What are the combination weight loss drugs, such as phentermine (Phentermine) and topiramate (Topiramate), or naltrexone (Naltrexone) and bupropion (Bupropion), used for weight loss?

Combination Weight Loss Medications

The FDA-approved combination weight loss drugs are phentermine/topiramate extended-release (Qsymia) and naltrexone/bupropion sustained-release (Contrave), both indicated for chronic weight management in adults with BMI ≥30 kg/m² or ≥27 kg/m² with weight-related comorbidities, used as adjuncts to reduced-calorie diet and increased physical activity. 1

Phentermine/Topiramate Extended-Release (Qsymia)

Mechanism and Efficacy

• Phentermine is a sympathomimetic amine that elevates norepinephrine in the CNS to suppress appetite, while topiramate modulates gamma-aminobutyric acid receptors, inhibits carbonic anhydrase, and antagonizes glutamate to reduce food intake and increase satiation 1
• This combination produces 7.8% weight loss at the 7.5/46 mg dose and 9.8% at the 15/92 mg dose compared to 1.2% with placebo, with 62% and 70% of patients achieving ≥5% weight loss at these respective doses 2, 3
• Long-term data from the SEQUEL trial demonstrated persistent weight loss at 108 weeks (9.3% and 10.5% at the two dose levels) 2

Dosing Protocol

• Start with 3.75/23 mg daily for 14 days, then increase to 7.5/46 mg daily as the standard maintenance dose 1, 2, 4
• If inadequate response at 12 weeks, escalate to 11.25/69 mg daily for 14 days, then to maximum dose of 15/92 mg daily 1, 4
• Discontinue if <3% weight loss after 12 weeks at 7.5/46 mg, or <5% weight loss after 12 weeks at 15/92 mg 1, 2, 4
• Take once daily in the morning; avoid late evening dosing due to insomnia risk 1

Critical Safety Considerations

• Absolute contraindications: pregnancy (risk of orofacial clefts), uncontrolled hypertension, active coronary disease, hyperthyroidism, glaucoma, history of drug abuse, MAOI use within 14 days 4, 5
• Obtain pregnancy test before initiating in women of childbearing potential and counsel about teratogenicity risk and reduced efficacy of hormonal contraceptives 2, 4
• Common adverse effects include paresthesias (14-21%), dry mouth (13-21%), constipation (15-17%), dizziness (7-10%), dysgeusia (7-10%), and insomnia (6-10%) 2, 3
• Depression-related adverse events occurred in 4-7% and anxiety-related events in 5-8% of patients 3
• Never stop abruptly—taper by taking one capsule every other day for at least 1 week to avoid precipitating seizures 4

Monitoring Requirements

• Monthly visits for the first 3 months, then every 3 months thereafter 2, 4
• Monitor blood pressure and heart rate at each visit 2, 4
• Repeat pregnancy tests as clinically indicated 4

Naltrexone/Bupropion Sustained-Release (Contrave)

Mechanism and Efficacy

• Bupropion (dopamine/norepinephrine reuptake inhibitor) and naltrexone (opioid receptor antagonist) work synergistically to activate POMC neurons in the arcuate nucleus, causing release of alpha-melanocyte-stimulating hormone, a potent anorectic neuropeptide 1
• This combination produces 4.0% placebo-subtracted weight reduction at 12 months 6

Dosing Protocol

• Each tablet contains 8 mg naltrexone and 90 mg bupropion 1
• Start with 1 tablet daily, increase by 1 tablet weekly to maximum dose of 2 tablets in the morning and 2 tablets in the evening (32/360 mg total daily) 1
• Discontinue if <5% weight loss at 12 weeks 1

Critical FDA Warning About Phentermine Monotherapy

The FDA explicitly states that phentermine monotherapy is indicated only for short-term use (a few weeks), and the safety and efficacy of combination therapy with phentermine and any other weight loss drugs have not been established for combinations other than the FDA-approved phentermine/topiramate ER formulation. 5

Historical Context on Phentermine Combinations

• Primary pulmonary hypertension and serious cardiac valvular disease were reported with the combination of phentermine plus fenfluramine or dexfenfluramine (now withdrawn from market) 5
• While the role of phentermine alone in these complications has not been definitively established, rare cases have been reported with phentermine monotherapy 5

Other FDA-Approved Medications (Non-Combination)

Liraglutide (Saxenda)

• GLP-1 analogue approved at 3.0 mg daily for chronic weight management, producing 5.4% placebo-subtracted weight reduction at 12 months 1, 6
• Start at 0.6 mg daily, increase by 0.6 mg weekly until 3.0 mg is reached 1
• Discontinue if <4% weight loss at 16 weeks 1

Lorcaserin (Belviq) - WITHDRAWN

• Previously approved in 2012 but withdrawn from market in February 2020 due to increased cancer risk 1, 6

Orlistat

• Lipase inhibitor producing 2.9% placebo-subtracted weight reduction at 12 months, the least effective of currently available agents 6

Clinical Decision Algorithm

For patients with BMI ≥30 kg/m² or ≥27 kg/m² with weight-related comorbidities requiring pharmacotherapy:

1. First-line choice: Phentermine/topiramate ER for greatest weight loss efficacy (6.8% placebo-subtracted reduction), particularly in younger patients requiring appetite suppression 1, 2, 6

2. Alternative: Naltrexone/bupropion SR if phentermine/topiramate is contraindicated or patient has comorbid depression or smoking cessation needs 1

3. Alternative: Liraglutide if patient has type 2 diabetes or prefers injectable therapy 1

4. Avoid orlistat unless other options are contraindicated, given inferior efficacy 6