Bupropion/Naltrexone is a combination drug treatment for obesity. As of 2014, the drug is marketed in the United States in a sustained release formulation under the name Contrave by Takeda for the drug's developer, Orexigen Therapeutics. An estimate from Wells Fargo places the potential revenue from this drug at US$600 million per year.
Bupropion/naltrexone is a combination of two FDA approved drugs, bupropion and naltrexone. Both drugs have individually shown some evidence of effectiveness in weight loss, and the combination is expected to have a synergistic effect. In clinical trials, patients taking Contrave combined with diet and exercise lost more weight than patients taking a placebo and following the same diet and exercise program.
Drug Development
On 31 March 2010, Orexigen submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for this drug combination. On 7 December 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave, and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study. Contrave's PDUFA date was 31 January 2011. Subsequently, on 2 February 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered. The recommended daily dose of Contrave is two (8Â mg naltrexone/90Â mg bupropion) tablets taken twice daily (4 tablets total - 32Â mg naltrexone, 360Â mg bupropion). Upon initiation, the drug will be started with a quarter-dose (or one tablet) for one week and a pill will be added to the regimen each week until the full recommended dose is reached on Week 4.
During phase 2 testing, different dosages were used in a once daily formula. These include:
- 16Â mg naltrexone - 400Â mg bupropion
- 32Â mg naltrexone - 400Â mg bupropion
- 48Â mg naltrexone - 400Â mg bupropion
The second dosage (32Â mg-400Â mg) on average showed the best benefit-to-risk ratio.
Treatment is designed to influence the hypothalamus in order to decrease food intake over an extended period of time. Studies of almost 700 patients, 90% female, ran up to 56 weeks. The control group, overall, lost 5% of their initial body weight, or 11-16Â lbs. The experimental (medicated) group lost 20-23Â lbs during the same amount of time. The average starting weight for participants was 223Â lbs. Current medical weight loss medications average 5-22Â lbs lost in 6 months.
Mechanism of Action
Combination of both Bupropion and Naltrexone targets CNS pathways that influence food intake. Bupropion is a dopamine and norepinephrine reuptake inhibitor,which also activates pro-opiomelanocortin (POMC) neurons in the hypothalamus which give an effect downstream, resulting in loss of appetite and increased energy output. POMC is regulated by endogenous opioids via opioid-mediated inhibitory feedback. Naltrexone, a pure opioid antagonist, is used to suppress POMC inhibition therefore augmenting greater effect of POMC activation. Bupropion/Naltrexone also has an effect on the reward pathway that result in lessening food craving.
Dosing
On the market, Contrave is available as an extended-release tablet of 8mg naltrexone HCl and 90mg bupropion HCl.
Week 1: take 1 tablet by mouth, once daily every morning.
Week 2: take 1 tablet by mouth every morning and evening.
Week 3: take 2 tablets by mouth every morning and 1 in the evening.
Week 4 and on: take 2 tablet by mouth every morning and evening. Total daily dose 32mg naltrexone/360mg bupropion. Daily doses higher than that are not recommended. This is the maintenance dose.
It is recommended to stop taking the medicine if the body weight has not decreased by 5% after 12 weeks at maintenance dose.
Safety and effectiveness in children under the age of 18 has not been studied.
Contraindications
Takeda recommends that Contrave should not be used in anyone who falls into any of the categories below:
• History of seizures
• History of an eating disorder such as bulimia or anorexia
• Taking opioid pain medicines, taking medicines to stop opioid addiction, or are in opiate withdrawal
• Currently taking an MAOI or have taken an MAOI in the last 14 days
• Pregnant
• Abrupt termination of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs
Safety Information
One of the medications in Contrave is bupropion. The FDA has put a boxed warning onto this medicine because it may affect mood and increase the likelihood of suicide. Although rare, signs of mood and behavioral changes should be reported to a doctor.