoints for the breast-fed child to be incorporated into 

223 the study. PD effects would be directly related to the drug, including extension of the 

224 pharmacologic effect or known adverse effects, and be measured objectively (e.g., blood 

glucose, platelet viscosity).4 225 Data collected in mother-infant pair studies allow for determination 

226 of the concentration-time profiles and subsequent PK estimates from maternal blood and/or 

227 plasma, breast milk, and infant samples. 

228 

229 This design can be considered if information is already known about the extent of drug transfer 

230 into breast milk, but the amount absorbed by the breast-fed child is not known. Other drugs that 

231 can be considered for a mother-infant pair design include drugs already approved and known to 

232 be used by lactating women who continue to breast-feed and drugs used to treat chronic maternal 

233 conditions. Drug or metabolite characteristics that favor selection of this study design include: 

234 

235 • High lipophilicity (weak bases) 

236 • Potential for accumulation in breast milk 

237 • Likelihood of being well absorbed by the breast-fed child 

238 • Wide distribution to multiple organs 

239 • Long half-life 

240 

241 B. Lactating Women Only Designs 

242 

243 1. Lactating Women (Plasma and Milk) 

244 

245 The lactating women (plasma and milk) study design provides data on the PK of a drug in 

246 lactating women, the amount of drug transferred into breast milk, and effects of a drug on milk 

247 production and composition. Infant sampling is not performed in this type of study; therefore, 

248 the systemic exposure of the infant cannot be measured (although total dose can be estimated). 

249 Data allow for determination of the concentration-time profiles and subsequent PK calculations 

250 from maternal blood and milk. This design enrolls lactating women and includes frequent 

251 collection of corresponding maternal blood and milk samples. Study subjects include lactating 

252 women who are planning to receive or are currently receiving study medication, lactating women 

253 who need the study medication and will interrupt breast-feeding their infant, and/or healthy 

254 lactating volunteers. 

255 

 

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256 In a sequential or step-wise approach to lactation studies, the lactating women (plasma and milk)

257 study design might be considered before the infant is exposed to drug via breast milk in a more 

258 complex study. Situations that might favor use of this design include newly approved drugs 

259 (especially for drugs with no pediatric data), short-term or acute maternal dosing, and unknown 

260 risk of exposure to the breast-fed child. Drug and metabolite characteristics that favor selection 

261 of this study design include: 

262 

263 • High lipophilicity (weak bases) 

264 • Presence in milk 

265 • Predictions that drug is present in milk 

266 • Knowledge of a class effect 

267 

268 2. Lactating Women (Milk Only) 

269 

270 The lactating women (milk only) study design enrolls lactating women and includes frequent 

271 maternal milk samples throughout the dosing interval, a specific time period (e.g., a 24-hour 

272 period), or the entire time course of lactating (e.g., months). This study design allows the 

273 detection of the presence of a drug in milk. It can also be useful to estimate ways to assess 

274 strategies to minimize exposure of the breast-fed child to a drug. Such data can be especially 

275 useful for drugs with short half-lives or those associated with sporadic or intermittent use (e.g., 

276 migraine therapy). For example: 

277 

278 • Milk only studies can provide information regarding timing of maternal dose relative to 

279 breast-feeding, the duration recommended to discard milk relative to maternal dose, and 

280 when to resume breast-feeding relative to maternal dose or drug exposure. 

281 • A finding that showed the amount of drug in breast milk to be exceedingly low could 

282 preclude the need for further studies depending on the drug and its clinical use and 

283 toxicity. 

284 • This study design could examine the effect of drug on milk production and composition. 

285 

286 Adequately designed studies would address baseline characteristics and diurnal variation 

287 including control group and run-in or lead-in periods prior to drug administration. 

288 

289 C. Other Design Considerations 

290 

291 1. Longitudinal Design 

292 

293 For drugs that are administered chronically or given for several treatment cycles, a longitudinal 

294 study design can be considered. Such a study would focus on comparing samples obtained from 

295 lactating patients at one postpartum time (e.g., 2-3 months postpartum) to samples obtained from 

296 the same patients at a different postpartum time (e.g., 5-6 months) and/or after weaning is 

297 complete. Each woman serves as her own control. The post-weaning sampling determines 

298 maternal PK and/or PD characteristics from serum sampling only and can capture information at 

299 similar times after weaning in all study subjects (e.g., 1 month post-weaning). This longitudinal 

300 design would minimize inter-individual variability across the postpartum period. Infant 
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301 sampling might also be included in a longitudinal study design (e.g., infant sampling in a 

302 longitudinal design might assess infant exposure to drug via breast milk over time in drugs 

303 chronically taken by lactating women). Longitudinal infant sampling could assess changes in 

304 drug absorption and clearance as well as PD effects at different stages of pediatric development. 

