#### CONCEPT PAPER ON PREGNANCY LABELING

SUMMARY OF COMMENTS FROM A PUBLIC HEARING AND MODEL PREGNANCY LABELING
BASED ON RECOMMENDATIONS

May 20, 1999

##### INTRODUCTION

This concept paper has been developed by the FDA Pregnancy Labeling
Taskforce to serve several purposes beginning with summarization of
concerns that have been raised about current regulations that guide
labeling of new drugs and biologic products for use in pregnancy \[CRF
312.57 (f)(6)\]. Second, it outlines recommendations to FDA from
multiple stockholders at a Part 15 public hearing held in September
1997. Third, this concept paper describes a (draft) model for pregnancy
labeling that begins to address the concerns and recommendations. It
outlines a format with general content designed to facilitate
discussion. Within the text of this concept paper, "issues" are
highlighted. These are placed in close proximity to parts of the draft
model to provide "food for though," for the reader. Some are statements
and other issues are posed as questions.

**PREGNANCY LABELING ISSUES**

Under current FDA regulations, unless a drug is not absorbed
systemically and is not known to have a potential for indirect harm to
the fetus, its labeling must include a Pregnancy subsection. The
Pregnancy subsection must contain information on the drugs teratogenic
effects and other effects on reproduction and pregnancy. When relevant,
effects on later growth, development, and functional maturation of the
child (21 CFR 201.57(f)(6) must also be included. The regulation
requires that each product be classified under one of five letter
categories (A, B, C, D, or X) on the basis of risk of reproductive and
developmental adverse effects or, for certain categories, on the basis
of such risk weighed against potential benefit. (See Appendix A).

##### Concerns with Current Pregnancy Labeling Requirements

Clinicians who treat pregnant women and women of childbearing potential,
academic and specialty medical organizations, womens health
organizations, and others have expressed concerns about the usefulness
of pregnancy labeling. They maintain that information contained in the
typical pregnancy labeling subsection, and the way it is presented under
current regulations, is not sufficient for practitioners and patients to
make informed decisions about drug therapy in pregnant women. Further,
most pregnancy sections of existing labels are not informative in
facilitating decisions about what to do in the event of inadvertent
fetal drug exposure. The pregnancy categories are considered a
significant part of the problem.

There have been two major criticisms of the categories. First, they
convey the incorrect impression that reproductive risk increases from
category A to B to C to D to X. This confusion occurs because the
criteria for inclusion in categories A, B, and to a certain extent C,
may reflect increasing risk from A to C, while criteria for inclusion in
categories D, X, and to a certain extent C, are based on risk weighed
against potential benefit. Thus, drugs in categories D, X, and in some
cases C, may pose similar risk, but be categorized differently on the
basis of different risk/benefit considerations. Second, the categories
create the impression, often mistaken, that the drugs within a given
category present similar reproductive risks. For drugs with identified
risks, existing inclusion criteria may permit, in the same category,
drugs that vary in the type, degree, or extent of risk. The category
inclusion criteria may also place drugs with known risks and drugs for
which there are no known risks in the same category. For example,
category C may include drugs with demonstrated adverse reproductive
effects in animals and drugs for which no animal studies have been
performed. Category B may include drugs which have no demonstrated
adverse reproductive or developmental effects in animals and for which
there are no adequate and well-controlled data in humans. Category B may
also include drugs that have demonstrated adverse reproductive or
developmental effects in animals but did not demonstrate adverse effects
in adequate and well-controlled trials in humans.

