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This guidance provides recommendations for how and when to conduct clinical lactation studies and how to assess the influence of drugs or biologic products2 on lactation. The goals of this guidance are to (1) provide the basic framework for designing, conducting, and analyzing clinical lactation studies and (2) stimulate further study and research to assist in rational therapeutics for lactating patients. Clinical lactation studies can be designed to assess:
This guidance will be most helpful when used in conjunction with other pharmacological and clinical literature on the design, conduct, and interpretation of PK studies. Because studies in lactating patients and their breast-fed children require specialized knowledge in a variety of areas, the investigators preparing to design and conduct such studies are encouraged to obtain advice from experts in specific fields (e.g., pediatrics, obstetrics, pharmacology, clinical pharmacology, pharmacometrics, statistics). FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
Breast milk is widely acknowledged to be the most complete form of nutrition for infants and to include a range of health benefits for breast-feeding women and infants. Accumulated data support the benefits of breast milk for infants including growth, immunity, and development. Specific data show decreased incidence and severity of diarrhea, respiratory infections, and ear infections. Maternal benefits of breast-feeding include reduction in postpartum bleeding, earlier return to prepregnancy weight, reduced risk of premenopausal breast cancer, and reduced risk of osteoporosis (U.S. Department of Health and Human Services (DHHS) 2000). The DHHS sponsored Healthy People 2010 Initiative targets to increase the percentage of mothers who breast-feed from the current rate to 75 percent in the early postpartum period, 50 percent at 6 months, and 15 percent at 1 year (DHHS Services 2000). The American Academy of Pediatrics (AAP) recommends that all new mothers who are able should breast-feed until the child reaches 1 year of age. A recent survey reports that 69.5 percent of women in the United States initiate breast-feeding and 32.5 percent continue to breast-feed their infants to 6 months of age, reflecting the highest percentage in recent history of women in the United States choosing to breast-feed (Ryan 2002). The AAP considers breast-feeding to be the ideal method of feeding and nurturing infants (AAP Work Group on Breastfeeding 1997). It is highly likely that a woman will need and take medications while she is breast-feeding, potentially exposing her child to the effects of these medications. Surveys in various countries indicate that 90-99 percent of nursing mothers receive a medication during the first week postpartum, 17-25 percent of nursing mothers will take medication by 4 months postpartum and 5 percent of nursing mothers receive long-term drug therapy (Bennett 1988). The presence of a drug in breast milk does not necessarily indicate a health risk for the breast-fed child. Detecting the presence or absence of the drug in milk is only the first step in determining risk. For most drugs, little scientific information is available about the extent of their passage into breast milk, their effects on milk production, their effects on the breast-fed infant, or whether a dose adjustment is needed to treat a lactating woman. Therefore, breast-feeding women and their health care providers must make decisions regarding treatment of maternal medical conditions in the absence of data. In some cases, this can result in a decision to stop breast-feeding to take needed drug therapy, unnecessarily eliminating the benefits of breast-feeding for mothers and their infants. The AAP has tried to fill the information void regarding infant safety by issuing consensus documents on the use of drugs in lactation or breast-feeding women (AAP 1989, 1994; AAP Committee on Drugs 2001), but data upon which to make these assessments is sparse. Clinical lactation studies would provide much needed additional data on which to base treatment decisions. Since data on dosing lactating women are rarely available, most clinicians treat lactating women with the dose studied in and recommended for nonpregnant adults. This practice disregards the impact of the physiologic changes that occur during lactation and the effects of additional breast and milk compartments. A variety of potential differences in PK might be important in the postpartum and lactating periods, including differences caused by endogenous hormonal changes, altered body fat proportion, and changes in weight or muscle mass. Most studies of drugs and breast-feeding focus on health risks for the nursing infant, not the mother. Even when studies collect drug concentrations in maternal serum and breast milk, individual PK is not often characterized, and customary PK parameters (e.g., clearance, half-life) are not reported. Some studies focus on the detection of drug in infant serum compared with maternal serum or milk at a single point in time, but they rarely include comparisons to the non-lactating state or control groups. Most studies do not account for changes in serum protein concentrations and unbound drug in serum, as well as other physiological changes in the early postpartum period, that can affect maternal PK and contribute to variability among data from lactating women (Fleishaker 1989). Many studies of drugs in breast milk