**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***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes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notice announcing the availability of the draft guidance.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**

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*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](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. BACKGROUND [2](#ii.-background) {#ii.-background-2 .TOC-1}

# III. CONSIDERATIONS FOR WHEN TO CONDUCT A CLINICAL LACTATION STUDY [4](#iii.-considerations-for-when-to-conduct-a-clinical-lactation-study) {#iii.-considerations-for-when-to-conduct-a-clinical-lactation-study-4 .TOC-1}

# IV. STUDY DESIGN CONSIDERATIONS [5](#iv.-study-design-considerations) {#iv.-study-design-considerations-5 .TOC-1}

## A. Mother-Infant Pair Design [5](#mother-infant-pair-design) {#a.-mother-infant-pair-design-5 .TOC-2}

## B. Lactating Women Only Designs [6](#b.-lactating-women-only-designs) {#b.-lactating-women-only-designs-6 .TOC-2}

### 1. Lactating Women (Plasma and Milk) [6](#lactating-women-plasma-and-milk) {#lactating-women-plasma-and-milk-6 .TOC-3}

### 2 Lactating Women (Milk Only) [7](#lactating-women-milk-only) {#lactating-women-milk-only-7 .TOC-3}

## C. Other Design Considerations [7](#c.-other-design-considerations) {#c.-other-design-considerations-7 .TOC-2}

### 1. Longitudinal Design [7](#longitudinal-design) {#longitudinal-design-7 .TOC-3}

### 2. Multiple Arm Design [8](#multiple-arm-design) {#multiple-arm-design-8 .TOC-3}

### 3. Study Participants [8](#study-participants) {#study-participants-8 .TOC-3}

### 4. Controls [9](#controls) {#controls-9 .TOC-3}

### 5. Sample Size [9](#sample-size) {#sample-size-9 .TOC-3}

### 6. Sample Collection and Analysis [9](#sample-collection-and-analysis) {#sample-collection-and-analysis-9 .TOC-3}

### 7. Population PK Studies [10](#population-pk-studies) {#population-pk-studies-10 .TOC-3}

### 8. Pharmacodynamic Assessments [11](#pharmacodynamic-assessments) {#pharmacodynamic-assessments-11 .TOC-3}

# V. DATA ANALYSIS [11](#v.-data-analysis) {#v.-data-analysis-11 .TOC-1}

## A. Parameter Estimation [11](#a.-parameter-estimation) {#a.-parameter-estimation-11 .TOC-2}

## B. Development of Dosing Recommendations for Lactating Women [13](#b.-development-of-dosing-recommendations-for-lactating-women) {#b.-development-of-dosing-recommendations-for-lactating-women-13 .TOC-2}

## C. Development of Recommendations to Minimize Infant Drug Exposure from Breast Milk [14](#c.-development-of-recommendations-to-minimize-infant-drug-exposure-from-breast-milk) {#c.-development-of-recommendations-to-minimize-infant-drug-exposure-from-breast-milk-14 .TOC-2}

# VI. LABELING [15](#vi.-labeling) {#vi.-labeling-15 .TOC-1}

## A. Clinical Pharmacology [15](#a.-clinical-pharmacology) {#a.-clinical-pharmacology-15 .TOC-2}

### 1. Pharmacokinetics Subsection [15](#pharmacokinetics-subsection) {#pharmacokinetics-subsection-15 .TOC-3}

### 2. Special Populations Subsection [15](#special-populations-subsection) {#special-populations-subsection-15 .TOC-3}

## B. Precautions/Nursing Mothers [16](#b.-precautionsnursing-mothers) {#b.-precautionsnursing-mothers-16 .TOC-2}

## C. Dosage and Administration [17](#c.-dosage-and-administration) {#c.-dosage-and-administration-17 .TOC-2}

# VII. CONSIDERATIONS FOR FUTURE RESEARCH [17](#vii.-considerations-for-future-research) {#vii.-considerations-for-future-research-17 .TOC-1}

# BIBLIOGRAPHY [18](#bibliography) {#bibliography-18 .TOC-1}

**Guidance for Industry**[^1]

**Clinical Lactation Studies: Study Design, Data Analysis, and
Recommendations for Labeling**

This draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the
FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.

# I. INTRODUCTION

This guidance provides recommendations for how and when to conduct
clinical lactation studies and how to assess the influence of drugs or
biologic products[^2] 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:

-   The influence of lactation on maternal pharmacokinetics (PK), and
    where appropriate pharmacodynamics (PD)

-   The extent of drug transfer into breast milk

-   The effects of drugs on milk production and composition

-   The extent and consequent effects on breast-fed infants[^3] of
    exposure to drugs in breast milk

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.

# II. BACKGROUND

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.

# III. CONSIDERATIONS FOR WHEN TO CONDUCT A CLINICAL LACTATION STUDY

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

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

-   After approval, use of a drug in lactating women becomes evident
    (e.g., via reports in the medical literature or lay press)

-   A new indication is being sought for an approved drug and there is
    evidence of use or anticipated use of the drug by lactating women

-   Marketed medications that are commonly used by women of reproductive
    age (e.g., antidepressants, antihypertensives, anti-infectives,
    diabetic and pain medications)

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.

# IV. STUDY DESIGN CONSIDERATIONS

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:

-   A study of lactating women (plasma and milk) or lactating women
    (milk only) would be performed before a mother-infant pair study.

-   Data from studies in lactating women coupled with what is known
    about a drug in the pediatric population can supplant the need for
    further lactation studies in the breast-fed child.

-   Any of these strategies could potentially provide data on the extent
    of drug transfer into breast milk, effect on milk production, and
    milk composition (e.g., volume, fat, protein, immunologic
    characteristics).

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.

## Mother-Infant Pair Design

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

-   Determine the PK of the drug in lactating women

-   Determine the amount of drug transferred into breast milk

-   Show effects of drug on milk production and composition

-   Assess drug exposure and PD in the breast-fed child

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:

-   High lipophilicity (weak bases)

-   Potential for accumulation in breast milk

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

-   Wide distribution to multiple organs

-   Long half-life

## B. Lactating Women Only Designs

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

The *lactating women (plasma and milk)* study design provides data on
the PK of a drug in lactating women, the amount of drug transferred into
breast milk, and effects of a drug on milk production and composition.
Infant sampling is not performed in this type of study; therefore, the
systemic exposure of the infant cannot be measured (although *total
dose* can be estimated). Data allow for determination of the
concentration-time profiles and subsequent PK calculations from maternal
blood and milk. This design enrolls lactating women and includes
frequent collection of corresponding maternal blood and milk samples.
Study subjects include lactating women who are planning to receive or
are currently receiving study medication, lactating women who need the
study medication and will interrupt breast-feeding their infant, and/or
healthy lactating volunteers.

In a sequential or step-wise approach to lactation studies, the
*lactating women (plasma and milk)* study design might be considered
before the infant is exposed to drug via breast milk in a more complex
study. Situations that might favor use of this design include newly
approved drugs (especially for drugs with no pediatric data), short-term
or acute maternal dosing, and unknown risk of exposure to the breast-fed
child. Drug and metabolite characteristics that favor selection of this
study design include:

-   High lipophilicity (weak bases)

-   Presence in milk

-   Predictions that drug is present in milk

-   Knowledge of a class effect

### 2. Lactating Women (Milk Only)

The *lactating women (milk only)* study design enrolls lactating women
and includes frequent maternal milk samples throughout the dosing
interval, a specific time period (e.g., a 24-hour period), or the entire
time course of lactating (e.g., months). This study design allows the
detection of the presence of a drug in milk. It can also be useful to
estimate ways to assess strategies to minimize exposure of the
breast-fed child to a drug. Such data can be especially useful for drugs
with short half-lives or those associated with sporadic or intermittent
use (e.g., migraine therapy). For example:

-   *Milk only* studies can provide information regarding timing of
    maternal dose relative to breast-feeding, the duration recommended
    to discard milk relative to maternal dose, and when to resume
    breast-feeding relative to maternal dose or drug exposure.

