in Sec. 201.56(b)(1).
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(c) * * *
(9) * * *
(i) 8.1 Pregnancy. This subsection of the labeling must contain the following information in the following order under the subheadings ``Pregnancy Exposure Registry,'' ``Risk Summary,'' ``Clinical Considerations,'' and ``Data'':
(A) Pregnancy exposure registry. If there is a scientifically acceptable pregnancy exposure registry for the drug, contact information needed to enroll in the registry or to obtain information about the registry must be provided following the statement: ``There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to (name of drug) during pregnancy.''
(B) Risk summary. The Risk Summary must contain risk statement(s) based on data from all relevant sources (human, animal, and/or pharmacologic) that describe, for the drug, the risk of adverse developmental outcomes (i.e., structural abnormalities, embryo-fetal and/or infant mortality, functional impairment, alterations to growth). When multiple data sources are available, the statements must be presented in the following order: Human, animal, pharmacologic. The source(s) of the data must be stated. The labeling must state the percentage range of live births in the United States with a major birth defect and the percentage range of pregnancies in the United States that end in miscarriage, regardless of drug exposure. If such information is available for the population(s) for which the drug is labeled, it must also be included. When use of a drug is contraindicated during pregnancy, this information must be stated first in the Risk Summary. When applicable, risk statements as described in paragraphs (c)(9)(i)(B)(1) and (2) of this section must include a cross-reference to additional details in the relevant portion of the ``Data'' subheading in the ``Pregnancy'' subsection of the labeling. If data demonstrate that a drug is not systemically absorbed following a particular route of administration, the Risk Summary must contain only the following statement: ``(Name of drug) is not absorbed systemically following (route of administration), and maternal use is not expected to result in fetal exposure to the drug.''
(1) Risk statement based on human data. When human data are available that establish the presence or absence of any adverse developmental outcome(s) associated with maternal use of the drug, the Risk Summary must summarize the specific developmental outcome(s); their incidence; and the effects of dose, duration of exposure, and gestational timing of exposure. If human data indicate that there is an increased risk for a specific adverse developmental outcome in infants born to women exposed to the drug during pregnancy, this risk must be quantitatively compared to the risk for the same outcome in infants born to women who were not exposed to the drug but who have the disease or condition for which the drug is indicated to be used. When risk information is not available for women with the disease or condition for which the drug is indicated, the risk for the specific outcome must be compared to the rate at which the outcome occurs in the general population. The Risk Summary must state when there are no human data or when available human data do not establish the presence or absence of drug-associated risk.
(2) Risk statement based on animal data. When animal data are available, the Risk Summary must summarize the findings in animals and based on these findings, describe, for the drug, the potential risk of any adverse developmental outcome(s) in humans. This statement must include: The number and type(s) of species affected, timing of exposure, animal doses expressed in terms of human dose or exposure equivalents, and outcomes for pregnant animals and offspring. When animal studies do not meet current standards for nonclinical developmental toxicity studies, the Risk Summary must so state. When there are no animal data, the Risk Summary must so state.
(3) Risk statement based on pharmacology. When the drug has a well-understood mechanism of action that may result in adverse developmental outcome(s), the Risk Summary must explain the mechanism of action and the potential associated risks.
(C) Clinical considerations. Under the subheading ``Clinical Considerations,'' the labeling must provide relevant information, to the extent it is available, under the headings ``Disease-associated maternal and/or embryo/fetal risk,'' ``Dose adjustments during pregnancy and the postpartum period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal adverse reactions,'' and ``Labor or delivery'':
(1) Disease-associated maternal and/or embryo/fetal risk. If there is a serious known or potential risk to the pregnant woman and/or the embryo/fetus associated with the disease or condition for which the drug is indicated to be used, the labeling must describe the risk.
(2) Dose adjustments during pregnancy and the postpartum period. If there are pharmacokinetic data that support dose adjustment(s) during pregnancy and the postpartum period, a summary of this information must be provided.
(3) Maternal adverse reactions. If use of the drug is associated with a maternal adverse reaction that is unique to pregnancy or if a known adverse reaction occurs with increased frequency or severity in pregnant women, the labeling must describe the adverse reaction and available intervention(s) for monitoring or mitigating the reaction. The labeling must describe, if known, the effect of dose, timing, and duration of exposure on the risk to the pregnant woman of experiencing the adverse reaction.
(4) Fetal/Neonatal adverse reactions. If it is known or anticipated that treatment of the pregnant woman increases or may increase the risk of an adverse reaction in the fetus or neonate, the labeling must describe the adverse reaction, the potential severity and reversibility of the adverse reaction, and available intervention(s) for monitoring or mitigating the reaction. The labeling must describe, if known, the effect of dose, timing, and duration of exposure on the risk.
(5) Labor or delivery. If the drug is expected to affect labor or delivery, the labeling must provide information about the effect of the drug on the pregnant woman and the fetus or neonate; the effect of the drug on the duration of labor and delivery; any increased risk of adverse reactions, including their potential severity and reversibility; and must provide information about available intervention(s) that can mitigate these effects and/or adverse reactions. The information described under this heading is not required for drugs approved for use only during labor and delivery.