**Public Hearing on the Pregnancy Labeling Categories**

In September of 1997, the agency held a public hearing on the current
category requirements for pregnancy labeling (62 FR 41061, July 31,
1997) to obtain comment on the practical utility, effects and problems
associated with the categories. The agency also sought input on ways to
address these problems, including possible alternatives to the
categories for communicating information on reproductive and
developmental toxicity. The following are the specific issues the agency
sought comment on and summaries of the comments received:

1.  **The extent to which the category designations are relied upon in
    making decisions about drug therapy in pregnant women and women of
    childbearing potential and decisions about inadvertent fetal
    exposure, the extent to which such reliance may be misplaced, and
    the extent to which such reliance may have untoward public health
    consequences:**

There was consensus that, because the category designations appear to
provide a simple, convenient measure of risk, they are routinely relied
upon by clinicians and others in making decisions about drug therapy in
pregnant women and women of childbearing potential. There was concern
that, because such decisions are more complex than the category
designations suggest, such reliance may often be inappropriate.

2.  The extent to which current pregnancy labeling (category designation
    and ccompanying narrative text) is effective in communicating risk
    of reproductive and developmental toxicity:

There was consensus that the current category system is confusing and
overly simplistic and, therefore, not adequate to effectively
communicate risk of reproductive and developmental toxicity. There was
concern that, because each category includes under a single letter
designation a wide range of products used in a wide range of potential
clinical situations, the category designation erroneously suggests that
drugs within a category present quite similar risks or risk-benefit
considerations.

3.  The extent to which current pregnancy labeling may not adequately
    address the range of issues that bear on decisions about drug
    therapy in pregnant women and women of childbearing potential and
    decisions about inadvertent fetal exposure (e.g.,
    indication-specific concerns, pregnancy status, magnitude of
    exposure, incidental exposure, chronic exposure, timing of
    exposure):

> There was consensus that current pregnancy labeling does not
> adequately address the range of clinical situations in which
> information about drug exposure in pregnancy is needed. There was
> concern that current pregnancy labeling focuses almost entirely on
> prospective consideration of whether to prescribe a drug for a
> pregnant woman, or a woman who may become pregnant, and usually does
> not address inadvertent exposure (where a woman is taking a drug and
> discovers she is pregnant). Because a majority of pregnancies are
> unplanned and, therefore, there is significant potential for
> inadvertent exposure to a drug before a pregnancy is detected, there
> was strong support for addressing inadvertent exposure issues in
> pregnancy labeling.

4.  **Additional information (data or interpretation of data) that could
    be included in pregnancy labeling to better address the range of
    issues that bear on decisions about drug therapy in pregnant women
    and women of childbearing potential and decisions about inadvertent
    fetal exposure:**

> There was consensus that current pregnancy labeling does not
> adequately address the full range of potential developmental
> toxicities\--fetal death, structural malformations, perturbations of
> fetal growth, and functional deficits. There was also concern that
> current labeling does not present enough of the evidentiary basis for
> the category designation or adequately discuss the potential relevance
> of animal data to humans. FDA was urged to implement a mechanism to
> routinely update the pregnancy section of labeling after a drug is
> marketed to include human exposure information, as it becomes
> available. FDA was also encouraged to incorporate discussions of a
> products effects on fertility, pregnancy, and lactation issues into a
> single labeling subsection.

5.  Options to improve communication of reproductive and developmental
    risk in labeling, which could include alternatives to the categories
    (both content and format options) or efforts to make the current
    category scheme and accompanying narrative text more consistent and
    informative:

There was consensus that the current letter categories should be
replaced. There was considerable support for replacing the categories
with a concise narrative summarizing a product's risks to pregnant women
and women of childbearing potential, and a separate statement discussing
the clinical implications of such risks. To aid comprehension and
facilitate evaluation of therapeutic options, it was recommended that
the narratives contain common core elements. Some comments also
supported providing a conclusive statement or recommendation about
clinical use. FDA was also encouraged to take steps to better understand
how language used to communicate risk (terms and statements) is
perceived by potential users of pregnancy labeling.

**Principle Recommendations from the Public Hearing**

From the hearing testimony and comments, FDAs Pregnancy Labeling
Taskforce has identified five major recommendations for changes in the
format and content of pregnancy labeling.

