The U.S. Food and Drug Administration (FDA) has proposed major revisions to prescription drug labeling in order to provide more accurate and helpful information on the effects of medications used during pregnancy and breastfeeding. The system used by the FDA for the last 30 years classifies the reproductive safety of medications using five risk categories (A, B, C, D and X) based on data derived from human and animal studies. While widely used to make decisions regarding the use of medications during pregnancy, many have criticized this system of classification, indicating that this type of drug labeling is often not helpful and, even worse, may be misleading.
The Pregnancy and Lactation Labeling Rule or PLLR will abolish the letter categories and instead will include more comprehensive information discussing the potential risks and benefits to the mother and the fetus, and how these risks may change during the course of pregnancy.
The information will be provided in a narrative form and will emphasize data derived from human studies. According to information provided by the FDA, the presented information on drug use during pregnancy will be organized into the following sections:
1) “Pregnancy Exposure Registry” informs health care providers of the availability of “scientifically acceptable” pregnancy exposure registries for a particular drug and includes contact information for these registries.
2) “Risk Summary” describes what is known about the effects of the drug on the fetus, if there is a risk of adverse outcomes and whether this calculation of risk is based on information from animal or human studies. Adverse outcomes include “structural abnormalities”, “embryo-fetal and/or infant mortality” (i.e., miscarriage, stillbirth, and infant death), “functional impairment” (for example, neurodevelopmental effects and impairment of reproduction), and “alterations to growth.”
3) “Clinical Considerations” provides information which further informs prescribing and risk-benefit counseling. Relevant information is grouped into the following categories: risks to the fetus and mother associated with untreated illness, dose adjustments during pregnancy and the postpartum period, maternal adverse reactions, fetal/neonatal adverse reactions, and effects of the drug on labor or delivery.
4) “Data” describes in greater detail the available data regarding use of the drug in humans and in animal studies that were used to develop the Risk Summary.
The breastfeeding section of the prescription drug labeling would provide information regarding the use of the drug while breastfeeding, including information on the amount of drug found in the breast milk and the risk of adverse events in the breastfed infant.
An Example of the New Labeling: Is It Better?
You can see an example of what the new labeling looks like for vilazodone (Viibryd) here (Section 8). Looking at the information included, there is very little available data specific to the reproductive safety of vilazodone. What is instead included is information describing the potential risks of exposure to SSRIs and SNRIs in general. However, the information provided is rather brief and seems to be somewhat skewed. For example, the discussion of persistent pulmonary hypertension of the newborn (PPHN) lists two studies which demonstrated an increased risk of PPHN in SSRI-exposed infants but failed to include the subsequent studies which did not demonstrate a significant association between prenatal SSRI exposure and PPHN.
Another concern is that medications approved before June 30, 2001 are not covered by the PLLR. While pharmaceutical companies will be required to remove the pregnancy letter categories from the labeling for all prescription drugs within three years, only medications approved by the FDA after June 30, 2001 will have to include the new formatting of information on reproductive safety. That means that for most of the SSRIs we typically use during pregnancy, the label will not include the additional information regarding safety during pregnancy and lactation.
This is certainly a step in the right direction, but it remains to be seen how clinicians will use and interpret the additional information included under the PLLR.
Ruta Nonacs, MD PhD