GAITHERSBURG, Md. — A Food and Drug Administration advisory panel voted 10 to 6 against recommending approval of a combination of phentermine and topiramate as a weight loss agent because of concerns over the treatment’s risk-benefit profile.
At the July 15 meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two clinical trials of the combination product that contains an immediate-release formulation of phentermine, which is a sympathomimetic amine approved as an obesity treatment, and a controlled-release formulation of topiramate, an antiepileptic drug approved for treating seizures and migraines. The two components are marketed separately, but at higher doses than those contained in the combination product, which is manufactured by Vivus, Inc.
The company has proposed that phentermine/topiramate CR be approved for treating obesity, including weight loss and maintenance of weight loss, in conjunction with diet and exercise, and that it be recommended for obese (BMI greater than 30 kg/m2 ) or overweight (BMI greater than 27 kg/m2) ) patients with weight-related co-morbidities.
Panelists agreed the combination was an effective weight loss agent, but expressed concern about the associated risks. These risks include: the potential for teratogenicity; psychiatric effects (depression, anxiety, and sleep disorders); neurocognitive effects (including attention, memory, and language issues); increases in heart rate; and drops in serum bicarbonate levels. A prominent concern was that if the drug were approved, it would be used widely in populations other than those in the proposed indication.
Several panelists who voted against approval said they would have supported the agent if there were some restrictions that would prevent widespread use, or if longer followup data were available.
Birth defects associated with in utero exposure to higher doses of topiramate have been reported, but the teratogenic potential of the lower doses is not known. Women of reproductive age in the studies were supposed to use contraceptives, but there were 34 unintended pregnancies. There were no birth defects reported in the 19 pregnancies carried to term, but panelists remained concerned about the potential for teratogenicity. They recommended that, if the drug is approved, this risk should be studied further and a pregnancy registry established, as proposed by the manufacturer.
The agent is available in three doses: the starting dose (3.75 mg of phentermine and 23 mg of topiramate), the recommended dose (7.5 mg/46 mg), and the highest dose (15 mg/92 mg) for patients not reaching their weight loss goal.
In two phase 3 trials, the three doses of phentermine/topiramate CR were compared to placebo in almost 4,000 patients, most of whom were women in their 40s and 50s. The mean weight of those enrolled in one study was 256 pounds; in the second study, the mean weight was 227 pounds. Each of the three doses was associated with significantly greater mean percent weight loss at one year compared with placebo.
The proportion of patients on the combination agent who had lost 5% of their weight at one year was also significantly greater (45% to 70% in the treatment group vs. 17%-21% in the placebo group). A lifestyle modification program, which included diet and exercise counseling, was included for all patients in the studies.
The FDA panel usually follows the recommendations of its advisory panels. The members of advisory panels have been cleared of conflict of interest related to the product under review before the meeting. The agency is expected to make a decision on the approval by October 28. If approved, Vivus plans to market the product as Qnexa.