FDA approves Qsymia for weight loss, with 10.9% average loss in key trial

The FDA approved Qsymia (phentermine and topiramate extended-release) on July 17, 2012, for weight loss ^[1]. The agency cleared the once-daily oral capsule as an addition to a reduced-calorie diet and increased physical activity for adults with a body mass index above 30, or a BMI of 27 or higher along with at least one weight-related condition such as high blood pressure, abnormal cholesterol, diabetes or prediabetes, or abdominal obesity ^[1].

Both ingredients were already on the market. Phentermine has been used for weight loss, and topiramate is an antiepileptic drug that is commonly linked to weight loss as a side effect ^[1]. The doses approved for weight reduction are lower than the doses used when either drug is prescribed for its existing purposes ^[1]. A 2013 review lists the previously approved weight-loss options as phentermine resin, phentermine HCl, diethylpropion, and orlistat, and notes that sibutramine had been removed from the U.S. market because of cardiovascular events ^[1]. The same review notes that lorcaserin was approved in June 2012, with its launch delayed to June 2013 ^[1].

What the EQUIP trial showed

The main supporting study, EQUIP (OB-302), ran 56 weeks. It was randomized, double-blind, and placebo-controlled, and enrolled 1,267 patients at 91 sites in the United States, including clinical practices, trial sites, and academic centers ^[1]. Participants were 18 to 70 years old with a BMI of 35 or higher, and the trial used a four-week titration period followed by 52 weeks at the assigned dose ^[1].

Average weight loss was 10.9% on the 15 mg/92 mg dose and 5.1% on the 3.75 mg/23 mg starting dose, compared with 1.6% on placebo ^[1][2]. Among patients on the top dose, 47% lost at least 10% of their body weight and 67% lost at least 5%, compared with 7% and 17% on placebo ^[2]. Everyone in the study was advised to cut about 500 calories a day, and nutrition and lifestyle counseling was offered ^[2].

Two other trials of the same combination reported different average losses: in CONQUER, 7.8% on the 7.5/46 mg dose and 9.8% on 15/92 mg versus 1.2% on placebo; in SEQUEL, 9.3% and 10.5% versus 1.8% ^[1].

Safety and monitoring

Qsymia is contraindicated in pregnancy ^[2]. Data from a pregnancy registry and epidemiology studies show that first-trimester exposure to topiramate, one of the two ingredients, raises the risk of oral clefts, meaning cleft lip with or without cleft palate ^[2]. Pregnancy testing is recommended before starting and monthly during treatment for patients who can become pregnant, along with effective contraception ^[2].

Topiramate also increases the risk of suicidal thoughts or behavior, and Qsymia is not recommended for people with a history of suicide attempts or active suicidal ideation ^[2]. In adults, side effects reported in at least 5% of patients and at least 1.5 times the rate seen with placebo were paraesthesia, dizziness, taste changes (dysgeusia), insomnia, constipation, and dry mouth ^[2]. The label also lists metabolic acidosis, increases in serum creatinine that reflect reduced kidney filtration, cognitive problems such as trouble concentrating or finding words, mood disorders including depression and anxiety, and vision problems including acute angle closure glaucoma and visual field defects ^[2]. The effect of Qsymia on cardiovascular illness and death has not been established ^[2].

In EQUIP, 58% of patients in the Qsymia groups completed a year of treatment, versus 47% on placebo. The most common reasons for stopping were loss to follow-up (14.7%), withdrawal of consent (13.1%), and adverse events (5.4%) ^[2].

Why it matters for patients

Qsymia is swallowed rather than injected, which matters for people who do not want to use injectable medicines or cannot use them ^[2]. It is also classified as a Schedule IV controlled substance ^[2]. The BMI cutoffs mean it was not approved for people below those thresholds or for people with overweight who do not have a related condition ^[1].

Because of the topiramate-related risk of oral clefts, patients who can become pregnant are advised to test before starting and monthly during treatment and to use effective contraception, which adds regular appointments to a treatment plan ^[2]. The risk of suicidal thoughts or behavior, plus the label's cognitive and mood warnings, means clinician monitoring is part of use ^[2]. The label also states that Qsymia is not indicated to treat high blood pressure, type 2 diabetes, stroke, or heart disease ^[2].

The current label covers adults with obesity or with overweight plus a related condition, and also pediatric patients aged 12 and older with obesity ^[2]. The 2013 review describes the indication for adults ^[1]; when pediatric use was added has not been reported.