FDA approves Contrave for chronic weight management with a boxed warning

In September 2014, the FDA approved Contrave for chronic weight management in adults ^[1]. The drug is a combination of naltrexone hydrochloride and bupropion hydrochloride in extended-release tablets ^[1][2]. Naltrexone is an opioid antagonist, and bupropion is an aminoketone antidepressant ^[2].

Contrave is indicated as an add-on to a reduced-calorie diet and increased physical activity for adults with a body mass index of 30 kg/m² or greater, or 27 kg/m² or greater with at least one weight-related condition such as hypertension, type 2 diabetes or dyslipidemia ^[1][2]. At the time of approval, the drug was developed by Orexigen Therapeutics and distributed by Takeda Pharmaceuticals America ^[1].

The approval was based on a series of trials that enrolled nearly 4,500 adults who had obesity or overweight, with and without weight-related conditions, and who were treated for one year. Everyone in the trials also received a reduced-calorie diet and regular physical activity ^[1]. In a trial that enrolled patients without diabetes, those taking Contrave lost an average of 4.1 percent more of their body weight than those taking placebo at one year. Forty-two percent of patients on Contrave lost at least 5 percent of their body weight, compared with 17 percent on placebo ^[1]. A separate trial in patients with type 2 diabetes found an average difference from placebo of 2 percent; 36 percent of patients taking Contrave lost at least 5 percent of their body weight, compared with 18 percent on placebo ^[1].

The most common adverse reactions reported in the trials were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea ^[1][2]. The label says the recommended dosing schedule is stepped up over four weeks and that tablets should not be taken with a high-fat meal ^[2].

Because Contrave contains bupropion, it carries a boxed warning about an increased risk of suicidal thoughts and behaviors associated with antidepressant drugs. The warning also notes that serious neuropsychiatric events have been reported in people taking bupropion for smoking cessation ^[1][2]. The label advises monitoring patients of all ages for worsening symptoms and for the emergence of suicidal thoughts ^[2].

The label lists contraindications including uncontrolled hypertension, seizure disorders, anorexia nervosa or bulimia, chronic opioid use, use of other bupropion-containing products, and use during or within 14 days of taking a monoamine oxidase inhibitor ^[2]. Contrave can cause seizures, raise blood pressure and increase heart rate, and it should not be given to patients with seizure disorders or uncontrolled hypertension ^[1].

Why it matters for patients

Contrave is a non-GLP-1 option, and its label draws lines that many people taking other weight-management drugs do not face. A history of seizures, an eating disorder such as anorexia nervosa or bulimia, or ongoing opioid use — including prescription pain medicines — rules out the drug, according to the prescribing information ^[2]. So does taking another bupropion product, such as Wellbutrin ^[2].

The boxed warning means people starting Contrave, and their families, are told to watch for worsening mood and for suicidal thoughts, and to contact a prescriber if those occur ^[2]. The label also directs monitoring of blood pressure and heart rate, with greater risk in the first three months of treatment ^[2].

The label has limits on what the drug has been shown to do. Its effect on cardiovascular illness and death has not been established, and its safety and effectiveness when combined with other weight-loss products — prescription, over-the-counter or herbal — have not been established ^[2]. Weight loss during pregnancy may cause fetal harm, and the label says to discontinue Contrave when a pregnancy is recognized ^[2].

Response is judged early. The label says patients should be evaluated after 12 weeks at the maintenance dose, and if they have not lost at least 5 percent of their baseline body weight, the drug should be stopped ^[1][2].

What happens next

As a condition of approval, Orexigen and Takeda agreed to post-marketing studies, including studies of Contrave for weight management in pediatric patients and a randomized, double-blind, placebo-controlled trial of long-term treatment and major adverse cardiovascular events in people who are overweight or have obesity with cardiovascular disease or multiple risk factors ^[1]. Completion dates for those studies were not disclosed in the approval announcement ^[1]. The prescribing information cited here is a 2021 revision, and the FDA notes it may not be the latest version approved ^[2].