Indications for: CONTRAVE
Adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of ≥30kg/m2 or ≥27kg/m2 in the presence of at least one weight-related comorbidity (eg, hypertension, type 2 diabetes, or dyslipidemia).
Limitations of Use:
The effect on cardiovascular morbidity and mortality has not been established. Safety and efficacy in combination with other weight loss products, including Rx or OTC drugs, and herbal preps, have not been established.
The effects of Contrave on weight loss in conjunction with reduced caloric intake and increased physical activity was studied in double-blind, placebo-controlled trials (BMI range 27 to 45 kg/m2) with study durations of 16 to 56 weeks randomized to naltrexone and/or bupropion or placebo.
Four 56-week multicenter, double-blind, placebo-controlled obesity trials (Contrave Obesity Research, or COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of Contrave in conjunction with lifestyle modification in 4,536 patients randomized to Contrave or placebo. The COR-I, COR-II, and COR-BMOD trials enrolled patients with obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) and at least one comorbidity (hypertension or dyslipidemia). The COR-Diabetes trial enrolled patients with BMI >27 kg/m2 with type 2 diabetes with or without hypertension and/or dyslipidemia.
- COR-I and COR-II included a program consisting of a reduced-calorie diet resulting in an approximate 500 kcal/day decrease in caloric intake, behavioral counseling, and increased physical activity.
- COR-BMOD included an intensive behavioral modification program consisting of 28 group counseling sessions over 56 weeks as well as a prescribed diet and exercise regimen.
- COR-Diabetes evaluated patients with type 2 diabetes not achieving glycemic goal of a HbA1c less than 7% either with oral antidiabetic agents or with diet and exercise alone.
- The co-primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight.
In the COR-I trial, the mean change in body weight was -5.4% among patients assigned to Contrave 32 mg/360 mg compared with -1.3% among those assigned to placebo (Intent-To-Treat [ITT] population). In this trial, the achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with Contrave 32 mg/360 mg compared with placebo (42% vs 17%).
In the COR-BMOD trial, the mean change in body weight was -8.1% among patients assigned to Contrave 32 mg/360 mg compared with -4.9% among those assigned to placebo. The achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with Contrave 32 mg/360 mg compared with placebo (57% vs 43%).
In the COR-Diabetes trial, the mean change in body weight was -3.7% among patients assigned to Contrave 32 mg/360 mg compared with -1.7% among those assigned to placebo. The achievement of at least a 5% reduction in body weight from baseline occurred more frequently for patients treated with Contrave 32 mg/360 mg compared with placebo (36% vs 18%).
The percentages of patients who achieved at least 10% body weight loss from baseline were greater among those assigned to Contrave vs placebo, in all four obesity trials. For more clinical trial data, see full labeling.
Swallow whole. Avoid high-fat meals. Escalate dose gradually. ≥18yrs: Week 1: 1 tab daily in the AM; Week 2: 1 tab daily in the AM and 1 tab daily in the PM; Week 3: 2 tabs in the AM and 1 tab in the PM; Week 4 and thereafter: 2 tabs in the AM and 2 tabs in the PM. Max 32mg/360mg per day. Evaluate response after 12 weeks. Discontinue if ≥5% weight loss is not achieved. Concomitant CYP2B6 inhibitors (eg, ticlopidine, clopidogrel), renal impairment (moderate or severe), hepatic impairment (moderate): max 2 tabs daily (1 tab each AM & PM).
<18yrs: not recommended.
Uncontrolled hypertension. Seizure disorder. Concomitant other bupropion-containing products. Bulimia. Anorexia nervosa. Use of chronic opioid or opiate agonist (eg, methadone), or partial agonists (eg, buprenorphine). Acute opiate withdrawal. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptics. During or within 14 days of discontinuing MAOIs. Concomitant linezolid or IV methylene blue.
Suicidal thoughts and behaviors.
Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults; monitor for clinical worsening or unusual changes in all patients. Monitor for neuropsychiatric reactions; discontinue if occurs. Increased risk of seizures with predisposing risk factors (eg, history of head trauma, prior seizure, severe stroke, arteriovenous malformation, CNS tumor or infection, others: see full labeling); discontinue if seizure occurs and do not restart. Diabetes. Hypoglycemia. Cardiac or cerebrovascular disease. Monitor BP, pulse, and blood glucose levels prior to starting and during treatment. Risk of hepatic injury; discontinue if signs/symptoms of acute hepatitis occur. Screen for bipolar disorder. Angle-closure glaucoma. ESRD or severe hepatic impairment: not recommended. Elderly. Pregnancy: discontinue if occurs. Nursing mothers.
Opioid antagonist + aminoketone.
See Contraindications. Vulnerability to opioid overdose with concurrent opioid analgesics; if chronic therapy needed, discontinue Contrave. To prevent precipitation of withdrawal: discontinue chronic opioids 7–10 days prior to initiation. Reduced benefit with opioid-containing drugs (eg, antitussives, antidiarrheals, analgesics). May be potentiated by CYP2B6 inhibitors (see Adults). Avoid concomitant CYP2B6 inducers (eg, ritonavir, lopinavir, efavirenz). Caution with CYP2D6 substrates (eg, tricyclics, SSRIs, antipsychotics [eg, haloperidol, risperidone, thioridazine], β-blockers [eg, metoprolol], Class 1C antiarrhythmics [eg, propafenone, flecainide]); consider dose reduction (esp. drugs with a narrow therapeutic index). Caution with drugs that lower seizure threshold (eg, antipsychotics, antidepressants, theophylline, steroids). Monitor for CNS toxicity with levodopa, amantadine. Avoid alcohol. May antagonize digoxin levels; monitor. Concomitant antidiabetics; adjust dose if hypoglycemia develops. May cause false (+) test results in urine immunoassay for amphetamines.
Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, diarrhea; allergic reactions.
Naltrexone and its metabolites are excreted primarily by the kidney (53% to 79% of the dose). Fecal excretion is a minor elimination pathway. Following single oral administration of Contrave, mean elimination half-life (T½) was ~5 hours for naltrexone.
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Following single oral administration of Contrave, mean elimination half-life (T½) was ~21 hours for bupropion.
Generic Drug Availability: