What are the dosing, titration, eligibility criteria, contraindications, and monitoring recommendations for initiating Contrave (naltrexone/bupropion) in adult patients?

Contrave Administration Recommendations

Contrave (naltrexone/bupropion ER) should be initiated with a structured 4-week titration schedule starting at 1 tablet (8mg/90mg) daily in the morning, escalating weekly to a maintenance dose of 2 tablets twice daily (32mg/360mg total daily), and should be discontinued if less than 5% weight loss is achieved after 12 weeks at the maintenance dose 1, 2.

Eligibility Criteria

Contrave is indicated for adults with 2:

• BMI ≥30 kg/m² (obese), OR
• BMI ≥27 kg/m² (overweight) with at least one weight-related comorbidity:
  • Hypertension
  • Type 2 diabetes mellitus
  • Dyslipidemia

The medication must be used as an adjunct to reduced-calorie diet and increased physical activity 2.

Dosing and Titration Schedule

The FDA-approved titration follows a strict 4-week escalation 1, 2:

Week	Morning Dose	Evening Dose
Week 1	1 tablet	None
Week 2	1 tablet	1 tablet
Week 3	2 tablets	1 tablet
Week 4 onward	2 tablets	2 tablets

Critical dosing considerations:

• Each tablet contains 8mg naltrexone HCl and 90mg bupropion HCl 2
• The second dose should not be taken late in the day to minimize insomnia risk 1
• Avoid high-fat meals with dosing to minimize seizure risk 2

Dose Adjustments for Organ Dysfunction

Renal impairment 1:

• Moderate to severe impairment: Reduce total daily dose by half (1 tablet twice daily)
• End-stage renal disease: Avoid use

Hepatic impairment 1:

• Moderate to severe impairment: Maximum dose of 1 tablet daily

CYP2B6 inhibitor co-administration (ticlopidine, clopidogrel) 2:

• Do not exceed 1 tablet twice daily

Absolute Contraindications

Contrave is contraindicated in 2:

• Uncontrolled hypertension
• Seizure disorders (current or history)
• Anorexia nervosa or bulimia
• Chronic opioid use (naltrexone will precipitate withdrawal or block analgesic effects)
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs
• Concurrent use of other bupropion-containing products
• MAOI use within 14 days (risk of hypertensive crisis)
• Known allergy to naltrexone or bupropion

Special Populations Requiring Caution

Patients at increased seizure risk 1, 2:

• Use with extreme caution or avoid entirely
• Risk factors include eating disorders, head trauma, CNS tumors, excessive alcohol use, or medications that lower seizure threshold

Patients requiring opioid analgesia 1:

• Discontinue Contrave before procedures requiring opioids (e.g., endoscopy with fentanyl)
• Naltrexone will block opioid efficacy and may precipitate withdrawal in opioid-dependent patients

Cardiovascular disease 1:

• The AGA guidelines note Contrave should be avoided in patients with history of cardiovascular disease 1
• Blood pressure increases are most prominent in the first 8 weeks 1

Monitoring Requirements

Blood pressure and heart rate 1, 2:

• Monitor periodically in all patients
• Especially critical during the first 12 weeks of treatment 1
• Monitor more frequently in patients with cardiac or cerebrovascular disease

Psychiatric monitoring 2:

• Monitor for suicidal ideation, depression, or mood changes (Black Box Warning for bupropion)
• Watch for neuropsychiatric adverse events: mania, psychosis, hallucinations, aggression, anxiety
• Discontinue immediately if these symptoms develop

Weight loss assessment 1:

• Evaluate at 12 weeks on maintenance dose
• Discontinue if <5% total body weight loss achieved (patient is likely a poor responder)

Blood glucose monitoring 2:

• Monitor in diabetic patients as weight loss may cause hypoglycemia
• Antidiabetic medication adjustments may be necessary

Hepatic function 2:

• Consider baseline and periodic monitoring given naltrexone's association with hepatotoxicity

Common Pitfalls and Adverse Effects

Most common adverse effects (≥5%) 2:

• Nausea (most common—reported in 5.7-33% depending on study) 1, 3, 4
• Constipation (5.7-28.6%) 3, 4
• Headache (2.5-19.4%) 3, 4
• Vomiting
• Dizziness
• Insomnia
• Dry mouth
• Diarrhea

Mitigation strategies:

• Gradual titration helps reduce nausea and vomiting 1
• 25% of patients discontinued due to adverse effects in clinical trials 1
• In real-world practice, discontinuation rates within 12 months reached 52.7% 4

Drug Interactions Requiring Action

CYP2D6 substrates 2:

• Bupropion inhibits CYP2D6
• Consider dose reduction for: SSRIs, tricyclic antidepressants, antipsychotics (haloperidol, risperidone, thioridazine), beta-blockers (metoprolol), Type 1C antiarrhythmics (propafenone, flecainide)

CYP2B6 inducers 2:

• Ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, phenytoin
• Avoid concomitant use (may reduce efficacy by decreasing bupropion exposure)

Dopaminergic drugs 2:

• Levodopa and amantadine: CNS toxicity can occur

Digoxin 2:

• May decrease plasma digoxin levels—monitor levels

Clinical Context and Positioning

The 2022 AGA guidelines provide a conditional recommendation for naltrexone-bupropion ER with moderate quality evidence 1. The guideline panel judged the magnitude of benefit as moderate (approximately 6% weight loss at 56 weeks vs 1% with placebo) with small magnitude of undesirable effects 5, 1.

Contrave may be preferentially considered for 5, 1:

• Patients with comorbid depression (bupropion has antidepressant effects)
• Patients attempting smoking cessation
• Patients seeking alcohol use reduction

However, Contrave is less effective than newer agents: semaglutide 2.4mg and tirzepatide produce substantially greater weight loss and may be prioritized when available 5, 1.

Real-world effectiveness shows mean weight loss of 4.05-11.5% at 6-12 months, with 42.5% achieving ≥5% weight loss and 15.5% achieving ≥10% weight loss 3, 4. Patients also report decreased appetite, cravings, and hunger 3, 6.

Key Safety Warnings

Black Box Warning 2:

• Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants
• Contrave has not been studied in pediatric patients and is not recommended

Cardiovascular outcomes 2:

• The effect of Contrave on cardiovascular morbidity and mortality has not been established
• Recent real-world data suggests no increased MACE risk compared to lorcaserin 7

Pregnancy 2:

• Weight loss during pregnancy may cause fetal harm
• Discontinue when pregnancy is recognized

False-positive drug tests 2:

• Contrave can cause false-positive urine test results for amphetamines