What is the appropriate dosing and management of immediate‑release bupropion in patients with renal impairment (mild, moderate, severe) and in elderly patients, and what alternative antidepressants are recommended?

Management of Bupropion in Renal Impairment

In patients with moderate to severe renal impairment, reduce the total daily dose of bupropion by 50%, and avoid use entirely in end-stage renal disease. 1

Dose Adjustments by Severity of Renal Impairment

Moderate to Severe Renal Impairment (GFR <90 mL/min)

• Reduce the total daily dose by half (e.g., if the standard dose is 300 mg/day, reduce to 150 mg/day). 1, 2
• For the naltrexone-bupropion ER combination used in weight management, limit dosing to 1 tablet twice daily (instead of the standard 2 tablets twice daily). 1
• This dose reduction is critical because bupropion and its active metabolites are cleared renally and accumulate significantly in renal impairment. 2, 3

End-Stage Renal Disease (ESRD)

• Avoid bupropion entirely in patients with ESRD. 1
• A single-dose pharmacokinetic study in hemodialysis patients demonstrated that bupropion metabolites accumulate substantially, with increased areas under the curve despite parent drug levels remaining similar to those in patients with normal renal function. 4
• For hemodialysis patients who absolutely require bupropion, consider 150 mg every 3 days rather than daily dosing, though this is based on limited single-dose data and requires further validation. 4
• Hemodialysis does not effectively clear the primary active metabolite hydroxybupropion, making dose reduction essential rather than relying on dialysis for clearance. 4

Mild Renal Impairment

• Consider dose reduction and/or decreased dosing frequency, though specific guidelines are less stringent than for moderate-to-severe impairment. 2

Critical Monitoring in Renal Impairment

Neuropsychiatric Toxicity

• Monitor closely for tremor, ataxia, altered mental status, visual hallucinations, myoclonic jerks, and delirium, as these are signs of bupropion accumulation and toxicity. 5
• A case report of an 84-year-old patient with stage III chronic kidney disease developed progressive tremor, truncal ataxia, and acute mental status changes after bupropion titration to 150 mg twice daily, with symptoms resolving 36-48 hours after dose reduction. 5
• Elderly patients with renal impairment have reduced clearance of bupropion, making them particularly vulnerable to toxicity even at standard doses. 5

Pharmacokinetic Changes

• In renally impaired patients, bupropion AUC increases by 126%, Cmax by 86%, clearance decreases by 63%, and half-life increases by 140% compared to patients with normal renal function. 3
• Despite these dramatic changes in parent drug, the concentrations of active metabolites (hydroxybupropion, threohydrobupropion, erythrohydrobupropion) show only minor changes, though the metabolite-to-parent drug ratios decrease significantly. 3
• The clinical significance of metabolite accumulation remains unclear, as these metabolites possess 20-50% of the pharmacological activity of the parent compound. 3, 6

Dosing Strategy for Elderly Patients with Renal Impairment

Initial Titration

• Start with 37.5 mg every morning, then gradually increase by 37.5 mg every 3 days as tolerated. 2
• Maximum dose should not exceed 150 mg twice daily (300 mg total daily dose) in older adults. 2
• Administer the second dose before 3 PM to minimize insomnia risk. 2

Rationale for Conservative Dosing

• Renal function declines by approximately 1% per year after age 30-40, resulting in an estimated 40% reduction by age 70, which increases the risk of drug accumulation. 7
• Lower starting doses (approximately 50% of standard dose) are appropriate for older adults due to increased risk of adverse reactions. 2

Alternative Antidepressants in Severe Renal Impairment

When bupropion is contraindicated or poorly tolerated due to renal impairment, consider:

Preferred Alternatives

• SSRIs (sertraline 50-200 mg daily or escitalopram 10-20 mg daily) achieve remission rates of 42-49%, equivalent to bupropion, though they lack bupropion's specific benefits for motivational symptoms and have higher rates of sexual dysfunction. 2
• SSRIs generally require less dose adjustment in renal impairment compared to bupropion, though monitoring remains necessary. 2

For Patients Requiring Opioid Therapy

• Methadone is the preferred opioid in renal impairment, as it is excreted fecally rather than renally, though it should only be used by experienced clinicians. 1
• Buprenorphine and fentanyl are the only opioids that do not require dose adjustment in renal impairment. 8
• Avoid morphine, meperidine, codeine, and tramadol in renal impairment due to accumulation of neurotoxic metabolites. 1

Absolute Contraindications Regardless of Renal Function

• Seizure disorders or any condition predisposing to seizures (history of head trauma, brain tumor, stroke). 1, 2
• Current or recent MAOI use (within 14 days of discontinuation). 2
• Eating disorders (bulimia or anorexia nervosa) due to increased seizure risk. 2
• Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. 2
• Uncontrolled hypertension, as bupropion can elevate blood pressure and heart rate. 2

Common Pitfalls to Avoid

• Do not use standard dosing (150 mg twice daily) in patients with moderate-to-severe renal impairment, as this leads to significant drug accumulation and toxicity risk. 5, 3
• Do not assume hemodialysis will clear bupropion metabolites—it does not effectively remove hydroxybupropion, the primary active metabolite. 4
• Do not overlook age-related renal decline in elderly patients who may not have documented chronic kidney disease but still have significantly reduced clearance. 7, 5
• Do not exceed 450 mg/day total dose in any patient, as seizure risk increases markedly above this threshold. 2
• Do not miss early signs of toxicity (tremor, ataxia, confusion) by attributing them to other causes—these symptoms may indicate bupropion accumulation requiring immediate dose reduction. 5