-   A finding that showed the amount of drug in breast milk to be
    exceedingly low could preclude the need for further studies
    depending on the drug and its clinical use and toxicity.

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

Adequately designed studies would address baseline characteristics and
diurnal variation including control group and run-in or lead-in periods
prior to drug administration.

## C. Other Design Considerations

### 1. Longitudinal Design

For drugs that are administered chronically or given for several
treatment cycles, a longitudinal study design can be considered. Such a
study would focus on comparing samples obtained from lactating patients
at one postpartum time (e.g., 2-3 months postpartum) to samples obtained
from the same patients at a different postpartum time (e.g., 5-6 months)
and/or after weaning is complete. Each woman serves as her own control.
The post-weaning sampling determines maternal PK and/or PD
characteristics from serum sampling only and can capture information at
similar times after weaning in all study subjects (e.g., 1 month
post-weaning). This longitudinal design would minimize inter-individual
variability across the postpartum period. Infant sampling might also be
included in a longitudinal study design (e.g., infant sampling in a
longitudinal design might assess infant exposure to drug via breast milk
over time in drugs chronically taken by lactating women). Longitudinal
infant sampling could assess changes in drug absorption and clearance as
well as PD effects at different stages of pediatric development. The
Agency encourages that an analytical plan of the study take into
consideration the repeat measures characteristics of a longitudinal
design.

### 2. Multiple Arm Design

For drugs that are given acutely (e.g., single dose or short course of
therapy), it is generally difficult to perform a longitudinal design
using the same patient throughout lactation. One alternative is to
conduct a multiple arm study designed to compare different lactating
patients at different postpartum times (e.g., a sample of women each at
2-3 months and 5-6 months postpartum). Each woman serves as her own
control and has PK and/or PD determinations performed after weaning is
complete.

In certain circumstances drug therapy is no longer clinically indicated
later in the postpartum period or when weaning is complete. If possible
a single-dose PK/PD study can be performed to allow each woman to serve
as her own control. This applies to drugs that possess linear PK. If it
is impossible to administer drug in the same women (study population),
then an additional arm of the study using a different population of
postpartum women (appropriately matched healthy female volunteers, as a
last resort) would be included.

### 3. Study Participants

Optimally, study participants represent a typical patient population,
including race and ethnicity, for the drug to be studied. Maternal
factors with significant potential to affect lactation (e.g., weight,
gravity, parity, stage of lactation, postpartum status, and episodes and
duration of previous lactation) and the PK of a drug to be studied
(e.g., diet, smoking, alcohol intake, concomitant medications,
ethnicity, other medical conditions) are important considerations.
Infant factors (e.g., age, term versus preterm neonates, extent of
breast-feeding, and age-related changes in absorption, distribution,
metabolism, and excretion) also might warrant special consideration,
depending on the drug. It is important to apply uniform diagnostic
factors to all patients enrolled in the study to ensure uniformity of
diagnosis of the condition for which treatment is being given and to
reduce disease-specific variability in PK.

For drugs that are hepatically metabolized and known to exhibit genetic
polymorphism (e.g., CYP2D6 or CYP2C19), the metabolic status of the
enrolled subjects (maternal and infant) can be important factors when
analyzing the results of the study.

### 4. Controls

Ideally the lactating woman would serve as her own control, for example,
by undergoing PK assessment(s) during lactation and again after weaning
is complete. For PK/PD studies, potential control groups include healthy
non-lactating female volunteers or non-lactating female volunteers with
the medical condition of interest. Studies that evaluate the effect of
drug on milk production and composition could include lactating female
volunteers who are not using the test drug or, preferably, lactating
female volunteers who have the medical condition of interest. If female
volunteers are used as controls, the Agency recommends matching them to
study subjects (e.g., postpartum status, age) and identifying time
windows (e.g., 3-4 months postpartum) to account for variability in
physiologic postpartum changes. The Agency recommends that the study
protocol provide the rationale for the make-up of the control group
selected.

