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Guidance for Industry
Clinical Lactation Studies – Study Design, Data Analysis, and
Recommendations for Labeling
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version of this document)
DRAFT GUIDANCE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being distributed for comment purposes only.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of the draft guidance.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
Additional copies are available
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http://www.fda.gov/cber/guidelines.htm
February 2005
Clinical Pharmacology
Guidance for Industry
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draft guidance, when finalized, will represent the Food and Drug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
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
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.
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:
- 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.
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.
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).
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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)
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-t
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:
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 Collection Interval (hrs) |
Milk Drug |
Milk Volume |
Drug in Milk (mg) |
Concentration (mg/mL) |
Expressed (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 AUCmilk to AUCplasma. The average
maternal serum concentration refers to AUC0-¥/dosing
interval after maternal ingestion of a single dose of drug or AUC0-t/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-t)
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.
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.
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
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]
was studied in [number of] lactating women from [a through b months
postpartum]. Lactation has little to no influence on [Drug X]
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]
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]/metabolite was
[reduced/increased] in lactating women compared to non-lactating
women. The terminal half-life of [Drug X]/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] 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] [t1
time] after dosing and drug concentrations in milk rapidly declined
over [the next time duration, t2 time]. The estimated
daily infant dose for [Drug
X] 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 [t3
time] or later after dosing.
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
As
appropriate, the following information would be included:
- A
statement describing the relationship between [Drug X]’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]
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] 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.
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.
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Date created: February 8, 2005 |
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