305 The Agency encourages that an analytical plan of the study take into consideration the repeat 

306 measures characteristics of a longitudinal design. 

307 

308 2. Multiple Arm Design 

309 

310 For drugs that are given acutely (e.g., single dose or short course of therapy), it is generally 

311 difficult to perform a longitudinal design using the same patient throughout lactation. One 

312 alternative is to conduct a multiple arm study designed to compare different lactating patients at 

313 different postpartum times (e.g., a sample of women each at 2-3 months and 5-6 months 

314 postpartum). Each woman serves as her own control and has PK and/or PD determinations 

315 performed after weaning is complete. 

316 

317 In certain circumstances drug therapy is no longer clinically indicated later in the postpartum 

318 period or when weaning is complete. If possible a single-dose PK/PD study can be performed to 

319 allow each woman to serve as her own control. This applies to drugs that possess linear PK. If it 

320 is impossible to administer drug in the same women (study population), then an additional arm 

321 of the study using a different population of postpartum women (appropriately matched healthy 

322 female volunteers, as a last resort) would be included. 

323 

324 3. Study Participants 

325 

326 Optimally, study participants represent a typical patient population, including race and ethnicity, 

327 for the drug to be studied. Maternal factors with significant potential to affect lactation (e.g., 

328 weight, gravity, parity, stage of lactation, postpartum status, and episodes and duration of 

329 previous lactation) and the PK of a drug to be studied (e.g., diet, smoking, alcohol intake, 

330 concomitant medications, ethnicity, other medical conditions) are important considerations. 

331 Infant factors (e.g., age, term versus preterm neonates, extent of breast-feeding, and age-related 

332 changes in absorption, distribution, metabolism, and excretion) also might warrant special 

333 consideration, depending on the drug. It is important to apply uniform diagnostic factors to all 

334 patients enrolled in the study to ensure uniformity of diagnosis of the condition for which 

335 treatment is being given and to reduce disease-specific variability in PK. 

336 

337 For drugs that are hepatically metabolized and known to exhibit genetic polymorphism (e.g., 

338 CYP2D6 or CYP2C19), the metabolic status of the enrolled subjects (maternal and infant) can be 

339 important factors when analyzing the results of the study. 

340 

341 4. Controls 

342 

343 Ideally the lactating woman would serve as her own control, for example, by undergoing PK 

344 assessment(s) during lactation and again after weaning is complete. For PK/PD studies, 

345 potential control groups include healthy non-lactating female volunteers or non-lactating female 
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346 volunteers with the medical condition of interest. Studies that evaluate the effect of drug on milk 

347 production and composition could include lactating female volunteers who are not using the test 

348 drug or, preferably, lactating female volunteers who have the medical condition of interest. If 

349 female volunteers are used as controls, the Agency recommends matching them to study subjects 

350 (e.g., postpartum status, age) and identifying time windows (e.g., 3-4 months postpartum) to 

351 account for variability in physiologic postpartum changes. The Agency recommends that the 

352 study protocol provide the rationale for the make-up of the control group selected. 

353 

354 5. Sample Size 

355 

356 Determination of an adequate sample size depends on the objective and design of a study. For a 

357 study that examines plasma PK in the mother or lactating woman, the Agency recommends that 

358 the number of patients enrolled in the study be sufficient to detect clinically significant 

359 differences (e.g., PK differences large enough to warrant dosage adjustments). The PK 

360 variability of the drug as well as the PK and PD relationships for both therapeutic and adverse 

361 responses (therapeutic range) would inform this decision. Sample size considerations include 

362 PK and PD variability for the drug being studied, the study design (i.e., single-dose vs. multiple363 dose), and the variability in lactation physiology. Inter- and intra-subject variability for mother 

364 and breast-fed child can be considered depending on the design and primary objective of the 

365 study. For a population PK approach, sparse sampling with a larger number of subjects might be 

considered if patients sufficiently span the postpartum time periods of interest.5 366 

367 

368 The final number of patients enrolled would likely be in excess of the number originally 

369 calculated by standard sample size calculations to take into account dropouts and subsequent 

370 exclusion from the study, especially for longitudinal study designs. The institution conducting 

371 the study can rely on past experience to aid in understanding the usual number of patients who 

372 complete a clinical lactation study, given dropouts or other issues. 

