What is the comparison between bupropion (Wellbutrin) XL (Extended Release) and SR (Sustained Release) formulations?

Comparison of Bupropion XL vs SR Formulations

Key Recommendation

Both bupropion XL (once-daily) and SR (twice-daily) formulations are bioequivalent in terms of systemic exposure and clinical efficacy for treating major depressive disorder, but XL offers superior convenience with once-daily dosing while SR provides more flexible dose titration options. 1, 2, 3

Pharmacokinetic Differences

Absorption Profile

• Bupropion XL has a prolonged absorption with Tmax of approximately 5 hours, compared to SR's Tmax of approximately 3 hours, allowing for true once-daily administration 3
• Despite different absorption profiles, all three formulations (IR, SR, and XL) are bioequivalent in terms of total systemic exposure to bupropion and its active metabolites 2, 4, 3

Active Metabolites

• All formulations produce the same three active metabolites: hydroxybupropion (primary metabolite, 50% as active as parent drug), threohydrobupropion, and erythrohydrobupropion (both approximately 20% as active) 3
• At steady state, hydroxybupropion concentrations are 4- to 7-fold higher at Cmax and approximately 10-fold greater in AUC compared to the parent drug, regardless of formulation 3

Dosing Regimens

Bupropion SR Dosing

• Standard dosing: 150 mg twice daily (total 300 mg/day) for both major depressive disorder and smoking cessation 5, 6, 1
• Initial titration: Start with 150 mg once daily for 3 days, then increase to 150 mg twice daily 6
• The second dose must be administered before 3 PM to minimize insomnia risk 6
• Maximum dose: 400 mg per day 6

Bupropion XL Dosing

• Standard dosing: 300 mg once daily in the morning 6, 1
• Initial titration: Start with 150 mg once daily for 4-7 days, then increase to 300 mg once daily 1
• Maximum dose: 450 mg per day 6
• Administered in the morning without regard to food 1, 3

Clinical Efficacy Comparison

Depression Treatment

• Both formulations demonstrate comparable efficacy to SSRIs and other antidepressants in treating major depressive disorder 2, 4
• Bupropion SR was as effective as SSRIs with advantages of less somnolence and sexual dysfunction 2, 4
• Bupropion XL established efficacy in 2 of 6 well-designed placebo-controlled studies for primary outcomes, and demonstrated efficacy in secondary outcomes in 5 studies 2, 4
• One study suggested that bupropion SR 150 mg once daily may be as effective as 150 mg twice daily, though this requires further validation 7

Smoking Cessation

• For smoking cessation, bupropion SR 150 mg twice daily (300 mg total) is the established regimen, with treatment beginning 1-2 weeks before the target quit date and lasting 7-12 weeks 5, 6
• No specific data supports XL formulation for smoking cessation in the guidelines reviewed 5

Tolerability and Safety Profile

Common Adverse Events

• Both formulations share similar adverse event profiles: headache, dry mouth, nausea, insomnia, constipation, and dizziness are most common 8
• Both formulations have among the lowest incidence of sexual dysfunction, weight gain, and somnolence compared to other antidepressants 2, 4, 8
• Minor weight loss observed: SR 150 mg once daily (0.5 kg), SR 300 mg daily (1.0 kg) versus placebo (0.2 kg) 7

Seizure Risk

• Both formulations lower seizure threshold; maximum doses should not exceed 450 mg/day for XL or 400 mg/day for SR to minimize seizure risk 6, 1
• Seizures are reported rarely, with approximately 10 cases among 13,000 study participants across formulations 5
• Both are contraindicated in patients with seizure disorders, eating disorders (bulimia/anorexia), or abrupt discontinuation of alcohol/benzodiazepines 6, 1

Clinical Decision-Making Algorithm

Choose Bupropion XL When:

• Patient adherence is a concern - once-daily dosing improves compliance 2, 4, 8
• Patient prefers simplified medication regimen 2, 4
• Standard dosing of 300 mg daily is appropriate from the start 1
• Patient has no issues with morning-only administration 1

Choose Bupropion SR When:

• More flexible dose titration is needed, particularly in patients with hepatic or renal impairment requiring dose adjustments 6
• Patient experiences insomnia with once-daily dosing and may benefit from split dosing 6
• Smoking cessation is the primary indication - this is the established formulation with guideline support 5, 6
• Patient is elderly or on multiple medications requiring gradual titration (can start at 37.5 mg increments) 6

Special Population Considerations

Hepatic Impairment

• For moderate to severe hepatic impairment (Child-Pugh 7-15): XL maximum dose is 150 mg every other day 1
• For SR formulation: total daily dose should not exceed 150 mg daily (one tablet) 6
• For mild hepatic impairment (Child-Pugh 5-6): consider reducing dose and/or frequency for both formulations 1

Renal Impairment

• For GFR <90 mL/min: reduce total daily dose by half for both formulations 6, 1
• Close monitoring required as bupropion and metabolites are cleared renally 6

Older Adults

• Start with 37.5 mg every morning, increase by 37.5 mg every 3 days as tolerated, maximum 150 mg twice daily (300 mg total) 6
• This gradual titration is more easily achieved with SR formulation 6

Critical Formulation Switching Considerations

Brand vs Generic and SR vs XL Switching

• Monitor patients closely when switching between brand and generic formulations or between SR and XL, as historical bioequivalence issues have been documented 6
• Some generic versions of bupropion SR were previously found not bioequivalent to brand-name Wellbutrin SR 6
• When switching from SR to XL or vice versa, give the same total daily dose when possible 1

Discontinuation

• When discontinuing XL 300 mg daily, taper to 150 mg once daily before stopping 1
• For SR formulation, gradual tapering is also recommended 1

Common Pitfalls to Avoid

• Never administer the second dose of SR after 3 PM - this significantly increases insomnia risk 6
• Do not crush, divide, or chew XL tablets - this destroys the extended-release mechanism 1
• Do not assume all generic formulations are equivalent - monitor for loss of efficacy when switching 6
• Avoid combining with MAOIs or within 14 days of MAOI discontinuation 1
• Do not use in patients with uncontrolled hypertension - monitor blood pressure regularly 6