Drug Categories in Pregnancy

Pregnancy category

FDA Pregnancy Risk Information: An Update

The FDA published the Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, referred to as the “Pregnancy and Lactation Labeling Rule” (PLLR or final rule).

In 2015 the FDA replaced the former pregnancy risk letter categories  on prescription and biological drug labeling more brief and understandable to both patients and healthcare providers. The FDA received comments that the old five-letter system left patients and providers ill-informed and resulted in false assumptions about the actual meaning of the letters.

The new labeling system allows better patient-specific counseling and informed decision making for pregnant women seeking medication therapies. While the new labeling improves the old format, it still does not provide a definitive “yes” or “no” answer in most cases. Clinical interpretation is still required on a case-by-case basis.

The A, B, C, D and X risk categories, in use since 1979:

Pregnancy Category	Description
A	No risk in controlled human studies: Adequate and well-controlled human studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).
B	No risk in other studies: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.
C	Risk not ruled out: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
D	Positive evidence of risk: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
X	Contraindicated in pregnancy: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
N	FDA has not yet classified the drug into a specified pregnancy category.

The Pregnancy and Lactation Labeling Final Rule (PLLR) went into effect on June 30, 2015; however, the timelines for implementing this new information on drug labels (also known as the package insert) is variable.

Prescription drugs submitted for FDA approval after June 30, 2015 will use the new format immediately, while labeling for prescription drugs approved on or after June 30, 2001 will be phased in gradually. Medications approved prior to June 29, 2001 are not subject to the PLLR rule; however, the pregnancy letter category must be removed by June 29, 2018. For generic drugs, if the labeling of a reference listed drug is updated as a result of the final rule, the abbreviated new drug application (ANDA) labeling must also be revised. Labeling for over-the-counter (OTC) medicines will not change, as OTC drug products are not affected by the new FDA pregnancy labeling.

Summary of the Major Provisions of the Regulatory Action in Question

The final rule requires that for the labeling of certain drug products (as described in the “Implementation” section of this document), the subsections “Pregnancy,” “Nursing mothers,” and “Labor and delivery” be replaced by three subsections entitled “Pregnancy,” “Lactation,” and “Females and Males of Reproductive Potential.” The final rule also requires the removal of the pregnancy categories A, B, C, D, and X from all drug product labeling.

“Pregnancy”

The final rule merges the current “Pregnancy” and “Labor and delivery” subsections into a single “Pregnancy” subsection of labeling. If there is a scientifically acceptable pregnancy exposure registry for the drug, the “Pregnancy” subsection must contain a specified statement about the existence of the registry, followed by contact information needed to enroll or to obtain information about the registry. The Agency has concluded that including information about pregnancy exposure registries in prescription drug labeling will encourage participation in registries, thereby improving data collection in pregnant women. Under “Pregnancy,” the final rule also requires that the labeling include a summary of the risks of using a drug during pregnancy. If data demonstrate that a drug is not absorbed systemically, the “Risk Summary” must contain only a specified statement regarding this fact. If data demonstrate that the drug is absorbed systemically, the “Risk Summary” must include risk statements based on data from all relevant sources (human, animal, and/or pharmacologic), that describe, for the drug, the risk of adverse developmental outcomes.

The labeling must also contain relevant information, if it is available, to help health care providers make prescribing decisions and counsel women about the use of the drug during pregnancy; this could include information on disease-associated maternal and/or embryo/fetal risk, dose adjustments during pregnancy and the postpartum period, maternal adverse reactions, fetal/neonatal adverse reactions, and/or the effect of the drug on labor or delivery. FDA believes that including such information supports
health care providers' understanding of drug product risks and benefits and facilitates informed prescribing decisions and patient counseling. The labeling must also describe the data that are the basis for the risk statements and clinical information included in the “Pregnancy” subsection of labeling.

“Lactation”

The final rule requires that the “Lactation” subsection of labeling contain a summary of the risks of using a drug during lactation. If data demonstrate that the drug is not absorbed systemically, this summary must contain only a specified statement regarding this fact. If data demonstrate that the drug is absorbed systemically by the mother, this summary must include, to the extent it is available, relevant information on the presence of the drug in human milk, effects of the drug on the breast-fed child, and effects of the drug on milk production. For drugs absorbed systemically, a risk and benefit statement must appear at the end of the summary of risks, unless breastfeeding is contraindicated during drug therapy. FDA has determined that the inclusion of a risk and benefit statement will provide a useful framework for health care providers to use when making prescribing decisions for a lactating patient.

The “Lactation” subsection must also include, to the extent information is available, relevant information concerning ways to minimize drug exposure in the breast-fed child in certain situations and concerning available interventions for monitoring or mitigating the adverse reactions presented elsewhere in the labeling. In addition, the labeling must also include pertinent information about the data that are the basis for the risk summary and clinical information included in the “Lactation” subsection of labeling.

“Females and Males of Reproductive Potential”

FDA determined that because there was no consistent placement in the labeling of information about pregnancy testing, contraception, and infertility, it was difficult for health care providers to find this important information that can affect decisionmaking before or during pregnancy. Thus, the final rule requires that the “Females and Males of Reproductive Potential” subsection include relevant information when pregnancy testing or contraception is required or recommended before, during, or after drug therapy or when there are human or animal data that suggest drug-associated fertility effects.

Removal of Pregnancy Categories

Through experience and stakeholder feedback, FDA learned that the pregnancy categories were confusing and did not accurately and consistently communicate differences in degrees of fetal risk. In addition, FDA learned that the pregnancy categories were heavily relied upon by clinicians but were often misinterpreted and misused in that prescribing decisions were being made based on the pregnancy category, rather than an understanding of the underlying information that informed the assignment of the pregnancy category. FDA believes that a narrative structure for pregnancy labeling, rather than a category system, is best able to capture and convey the potential risks of drug exposure based on animal or human data, or both. FDA has determined that retaining the pregnancy categories is inconsistent with the need to accurately and consistently communicate differences in degrees of fetal risk. Therefore, the final rule requires the removal of the pregnancy categories A, B, C, D, and X from all drug product labeling.