SILVER SPRING, MD. – The combination formulation of phentermine and topiramate should be approved as a weight-loss treatment, with a risk-management plan that addresses the teratogenic effects of topiramate and a postmarketing study that evaluates cardiovascular outcomes associated with treatment, the majority of a Food and Drug Administration panel agreed at a meeting on Feb. 22.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 20 to 2 that the benefit-risk profile of the phentermine-topiramate combination supported its approval for the treatment of obesity in people with a body mass index (BMI) of at least 30 kg/m², or those with a BMI of at least 27 kg/m² who also have weight-related comorbidities. The manufacturer, Vivus, has proposed that the combination product – in three fixed-dose combinations – be approved for this population, in combination with diet and exercise.

If approved, this will be the first new obesity drug treatment approved in 13 years and will be marketed as Qnexa by Vivus. The combination product contains an immediate-release formulation of phentermine, which is a sympathomimetic amine approved for short-term weight loss, on the market in the United States since 1959; and a controlled-release formulation of topiramate, an antiepileptic drug approved for treating epilepsy in 1996, for migraine prophylaxis in 2004, and for pediatric epilepsy in 2011. Qnexa is manufactured in three fixed-dose combinations: the starting low dose of 3.75 mg of phentermine and 23 mg of topiramate, the recommended dose of 7.5 mg/46 mg, and the highest dose (15 mg/92 mg) for patients not reaching their weight-loss goal.

The two separate components are available at higher doses than those contained in the combination product.

At a meeting in July 2010, the same panel had agreed that the same product had been shown to be effective as a weight-loss agent, compared with placebo in two 1-year, pivotal studies in this patient population, but the majority voted against recommending approval of the agent because of concerns over the risk-benefit profile, particularly the potential for teratogenicity and increases in heart rate associated with treatment.

The FDA advised the company in October 2010 that the cardiovascular risks and teratogenic potential associated with treatment had not been adequately assessed, and requested that the company provide evidence that an increase in heart rate (a mean of 1.6 beats/minute at the highest dose) did not increase the risk for major adverse cardiovascular events, further evaluate the potential risk for oral clefts associated with prenatal exposure to the topiramate component, provide 2-year data, and develop a Risk Evaluation and Mitigation Strategy (REMS).

Components of the REMS as now planned include a patient medication guide explaining the risk of oral clefts (cleft lip with or without cleft palate) associated with first trimester exposure in studies and pregnancy registries, a certified pharmacy network that dispenses a month’s supply at a time via mail order, and a plan to educate prescribers about the teratogenic risk and train them to prescribe the drug appropriately. The product would be a category X drug, contraindicated during pregnancy, with the recommendation to immediately stop taking the drug if a woman becomes pregnant during treatment.