Regulatory Decision Summary for Contrave
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
With this New Drug Submission (NDS), the sponsor is seeking marketing authorization of Contrave (naltrexone/bupropion), for chronic weight management in adult obese patients or patients with an initial body index greater than 27kg/m2 with at least one weight-related comorbidity such as controlled hypertension, type 2 diabetes mellitus, or dyslipidemia.
Why was the decision issued?
The efficacy of Contrave in weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults who are obese, or who are overweight with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia), was demonstrated in 3 adequately designed randomised, double-blind, placebo-controlled trials with treatment duration up to 56 weeks. In all 3 studies, Contrave was superior to placebo for the co-primary efficacy parameters, the percent change in body weight from baseline, and the proportion of subjects with ≥ 5% decrease in body weight from baseline (5% responders). In patients who completed double-blind treatment, mean change from baseline in the Contrave group showed a tendency to plateau after week 28.
Contrave was also significantly better than placebo for some key secondary efficacy parameters, such as the proportion of subjects with ≥ 10% decrease in body weight from baseline (10% responders), and changes from baseline in waist circumference, fasting triglycerides and fasting High-density lipoprotein (HDL) cholesterol in the studies including non-diabetic or diabetic patients. In the study involving diabetic patients, Contrave was also superior to placebo for improvements in HbA1c. However, despite greater weight loss in the drug groups, Contrave was not superior to placebo for the mean changes in blood pressure and heart rate.
The difference between Contrave and placebo for the mean changes in blood pressure (BP) and heart rate were increases in both subgroups of responders (lost at least 5% of baseline weight) and non-responders. In the subgroup of patients who lost significant weight, small mean increases from baseline in BP were seen initially in the Contrave group, followed by mean decreases which were in comparison smaller than in the placebo group. For heart rate, mean changes were no change or small increases from baseline in the Contrave group, and decreases from baseline in the placebo group throughout the study. Therefore, weight loss with Contrave, in average, was not associated with improvements in blood pressure and heart rate at the same extent as those associated with weight loss in the placebo group.
In the subgroup of Contrave-treated patients who did not lose significant weight from baseline, small mean increases from baseline in BP at the beginning of treatment, and in heart rate throughout the study were seen in the Contrave group, whereas in the placebo group, small mean decreases in BP and small mean increases in heart rate were observed throughout the study.
The safety of Contrave was evaluated in 26 studies: seventeen Phase 1, five Phase 2, and four Phase 3 studies. In the Phase 2/3 placebo-controlled trials, 3239 patients received the naltrexone/bupropion (NB) combination, 1663 for at least one year, and 1515 patients received placebo. A total of 3473 patients received NB treatment in controlled and uncontrolled Phase 2/3 trials, including 1666 patients for ≥1 year.
The most common treatment-emergent adverse events (incidence ≥5%) in the Contrave group and with incidences higher than in placebo were: nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth and diarrhea. The main safety issues known for each component of Contrave are:
Bupropion: seizures, hypertension, suicidality, activation of psychosis/mania and other psychiatric events
Naltrexone: acute withdrawal with concomitant opioids, hepatotoxicity. Except for hypertension, no new increased risks for these events were seen with Contrave, and the approved Contrave Product Monograph (PM) contains appropriate contraindications and warnings consistent with the approved bupropion and naltrexone products.
Consistent with the increased risks of blood pressure and heart rate elevations in the obese patient population, the approved Contrave PM contains stricter recommendations than those for the previously approved bupropion products as related to these events. Contrave is contraindicated in patients with uncontrolled hypertension and should be used with caution in patients with controlled hypertension. In a warning, it is recommended that blood pressure and pulse should be measured prior to starting therapy with Contrave and should be monitored at regular intervals consistent with usual clinical practice. If patients experience clinically relevant and sustained increases in blood pressure or pulse rate as a result of Contrave treatment, it should be discontinued. Also, Contrave should be discontinued in patients who do not lose at least 5% of their baseline weight at Week 16.
The benefit-harm-uncertainty assessment for Contrave is considered acceptable at this time when Contrave is used as described in the approved PM, and, as such, a Notice of Compliance was issued.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.