373 

374 Since milk only studies are more exploratory in nature, a minimum of 6-8 subjects can be 

375 sufficient. 

376 

377 6. Sample Collection and Analysis 

378 

379 The Agency recommends that the frequency and duration of sampling be sufficient to accurately 

380 detect the outcome selected (e.g., estimate the relevant PK parameters for the parent drug and 

381 metabolites — see Section V., Data Analysis). It is important to collect samples to characterize 

382 the complete dosing interval; each breast would be completely emptied and the volume of milk 

383 recorded. An electric milk pump is recommended since milk composition can vary with the 

384 method used. Separate collection containers would be used for each milk collection. Separate 

385 milk samples obtained within each collection interval might be pooled (e.g., 4-8 hour post386 dosing) and an aliqout removed for analysis. Multiple collection time intervals of milk would 

387 permit the full milk concentration-time profile and subsequent estimation of PK parameters in 

 

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388 milk. It is recommended that the protocol specify instructions for sample handling, especially 

389 for milk samples (e.g., methods to minimize contamination). 

390 

391 The Agency recommends that milk be completely expressed from each breast, mixed, and a 

392 sample removed for analysis. For mother-infant pair studies, the infant can be bottle-fed 

393 expressed milk. Infant milk consumption can be determined by measuring the volume of 

394 expressed breast milk consumed or, alternatively, by weighing the infant before and after 

395 feeding. Weighing the infant before and after feeding can be a more accurate method of 

396 determining milk consumption because it accounts for any milk volume lost via dribbling, 

397 drooling, and burping the breast-fed infant. This post-feeding weight accounts for any infant 

398 voiding (e.g., urine, stool) that occurred during feeding. For characterization of the terminal 

399 elimination phase of the drug in the breast-fed child, previously collected drug-free breast milk 

400 or formula can be substituted at subsequent feedings. 

401 

402 The Agency recommends that total and unbound concentrations of drug and metabolites in 

403 plasma be determined; for other biological matrices (e.g., breast milk) total concentrations of 

404 drug and metabolites are likely sufficient. It is important that method validation address 

accuracy, precision, selectivity, sensitivity, reproducibility, and stability.6 405 Because of varying 

406 lipophilicity among drugs, it is also important to assay milk samples for milk fat. 

407 

408 Alternative, noninvasive pediatric sampling strategies (e.g., saliva, tears) might also be used to 

409 estimate drug levels in infants. However, drug concentrations obtained from alternative fluids 

410 (e.g., saliva, tears) might not be equivalent to those obtained from plasma. Sponsors are, 

411 therefore, encouraged to demonstrate the relationship of the drug concentration between plasma 

412 and alternative fluids in adults. Estimating infant drug exposure via breast milk solely from 

413 excretion of unchanged drug in infant urine can be of limited utility because of the difficulty 

414 with urine collection and the variability of renal clearance and urine production in infants. 

415 

416 7. Population PK Studies 

417 

418 A population PK approach is a possible alternative way to enroll lactating women (and breast419 fed children) in PK studies and minimize the number of blood draws and PD assessments. The 

420 population PK approach assesses the impact of various covariates on the PK of a drug. Practical 

421 difficulties in conducting a population study can limit the value of such a study. Validated 

422 sparse sampling methods based on optimal sampling theory and limited sampling methods are 

423 useful in determining the optimal sampling times to best estimate PK parameters. Further 

information on this approach is available in Agency guidance.7 424 

425 

426 8. Pharmacodynamic Assessments 

427 

428 Whenever appropriate, the Agency encourages PD assessment to be included in clinical lactation 

429 studies and discussed with the appropriate FDA review staff. Given the assumption of an 

 

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430 unaltered PK/PD relationship, PK measurements alone would generally be recommended for 

431 lactation studies, although PD studies might sometimes provide additional useful information. If 

432 studied, the PD endpoints chosen can be based on the pharmacological characteristics of the 

433 parent drug and metabolites (e.g., extent of protein binding, therapeutic range, and the behavior 

434 of other drugs in the same class in lactating patients). Similarly, biomarkers might be used to 

435 measure PD endpoints of interest. PD assessments in the breast-fed child can also be considered 

436 (e.g., heart rate and rhythm response to maternal administration of drug). 

