FDA to Revise Pregnancy and Lactation Labeling

July 15, 2008

July 2008, ObGyn News, Lee S. Cohen, MD

The Food and Drug Administration has proposed revisions to the longstanding system of pregnancy category labeling for all medications. The current system has classified the reproductive safety of medications across five risk categories—A, B, C, D and X—usually based on available data when a drug is approved. The proposed system will eliminate the letter categories and instead will include sections on pregnancy and lactation, each with information summarizing risks, clinical considerations, and available human and animal data.

The implications of the proposed system with respect to psychiatric medications are significant. In previous columns, I have discussed some of the limitations of the category label system for various psychiatric medications. There are examples of medications with a sparse amount of reproductive safety information that does not indicate an adverse effect, which are inbear a a more favorable category label than other medicines for which very extensive reproductive safety are available, but perhaps where animal safety data suggest some cause for concern. There are also examples where evidence of adverse reproductive effects in animals dosed with toxic amounts of a medicine can trump significant amounts of human data supporting reproductive safety.

A dramatic example of the current system’s limitations is lithium, a category D drug because of clear evidence of Ebstein’s anomaly associated with first-trimester exposure. Yet the absolute risk of the cardiac anomaly is only 0.05% following first-trimester exposure. Considering the high rate of relapse of bipolar disorder associated with stopping lithium before or during pregnancy, this may be a risk many patients are willing to take, in collaboration with their psychiatrists.

The current system also does not distinguish between relative amounts of data, and typically lumps a class of medications into one category, instead of considering the drugs as individual molecules. All the selective serotonin reuptake inhibitors are labeled category C, yet the amount of reproductive safety data available for the individual SSRIs is highly variable. Moreover, information in the letter category system has been limited to reproductive safety during the first trimester and does not address some of the potential risks of exposure during the second and third trimesters, and peripartum period.

Part of the problem is that with few exceptions, industry has failed to embrace a global product safety initiative regarding establishing registries for these products in a systematic way shortly after a drug is marketed.

In May, after almost a decade after indicating that the pregnancy and lactation labeling system would be changed, the FDA announced the proposed changes, which address these limitations.

The pregnancy section would include a fetal risk summary, which would describe the risks to the fetus associated with exposure to the medicine based on available data; and clinical considerations, which would include information about the effects of the drug if a woman takes it before she knows she is pregnant and the risks of the disease for the mother and baby. A third section would summarize the available human and animal data that provide the basis of the fetal risk summary. The labor and delivery section in the current drug label would be eliminated, with this information included in the pregnancy section. The section on lactation would include the same sections on risk summary, clinical considerations, and data.

The clinical implications of dropping the letter category system are considerable. These categories have frequently been used to switch patients from one medicine to another somewhat arbitrarily. Even well-intentioned clinicians have switched a patient to a medicine based on the category label, when there are less available reproductive safety data in humans, but perhaps animal data were of some concern. For example, a patient who is exquisitely responsive to a category C drug may have been switched to a category B drug during pregnancy even though there are very sparse data for the drug with the category B rating, but none of it adverse.

Once the new system is in place, this type of arbitrary change in a patient’s medication based on the category label will hopefully cease. Moving from a categorical system of classification to a system that is more inclusive of available reproductive safety information should help clinicians rather than confuse them. Clinicians will be provided with more information in a drug’s label that actually describes results of studies and will be able to see firsthand the type of information that is available and the quality of data, as well as references to studies. As a result, we will be provided with a more global risk assessment across pregnancy, including the peripartum period and lactation.

Regardless of the system used, the process of making decisions about the use of any medicine, particularly psychotropics, during pregnancy should be made on a case-by-case basis, weighing the varying amounts of information on the medicine and the patient’s underlying disease state. Many clinicians might believe that more information will provide an opportunity to thread the clinical needle associated with the risk benefit decision in a more precise fashion. This may not always be the case but at least we can come that much closer to refining the risk-benefit decision for patients who need to make these types of clinical decisions with their doctors.

Some clinicians may miss the category label system because it is simple, despite its flaws. The current plan may make the reproductive safety information less black and white, but that is indeed the current state of the science when it comes to reproductive safety. No decision is perfect and no decision is risk free.

Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, Boston, which provides information about pregnancy and mental health at www.womensmentalhealth.org. He also is a consultant to manufacturers of some psychiatric drugs, including antidepressants.