What are the next steps for an adult patient who has been on Contrave (bupropion SR 150 mg + naltrexone SR 8 mg) for at least 12 weeks at the target dose, follows a reduced‑calorie diet and regular exercise, but has achieved less than 5 % weight loss?

Discontinue Contrave and Switch to a GLP-1 Receptor Agonist

When a patient on Contrave (naltrexone SR 8 mg/bupropion SR 90 mg) at the full maintenance dose (32 mg/360 mg daily) for 12 weeks achieves less than 5% weight loss despite adherence to lifestyle modifications, the medication must be discontinued per FDA labeling and guideline recommendations. 1

Why Discontinuation is Mandatory at 12 Weeks

• The American Gastroenterological Association explicitly states that Contrave should be discontinued if a patient has not achieved 5% weight loss at 12 weeks on the maintenance dose. 1
• This 5% threshold at 12 weeks is the FDA-approved efficacy checkpoint; continuing beyond this point without adequate response exposes the patient to ongoing cardiovascular and neuropsychiatric risks without meaningful benefit. 1, 2
• The discontinuation rule applies specifically to patients who have completed the full 4-week titration and maintained the target dose (two tablets twice daily = 32 mg naltrexone/360 mg bupropion) for the remaining 8 weeks. 1

First-Line Alternative: GLP-1 Receptor Agonists

Switch to semaglutide 2.4 mg subcutaneously weekly (Wegovy) or liraglutide 3.0 mg subcutaneously daily (Saxenda) as the next pharmacotherapy option. 1

Why GLP-1 Agonists Are Superior After Contrave Failure

• Semaglutide 2.4 mg produces 10.3–12.4% total body weight loss at 68 weeks and 12.6% at 104 weeks in patients without diabetes—substantially greater than the 5–6% achieved with naltrexone-bupropion in responders. 1
• In patients with type 2 diabetes, semaglutide still achieves 6.2% weight loss at 68 weeks, outperforming Contrave's efficacy in this population. 1
• Liraglutide 3.0 mg is an alternative if semaglutide is unavailable or unaffordable; it has no seizure risk or stimulant interactions that complicate Contrave use. 2
• A recent meta-analysis demonstrated that tirzepatide 15 mg weekly (approved November 2023) produces even greater weight loss than semaglutide (mean difference 5.1%), achieving 20.9% total body weight loss at 72 weeks. 1

Practical GLP-1 Titration Protocol

• Semaglutide 2.4 mg: Start at 0.25 mg subcutaneously weekly for 4 weeks, then escalate monthly (0.5 mg → 1.0 mg → 1.7 mg → 2.4 mg maintenance). 1
• Liraglutide 3.0 mg: Start at 0.6 mg subcutaneously daily, increase by 0.6 mg weekly to 3.0 mg maintenance dose. 1
• Discontinue liraglutide if less than 4% weight loss after 16 weeks at the 3.0 mg dose. 1
• Common adverse effects (nausea, vomiting, diarrhea) are usually transient and resolve with continued use; taking the injection with food and staying hydrated reduces gastrointestinal symptoms. 1

Second-Line Alternative: Phentermine-Topiramate ER

If GLP-1 agonists are contraindicated (personal or family history of medullary thyroid cancer or MEN2), pancreatitis history, or cost-prohibitive, switch to phentermine-topiramate ER (Qsymia). 1

• Phentermine-topiramate ER 15 mg/92 mg produces 10.9% weight loss at 56 weeks, significantly greater than naltrexone-bupropion (approximately 6%) and orlistat (2.8–4.8%). 1
• The lower dose (7.5 mg/46 mg) achieves 5.1% weight loss and may be appropriate for patients with cardiovascular concerns. 1
• Discontinue if less than 3% weight loss after 12 weeks on the 7.5 mg/46 mg dose, or escalate to 15 mg/92 mg; discontinue if less than 5% weight loss after 12 additional weeks on the maximum dose. 1
• This combination may be particularly useful in patients with comorbid migraine headaches, as topiramate is FDA-approved for migraine prophylaxis. 1

Critical Contraindications to Phentermine-Topiramate

• Pregnancy (teratogenic risk requires negative pregnancy test before initiation and monthly thereafter, plus two forms of contraception). 1
• Glaucoma, hyperthyroidism, or use of MAOIs within 14 days. 1
• Cardiovascular disease including uncontrolled hypertension, recent myocardial infarction, or stroke. 1

Third-Line Option: Orlistat (When Other Agents Are Contraindicated)

• Orlistat 120 mg three times daily with meals is appropriate only when GLP-1 agonists and phentermine-topiramate are contraindicated, unavailable, or unaffordable. 1
• The American Gastroenterological Association conditionally recommends against orlistat due to modest weight loss (2.8–4.8%) and frequent gastrointestinal adverse effects (flatulence, steatorrhea, diarrhea). 1
• Patients must take a daily multivitamin containing fat-soluble vitamins (A, D, E, K) at least 2 hours apart from orlistat to prevent malabsorption. 1

Monitoring Requirements After Switching

• GLP-1 agonists: Monitor for pancreatitis symptoms (severe abdominal pain radiating to the back), acute gallbladder disease, and suicidal ideation (particularly in patients <24 years old). 1
• Phentermine-topiramate: Measure blood pressure and heart rate at baseline and monthly; assess for cognitive impairment, mood changes, and metabolic acidosis (obtain baseline bicarbonate). 1
• All agents: Reassess efficacy at 12–16 weeks using the medication-specific weight loss thresholds above; discontinue if targets are not met. 1

Critical Pitfalls to Avoid

• Do not continue Contrave beyond 12 weeks without ≥5% weight loss—this violates FDA labeling and exposes patients to unnecessary cardiovascular (hypertension, tachycardia) and neuropsychiatric (suicidal ideation, seizure) risks. 1, 2, 3
• Do not increase the Contrave dose above 32 mg naltrexone/360 mg bupropion daily—seizure risk increases markedly above this threshold (>0.1%). 2, 4
• Do not prescribe phentermine-topiramate to women of childbearing potential without documented negative pregnancy test and dual contraception—topiramate carries significant teratogenic risk. 1
• Do not prescribe GLP-1 agonists to patients with personal or family history of medullary thyroid cancer or MEN2—these are absolute contraindications. 1