437 

438 

439 V. DATA ANALYSIS 

440 

441 The primary intent of the data analysis is to estimate or assess the clinical impact of drug use by 

442 lactating women. The categorization of stage of lactation (or weeks postpartum) might direct the 

443 type of analysis performed. Special analytical considerations are important for longitudinal 

444 study designs and the baseline comparisons; however, data analysis typically consists of the 

445 following steps: 

446 

447 • Estimation of PK parameters in maternal serum/plasma, breast milk, and the breast-fed 

448 child 

449 • Comparison of PK parameters in the lactating women to those in non-lactating women 

450 • Estimation or measures of exposure of the drug in the breast-fed child 

451 • Estimation of alterations of breast milk (e.g., production and composition) and the 

452 resulting impact on the breast-fed child 

453 • Development of dosing recommendations including an assessment of whether dosage 

454 adjustment is warranted in lactating patients 

455 • Estimation of ways to minimize exposure of the breast-fed child to drug via breast milk 

456 (e.g., timing of maternal dose relative to breast-feeding, recommended duration to discard 

457 milk relative to maternal dose, resumption of breast-feeding relative to maternal dose or 

458 drug exposure)

459 

460 A. Parameter Estimation 

461 

462 The Agency recommends that total and unbound plasma and milk concentration data (and 

463 urinary excretion data, if collected) be used to estimate PK parameters of the parent drug and 

464 metabolites. Maternal plasma PK parameter estimates might include: the area under the plasma 

465 concentration curve (AUCp; AUC0-t or AUC0-∞ in single-dose studies and AUC0-τ at steady state), 

466 peak plasma concentration (Cmax), time to peak plasma concentration (tmax), plasma clearance 

467 (CLT) or apparent oral clearance (CL/F), apparent volume of distribution (VZ/F or Vss/F), and 

468 terminal half-life (t1/2). The Agency recommends that the area under the milk concentration-time 

469 curve over 24 hours (AUCm; AUC0-24) be calculated. PK parameters would be expressed in 

470 terms of total and unbound concentrations. For drugs and metabolites with a relatively low 

471 extent of plasma protein binding (e.g., extent of binding less than 80 percent), description and 

472 analysis of the PK in terms of total concentrations is recommended. Infant PK parameter 

473 estimates can be obtained, as appropriate. The PK parameters of metabolites in maternal plasma, 

474 in breast milk, and ingested by the breast-fed child can be estimated. If the samples (e.g., 
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475 number, volume) obtained from the breast-fed child do not permit determination of total and 

476 unbound concentrations, the average fraction of drug bound would then be determined. 

477 Noncompartmental and/or compartmental modeling approaches to parameter estimation are 

478 recommended. 

479 

480 The amount of drug or metabolite consumed in a day by the breast-fed infant, the infant dosage, 

481 can be determined: 

482 

483 Daily Infant Dosage (mg/day) = total drug excreted in milk and consumed by the infant 

484 per day. 

485 

486 Theoretically, any time frame could be chosen (e.g., dosing interval); however, it is likely easier 

487 to interpret daily dosage information. 

488 

489 The Agency recommends that the infant dosage be calculated by summing the product of drug 

490 concentration times the volume of milk for each sample time: 

491 

492 Daily Infant Dosage (mg/day) = Σ (total drug concentration in each milk collection × 

493 expressed milk volume in each milk collection) 

494 

495 EXAMPLE: Daily infant dosage 

496 The data in the table below reflect milk collected for 24 hours with the following drug 

497 concentrations and volumes for each sampling interval. 

