Since the FDA pried open the doors for Vivus and Orexigen to have a second bite at approval for their anti-obesity drugs, researchers and clinicians have seen some hope for approval on the horizon and investors have pushed their stock prices up. But they still have many obstacles to overcome. On September 23, 2011, the FDA Pediatric Advisory Committee reviewed safety information for topirmate, which, with phentermine, is one of the two ingredients in Vivus’s drug, Qnexa ®. One of the FDA’s reviews, Topirmate’s Use During Pregnancy, provides some insights into issues the FDA will be looking at down the road. 

The bottom line is that the review indicates topiramate contributes to an elevated risk of oral clefts and to decreased fetal weight at birth. The report notes that topiramate is used off-label for weight loss purposes but the exact mechanism is not known. The hypothesized mechanism is increased energy expenditure secondary to anorexia; reduction in the activity of salivary enzymes (which are partially responsible for taste); reduction in leptin and corticosteroid concentrations) and reduction in blood glucose and insulin concentrations. The reviewer comments, “ The off-label use of topiramate for weight-loss is particularly concerning, as it would presumably be prescribed to a wider population of women of childbearing age than for epilepsy and migraine. In addition, the practitioners prescribing topiramate for weight loss may not be as familiar with its safety profile as a neurologist, and therefore less likely to counsel patients on potential pregnancies.”

The review examines pregnancies in the Qnexa development program, noting that the data are confounded as phentermine, the other component, is classified as a Pregnancy Category C, which may also contribute to malformations. There were 34 pregnancies during the Qnexa trials despite instructions to use two forms of  birth control, noting that this is consistent with previous evidence that such instructions are “not strictly followed by patients.” Of the 34 pregnancies, there were 18 live births and no anomalies.  However, one pregnancy was on-going at the time of the NDA submission. The fetus has been diagnosed with Down’s syndrome via pre-natal testing, including amniocentesis. The review concludes that the division found the relationship of topiramate and oral clefts was probably causal and was described in the labeling but the low birth weight and hypospadias had insufficient evidence for monitoring. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM272371.pdf

Beyond the scope of this FDA review (but hopefully not of the review for Qnexa for the next Advisory Committee) is the issue of birth defects, specifically cleft palates in children of mothers who are obese. This has been a topic of major concern with some studies showing a relationship and some studies not supporting such a relationship. A recent study of 229,328 Swedish women between their first two pregnancies showed that those whose second-pregnancy weight gain was 3 or more BMI units higher than their first-pregnancy weight gain had a 2.3 times higher risk of having a child with cleft palate compared with women whose BMI did not change substantially. The incidence of cleft palate also increased with the length of the interpregnancy interval. Risk of Oral Clefts in Relation to Prepregnancy Weight Change and Interpregnancy Interval

Of course this issue can affect a future FDA review. Do you look at a drug’s side effect, in this case cleft palate, comparing women with obesity on the drug to normal weight women not taking the drug or to women with obesity not taking the drug? This could significantly change the baseline prevalence of such birth malformations.  On the other hand, what are the benefits in terms of fertility and reduction in birth defects for women of child bearing age who achieve significant weight loss. Unfortunately, the data is limited to bariatric surgery and is not overwhelming but a review in the Journal of the American Medical Association in 2008 pointed strongly to improvements in both categories. Pregnancy and fertility following bariatric surgery: a … [JAMA. 2008] – PubMed – NCBI   Will these benefits be weighed by the FDA in their future risk-benefit calculus? Only time will tell.