are performed only during the first few postnatal days, or they fail to define when samples were obtained or whether milk samples were drawn from foremilk, milk obtained at the onset of feeding or manual expression, or hindmilk, milk obtained at the end of feeding or expression. Human milk fat and protein content change dramatically in the first several weeks postpartum (Hibberd 1982). Breast milk is high in lipid and has a pH that is more acidic than plasma and varies in content by stage of lactation, the time of expression, and diurnally (Neville 2001). Colostrum has a lower fat content and smaller volume relative to mature milk. Foremilk is more aqueous with a lower fat content relative to hindmilk. Because of these variations and their potential to alter the effects of drugs during lactation, it is recommended that studies be designed and conducted to capture data that takes these variations into account. Experts in environmental health have substantial experience in assessing chemical exposures through breast milk. The World Health Organization (WHO) European Centre for Environment and Health has been involved with monitoring environmental exposures via studies on levels of chemicals in human milk, particularly polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) (WHO 1989). A WHO Working Group has also published guidelines for studies on the passage of drugs into breast milk (Bennett 1988, 1996). A 2001 Expert Panel Workshop on Breast Milk Monitoring for Environmental Chemicals in the United States sponsored by the Milton S. Hershey Medical Center made recommendations on the methods for obtaining human milk, detecting chemicals in those samples, and interpreting and communicating the results of such surveillance and research (Berlin 2002). Some of these methodologies used by the environmental health community are applicable to assessing exposures to pharmaceuticals in breast milk. The environmental health model can also be useful when designing clinical lactation studies. The consistent application of adequate study designs as described in this guidance would improve the quality and quantity of data available regarding lactation and assist patients and health care providers in making decisions about the use of drugs in lactating women.
Circumstances for which the Agency recommends clinical studies in lactating women be done include:
If a drug is not used in lactating women or women of reproductive age, then clinical studies in lactation are usually not needed. Information on experiences and exposure in lactating women will emerge after approval during marketing for virtually all drug products, and sponsors should send information about such experience to the FDA on a routine basis. The International Conference on Harmonisation guidance for industry E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs lists "positive or negative experiences during pregnancy or lactation" as one safety issue to be explicitly addressed in the Overall Safety Evaluation section of the Periodic Safety Update Report. Other sources of information that can help determine whether to conduct clinical lactation studies or which study design to use include (1) publications of safety or efficacy data in lactating women or safety in breast-fed children via exposure to drugs in breast milk, including case reports describing use of a drug in this population, (2) publications on the effects in breast-fed children of maternal ingestion of a drug, and (3) information from medical specialty groups (e.g., consensus documents or opinion papers). Even when use is expected to be rare (e.g., with rare diseases such as multiple sclerosis or infrequent use such as vaccines or radioimaging agents), it is advisable to conduct lactation studies if there is concern that the consequences of uninformed dosages are potentially great. The applicability and predictability of nonclinical models (e.g., predictions of drug transfer or milk/plasma (M/P) ratios using physicochemical properties of the drug) are still under consideration, but these models do not help in deciding whether to conduct a study in lactating women.
The clinical question at hand will determine whether a study of breast milk only, breast milk and maternal PK, or these components plus the infant are warranted. The latter, mother-infant pair studies (1) characterize the PK of the drug in lactating women, (2) measure the amount of parent compound and metabolites transferred into breast milk over the dosing interval, and (3) assess drug exposure in the breast-fed child via breast milk. In addition, depending on the study's primary objective:
Regardless of the design chosen, for drugs that are used chronically, the Agency recommends that subjects be studied at steady state. However, for drugs that do not accumulate with chronic dosing, a single-dose study might be sufficient. For drugs that are used to treat acute medical conditions, a single-dose study might be sufficient. It is possible to nest clinical lactation studies within a larger clinical study on safety or efficacy outcomes or in combination with the postpartum assessment of the effects of pregnancy on the PK and/or PD of a drug. Data obtained from single-dose studies are useful and might be considered more acceptable to volunteers and aid in recruitment. Ultimately, standard therapeutic practice (e.g., dose, frequency, and route of administration) is an important consideration in deciding which study design is rational for the drug in question.