Sample Collection Milk Drug Milk Volume 

Interval (hrs) Concentration (μg/mL) Expressed (mL) 

Drug in Milk 

(μg) 

0-4 0.27 98 26.46 

4-8 0.24 146 35.04 

8-12 0.16 125 20.0 

12-16 0.022 110 2.42 

16-24 0.008 245 1.96 

498 

499 In the example above, the Daily Infant Dosage is equal to 85.88μg or 0.086 mg/day 

500 

501 Alternatively, the infant daily dose might be estimated with the following equation: 

502 

503 Estimated Daily Infant Dosage (mg/kg/day) = M/P × average maternal serum 

504 concentration × 150 mL/kg/day

505 

506 In this case M/P (milk-to-plasma ratio) is the ratio of AUCmilk to AUCplasma. The average 

507 maternal serum concentration refers to AUC0-∞/dosing interval after maternal ingestion of a 

508 single dose of drug or AUC0-τ/dosing interval at steady state during chronic maternal dosing 

509 (Bennett 1988, 1996). When using this approach to estimate daily infant dosage, the AUC is 

510 either the AUC from time zero to infinity (AUC0-∞) after maternal ingestion of a single dose of 
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511 drug or the AUC within a dosing interval (AUC0-τ) at steady state during chronic maternal 

512 dosing. 

513 

514 Calculation of the M/P ratio from single paired maternal milk and plasma concentrations 

515 obtained at one sampling time is not recommended. The M/P ratio using AUCs has been shown 

516 to provide a more accurate estimate of breast milk content of drug compared to the milk to 

517 plasma ratio from isolated samples (Begg 1999; Wojhar-Horton 1996; Wilson 1985). The 

518 standardized milk consumption of 150 mL/kg/day, the mean milk intake of a fully breast-fed 2-

519 month old infant (Begg 1999; Bennett 1988; Hagg 2000; Kristensen 1999) is used. 

520 

521 The Agency recommends that the percent of the weight-adjusted maternal dose consumed in 

522 breast milk over 24 hours be calculated: 

523 

524 % Maternal Dosage = (Infant Dosage (mg/kg/day)/Maternal dosage (mg/kg/day)) × 100 

525 

526 Similarly, this might be calculated for a dosing interval. If the pediatric or infant dose is known 

527 (i.e., the drug is approved for pediatric use), it is possible to estimate the percent weight-adjusted 

528 pediatric dose ingested as well. 

529 

530 The infant serum concentration is probably the most direct measure of infant risk from a drug 

531 received from breast milk. If infant serum data are not collected, it is possible to estimate the 

532 average infant serum concentration (Css,ave) by: 

533 

534 Css,ave = F x infant dosage/CL 

535 

536 where F is the bioavailability and CL is the drug clearance in the infant, if these data are known 

537 for the pediatric population. 

538 

539 If other methods are used to determine infant exposure to drug from breast milk, those 

540 methodologies should be comparable to those in this guidance. 

541 

542 B. Development of Dosing Recommendations for Lactating Women 

543 

544 If, based on studies, a dosage adjustment is important when a woman is lactating, the Agency 

545 recommends that the labeling describe the relationship between the drug’s PK and lactation. 

546 Typically, the dose is adjusted to produce a comparable range of unbound plasma concentrations 

547 of drug or metabolites in both normal adult patients and lactating patients. Simulations are 

548 encouraged as a means to identify doses and dosing intervals that achieve that goal. For some 

549 drugs, lactation may not alter PK sufficiently to warrant dosage adjustment. A sponsor might 

550 make this claim by providing an analysis of the study data to show that the PK measurements 

551 most relevant to therapeutic outcome in lactating patients are similar or equivalent to those in 

552 normal adult or post-weaning patients. 

553 

554 Results of the impact of lactation on the maternal PK of medical products can be reported as 90 

555 percent confidence intervals about the geometric mean ratio of the observed PK measures. 
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556 When an impact of lactation is clearly present (e.g., a comparison indicates twofold or greater 

557 change in systemic exposure measures), the sponsor would provide specific recommendations 

558 regarding the clinical significance of the interaction based on what is known about the dose559 response and/or PK/PD relationship. This information would form the basis for reporting study 

560 results and for making recommendations in the package insert. 

561 

562 The sponsor may wish to make specific claims in the package insert that no impact is expected 

563 from lactation on the PK of a medical product. In this instance it is possible for the sponsor to 

564 recommend specific no effect boundaries or clinical equivalence intervals for the impact of 

565 lactation on the PK of a medical product. There are two approaches to define no effect

566 boundaries. 

567 

568 Approach 1: The sponsor would recommend, prior to the conduct of the studies, specific no 

569 effect boundaries for the mean geometric ratio of Cmax and AUC. They might be based on 

570 population (group) average dose and/or concentration-response relationships, PK/PD models, 

571 and other available information. If the 90 percent confidence interval for the systemic exposure 

572 measurement in the lactation study falls completely within the no effect boundaries, the sponsor 

573 can conclude that no clinically significant impact of lactation on the PK of the medical product 

574 was present. 

