FDA’s new labeling rule: clinical implications


As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.

The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.

Dr. Lee S. Cohen

Dr. Lee S. Cohen

From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.

With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.

Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.

Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.

Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.

For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.

Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.

If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.


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