The mother-infant pair design allows for data collection in one study to potentially:
Such a study usually enrolls mother-infant pairs who are planning to or are currently receiving study medication. Its hallmark is the frequent collection of corresponding maternal blood and milk samples as well as sampling of infant blood and/or urine. Infant sampling provides information regarding the fraction of drug that is systemically available to the breast-fed child. Total clearance of the drug or metabolite by the breast-fed child can be estimated as well. If possible, the Agency encourages PD endpoints for the breast-fed child to be incorporated into the study. PD effects would be directly related to the drug, including extension of the pharmacologic effect or known adverse effects, and be measured objectively (e.g., blood glucose, platelet viscosity).4 Data collected in mother-infant pair studies allow for determination of the concentration-time profiles and subsequent PK estimates from maternal blood and/or plasma, breast milk, and infant samples. This design can be considered if information is already known about the extent of drug transfer into breast milk, but the amount absorbed by the breast-fed child is not known. Other drugs that can be considered for a mother-infant pair design include drugs already approved and known to be used by lactating women who continue to breast-feed and drugs used to treat chronic maternal conditions. Drug or metabolite characteristics that favor selection of this study design include:
The primary intent of the data analysis is to estimate or assess the clinical impact of drug use by lactating women. The categorization of stage of lactation (or weeks postpartum) might direct the type of analysis performed. Special analytical considerations are important for longitudinal study designs and the baseline comparisons; however, data analysis typically consists of the following steps:
The Agency recommends that total and unbound plasma and milk concentration data (and urinary excretion data, if collected) be used to estimate PK parameters of the parent drug and metabolites. Maternal plasma PK parameter estimates might include: the area under the plasma concentration curve (AUCp; AUC0-t or AUC0-∞ in single-dose studies and AUC0-τ at steady state), peak plasma concentration (Cmax), time to peak plasma concentration (tmax), plasma clearance (CLT) or apparent oral clearance (CL/F), apparent volume of distribution (VZ/F or Vss/F), and terminal half-life (t1/2). The Agency recommends that the area under the milk concentration-time curve over 24 hours (AUCm; AUC0-24) be calculated. PK parameters would be expressed in terms of total and unbound concentrations. For drugs and metabolites with a relatively low extent of plasma protein binding (e.g., extent of binding less than 80 percent), description and analysis of the PK in terms of total concentrations is recommended. Infant PK parameter estimates can be obtained, as appropriate. The PK parameters of metabolites in maternal plasma, in breast milk, and ingested by the breast-fed child can be estimated. If the samples (e.g., number, volume) obtained from the breast-fed child do not permit determination of total and unbound concentrations, the average fraction of drug bound would then be determined. Noncompartmental and/or compartmental modeling approaches to parameter estimation are recommended. The amount of drug or metabolite consumed in a day by the breast-fed infant, the infant dosage, can be determined:
Theoretically, any time frame could be chosen (e.g., dosing interval); however, it is likely easier to interpret daily dosage information. The Agency recommends that the infant dosage be calculated by summing the product of drug concentration times the volume of milk for each sample time:
Daily Infant Dosage (mg/day) = Σ (total drug concentration in each milk collection x expressed milk volume in each milk collection)
Alternatively, the infant daily dose might be estimated with the following equation:
In this case M/P (milk-to-plasma ratio) is the ratio of AUCmilk to AUCplasma. The average maternal serum concentration refers to AUC0-∞/dosing interval after maternal ingestion of a single dose of drug or AUC0-τ/dosing interval at steady state during chronic maternal dosing (Bennett 1988, 1996). When using this approach to estimate daily infant dosage, the AUC is either the AUC from time zero to infinity (AUC0-∞) after maternal ingestion of a single dose of drug or the AUC within a dosing interval (AUC0-τ) at steady state during chronic maternal dosing. Calculation of the M/P ratio from single paired maternal milk and plasma concentrations obtained at one sampling time is not recommended. The M/P ratio using AUCs has been shown to provide a more accurate estimate of breast milk content of drug compared to the milk to plasma ratio from isolated samples (Begg 1999; Wojhar-Horton 1996; Wilson 1985). The standardized milk consumption of 150 mL/kg/day, the mean milk intake of a fully breast-fed 2-month old infant (Begg 1999; Bennett 1988; Hagg 2000; Kristensen 1999) is used. The Agency recommends that the percent of the weight-adjusted maternal dose consumed in breast milk over 24 hours be calculated:
Similarly, this might be calculated for a dosing interval. If the pediatric or infant dose is known (i.e., the drug is approved for pediatric use), it is possible to estimate the percent weight-adjusted pediatric dose ingested as well. The infant serum concentration is probably the most direct measure of infant risk from a drug received from breast milk. If infant serum data are not collected, it is possible to estimate the average infant serum concentration (Css,ave) by:
where F is the bioavailability and CL is the drug clearance in the infant, if these data are known for the pediatric population. If other methods are used to determine infant exposure to drug from breast milk, those methodologies should be comparable to those in this guidance.