-   The current pregnancy letter category designations and accompanying
    text should be replaced by narrative text that is more informative
    and less prone to misinterpretation or misapplication.

-   The narrative text should provide more detailed clinical management
    advice than it presently does, including advice relevant to
    inadvertent fetal exposure. This advice should more specifically
    address the unique situations presented by a product and its
    indication(s), but have a structure that is similar enough from drug
    to drug to allow users to readily find information and to compare
    therapeutic alternatives.

-   The labeling should provide a concise summary of risks associated
    with a product, including the settings in which the relevant
    toxicities occurred.

-   The labeling should contain a broader and more meaningful discussion
    of the data, animal and human, that underlie the evaluation of risks
    associated with a product.

-   Fertility, pregnancy, and lactation are a clinical continuum,
    therefore it would be logical and useful to address these situations
    in the same section of the labeling.

##### Draft Model Labeling: Content and Format

To illustrate possible applications of these recommendations the
Taskforce has developed a model labeling format. The Taskforce has also
applied the format to two fictitious drug products (Appendices B and C).
These labeling examples are being provided solely for the purpose of
illustrating the model format and not to generate specific comment on
the details of the underlying data. In describing the format and content
of the model labeling issues that offer "food for thought" are
interspersed, highlighted by italics. These may speak to practicality,
controversy, or simply offer challenges for further consideration.

The model pregnancy labeling is organized into three major subsections:

-   Clinical Management Statement

-   Summary Risk Assessment

-   Discussion of Data

This format is intended to prominently display important conclusions
about risk management in the context of clinical care; provide a summary
of the risks that are the basis for the management statement; and place
in close proximity more detailed information about the data that are the
basis for the risk analysis. In making a clear distinction between the
Clinical Management Statement and the Summary Risk Assessment, the
intent is to clearly separate the clinical management recommendations
and the actual risk information that underlies it.

*Consider the practical implications (e.g., advantages; applicability in
the absence of data; length of summaries) of a pregnancy labeling format
that includes a Clinical Management Statement, a separate Summary Risk
Assessment and a broader Discussion of Data that underlie the risk
assessment.*

# 

# Clinical Management Statement

In the comments and testimony from the public hearing there was
consensus that the currently required management statements are overly
general (e.g., \[*name of drug*\] should be given to pregnant women
only if clearly needed). The clinical management statement in the
labeling model here is intended to provide clinical management advice
that is more product-specific and clinically relevant (to the
risk-benefit decision to be made) than the information required under
the current regulation. Such advice might include discussion of specific
clinical settings in which the drug should be avoided, dosage
adjustments, necessary monitoring, and, for drugs with multiple
indications, management considerations that are unique to certain
indications.

> ***There is tension between providing management information that is
> product-specific and clinically relevant and providing information
> that is sufficiently structured to ensure that it is informative.
> Statements should also be reasonably consistent across drug products
> to allow evaluation of a range of therapeutic alternatives.***

*Consider the types of issues that should routinely be addressed in
Clinical Management Statements (e.g., uncertainties or toxicities that
are unique, or of particular concern, to the health of a pregnant
woman).*

In the examples, the Clinical Management Statement specifically
addresses inadvertent exposure (i.e., exposure that occurs when a woman
who is taking a drug becomes pregnant without having previously
considered whether to expose the fetus to drug). Current pregnancy
labeling focuses primarily on prospective consideration of riskwhether
to expose a pregnant woman to a drug or whether to discontinue a drug
prior to conception. Such advice may not be helpful in evaluating risks
and options after exposure has occurred. There was considerable
agreement among presenters at the public hearing that pregnancy labeling
should provide clinical management information that more specifically
addresses retrospective consideration of drug exposure.

