What off-label medications (off-label drugs) can be used for obesity treatment?

Off-Label Medications for Obesity Treatment

For patients with obesity (BMI ≥30 kg/m²) or overweight with complications (BMI ≥27 kg/m²) who fail lifestyle interventions, phentermine monotherapy and diethylpropion are the primary off-label medications recommended, with metformin, bupropion, topiramate, and zonisamide as additional options when FDA-approved medications are contraindicated or unavailable. 1, 2

Primary Off-Label Medications

Phentermine Monotherapy (Most Commonly Used)

• Phentermine alone is the most frequently prescribed off-label obesity medication in the United States, used long-term despite FDA approval only for short-term use (<12 weeks). 3
• Dosing ranges from 15-37.5 mg orally once daily in the morning, with a low-dose 8 mg formulation (Lomaira) available up to 3 times daily. 1
• Achieves approximately 6.0 kg weight loss at 28 weeks, with 46% of patients achieving ≥5% total body weight loss and 20.8% achieving ≥10% weight loss. 1
• Avoid in patients with cardiovascular disease, uncontrolled hypertension, hyperthyroidism, or those taking monoamine oxidase inhibitors. 1
• Monitor blood pressure and heart rate periodically, though observational data show phentermine monotherapy does not significantly increase these parameters. 1
• Common adverse effects include dry mouth, constipation, insomnia, palpitations, and irritability. 1

Diethylpropion

• The AGA conditionally recommends diethylpropion with lifestyle interventions for adults with obesity or overweight with weight-related complications. 1
• FDA-approved for short-term use (12 weeks), but commonly used off-label for longer durations given obesity's chronic nature. 1
• Produces mean 5.36% total body weight loss (95% CI: 3.50%-7.23%) and absolute weight loss of 4.74 kg (95% CI: 3.08-6.40 kg) compared to placebo. 1
• Avoid in patients with cardiovascular disease and monitor blood pressure and heart rate periodically. 1
• Studies enrolled predominantly female patients (mean age 34-38 years, baseline BMI ~34 kg/m²) with lifestyle interventions including 500-600 kcal/day deficit or 1000-1200 kcal/day target. 1

Secondary Off-Label Medications

Metformin

• Associated with approximately 3% weight loss in patients with obesity. 2
• Promotes weight loss through multiple mechanisms beyond glycemic control. 1
• Potential side effects include gastrointestinal symptoms and vitamin B12 deficiency. 2

Bupropion Monotherapy

• Produces modest weight loss of 2.8 kg at 6-12 months. 2
• Weight-neutral or promotes weight loss compared to other antidepressants. 1

Topiramate and Zonisamide (Anticonvulsants)

• Both anticonvulsants are associated with weight loss when used off-label. 1
• Topiramate is FDA-approved in combination with phentermine but used off-label as monotherapy. 4

Clinical Decision Algorithm

Step 1: Verify Patient Eligibility

• BMI ≥30 kg/m² OR BMI ≥27 kg/m² with weight-related comorbidities (hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea). 2, 5
• Failed lifestyle modifications (diet, exercise, behavioral counseling) for adequate duration. 2

Step 2: Consider FDA-Approved Options First

• FDA-approved medications (orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide) should be prioritized before off-label options. 2, 6
• Off-label medications should only be considered when FDA-approved options are contraindicated, unavailable, or unaffordable. 2

Step 3: Select Off-Label Medication Based on Patient Profile

For younger patients without cardiovascular disease or hypertension:

• First choice: Phentermine monotherapy 15-37.5 mg daily for appetite suppression with proven long-term safety record. 1, 3

For patients with cardiovascular concerns or hypertension:

• Avoid phentermine and diethylpropion. 1
• Consider metformin, especially if prediabetic or insulin resistant. 1, 2

For patients with anxiety or insomnia:

• Avoid phentermine as it may exacerbate these conditions. 1
• Consider metformin or anticonvulsants. 1, 2

For patients with depression:

• Consider bupropion monotherapy as dual-purpose treatment. 1, 2

Step 4: Set Realistic Expectations

• Off-label medications produce modest weight loss (<5 kg at 1 year) compared to newer FDA-approved agents. 2
• Long-term safety data (>12 months) are lacking for most off-label medications. 2
• Weight regain typically occurs when medications are discontinued. 5

Critical Pitfalls to Avoid

• Never prescribe weight loss medications to patients with normal BMI (<25 kg/m²) based solely on patient request - the risk-benefit ratio is unfavorable. 5
• Do not use phentermine within 14 days of monoamine oxidase inhibitors due to risk of hypertensive crisis. 1
• Avoid β-blockers (atenolol, metoprolol, nadolol, propranolol) as antihypertensives in patients with obesity as they promote weight gain and prevent weight loss. 1
• Do not prescribe phentermine in patients with untreated hyperthyroidism due to concerns for arrhythmias and seizures. 1
• Recognize that phentermine has been inappropriately maligned due to structural similarity to amphetamine, despite decades of safe use when prescribed appropriately. 3

Monitoring Requirements

• Periodic blood pressure and heart rate monitoring for sympathomimetic agents (phentermine, diethylpropion). 1
• Assess for vitamin B12 deficiency with long-term metformin use. 2
• Evaluate weight loss response at 12 weeks - if <5% total body weight loss achieved, consider discontinuing or switching medications. 2
• Emphasize that obesity is a chronic disease requiring long-term treatment, not short-term intervention. 1, 4