### 5. Sample Size

Determination of an adequate sample size depends on the objective and
design of a study. For a study that examines plasma PK in the mother or
lactating woman, the Agency recommends that the number of patients
enrolled in the study be sufficient to detect clinically significant
differences (e.g., PK differences large enough to warrant dosage
adjustments). The PK variability of the drug as well as the PK and PD
relationships for both therapeutic and adverse responses (therapeutic
range) would inform this decision. Sample size considerations include PK
and PD variability for the drug being studied, the study design (i.e.,
single-dose vs. multiple-dose), and the variability in lactation
physiology. Inter- and intra-subject variability for mother and
breast-fed child can be considered depending on the design and primary
objective of the 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]

The final number of patients enrolled would likely be in excess of the
number originally calculated by standard sample size calculations to
take into account dropouts and subsequent exclusion from the study,
especially for longitudinal study designs. The institution conducting
the study can rely on past experience to aid in understanding the usual
number of patients who complete a clinical lactation study, given
dropouts or other issues.

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

### 6. Sample Collection and Analysis

The Agency recommends that the frequency and duration of sampling be
sufficient to accurately detect the outcome selected (e.g., estimate the
relevant PK parameters for the parent drug and metabolites --- see
Section V., Data Analysis). It is important to collect samples to
characterize the complete dosing interval; each breast would be
completely emptied and the volume of milk recorded. An electric milk
pump is recommended since milk composition can vary with the method
used. Separate collection containers would be used for each milk
collection. Separate milk samples obtained within each collection
interval might be pooled (e.g., 4-8 hour post-dosing) and an aliqout
removed for analysis. Multiple collection time intervals of milk would
permit the full milk concentration-time profile and subsequent
estimation of PK parameters in milk. It is recommended that the protocol
specify instructions for sample handling, especially for milk samples
(e.g., methods to minimize contamination).

The Agency recommends that milk be completely expressed from each
breast, mixed, and a sample removed for analysis. For *mother-infant
pair* studies, the infant can be bottle-fed expressed milk. Infant milk
consumption can be determined by measuring the volume of expressed
breast milk consumed or, alternatively, by weighing the infant before
and after feeding. Weighing the infant before and after feeding can be a
more accurate method of determining milk consumption because it accounts
for any milk volume lost via dribbling, drooling, and burping the
breast-fed infant. This post-feeding weight accounts for any infant
voiding (e.g., urine, stool) that occurred during feeding. For
characterization of the terminal elimination phase of the drug in the
breast-fed child, previously collected drug-free breast milk or formula
can be substituted at subsequent feedings.

The Agency recommends that total and unbound concentrations of drug and
metabolites in plasma be determined; for other biological matrices
(e.g., breast milk) total concentrations of drug and metabolites are
likely sufficient. It is important that method validation address
accuracy, precision, selectivity, sensitivity, reproducibility, and
stability.[^6] Because of varying lipophilicity among drugs, it is also
important to assay milk samples for milk fat.

Alternative, noninvasive pediatric sampling strategies (e.g., saliva,
tears) might also be used to estimate drug levels in infants. However,
drug concentrations obtained from alternative fluids (e.g., saliva,
tears) might not be equivalent to those obtained from plasma. Sponsors
are, therefore, encouraged to demonstrate the relationship of the drug
concentration between plasma and alternative fluids in adults.
Estimating infant drug exposure via breast milk solely from excretion of
unchanged drug in infant urine can be of limited utility because of the
difficulty with urine collection and the variability of renal clearance
and urine production in infants.