*In considering how to address risk relevant to both planned and
inadvertent exposure, a range of data quantity and quality is likely.
With regard to offering clinical management advice for the patient
exposed to a product without knowledge of her pregnancy, consider the
types of recommendations that might be included and in how much detail.
It will be important to balance informative recommendations with
directives.*

[Summary Risk Assessment]{.underline}

The Summary Risk Assessment in this model is intended to distill risk
information presented in the Discussion of Data section into a concise
overview of specific fetal abnormalities and other potential hazards
identified. It includes information about the setting or settings in
which hazards occurred (e.g., relative exposure, gestational stage or
stages). The statement is intended to bridge the more detailed
Discussion of Data and the Clinical Management Statement derived from
that data.

*Consider the utility of such a summary risk assessment and how to make
it most informative.*

[Discussion of Data]{.underline}

The Discussion of Data subpart in this model provides a comprehensive
presentation of the data that contributed to the risk summary. Its role
is to describe the risk findings in a way that their potential relevance
to clinical decision making can be best understood by the clinician. In
order to address the full range of possible reproductive and
developmental toxicities, the following subheadings (to the extent
relevant to an individual drug) would be included:

-   Structural alteration (or dysmorphogenesis)

-   Embryo-fetal death

-   Growth retardation (irreversible and reversible)

-   Functional toxicities

-   Maternal toxicity

-   Labor and delivery

In describing and discussing individual data sources a challenge will be
to provide sufficient information to meaningfully inform clinicians
while avoiding excessive detail that might make information less
accessible. The following are elements that could be addressed in
describing an individual study or other data source:

(1) Description of data source (e.g., human, case control study or rat
    toxicology study) and the specific findings.

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(2) Specific conditions under which the identified or suspected hazard
    is present in the study(s) and the nature of the adverse effect
    seen, which may include discussion of:

-   species

-   dose

-   dose-response

-   exposure/duration

-   timing of effect (e.g., phase of pregnancy)

-   magnitude of effect (severity)

-   incidence of effect

-   biological plausibility of observed effect

(3) Where the hazard is identified in animal data, information that
    addresses the potential relevance of the hazard to humans.

*Please consider ways in which the Discussion of Data subsection can
meet the goal of being sufficiently comprehensive to be useful to
clinicians while avoiding excessive detail. For example, under what
conditions should a data source be described and how comprehensively
(keeping in mind that literature references are generally avoided in
product labels).*

[Fertility, Pregnancy, and Lactation Information in the Same
Section]{.underline}

Fertility, pregnancy, and lactation represent a clinical continuum,
therefore the labeling examples in the Appendices present these
subsections of labeling in contiguous subsections. Also, because
fertility and lactation present issues similar to those presented by
pregnancy, the model assigns the same internal subsections for Pregnancy
as illustrated below:

+-----------------------------------------------------------------------+
| Fertility, Pregnancy and Lactation                                    |
|                                                                       |
| ## Fertility                                                          |
|                                                                       |
| ## • Clinical management statement                                    |
|                                                                       |
| > • Summary risk assessment                                           |
| >                                                                     |
| > • Discussion of data                                                |
|                                                                       |
| ### Pregnancy                                                         |
|                                                                       |
| > • Clinical management statement                                     |
| >                                                                     |
| > • Summary risk assessment                                           |
| >                                                                     |
| > • Discussion of data                                                |
|                                                                       |
| ### Lactation                                                         |
|                                                                       |
| > • Clinical management statement                                     |
| >                                                                     |
| > • Summary risk assessment                                           |
| >                                                                     |
| > • Discussion of data                                                |
+-----------------------------------------------------------------------+

*Consider the applicability and usefulness of the overall format,
particularly whether having a Clinical Management Statement, Summary
Risk Assessment, and Discussion of Data would be useful applied to the
Fertility and Lactation discussions in labeling (See Appendices B and
C).*