575 

576 Approach 2: In the absence of no effect boundaries defined above, a sponsor might use a 

577 default no effect boundary of 80-125 percent. When the 90 percent confidence intervals for 

578 systemic exposure ratios fall entirely within the equivalence range of 80-125 percent, standard 

579 Agency practice is to conclude that no clinically significant differences are present. 

580 

581 If, based on lactation studies, there is a need for dose adjustment while a women is lactating, the 

582 labeling would describe the relationship between the medical product’s PK and lactation. 

583 Typically the dose regimen is adjusted to produce comparable Cmax and AUC values. 

584 Simulations are encouraged as a means to identify doses and dosing intervals that achieve that 

585 goal. 

586 

587 C. Development of Recommendations to Minimize Infant Drug Exposure from 

588 Breast Milk 

589 

590 It is possible to use data from kinetic profiles in milk to provide recommendations for ways to 

591 minimize exposure of the breast-fed child to a drug via breast milk. The Agency recommends 

592 that the labeling describe the relationship between maternal drug administration and breast593 feeding, taking into account drug kinetics such as half-life in milk. For example, ways to 

594 minimize exposure to drug in breast milk might include information regarding (1) the timing of 

595 maternal dose relative to breast-feeding, (2) the duration of time relative to maternal drug 

596 administration to discard breast milk (e.g., “pump and dump”), and (3) how long to wait until 

597 resuming breast-feeding relative to maternal dose. 

598 

599 
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600 VI. LABELING 

601 

602 The Agency recommends that labeling reflect the data from clinical lactation studies and, if 

603 known, dosing recommendations during lactation. The labeling would reflect the data pertaining 

604 to the effect of lactation on the PK and PD (if known) obtained from studies conducted. If the 

605 PK and/or PD are altered during lactation, the Agency recommends that the appropriate 

606 description of such and recommendations for dosing be stated in labeling. The labeling would 

607 contain information pertaining to drug transfer into breast milk, the exposure of breast-fed 

608 infants to drugs in breast milk, and the drug effect on milk production and composition, if 

609 known. Non-positive findings are to be interpreted as indicating failure to detect an impact of 

610 lactation on PK or PD rather than lack of an effect. 

611 

612 The various permutations of intrinsic drug characteristics and the effect of lactation on drug 

613 performance preclude precise specification of how such drugs can be labeled. The following 

614 comments offer general suggestions on labeling. 

615 

616 A. Clinical Pharmacology 

617 

618 1. Pharmacokinetics Subsection 

619 

620 This section would include information pertinent to lactation on the: 

621 

622 • Disposition of parent drug and metabolites, if applicable 

623 • Effects of lactation on protein binding, if applicable 

624 

625 2. Special Populations Subsection 

626 

627 This section would recapitulate, in brief, the PK changes found in lactation and, if needed, 

628 dosing adjustments for lactating patients. The section would briefly describe any data regarding 

629 drug transfer into breast milk, the exposure of breast-fed infants to drugs in breast milk, and the 

630 drug effect on milk production and composition, if known. This information would be based on 

631 the studies performed as described in this guidance. Reference would be made to the 

632 PRECAUTIONS/NURSING MOTHERS and the DOSAGE AND ADMINISTRATION 

633 sections. The following text provides examples of possible wording for these sections. 

634 

635 The simplest situation involves drugs for which lactation has little to no effect on PK: 

636 

637 The disposition of [Drug X] was studied in [number of] lactating women from [a through 

638 b months postpartum]. Lactation has little to no influence on [Drug X]

639 pharmacokinetics and no dosing adjustment is needed. 

640 

641 Similarly, for drugs whose PK is influenced by lactation, the following statement can be 

642 modified in accordance with what is known about the drug (e.g., active or toxic metabolite) and 

643 from the studies performed in accordance with this guidance: 

644 
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645 The disposition of [Drug X] was studied in [number of] lactating women from [a through 

646 b months postpartum]. Elimination of the drug (and metabolite, if applicable) is 

647 significantly changed during lactation. Total body clearance of (unbound, if applicable) 

648 [Drug X]/metabolite was [reduced/increased] in lactating women compared to non649 lactating women. The terminal half-life of [Drug X]/metabolite is [prolonged/decreased] 

650 by [Y-fold]. (See DOSAGE AND ADMINISTRATION.)

