FDA approves Qsymia (phentermine/topiramate ER)

The U.S. Food and Drug Administration approved Qsymia (phentermine plus extended-release topiramate, from Vivus) on July 17, 2012, for weight loss ^[1]. The capsule, once known as Qnexa, pairs an immediate-release appetite suppressant with extended-release beads of topiramate, an anti-seizure drug long noticed to cause weight loss as a side effect ^[1]. Both are used at lower doses than in their original indications ^[1].

Qsymia is cleared as an add-on to a reduced-calorie diet and increased physical activity for people with a body mass index above 30, or 27 or higher with at least one weight-related condition such as high blood pressure, abnormal cholesterol, diabetes or prediabetes, or abdominal obesity ^[1].

What the pivotal trial showed

The main study, EQUIP (OB-302), was a 56-week randomized, double-blind, placebo-controlled trial in 1,267 adults at 91 U.S. sites ^[1]. Participants were 18 to 70 years old with a BMI of 35 or higher, triglycerides of 200 mg/dL or below, blood pressure of 140/90 mm Hg or below, and fasting glucose of 110 mg/dL or less ^[1]. There was a four-week dose titration, then 52 weeks at the assigned dose ^[1]. Average starting weight was about 256 pounds with a BMI near 42; the manufacturer's site lists the BMI range as 35 to 70 in one place and 35 to 79 in another ^[2].

Using an intent-to-treat, last-observation-carried-forward analysis, average weight loss was 10.9% on the top 15/92 mg dose and 5.1% on the 3.75/23 mg starting dose, versus 1.6% on placebo ^[1][2]. At one year, 67% of top-dose patients and 45% on the starting dose lost at least 5% of body weight, compared with 17% on placebo; 47% and 19% lost at least 10%, versus 7% on placebo ^[2]. Completion rates were 58% in the Qsymia groups and 47% on placebo, with loss to follow-up (14.7%), withdrawal of consent (13.1%) and adverse events (5.4%) the leading reasons for dropping out ^[2].

Two other trials found smaller average losses: CONQUER reported 9.8% at 15/92 mg and 7.8% at 7.5/46 mg versus 1.2% on placebo, and SEQUEL reported 10.5% and 9.3% versus 1.8% ^[1].

On secondary measures in EQUIP, the top dose beat placebo by 3.8 mm Hg on systolic blood pressure, 7.8 cm on waist circumference, 14.3% on triglycerides and 2.5 mg/dL on fasting glucose, while raising heart rate by 1.8 beats per minute relative to placebo ^[2]. The label states that an effect on cardiovascular illness or death has not been established, and the drug is not indicated to treat high blood pressure, type 2 diabetes, stroke or heart disease ^[2].

Why it matters for patients

Before this approval, prescription options were limited and modest. Sibutramine (Meridia) was pulled from the U.S. market in 2010 over cardiovascular events, and orlistat produced average losses of roughly 2.2 to 3.31 kg in a meta-analysis, often with diarrhea and gas ^[1]. Lorcaserin (Belviq) was approved in June 2012 — a month before Qsymia — with 4.5 to 5.8 kg of weight loss in trials, but its launch was delayed until June 2013 while its Schedule IV classification was settled ^[1]. Against that backdrop, double-digit average weight loss from a daily oral capsule was a step up.

The trade-off is a long safety list. Qsymia is contraindicated in pregnancy and in people with glaucoma or hyperthyroidism, and within 14 days of taking an MAOI ^[2]. Topiramate exposure in the first trimester raises the risk of oral clefts, so pregnancy testing before starting and monthly during treatment is recommended ^[2]. The label also warns about suicidal thoughts or behavior, acute angle closure glaucoma, visual field defects, mood changes and insomnia, cognitive problems including word-finding difficulty, metabolic acidosis, and increases in serum creatinine that peaked at 4 to 8 weeks in phase 3 trials ^[2]. The most common adult side effects were tingling, dizziness, altered taste, insomnia, constipation and dry mouth ^[2].

EQUIP enrolled a screened population — people with recent large weight swings, eating disorders, prior bariatric surgery, kidney stones, bipolar disorder or recent heart events were excluded — so results may not carry over to everyone ^[1]. How Qsymia performs against later injectable options is not addressed in these sources.