**Appendix A**

**Pregnancy Categories**

> The regulation specifies the following language for the category
> designations:
>
> Pregnancy Category A. Studies in pregnant women have not shown that
> (*name of drug*) increases the risk of fetal abnormalities if
> administered during the first (*second, third or all*) trimester(s) of
> pregnancy. If this drug is used during pregnancy, the possibility of
> fetal harm appears remote. Because studies cannot rule out the
> possibility of harm, however, (*name of drug*) should be used during
> pregnancy only if clearly needed.
>
> Pregnancy Category B. Reproduction studies have been performed in
> (*kind(s) of animal(s)*) at doses up to (*x*) times the human dose and
> have revealed no evidence of impaired fertility or harm to the fetus
> due to (*name of drug*). There are, however, no adequate and
> well-controlled studies in pregnant women. Because animal reproduction
> studies are not always predictive of human response, this drug should
> be used in pregnancy only if clearly needed.
>
> Or, if animal studies have shown an adverse effect (other than
> decrease in fertility), but adequate and well-controlled studies in
> pregnant women have failed to demonstrate a risk to the fetus during
> the first trimester of
>
> pregnancy (and there is no evidence of a risk in later trimesters),
> the labeling shall state:
>
> Pregnancy Category B. Reproduction studies in (*kind(s) of
> animal(s)*) have shown (*describe findings*) at (*x*) times the human
> dose. Studies in pregnant women, however, have not shown that (*name
> of drug*) increases the risk of abnormalities when administered during
> the first (*second, third, or all*) trimester(s) of pregnancy. Despite
> the animal findings, it would appear that the possibility of fetal
> harm is remote, if the drug is used during pregnancy. Nevertheless,
> because the studies in humans cannot rule out the possibility of harm,
> (*name of drug*) should be used during pregnancy only if clearly
> needed.
>
> Pregnancy Category C. (*Name of drug*) has been shown to be
> teratogenic (or to have an embryocidal effect or other adverse effect)
> in (*name(s) of species*) when given in doses ([x]{.underline}) times
> the human dose. There are no adequate and well-controlled studies in
> pregnant women. (*Name of drug*) should be used during pregnancy only
> if the potential benefit justifies the potential risk to the fetus.
>
> Or, if there are no animal reproduction studies and no adequate and
> well-controlled studies in humans,
>
> Pregnancy Category C. Animal reproduction studies have not been
> conducted with (*name of drug*). It is also not known whether (*name
> of drug*) can cause fetal harm when administered to a pregnant woman
> or can affect reproduction capacity. (*Name of drug*) should be given
> to a pregnant woman only if clearly needed.
>
> Pregnancy Category D. See Warnings section. Under the Warnings
> section the labeling states: *(Name of drug*) can cause fetal harm
> when administered to a pregnant woman. (*Describe the human data and
> any pertinent animal data*). If this drug is used during pregnancy, or
> if this patient becomes pregnant while taking this drug, the patient
> should be apprised of the potential hazard to the fetus.
>
> Pregnancy Category X. See Contraindications section. Under
> Contraindications, the labeling shall state: (*Name of drug*) may
> (*can*) cause fetal harm when administered to a pregnant woman.
> (*Describe the human data and any pertinent animal data*.) (*Name of
> drug*) is contraindicated in women who are or may become pregnant. If
> this drug is used during pregnancy, or if this patient becomes
> pregnant while taking this drug, the patient should be apprised of the
> potential hazard to the fetus.

**APPENDIX B**

**Sample Fertility, Pregnancy, and Lactation Labeling Subsection for
Fictitious Product**

**ROSELENS**

**Fertility**

**Clinical Management:** No specific precautions are indicated when
Roselens is used by men or women who are intending to conceive.

**Summary Risk Assessment:** Based on data from animal studies, there
are no known concerns or suspected consequences for fertility in persons
taking Roselens.