651 

652 Similarly, the following statement can be modified as appropriate to describe drug transfer into 

653 breast milk: 

654 

655 A [dose (mg), single or multiple dose] of [Drug X] was administered [route of drug 

656 administration (e.g., oral, intravenous)] to [number of] lactating women who were [a 

657 through b months postpartum]. Breast milk obtained for [c hours] after dosing revealed 

658 a maximum concentration of [y concentration] [t1 time] after dosing and drug 

659 concentrations in milk rapidly declined over [the next time duration, t2 time]. The 

660 estimated daily infant dose for [Drug X] from breast milk is [z dose or z mg] which 

661 represents [_____%] of maternal dose and [_____%] of the lowest approved pediatric 

662 dose (if applicable). No drug was detectable in milk samples obtained [t3 time] or later 

663 after dosing. 

664 

665 B. Precautions/Nursing Mothers 

666 

667 In addition to standard labeling for use in lactation, if studies performed during lactation 

668 demonstrate clinically important changes, the Agency recommends that such information be 

669 included in the PRECAUTIONS/NURSING MOTHERS section with cross-reference to 

670 DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections. It is 

671 recommended that labeling contain information, to the extent possible, based on the lactation 

672 study conducted, including: 

673 

674 • PK/PD in lactation 

675 • The effect of drug on milk production (e.g., quality and quantity of milk including milk 

676 production and composition) 

677 • The presence of drug or metabolite in milk, including the limitation of the assay used if 

678 drug/metabolites are not detected in milk 

679 • The amount of drug or metabolite in breast milk over a 24-hour period

680 • The amount of drug or metabolite consumed daily by the breast-fed infant 

681 • The percent of maternal dose delivered via breast milk and consumed daily by the breast682 fed infant (i.e., daily dose in human milk compared to the usual adult dose, or pediatric 

683 dose, if known) 

684 • Possible ways to minimize exposure in the breast-fed child to drug via breast milk taking 

685 into account drug kinetics such as half-life in milk (e.g., timing of maternal dose relative 

686 to breast-feeding, the duration to discard breast milk relative to maternal dose, and how 

687 long to wait until resuming breast-feeding relative to maternal dose) 

688 • Effects of drug exposure via breast milk in the breast-fed infant 

689 • PK of drug in the breast-fed infant 
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690 

691 C. Dosage and Administration 

692 

693 As appropriate, the following information would be included: 

694 

695 • A statement describing the relationship between [Drug X]’s clearance and lactation 

696 • A statement describing how the dose would be adjusted during lactation within the 

697 approved therapeutic range: 

698 

699 The dose of [Drug X] should be [increased/decreased] by [_____%] during lactation.

700 

701 • If no dose adjustment is needed, the following statement might be used: 

702 

703 The influence of lactation on [Drug X] pharmacokinetics is sufficiently small that no 

704 dosing adjustment is needed. 

705 

706 • A statement cross-referencing the Precautions/Nursing Mothers section of labeling when 

707 possible ways to minimize exposure in the breast-fed child with respect to timing of 

708 maternal dose relative to breast-feeding are included in the Precautions/Nursing Mothers 

709 section. 

710 

711 

712 VII. CONSIDERATIONS FOR FUTURE RESEARCH 

713 

714 Although nonclinical models (e.g., mechanistic, in vitro, animal, physicochemical-based, and 

715 physiological-based PK (PBPK)) have demonstrated limited success in predicting the amount of 

716 drug in breast milk and in predicting infant exposures to drug in breast milk (Oo, Transport of 

717 Cimetidine, 1995; Oo, Alprazolam Transfer, 1995) the applicability of nonclinical predictive 

718 models is still under investigation. Because of this, data obtained from clinical lactation studies 

719 would enable testing of the predictive value of these nonclinical models. The incorporation of 

720 the additional information obtained from clinical lactation studies into nonclinical models would 

721 strengthen the association between predicted and observed exposures and optimally improve the 

722 predictability of such approaches. 

723 

724 
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724 BIBLIOGRAPHY 

725 

726 American Academy of Pediatrics (AAP), 1989, American Academy of Pediatrics Committee on 

727 Drugs: Transfer of Drugs and Other Chemicals into Human Milk, Pediatrics, 84(5):924-

728 36. 

