FDA approves Contrave (naltrexone/bupropion ER) with a boxed warning

The FDA approved Contrave, a combination of naltrexone and bupropion in an extended-release tablet, as an add-on to diet and exercise for chronic weight management in adults with a body mass index of 30 or higher, or 27 or higher with a weight-related condition such as high blood pressure, type 2 diabetes, or high cholesterol ^[1][2]. The drug pairs naltrexone, an opioid antagonist previously approved for alcohol and opioid dependence, with bupropion, an antidepressant also used for smoking cessation ^[1].

Because it contains bupropion, Contrave carries a boxed warning about increased risk of suicidal thoughts and behavior, a warning shared with antidepressant drugs ^[1][2]. The label also lists a long set of contraindications: seizure disorders, anorexia nervosa or bulimia, chronic opioid use, uncontrolled hypertension, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs ^[2]. The drug should not be combined with other bupropion-containing products or taken during or within 14 days of monoamine oxidase inhibitors ^[2].

The approval rested on trials involving nearly 4,500 obese and overweight adults treated for one year alongside a reduced-calorie diet and exercise ^[1]. In a trial of people without diabetes, patients on Contrave lost 4.1 percentage points more weight than those on placebo, and 42 percent lost at least 5 percent of their body weight compared with 17 percent on placebo ^[1]. In a separate trial of people with type 2 diabetes, the average weight loss over placebo was 2 percentage points, with 36 percent of Contrave patients losing at least 5 percent of body weight versus 18 percent on placebo ^[1]. The most common side effects across trials were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea ^[1][2].

Dosing starts low and escalates over four weeks to a maintenance dose of two tablets twice daily, and the label instructs against taking the drug with a high-fat meal because that raises drug exposure ^[2]. The label also directs that patients be evaluated after 12 weeks on the maintenance dose, and that Contrave be stopped if a patient has not lost at least 5 percent of starting body weight, since further meaningful weight loss becomes unlikely ^[1][2].

Why it matters for patients

Contrave works differently from GLP-1 drugs like semaglutide (Ozempic, Wegovy, Rybelsus) or tirzepatide (Mounjaro, Zepbound): it combines an opioid antagonist with an antidepressant rather than acting on gut hormone receptors ^[1]. That mechanism brings its own warning profile, including the boxed suicidality warning and a long contraindication list covering seizure disorders, eating disorders, and chronic opioid use ^[1][2]. People considering treatment options who have a history of these conditions, or who take other medications affecting seizure threshold or the CYP2D6 or CYP2B6 liver enzymes, may find those factors relevant to what a doctor screens for before prescribing ^[2]. The weight-loss effect sizes reported in the approval trials, roughly 2 to 4 percentage points more weight loss than placebo depending on diabetes status, are also useful context for comparing across obesity treatments ^[1].

What happens next

At the time of approval, the FDA required the drug's sponsors, Orexigen Therapeutics and Takeda Pharmaceuticals America, to conduct post-marketing studies, including a pediatric weight-management study and a randomized cardiovascular outcomes trial in overweight and obese adults with cardiovascular disease or multiple risk factors ^[1]. The current FDA label, last revised in March 2021 and now administered by Currax Pharmaceuticals, still notes that Contrave's effect on cardiovascular illness and death has not been established ^[2].