**Discussion of Data:** There are no human data on the effects of
Roselens on male or female fertility. Male and female rats were treated
with Roselens at doses of 8 to 13 milligrams (mg)/kilogram (kg)
(equivalent to 2 and 4 times the maximum recommended human dose (MRHD)
of 80 mg daily when normalized for interspecies differences based on
body surface area) for greater than 3 weeks prior to, and throughout,
mating. There were no reported adverse effects on mating behavior,
fertility, or viability of the conceptus.

**Pregnancy**

**Clinical Management**: Use of Roselens should not effect the obstetric
or psychiatric management of patients who are in early pregnancy or
considering becoming pregnant. Women in the latter months of pregnancy
should be evaluated for the need to continue Roselens therapy and, if
therapy is to be continued, monitored for appropriate fetal growth.

**Summary Risk Assessment:** Based on studies in animals and limited
human data, there is no known concern for malformations or abnormal
neurobehavioral function in infants born to mothers treated with
Roselens. There is some concern, based on animal studies, for an
increased risk of impaired fetal growth and late fetal and neonatal
mortality when Roselens is administered during the third trimester of
pregnancy.

**Discussion of Data:** In one epidemiological study, the frequency of
congenital anomalies was no greater than expected among the infants of
90 women who took Roselens during the first trimester of pregnancy
(Stevens et al., 1993). In an observational study, six infants from 107
pregnancies in which the mother took Roselens at various times during
pregnancy had congenital anomalies. In at least two of these cases, the
malformations developed prior to treatment (Smith et al., 1992). The
frequency of congenital anomalies did not appear unusual among the
infants of 59 women who became pregnant while taking part in clinical
trials of Roselens or among the children of 485 women who took Roselens
for varying amounts of time during pregnancy and voluntarily reported
those exposures to the manufacturer. The manufacturer has received a
total of 28 reports, from a variety of sources, of infants with major
congenital anomalies born to women who had taken Roselens during
pregnancy. No consistent pattern of malformations was apparent (Stevens
and Stevens, 1993).

> [Dysmorphogenesis]{.underline}. Pregnant rats and rabbits were treated
> throughout organogenesis with doses  12.5 and 15 mg/kg, respectively
> (equivalent to 1.5 and 3.6 times the MRHD when normalized for
> interspecies differences based on body surface area). There were no
> teratogenic effects reported.
>
> [Mortality]{.underline}. In pregnant rats treated during organogenesis
> (see [Dysmorphogenesis]{.underline}), there was no evidence of fetal
> loss or resorptions. In rats treated during mid and late gestation and
> late gestation and lactation at doses of 5 and 7.5 mg/kg
> (approximately equivalent to the MRHD when normalized for interspecies
> differences based on body surface area), there were increases in the
> number of stillborn pups and reductions in neonatal viability at the
> higher dose. No effects on mortality were observed at the lower dose.
>
> [Growth]{.underline}. There were no reductions in body weights in
> fetuses of rats treated during organogenesis (see
> [Dysmorphogenesis]{.underline}). There were reductions in body weights
> of rats treated during mid and late gestation or late gestation and
> lactation (see [Mortality]{.underline}). There was no effect on pups
> when treatment ended at day 16 (of 28) of gestation.
>
> [Functional toxicities]{.underline}. In a study in rat pups born to
> dams treated with 5 and 7.5 mg/kg (approximately equivalent to the
> MRHD when normalized for interspecies differences based on body
> surface area) during mid and late gestation, there was no evidence of
> developmental neurotoxicity among surviving offspring.

**Lactation**

**Clinical Management:** Breast-feeding while on Roselens is not
recommended. If the decision is made to nurse while on Roselens, the
infant should be followed for signs of decreased growth, altered feeding
behavior, and other potential effects based on the known pharmacology
and toxicity profile of Roselens.

**Summary Risk Assessment**: Based on human and animal data, there is
significant concern for the infant when Roselens is used by the
breast-feeding mother.

