In January 2011, the FDA requested further data from Vivius Inc on birth defects in association with topiramate prior to considering the approval of Qnexa® (phentermine and topiramate); its treatment for obesity. The Agency asked the company to assess the feasibility of analysing existing healthcare databases to determine the historical incidence of oral cleft (OC) in offspring of women treated with topiramate for migraine prophylaxis. This is believed to have stemmed from two published reports citing two OCs in the UK Epilepsy and Pregnancy Register and four (including two isolated cleft lips) from the North American AED Pregnancy Registry.

VIVUS, Inc. has now completed one study of OC and major congenital malformations (MCMs) associated with in utero topiramate exposure, the findings of which will be presented at the 29th International Epilepsy Congress (IEC) on August 31, 2011. This retrospective study examined medical claims and pharmacy prescription data from the Wolters Kluwer Pharma Solutions Source® Lx Patient Longitudinal Database, and involved 778 mother-infant dyads exposed to topiramate within 10 months prior to giving birth (January 2003 to December 2010). The study also included two non-topiramate-exposed control groups, comprising 3431 dyads exposed to other antiepileptic drugs (AEDs) during pregnancy and a group of 2307 dyads with a diagnosis of epilepsy, but no exposure to topiramate during pregnancy. In all cohorts, known or suspected teratogens, including valproate, and phenytoin were excluded.

The following findings were reported:

• The frequency of oral cleft was 0.26% in the topiramate group, 0.20% in the other AED group and 0.30% the group not exposed to topiramate. The corresponding figures for the frequency of major malformations were 4.11%, 3.50% and 4.72%.

• The relative risk (95% CI) for the topiramate group vs. other AEDs group for OCs was 1.26 (0.26 to 6.05) and the relative risk of MCMs was 1.18 (0.80 to 1.72).

• For the topiramate vs. the non-topiramate exposed epilepsy group, the relative risk was 0.85 (0.18 to 4.07) for OCs and 0.87 (0.59 to 1.28) for MCMs.

• There were no statistically significant differences in OC or MCM frequency between the topiramate and control groups.

The president of VIVUS, Inc commented that “the results of this retrospective study show that in comparison to the other non-teratogenic AED group or non-topiramate exposed epileptic group, topiramate exposure during pregnancy does not appear to significantly increase the risk of oral clefts or major congenital malformations." He stressed that this is not the ongoing, larger FORTRESS study, which utilises medical claims databases from different sources than Wolters Kluwer. The FORTRESS results, expected in the fourth quarter of 2011, along with the results from this current study, will be used as part of the QNEXA new drug application resubmission to the FDA.

In March 2011, the FDA informed healthcare professionals and the public of new data suggesting that there is an increased risk of cleft lip and/or palate (OC) in infants born to women treated with another topiramate preparation, Topamax®, during pregnancy.