If, based on studies, a dosage adjustment is important when a woman is lactating, the Agency recommends that the labeling describe the relationship between the drug's PK and lactation. Typically, the dose is adjusted to produce a comparable range of unbound plasma concentrations of drug or metabolites in both normal adult patients and lactating patients. Simulations are encouraged as a means to identify doses and dosing intervals that achieve that goal. For some drugs, lactation may not alter PK sufficiently to warrant dosage adjustment. A sponsor might make this claim by providing an analysis of the study data to show that the PK measurements most relevant to therapeutic outcome in lactating patients are similar or equivalent to those in normal adult or post-weaning patients. Results of the impact of lactation on the maternal PK of medical products can be reported as 90 percent confidence intervals about the geometric mean ratio of the observed PK measures. When an impact of lactation is clearly present (e.g., a comparison indicates twofold or greater change in systemic exposure measures), the sponsor would provide specific recommendations regarding the clinical significance of the interaction based on what is known about the dose-response and/or PK/PD relationship. This information would form the basis for reporting study results and for making recommendations in the package insert. The sponsor may wish to make specific claims in the package insert that no impact is expected from lactation on the PK of a medical product. In this instance it is possible for the sponsor to recommend specific no effect boundaries or clinical equivalence intervals for the impact of lactation on the PK of a medical product. There are two approaches to define no effect boundaries. Approach 1: The sponsor would recommend, prior to the conduct of the studies, specific no effect boundaries for the mean geometric ratio of Cmax and AUC. They might be based on population (group) average dose and/or concentration-response relationships, PK/PD models, and other available information. If the 90 percent confidence interval for the systemic exposure measurement in the lactation study falls completely within the no effect boundaries, the sponsor can conclude that no clinically significant impact of lactation on the PK of the medical product was present. Approach 2: In the absence of no effect boundaries defined above, a sponsor might use a default no effect boundary of 80-125 percent. When the 90 percent confidence intervals for systemic exposure ratios fall entirely within the equivalence range of 80-125 percent, standard Agency practice is to conclude that no clinically significant differences are present. If, based on lactation studies, there is a need for dose adjustment while a women is lactating, the labeling would describe the relationship between the medical product's PK and lactation. Typically the dose regimen is adjusted to produce comparable Cmax and AUC values. Simulations are encouraged as a means to identify doses and dosing intervals that achieve that goal.
It is possible to use data from kinetic profiles in milk to provide recommendations for ways to minimize exposure of the breast-fed child to a drug via breast milk. The Agency recommends that the labeling describe the relationship between maternal drug administration and breast-feeding, taking into account drug kinetics such as half-life in milk. For example, ways to minimize exposure to drug in breast milk might include information regarding (1) the timing of maternal dose relative to breast-feeding, (2) the duration of time relative to maternal drug administration to discard breast milk (e.g., "pump and dump"), and (3) how long to wait until resuming breast-feeding relative to maternal dose.
The Agency recommends that labeling reflect the data from clinical lactation studies and, if known, dosing recommendations during lactation. The labeling would reflect the data pertaining to the effect of lactation on the PK and PD (if known) obtained from studies conducted. If the PK and/or PD are altered during lactation, the Agency recommends that the appropriate description of such and recommendations for dosing be stated in labeling. The labeling would contain information pertaining to drug transfer into breast milk, the exposure of breast-fed infants to drugs in breast milk, and the drug effect on milk production and composition, if known. Non-positive findings are to be interpreted as indicating failure to detect an impact of lactation on PK or PD rather than lack of an effect. The various permutations of intrinsic drug characteristics and the effect of lactation on drug performance preclude precise specification of how such drugs can be labeled. The following comments offer general suggestions on labeling.
In addition to standard labeling for use in lactation, if studies performed during lactation demonstrate clinically important changes, the Agency recommends that such information be included in the PRECAUTIONS/NURSING MOTHERS section with cross-reference to DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections. It is recommended that labeling contain information, to the extent possible, based on the lactation study conducted, including:
As appropriate, the following information would be included:
Although nonclinical models (e.g., mechanistic, in vitro, animal, physicochemical-based, and physiological-based PK (PBPK)) have demonstrated limited success in predicting the amount of drug in breast milk and in predicting infant exposures to drug in breast milk (Oo, Transport of Cimetidine, 1995; Oo, Alprazolam Transfer, 1995) the applicability of nonclinical predictive models is still under investigation. Because of this, data obtained from clinical lactation studies would enable testing of the predictive value of these nonclinical models. The incorporation of the additional information obtained from clinical lactation studies into nonclinical models would strengthen the association between predicted and observed exposures and optimally improve the predictability of such approaches.
