Naltrexone/Bupropion Approved for Chronic Weight Management

The U.S. Food and Drug Administration (FDA) has approved the combination agent naltrexone/bupropion (Contrave) extended release tablets as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults who are obese (BMI ≥ 30 kg/m2) or overweight (27 kg/m2) and have at least one weight-related comorbidity, including hyperension, type 2 diabetes, and dyslipidemia.

Light Study
The FDA has required several postmarketing studies, including one to assess for any cardiovascular effects associated with use of naltrexone/bupropion. The agent’s manufacturers are currently conducting a cardiovascular-outcomes trial involving approximately 8,900 patients known as the Light Study. An interim analysis showed positive results.

Effects Two Areas of the Brain
The agent is a combination of the opioid antagonist naltrexone and the aminoketone antidepressant bupropion, which is a relatively weak inhibitor of neuronal uptake of dopamine and norepinephrine. Nonclinical studies suggest that naltrexone and bupropion have effects on two separate areas of the brain involved in the regulation of food intake: the hypothalamus (which regulates appetite) and the mesolimbic dopamine circuit (a reward pathway). Separately, naltrexone is approved to treat alcohol and opioid dependence, while bupropion is approved to treat depression, seasonal affective disorder, and as an aid to smoking cessation treatment. 

Clinical Trial Findings
The effectiveness of naltrexone/bupropion was evaluated in four 56-week multicenter, double-blind, placebo-controlled trials involving more than 4,500 obese and overweight patients with and without weight-related comorbidities. All patients received lifestyle modification that consisted of a reduced-calorie diet and regular physical activity.

In one of the clinical trials that involved overweight and obese patients with comorbid type 2 diabetes, the naltrexone/bupropion group showed significantly greater weight loss (-5.0% vs. -1.8%; P<0.001) and a greater proportion of patients achieving a ≥5% weight loss (44.5% vs. 18.9%; P<0.001) compared with the placebo group, as reported by Hollander et al. In addition, naltrexone/bupropion was linked to significantly greater improvement in hemoglobin A1C level (-0.6 vs -0.1%; P<0.001) and a significantly greater percentage of patients reaching an A1C <7% (44.1% vs 26.3%; P<0.001).

Results from another clinical trial involving overweight and obese patients with type 2 diabetes showed that patients had an average weight loss of 2% over treatment with placebo at 1 year, according to a press release from Orexigen Therapeutics and Takeda Pharmaceuticals. In this trial, the proportion of patients who achieved ≥5% weight loss was greater with naltrexone/bupropion (36% vs. 18% with placebo).

Common Adverse Reactions
The most common adverse reactions reported with naltrexone/bupropion in clinical trials include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.

Naltrexone/bupropion is contraindicated in patients with seizure disorders, uncontrolled hypertension, or eating disorders; women who are pregnant or trying to become pregnant; or in patients undergoing abrupt withdrawal of alcohol, barbiturates, and antiepileptic drugs.

In addition, the agent should not be used in combination with bupropion-containing products, opioids, or within 14 days of using monoamine oxidase inhibitors. As with all antidepressant medications, the prescribing information for naltrexone/bupropion contains a black box warning regarding an increased risk for suicidal thoughts and behaviors.

September 30, 2014

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