The FDA has approved extended-release phentermine plus topiramate as an addition to a reduced-calorie diet and exercise for chronic weight management in overweight or obese adults. The agency’s decision represents only the second approval of a weight-loss drug in more than a decade.
The drug, to be marketed as Qsymia (Vivus) is a combination of phentermine (Adipex, Gate), a sympathomimetic amine anorectic, and extended-release topiramate (Topamax, Janssen), an antiepileptic drug. The FDA has approved it for use in adults with an initial BMI of at least 30 or in those with a BMI of 27 or greater and at least one weight-related condition, such as hypertension, type 2 diabetes or dyslipidemia, according to a press release from the agency.
The recommended daily dose contains 7.5 mg of phentermine and 46 mg of extended-release topiramate. The drug will also be available at a higher dose, 15 mg of phentermine and 92 mg of topiramate, for select patients.
The approval of extended-release phentermine/topiramate follows the approval of another weight-loss drug, lorcaserin (Belviq, Arena Pharmaceuticals), with identical indications in June.
“Obesity threatens the overall well-being of patients and is a major public health concern,” Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release. “Qsymia, used responsibly in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, provides another treatment option for chronic weight management in Americans who are obese or are overweight and have at least one weight-related comorbid condition.”
Advisory panel decisions
In July 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended against approval of extended-release phentermine/topiramate, then referred to as Qnexa, and issued a complete response letter in October 2010. Although the drug met the two efficacy benchmarks, the agency said, the adverse effects associated with the drug, particularly psychiatric and cognitive events, teratogenicity, metabolic acidosis and cardiovascular events required further study.
During the July 2010 advisory committee meeting, panel member Elaine H. Morrato, DrPH, MPH, assistant professor in the department of health systems, management and policy at the University of Colorado, Denver, expressed apprehension about the drug’s approval.
“While I agree there is a significant obesity epidemic in the United States … my concerns were the public health consequences, given the long list of safety risks and the strong pent-up market demand,” Morrato said. “The drug will be used by millions of patients over long periods of time far exceeding the label indications for use and duration of clinical experience that we have.”
However, in February, the same advisory committee recommended approval of extended-release phentermine/topiramate, with the suggestion that the manufacturer conduct a postmarket, cardiovascular outcomes trial.
“The sponsor has done a good job at demonstrating efficacy, and they need to step up to the plate and do the cardiovascular outcomes trial and do it fast,” committee member Sanjay Kaul, MD, said during the second meeting. “There is opportunity for the sponsor to fully characterize the impact of the drug on heart rate and blood pressure.”
The safety and efficacy of extended-release phentermine/topiramate were evaluated in two randomized, placebo-controlled trials including 3,700 obese and overweight patients, with or without significant weight-related conditions. The patients received lifestyle modification consisting of a reduced calorie diet and regular physical activity.
Results from the trials showed that after 1 year of treatment with the recommended dose (7.5 mg phentermine, 46 mg of topiramate), patients experienced an average weight loss of 6.7%, and those who were treated with the highest daily dose (15 mg phentermine, 92 mg topiramate) had an average weight loss of 8.9%. Sixty-two percent of patients lost at least 5% of their body weight with the recommended dose and 69% lost at least 5% with the highest dose, compared with approximately 20% of patients treated with placebo.
The approval comes with a warning for patients and clinicians under the Risk Evaluation and Mitigation Strategy (REMS), consisting of a medication guide designed to educate patients and clinicians about the important safety information to assure it is prescribed and taken properly. Moreover, the drug will only be dispensed through specially certified pharmacies, according to the FDA.
In addition to this safety measure, the manufacturer will conduct 10 postmarketing studies, including the long-term CV outcomes trial suggested by the advisory panel to investigate the effect of extended-release phentermine/topiramate on risk for major adverse CV events, such as MI and stroke.
Researchers found that patients who did not lose at least 3% of their body weight after 12 weeks of treatment with extended-release phentermine/topiramate were unlikely to lose weight and maintain weight loss. For this reason, it is recommended that patients who have not lost at least 5% of their body weight after 12 weeks should discontinue use of the drug.
Based on data from clinical trials, patients with glaucoma or hyperthyroidism should not take extended-release phentermine/topiramate. Additionally, the drug is contraindicated for pregnant women, as it can cause harm to the fetus. Further, because the drug can increase heart rate, it use is also contraindicated for patients with recent or unstable CVD or stroke, and regular monitoring of heart rate is recommended for all patients.
The common side effects associated with the drug are parenthesis, dizziness, altered taste sensation, insomnia, constipation and dry mouth.