(D) Data--(1) ``Data'' subheading. Under the subheading ``Data,'' the labeling must describe the data that are the basis for the Risk Summary and Clinical Considerations.
(2) Human and animal data headings. Human and animal data must be presented separately, beneath the headings ``Human Data'' and ``Animal Data,'' and human data must be presented first.
(3) Description of human data. For human data, the labeling must describe adverse developmental outcomes, adverse reactions, and other adverse effects. To the extent applicable, the labeling must describe the types of studies or reports, number of subjects and the duration of each study, exposure information, and limitations of the data. Both positive and negative study findings must be included.
(4) Description of animal data. For animal data, the labeling must describe the following: Types of studies, animal species, dose, duration and timing of exposure, study findings, presence or absence of maternal toxicity, and limitations of the data. Description of maternal and offspring findings must include dose-response and severity of adverse developmental outcomes. Animal doses or exposures must be described in terms of human dose or exposure equivalents and the basis for those calculations must be included.
(ii) 8.2 Lactation. This subsection of the labeling must contain the following information in the following order under the subheadings ``Risk Summary,'' ``Clinical Considerations,'' and ``Data'':
(A) Risk summary. When relevant human and/or animal lactation data are available, the Risk Summary must include a cross-reference to the ``Data'' subheading in the ``Lactation'' subsection of the labeling. When human data are available, animal data must not be included unless the animal model is specifically known to be predictive for humans. When use of a drug is contraindicated during breastfeeding, this information must be stated first in the Risk Summary.
(1) Drug not absorbed systemically. If data demonstrate that the drug is not systemically absorbed by the mother, the Risk Summary must contain only the following statement: ``(Name of drug) is not absorbed systemically by the mother following (route of administration), and breastfeeding is not expected to result in exposure of the child to (name of drug).''
(2) Drug absorbed systemically. If the drug is absorbed systemically, the Risk Summary must describe the following to the extent relevant information is available:
(i) Presence of drug in human milk. The Risk Summary must state whether the drug and/or its active metabolite(s) are present in human milk. If there are no data to assess this, the Risk Summary must so state. If studies demonstrate that the drug and/or its active metabolite(s) are not detectable in human milk, the Risk Summary must state the limits of the assay used. If studies demonstrate the presence of the drug and/or its active metabolite(s) in human milk, the Risk Summary must state the concentration of the drug and/or its active metabolite(s) in human milk and the actual or estimated daily dose for an infant fed exclusively with human milk. The actual or estimated amount of the drug and/or its active metabolite(s) ingested by the infant must be compared to the labeled infant or pediatric dose, if available, or to the maternal dose. If studies demonstrate the presence of the drug and/or its active metabolite(s) in human milk but the drug and/or its active metabolite(s) are not expected to be systemically bioavailable to the breast-fed child, the Risk Summary must describe the disposition of the drug and/or its active metabolite(s). If only animal lactation data are available, the Risk Summary must state only whether or not the drug and/or its active metabolite(s) were detected in animal milk and specify the animal species.
(ii) Effects of drug on the breast-fed child. The Risk Summary must include information, on the known or predicted effects on the child from exposure to the drug and/or its active metabolite(s) through human milk or from contact with breast or nipple skin (for topical products). The Risk Summary also must include information on systemic and/or local adverse reactions. If there are no data to assess the effects of the drug and/or its active metabolite(s) on the breast-fed child, the Risk Summary must so state.
(iii) Effects of drug on milk production. The Risk Summary must describe the effects of the drug and/or its active metabolite(s) on milk production. If there are no data to assess the effects of the drug and/or its active metabolite(s) on milk production, the Risk Summary must so state.
(3) Risk and benefit statement. For drugs absorbed systemically, unless breastfeeding is contraindicated during drug therapy, the following risk and benefit statement must appear at the end of the Risk Summary: ``The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for (name of drug) and any potential adverse effects on the breast-fed child from (name of drug) or from the underlying maternal condition.''
(B) Clinical considerations. Under ``Clinical Considerations,'' the following information must be provided to the extent it is available and relevant:
(1) Minimizing exposure. The labeling must describe ways to minimize exposure in the breast-fed child if: The drug and/or its active metabolite(s) are present in human milk in clinically relevant concentrations; the drug does not have an established safety profile in infants; and the drug is used either intermittently, in single doses, or for short courses of therapy. When applicable, the labeling must also describe ways to minimize a breast-fed child's oral intake of topical drugs applied to the breast or nipple skin.
(2) Monitoring for adverse reactions. The labeling must describe available intervention(s) for monitoring or mitigating the adverse reaction(s) presented in the Risk Summary.
(C) Data. Under the subheading ``Data,'' the labeling must describe the data that are the basis for the Risk Summary and Clinical Considerations.
(iii) 8.3 Females and males of reproductive potential. When pregnancy testing and/or contraception are required or recommended before, during, or after drug therapy and/or when there are human and/or animal data that suggest drug-associated fertility effects, this subsection of labeling must contain this information under the subheadings ``Pregnancy Testing,'' ``Contraception,'' and ``Infertility,'' in that order.
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