**Discussion of Data:** Roselens is excreted in human milk and can
achieve concentrations in the nursing infant that are equivalent to or
exceed therapeutic levels in adults. In one breast milk sample of a
mother receiving Roselens, the concentration of the drug was twice the
maternal plasma level. No adverse effects in the infant were noted. In
two other cases of infants nursed by mothers on Roselens, the infants
plasma levels were similar to their mothers and the infants developed
vomiting and diarrhea. There is no information regarding timing of
administration of Roselens and its excretion in breast milk. In rat pups
of dams that were administered Roselens postpartum, feeding time was
significantly decreased (see Pregnancy\--Discussion of Data).

**Appendix B**

**Sample Fertility, Pregnancy, and Lactation Subsection for Fictitious
Product**

**LEURAL**

**Fertility**

**Clinical Management:** Men and women attempting to conceive should be
advised of the potential for reduced fertility while taking Leural (also
see Pregnancy).

**Summary Risk Assessment:** Based on studies in animals, there is some
concern for risk of reduced fertility in persons taking Leural.

**Discussion of Data:** There are no human data addressing the effects
of Leural on fertility. In animal reproductive/fertility studies, Leural
had no effect on pregnancy rates in rats at oral doses up to 400 mg/kg
(systemic exposures equivalent to 8 times (male rats) and 18 times
(female rats) that of humans at maximum recommended human dose (MRHD)).
However, reduction in fetal implants was observed at doses of 150 mg/kg
and higher (systemic exposure equivalent to 9 times that of humans at
MRHD). There was also evidence of testicular atrophy in dogs treated
chronically at doses of 15 mg/kg (systemic exposure equivalent to 20
times that of humans at MRHD).

**Pregnancy**

**Clinical Management:** Women who are taking Leural and become pregnant
should be advised to consider discontinuing the drug and may warrant
evaluation for potential effects on fetal growth and development. Women
who are considering pregnancy should be advised to consider alternative
treatments for asthma maintenance when feasible.

**Summary Risk Assessment:** Based on studies in animals, there is some
concern for an increased risk of mortality and decreased growth in
fetuses exposed to Leural. The time of gestation at which risk may be
greatest is unknown. Also, based on animal studies, there is some
concern for increased risk of fetal malformations.

**Discussion of Data:** There are no human data addressing the effects
of Leural on pregnancy and its outcomes. In rats, the drug and its
metabolites cross the placenta. Leural is also known to alter cellular
signal transduction*,* a function important in embryogenesis (see
Clinical Pharmacology).

[Dysmorphogenesis]{.underline}. In studies in rats at 400 mg/kg
(systemic exposure equivalent to 18 times that of humans at MRHD), there
was an increased rate of skeletal variation. A greater than expected
rate of cleft palate (3 of 118, or 2.5%) was observed in fetuses of
rabbits treated with 100 mg/kg/day (systemic exposure equivalent to that
of humans at MRHD).

[Mortality and Growth]{.underline}. In a study in rats treated
throughout gestation at doses of 70 mg/kg (systemic exposure equivalent
to approximately 4 times the recommended dose) and higher, there was an
increased rate of stillbirths and, at doses of 400 mg/kg, there were
also reduced body weights of fetuses. In a study in rats treated in late
gestation through lactation at 400 mg/kg (systemic exposure equivalent
to approximately 18 times that of humans at MRHD), there was reduced pup
survival and body weight.

[Functional toxicities]{.underline}. There are no studies that assess
infant neurobehavioral effects of Leural related to intrauterine
exposure.

**Lactation**

**Clinical Management:** Women who are breast-feeding should be advised
of the potential risk for long term effects to the infant due to
exposure to Leural.

**Summary Risk Assessment:** Based on animal carcinogenicity data, there
is some concern for the infant who is exposed to Leural.

**Discussion of Data:** There are no human data on the excretion of
Leural into human breast milk or on the safety of Leural exposure in
infants. Leural and its metabolites are excreted into rat milk (also see
Carcinogenicity).