American Academy of Pediatrics (AAP), 1989, American Academy of Pediatrics Committee on Drugs: Transfer of Drugs and Other Chemicals into Human Milk, Pediatrics, 84(5):924-36. American Academy of Pediatrics (AAP), 1994, American Academy of Pediatrics Committee on Drugs: Transfer of Drugs and Other Chemicals into Human milk, Pediatrics, 93(1):137-50. AAP Committee on Drugs, 2001, Transfer of Drugs and Other Chemicals into Human Milk, Pediatrics, 108(3):776-89. AAP Work Group on Breastfeeding, 1997, Breastfeeding and the Use of Human Milk, Pediatrics, 100(6):1035-1039. Begg, EJ, SB Duffull, DA Saunders et al., 1999, Paroxetine in Human Milk, Br J Clin Pharmacol, 48:142-147. Bennett, PN (ed), 1988, Drugs and Human Lactation, Amsterdam: Elsevier. Bennett, PN (ed), 1996, Drugs and Human Lactation, 2nd edition, Amsterdam: Elsevier. Berlin, CM Jr, JS LaKind, BR Sonawane et al., 2002, Conclusions, Research Needs and Recommendations of the Expert Panel: Technical Workshop on Human Milk Surveillance and Research for Environmental Chemicals in the United States, J. Toxicol. Environ. Health, Part A, 65:1929-1935. Fleishaker, JC, N Desai, and PJ McNamara, 1989, Possible Effect of Lactational Period on the Milk-to-Plasma Drug Concentration Ratio in Lactating Women: Results of an In Vitro Evaluation, J Pharm Sci, 78(2):137-141. Hagg, S and O Spigset, 2000, Anticonvulsant Use During Lactation, Drug Saf, 22:425-440. Hibberd, CM, OG Brooke, ND Carter et al., 1982, Variation in the Composition of Breast Milk During the First 5 Weeks of Lactation: Implications for the Feeding of Preterm Infants, Arch Dis Child, 57(9):658-662. Kristensen, JH, KF Ilett, LP Hackett et al., 1999, Distribution and Excretion of Fluoxetine and Norfluoxetine in Human Milk, Br J Clin Pharmacol, 48:521-527. Neville, MC, 2001, Anatomy and Physiology of Lactation, Pediatr Clin North Am, 48(1):13-34. Oo, YC, RJ Kuhn, N Desai, and PJ McNamara, 1995, Active Transport of Cimetidine into Human Milk, Clin Pharmacol Ther, 58:548-555. Oo, YC, RJ Kuhn, N Desai et al., 1995, Pharmacokinetics in Lactating Women: Prediction of Alprazolam Transfer into Milk, Br J Clin Pharmacol, 40:231-236. Ryan, AS, Z Wenjun, and A Acosta, 2002, Breastfeeding Continues to Increase into the New Millennium, Pediatrics, 110:1103-1109. U.S. Department of Health and Human Services (DHHS), 2000, Healthy People 2010: Understanding and Improving Health, 2nd ed., Washington, DC: U.S. Government Printing Office (http://www.health.gov/healthypeople/document/). World Health Organization, 1989, Levels of PCBs, PCDDs and PCDFs in Breast Milk: Results of WHO-Coordinated Interlaboratory Quality Control Studies and Analytical Field Studies, in Yrjanheikki EJ (ed), Environmental Health Series RPt 34, Copenhagen: World Health Organization Regional Office for Europe. Wilson, JT, RD Brown, JL Hinson, and JW Daily, 1985, Pharmacokinetic Pitfalls in the Estimation of the Breast Milk/Plasma Ratio for Drugs, Ann Rev Pharmacol Toxicol, 25:667-689. Wojnar-Horton, RE, LP Hackett, P Yapp et al., 1996, Distribution and Excretion of Sumatriptan in Human Milk, Br J Clin Pharmacol, 41:217-221.
1This 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. 2Throughout this document, the term medical product or drug means drug and biological products and their metabolites, including vaccines. 3The terms child(ren) and infant(s) are used interchangeably in this guidance to refer to human breast-feeding offspring of any age. 4Guidance for Industry Exposure-Response Relationships: Study Design, Data Analysis, and Regulatory Applications. 5Guidance for Industry Population Pharmacokinetics. 6Guidance for Industry Bioanalytical Method Validation. 7Guidance for Industry Population Pharmacokinetics.
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