729 

730 American Academy of Pediatrics (AAP), 1994, American Academy of Pediatrics Committee on 

731 Drugs: Transfer of Drugs and Other Chemicals into Human milk, Pediatrics, 93(1):137-

732 50. 

733 

734 AAP Committee on Drugs, 2001, Transfer of Drugs and Other Chemicals into Human Milk, 

735 Pediatrics, 108(3):776-89. 

736 

737 AAP Work Group on Breastfeeding, 1997, Breastfeeding and the Use of Human Milk, 

738 Pediatrics, 100(6):1035-1039. 

739 

740 Begg, EJ, SB Duffull, DA Saunders et al., 1999, Paroxetine in Human Milk, Br J Clin 

741 Pharmacol, 48:142-147. 

742 

743 Bennett, PN (ed), 1988, Drugs and Human Lactation, Amsterdam: Elsevier. 

744 

745 Bennett, PN (ed), 1996, Drugs and Human Lactation, 2nd edition, Amsterdam: Elsevier. 

746 

747 Berlin, CM Jr, JS LaKind, BR Sonawane et al., 2002, Conclusions, Research Needs and 

748 Recommendations of the Expert Panel: Technical Workshop on Human Milk 

749 Surveillance and Research for Environmental Chemicals in the United States, J. Toxicol. 

750 Environ. Health, Part A, 65:1929-1935. 

751 

752 Fleishaker, JC, N Desai, and PJ McNamara, 1989, Possible Effect of Lactational Period on the 

753 Milk-to-Plasma Drug Concentration Ratio in Lactating Women: Results of an In Vitro 

754 Evaluation, J Pharm Sci, 78(2):137-141. 

755 

756 Hagg, S and O Spigset, 2000, Anticonvulsant Use During Lactation, Drug Saf, 22:425-440. 

757 

758 Hibberd, CM, OG Brooke, ND Carter et al., 1982, Variation in the Composition of Breast Milk 

759 During the First 5 Weeks of Lactation: Implications for the Feeding of Preterm Infants, 

760 Arch Dis Child, 57(9):658-662. 

761 

762 Kristensen, JH, KF Ilett, LP Hackett et al., 1999, Distribution and Excretion of Fluoxetine and 

763 Norfluoxetine in Human Milk, Br J Clin Pharmacol, 48:521-527. 

764 

765 Neville, MC, 2001, Anatomy and Physiology of Lactation, Pediatr Clin North Am, 48(1):13-34. 

766 

767 Oo, YC, RJ Kuhn, N Desai, and PJ McNamara, 1995, Active Transport of Cimetidine into 

768 Human Milk, Clin Pharmacol Ther, 58:548-555. 
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769 

770 Oo, YC, RJ Kuhn, N Desai et al., 1995, Pharmacokinetics in Lactating Women: Prediction of 

771 Alprazolam Transfer into Milk, Br J Clin Pharmacol, 40:231-236. 

772 

773 Ryan, AS, Z Wenjun, and A Acosta, 2002, Breastfeeding Continues to Increase into the New 

774 Millennium, Pediatrics, 110:1103-1109. 

775 

776 U.S. Department of Health and Human Services (DHHS), 2000, Healthy People 2010: 

777 Understanding and Improving Health, 2nd ed., Washington, DC: U.S. Government 

778 Printing Office (http://www.health.gov/healthypeople/document/). 

779 

780 World Health Organization, 1989, Levels of PCBs, PCDDs and PCDFs in Breast Milk: Results 

781 of WHO-Coordinated Interlaboratory Quality Control Studies and Analytical Field 

782 Studies, in Yrjanheikki EJ (ed), Environmental Health Series RPt 34, Copenhagen: 

783 World Health Organization Regional Office for Europe. 

784 

785 Wilson, JT, RD Brown, JL Hinson, and JW Daily, 1985, Pharmacokinetic Pitfalls in the 

786 Estimation of the Breast Milk/Plasma Ratio for Drugs, Ann Rev Pharmacol Toxicol, 

787 25:667-689. 

788 

789 Wojnar-Horton, RE, LP Hackett, P Yapp et al., 1996, Distribution and Excretion of Sumatriptan 

790 in Human Milk, Br J Clin Pharmacol, 41:217-221.