GAITHERSBURG, MD. — A Food and Drug Administration advisory panel voted 10 to 6 against recommending the approval of a combination of phentermine and topiramate as a weight-loss agent because of concerns over the treatment's risk-benefit profile.
At a meeting last month, the committee members 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, which is an antiepileptic drug approved for treating seizures and migraine headaches. 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 patients (BMI greater than 30 kg/m2) or overweight patients (BMI greater than 27 kg/m2) with weight-related comorbidities.
The 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 among panelists was that if the drug were approved, it would be used widely in populations other than those mentioned in the proposed indication.
Several of those who voted against approval said that they would have supported the agent if there were some restrictions that would prevent widespread use, or if longer follow-up data were available.
Dr. Eric C. Colman, deputy director of the Division of Metabolism and Endocrinology Products, said after the meeting that he a “was a little surprised that the vote went as it did.” Panel members “weren't strongly against the drug, but they had some lingering concerns that were enough to make them lead toward voting no,” he added.
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 that were carried to term, but the panelists remained concerned about the potential for teratogenicity. They recommended that, if the drug were to be approved, this risk should be studied further and a pregnancy registry established, as has been proposed by the manufacturer.
The agent is available in three doses: the starting dose (3.75 mg phentermine and 23 mg 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 III trials, the three doses of phentermine-topiramate CR were compared with 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 percentage weight loss at 1 year compared with placebo.
The proportion of patients who were on the combination agent and who had lost 5% of their weight at 1 year was also significantly greater (45% to 70% in the treatment group, compared with 17%-21% in the placebo group).
A lifestyle modification program, which included diet and exercise counseling, was included for all of the patients in the studies.
The FDA panel, which is expected to make a decision on the application by Oct. 28, usually follows the recommendations of its advisory panels. If the treatment is approved, Vivus plans to market the product as Qnexa.
The members of advisory panels have been cleared of conflict of interest related to the product under review before the meeting.
Cathy Dombrowski of “The Pink Sheet” contributed to this report. “The Pink Sheet” and this publication are owned by Elsevier.
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