Contrave, a novel combination of naltrexone and bupropion for obesity

Highlights of the document of 7th December, 2010 summarizing the data in support of the approval of Contrave, a novel combination product for the treatment of obesity composed of bupropion and naltrexone developed by Orexigen, Inc. of La Jolla, California.

Proposed Indication: The treatment of obesity and weight management, including weight loss and maintenance of weight loss, used in conjunction with lifestyle modification. Recommended for patients with an initial body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more risk factors (e.g. diabetes, dyslipidemia, or hypertension).

Proposed Dosing: The recommended daily dose of Contrave is two 8 mg naltrexone/90 mg bupropion (8/90) tablets taken twice daily for a total daily dose of 32 mg naltrexone/360 mg bupropion (32/360). Upon initiation, Contrave dosing should be escalated starting with one tablet taken daily for the first week, followed by the addition of another tablet each day during each subsequent week, until the total daily maintenance dose of two tablets twice a day (32/360)is reached at the start of Week 4.

Contrave, a novel combination product for the treatment of obesity, is composed of bupropion (a relatively weak inhibitor of the neuronal uptake of norepinephrine [NE] and dopamine [DA]) combined with naltrexone (a mu-opioid receptor antagonist).

Bupropion has been shown to stimulate hypothalamic proopiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α- MSH) which, in turn, binds to melanocortin 4 (MC4) receptors. The binding of α-MSH to MC4 receptors initiates a cascade of actions that results in weight loss via reduced energy intake and increased energy expenditure. When α-MSH is released, POMC neurons simultaneously release β-endorphin, an endogenous agonist of the mu-opioid

receptor that mediates a negative feedback loop on POMC neurons leading to a decrease in

the release of α-MSH. Blocking this inhibitory feedback loop with naltrexone is proposed to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying effects on energy balance. As a result, co-administration of bupropion and naltrexone produces a substantially greater effect on the POMC firing rate than either compound administered

alone, suggesting that the drugs act synergistically.

Adverse events: The observed Contrave safety and tolerability profile was generally comparable to the well-established safety profiles associated with naltrexone and bupropion, each with more

than 20 years of post-marketing experience and approximately 1 million and more than 50 million unique exposures, respectively.  With the exception of nausea and vomiting, the NB combination of naltrexone and bupropion did not appear to be associated with increased adverse events (AEs) relative to the individual components. The adverse events were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM235672.pdf