Contrave (bupropion hydrochloride; naltrexone hydrochloride): NDA 200063

The Office of Clinical Pharmacology/Division of Clinical Pharmacology-2 recommends approval.

They recommended a thorough QT study as part of the PMR/PMC, if the product is approved.

Dr. Brundage, the primary nonclinical reviewer, concludes that the pharmacology and toxicology data support approval of Contrave for the proposed obesity indication.

At Week 26, the LS mean percent change in body weight from baseline was statistically significantly greater with NB (-2.6%) compared to placebo (0.0%; p<0.0001); the LS mean treatment difference (NB minus placebo) was -2.6%.

At Week 52, the LS mean percent change in body weight from baseline remained statistically significantly greater with NB (-2.7%) compared to placebo (0.03%; p<0.0001); the LS mean treatment difference was -2.8%.

The trial should be designed to show that the upper bound of the 95% confidence interval for the estimated risk ratio (CONTRAVE to placebo) for MACE is less than 1.4.

For the ITT (with LOCF) Population, mean body weight was similar across the treatment groups at baseline (106.3 kg placebo; 105.7 kg NB).

However, there were statistically significant treatment differences for subjects that were female (LS mean difference from placebo 0.8 mg Hg; p=0.02), nonwhite (LS mean difference from placebo 1.8 mg Hg; p=0.004), or had a BMI <35 kg/m2 (LS mean difference from placebo 0.9 mg Hg; p=0.03).

The primary efficacy analysis was based on the percentage (%) change in total body weight, measured as the difference between baseline and Week 16. In order to maintain the family-wise type I error rate to within the pre-specified 1-tailed alpha level of 5%, comparisons within each treatment family were done according to the Min Test procedure.

Therefore, before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug's benefit-risk profile.

Nausea: No TEAE of nausea was considered serious; it was considered severe in 1.9% of subjects in the Total NB group (compared with <0.1% of subjects in the placebo group).

The sponsor proposed a REMS comprising a communication plan and a Medication Guide during the previous review cycle.

The previous REMS proposal was submitted at the end of the previous review cycle, and the REMS was not reviewed before the Complete Response (CR) letter was issued, 10 days after the submission of the REMS.

With release of the REMS, the requirement for the sponsor to assess patient understanding of the risk is removed, but dispensing of the Medication Guide is still required.

DMEP does not plan to address labeling or REMS during this review cycle.

Because of this, Dr. Brundage recommends, as a postmarketing requirement (PMR), a juvenile animal study with the combination of bupropion and naltrexone to assess behavior/motor activity, learning and memory, growth, sexual maturation, and mating/fertility prior to initiating pediatric safety and efficacy studies.

We are not confident that one would ultimately be able to detect or exclude the possibility that these activities may have biased the trial's results or otherwise compromised its integrity and have concluded, therefore, that the LIGHT trial will not satisfy a post-marketing requirement (PMR) related to cardiovascular safety.

Therefore, the clinical pharmacology team is recommending a postmarketing commitment for the applicant to characterize the systematic evaluation of PK in subjects with mild, moderate, and severe hepatic impairment.