CONTRAVE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CONTRAVE (CONTRAVE).
Contrave is a combination of bupropion, a norepinephrine and dopamine reuptake inhibitor, and naltrexone, a mu-opioid receptor antagonist. The combination is thought to act synergistically on the hypothalamic melanocortin system to reduce food intake and increase energy expenditure.
| Metabolism | Bupropion: extensively metabolized in the liver by CYP2B6 to hydroxybupropion. Naltrexone: primarily metabolized in the liver by dihydrodiol dehydrogenase to 6β-naltrexol. |
| Excretion | Naltrexone and bupropion are primarily eliminated renally. Naltrexone: 60% renal (mostly metabolites), 30% biliary/fecal. Bupropion: 87% renal (10% unchanged, 87% as metabolites), 10% fecal. |
| Half-life | Naltrexone: 4 hours (terminal half-life of 6-beta-naltrexol is 13 hours). Bupropion: 21 hours (hydroxybupropion: 20 hours, threohydrobupropion: 37 hours, erythrohydrobupropion: 33 hours). Clinical context: steady-state reached in ~5 days; once-daily dosing. |
| Protein binding | Naltrexone: 21% bound to plasma proteins. Bupropion: 84% bound to albumin. Hydroxybupropion: 4% bound. |
| Volume of Distribution | Naltrexone: Vd 19 L/kg (extensive tissue distribution). Bupropion: Vd 27 L/kg (large, indicating extensive tissue binding). |
| Bioavailability | Naltrexone: oral bioavailability 5–40% (extensive first-pass metabolism). Bupropion: oral bioavailability 5–20% (extensive first-pass metabolism). Combination tablet: relative bioavailability similar to individual components. |
| Onset of Action | Oral: clinical effect (weight loss) typically observed after 4–12 weeks of therapy. Not immediate; gradual reduction in appetite. |
| Duration of Action | Oral: sustained release formulation provides 24-hour coverage with once-daily dosing. Clinical effect persists as long as treatment continues; discontinuation leads to gradual return of weight. |
One tablet (naltrexone 8 mg/bupropion 90 mg) orally once daily for the first week, then one tablet twice daily starting week 2; maximum two tablets twice daily.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | Contraindicated in end-stage renal disease (eGFR <30 mL/min/1.73 m²); for eGFR 30-59 mL/min/1.73 m², maximum dose is one tablet (8/90 mg) twice daily. |
| Liver impairment | Contraindicated in Child-Pugh Class C; for Child-Pugh Class B, maximum dose is one tablet (8/90 mg) once daily; no adjustment for Class A. |
| Pediatric use | Safety and efficacy not established in pediatric patients under 18 years; use not recommended. |
| Geriatric use | Limited data; use with caution in patients aged 65 years and older due to potential for increased sensitivity; no specific dose adjustment recommended, but monitor renal function and CNS effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CONTRAVE (CONTRAVE).
| Breastfeeding | Not recommended during breastfeeding. Bupropion and its metabolites are excreted in breast milk with an average M/P ratio (milk/plasma) of approximately 2.5 for bupropion. Naltrexone and 6β-naltrexol also pass into milk. Potential adverse effects include irritability, poor feeding, and seizures in the infant. |
| Teratogenic Risk | CONTRAVE (naltrexone/bupropion) is contraindicated in pregnancy due to increased risk of neural tube defects (NTDs) and congenital malformations. Studies show bupropion exposure in first trimester is associated with elevated risk of NTDs (odds ratio ~2.5). Second and third trimester exposure may increase risk of premature birth, low birth weight, and neonatal withdrawal (bupropion) or opioid withdrawal (naltrexone). |
■ FDA Black Box Warning
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC REACTIONS. Bupropion, a component of Contrave, is associated with an increased risk of suicidal thoughts and behaviors in pediatric and young adult patients. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. Additionally, Contrave is not approved for smoking cessation; however, bupropion has been associated with serious neuropsychiatric reactions including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts/behaviors, and attempted suicide in patients treated for smoking cessation.
| Serious Effects |
["Uncontrolled hypertension (≥140/90 mmHg)","Seizure disorder or history of seizures","Bulimia or anorexia nervosa","Use of MAOIs (monoamine oxidase inhibitors) within 14 days","Chronic opioid use or opioid withdrawal","Concomitant use of other bupropion-containing products","Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, or antiepileptic drugs","Hepatic impairment (Child-Pugh class B or C)"]
| Precautions | ["Suicidal thoughts and behaviors","Neuropsychiatric reactions","Seizure risk (dose-related; contraindicated in patients with seizure disorder or conditions that lower seizure threshold)","Increased blood pressure and heart rate","Angle-closure glaucoma","Hepatotoxicity (naltrexone component)","Allergic reactions (including anaphylaxis, angioedema, urticaria)","Opioid withdrawal (naltrexone is an opioid antagonist)","Use with opioids or opioid agonists is contraindicated","Monitor for depression, suicidal ideation, and behavior"] |
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| Fetal Monitoring | During pregnancy: fetal ultrasound at 18-20 weeks to assess for NTDs; monitor fetal growth and amniotic fluid index; neonatal monitoring for signs of withdrawal (opioid withdrawal syndrome or bupropion-related neurobehavioral symptoms). In breastfeeding: monitor infant for sedation, poor suckling, weight loss. |
| Fertility Effects | May impair fertility due to ovulation disruption (bupropion can cause menstrual irregularities and ovulatory dysfunction). Naltrexone may affect the hypothalamic-pituitary-gonadal axis, potentially altering gonadotropin secretion. Use of CONTRAVE for weight loss may improve fertility in obese women, but hypothalamic effects of naltrexone can reduce luteinizing hormone (LH) pulsatility. |