### 7. Population PK Studies

A population PK approach is a possible alternative way to enroll
lactating women (and breast-fed children) in PK studies and minimize the
number of blood draws and PD assessments. The population PK approach
assesses the impact of various covariates on the PK of a drug. Practical
difficulties in conducting a population study can limit the value of
such a study. Validated sparse sampling methods based on optimal
sampling theory and limited sampling methods are useful in determining
the optimal sampling times to best estimate PK parameters. Further
information on this approach is available in Agency guidance.[^7]

### 8. Pharmacodynamic Assessments

Whenever appropriate, the Agency encourages PD assessment to be included
in clinical lactation studies and discussed with the appropriate FDA
review staff. Given the assumption of an unaltered PK/PD relationship,
PK measurements alone would generally be recommended for lactation
studies, although PD studies might sometimes provide additional useful
information. If studied, the PD endpoints chosen can be based on the
pharmacological characteristics of the parent drug and metabolites
(e.g., extent of protein binding, therapeutic range, and the behavior of
other drugs in the same class in lactating patients). Similarly,
biomarkers might be used to measure PD endpoints of interest. PD
assessments in the breast-fed child can also be considered (e.g., heart
rate and rhythm response to maternal administration of drug).

# V. DATA ANALYSIS

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:

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

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

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

-   Estimation of alterations of breast milk (e.g., production and
    composition) and the resulting impact on the breast-fed child

-   Development of dosing recommendations including an assessment of
    whether dosage adjustment is warranted in lactating patients

-   Estimation of ways to minimize exposure of the breast-fed child to
    drug via breast milk (e.g., timing of maternal dose relative to
    breast-feeding, recommended duration to discard milk relative to
    maternal dose, resumption of breast-feeding relative to maternal
    dose or drug exposure)

## A. Parameter Estimation

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; AUC~0-t~ or AUC~0-∞~ in single-dose studies
and AUC~0-τ~ at steady state), peak plasma concentration (C~max~), time
to peak plasma concentration (t~max~), plasma clearance (CL~T~) or
apparent oral clearance (CL/F), apparent volume of distribution (V~Z~/F
or V~ss~/F), and terminal half-life (t~1/2~). The Agency recommends that
the area under the milk concentration-time curve over 24 hours (AUCm;
AUC~0-24~) 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:

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

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 ×

expressed milk volume in each milk collection)

> EXAMPLE: Daily infant dosage
>
> The data in the table below reflect milk collected for 24 hours with
> the following drug concentrations and volumes for each sampling
> interval.

  ----------------- --------------------- --------------- ----------------
  **Sample          **Milk Drug**         **Milk Volume** **Drug in Milk
  Collection                                              (μg)**
  Interval (hrs)**                                        

                    **Concentration       **Expressed     
                    (μg/mL)**             (mL)**          

  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
  ----------------- --------------------- --------------- ----------------

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

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

> Estimated Daily Infant Dosage (mg/kg/day) = M/P × average maternal
> serum concentration × 150 mL/kg/day

In this case M/P (milk-to-plasma ratio) is the ratio of AUC~milk~ to
AUC~plasma~. The average maternal serum concentration refers to
AUC~0-∞~/dosing interval after maternal ingestion of a single dose of
drug or AUC~0-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
(AUC~0-∞~) after maternal ingestion of a single dose of drug or the AUC
within a dosing interval (AUC~0-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:

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

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:

> Css,ave = F x infant dosage/CL

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.

## B. Development of Dosing Recommendations for Lactating Women

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
C~max~ 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 C~max~ and AUC values.
Simulations are encouraged as a means to identify doses and dosing
intervals that achieve that goal.

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

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.

# VI. LABELING

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.

## A. Clinical Pharmacology

### 1. Pharmacokinetics Subsection

This section would include information pertinent to lactation on the:

-   Disposition of parent drug and metabolites, if applicable

-   Effects of lactation on protein binding, if applicable

### 2. Special Populations Subsection

This section would recapitulate, in brief, the PK changes found in
lactation and, if needed, dosing adjustments for lactating patients. The
section would briefly describe any data regarding 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. This
information would be based on the studies performed as described in this
guidance. Reference would be made to the PRECAUTIONS/NURSING MOTHERS and
the DOSAGE AND ADMINISTRATION sections. The following text provides
examples of possible wording for these sections.

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

> *The disposition of [\[Drug X\]]{.underline} was studied in \[number
> of\] lactating women from \[a through b months postpartum\]. Lactation
> has little to no influence on [\[Drug X\]]{.underline}
> pharmacokinetics and no dosing adjustment is needed.*

Similarly, for drugs whose PK is influenced by lactation, the following
statement can be modified in accordance with what is known about the
drug (e.g., active or toxic metabolite) and from the studies performed
in accordance with this guidance:

> *The disposition of [\[Drug X\]]{.underline} was studied in \[number
> of\] lactating women from \[a through b months postpartum\].
> Elimination of the drug (and metabolite, if applicable) is
> significantly changed during lactation. Total body clearance of
> (unbound, if applicable) [\[Drug X\]]{.underline}/metabolite was
> \[reduced/increased\] in lactating women compared to non-lactating
> women. The terminal half-life of [\[Drug X\]]{.underline}/metabolite
> is \[prolonged/decreased\] by \[Y-fold\]. (See DOSAGE AND
> ADMINISTRATION.)*

Similarly, the following statement can be modified as appropriate to
describe drug transfer into breast milk:

> *A \[dose (mg), single or multiple dose\] of [\[Drug X\]]{.underline}
> was administered \[route of drug administration (e.g., oral,
> intravenous)\] to \[number of\] lactating women who were \[a through b
> months postpartum\]. Breast milk obtained for \[c hours\] after dosing
> revealed a maximum concentration of \[y concentration\] \[t~1~ time\]
> after dosing and drug concentrations in milk rapidly declined over
> \[the next time duration, t~2~ time\]. The estimated daily infant dose
> for [\[Drug X\]]{.underline} from breast milk is \[z dose or z mg\]
> which represents \[\_\_\_\_\_%\] of maternal dose and \[\_\_\_\_\_%\]
> of the lowest approved pediatric dose (if applicable). No drug was
> detectable in milk samples obtained \[t~3~ time\] or later after
> dosing.*

## B. Precautions/Nursing Mothers

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:

-   PK/PD in lactation

-   The effect of drug on milk production (e.g., quality and quantity of
    milk including milk production and composition)

-   The presence of drug or metabolite in milk, including the limitation
    of the assay used if drug/metabolites are not detected in milk

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

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

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

-   Possible ways to minimize exposure in the breast-fed child to drug
    via breast milk taking into account drug kinetics such as half-life
    in milk (e.g., timing of maternal dose relative to breast-feeding,
    the duration to discard breast milk relative to maternal dose, and
    how long to wait until resuming breast-feeding relative to maternal
    dose)

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

-   PK of drug in the breast-fed infant

## C. Dosage and Administration

As appropriate, the following information would be included:

-   A statement describing the relationship between [\[Drug
    X\]]{.underline}'s clearance and lactation

-   A statement describing how the dose would be adjusted during
    lactation within the approved therapeutic range:

> *The dose of [\[Drug X]{.underline}\] should be
> \[increased/decreased\] by \[\_\_\_\_\_%\] during lactation.*

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

> *The influence of lactation on [\[Drug X\]]{.underline}
> pharmacokinetics is sufficiently small that no dosing adjustment is
> needed.*

-   A statement cross-referencing the Precautions/Nursing Mothers
    section of labeling when possible ways to minimize exposure in the
    breast-fed child with respect to timing of maternal dose relative to
    breast-feeding are included in the Precautions/Nursing Mothers
    section.

# VII. CONSIDERATIONS FOR FUTURE RESEARCH

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.

# BIBLIOGRAPHY

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.

[^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.

[^4]: Guidance for Industry *Exposure-Response Relationships: Study
    Design, Data Analysis, and Regulatory Applications*.

[^5]: Guidance for Industry *Population Pharmacokinetics*.

[^6]: Guidance for Industry *Bioanalytical Method Validation*.

[^7]: Guidance for Industry *Population Pharmacokinetics*.