How should bupropion be dosed and monitored in a patient with renal impairment (eGFR ≥ 50 mL/min, 30–49 mL/min, <30 mL/min, or on chronic dialysis) to minimize seizure risk and toxicity?

Management of Bupropion in Renal Failure

In patients with renal impairment (eGFR <90 mL/min), reduce the bupropion dose and/or frequency to prevent accumulation of the parent drug and its active metabolites, which increases seizure risk and toxicity. 1, 2

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Dose Adjustments by Renal Function

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

• Reduce the total daily dose of bupropion by approximately 50% in patients with moderate to severe renal impairment (eGFR <90 mL/min). 1
• The FDA label states: "Consider reducing the dose and/or frequency of bupropion hydrochloride extended-release tablets (XL) in patients with renal impairment (glomerular filtration rate less than 90 mL/min)." 2
• For example, if the standard dose is 300 mg/day, reduce to 150 mg/day in patients with eGFR <90 mL/min. 1

End-Stage Renal Disease (ESRD) / Hemodialysis

• Bupropion should be avoided entirely in patients with end-stage renal disease or on dialysis. 1
• If bupropion must be used in hemodialysis patients, a dose of 150 mg every 3 days is more appropriate than the manufacturer's recommendation of 150 mg daily, based on pharmacokinetic data showing significant accumulation of active metabolites. 3
• Hemodialysis does not effectively clear hydroxybupropion (the primary active metabolite), making dose reduction insufficient to prevent toxicity. 1, 3

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Pharmacokinetic Rationale

Parent Drug vs. Metabolites

• Bupropion itself shows minimal accumulation in renal impairment, with pharmacokinetics similar to those in patients with normal renal function. 3, 4
• However, the active metabolites hydroxybupropion and threohydrobupropion accumulate significantly in renal failure, with AUC increases of 126% for bupropion and even greater increases for metabolites. 3, 4
• In patients with renal impairment, bupropion AUC was 126% higher, Cmax 86% higher, clearance 63% lower, and half-life 140% longer compared to controls. 4
• The hydroxybupropion:bupropion AUC ratio decreased by 66%, and the threohydrobupropion:bupropion AUC ratio decreased by 69% in renally impaired subjects, indicating impaired metabolite clearance. 4

Clinical Implications

• Because the principal metabolites of bupropion possess similar pharmacological activity and seizure risk to the parent compound, accumulation of these metabolites in renal impairment increases toxicity risk. 4
• The seizure threshold is lowered by both bupropion and its metabolites, making dose reduction critical in renal impairment. 1, 2

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Monitoring and Safety Considerations

Baseline Assessment

• Calculate creatinine clearance using the Cockcroft-Gault equation before initiating bupropion, as eGFR alone may not accurately reflect renal function for dosing purposes. 1, 5
• Screen for absolute contraindications, including seizure history, eating disorders (bulimia/anorexia), abrupt discontinuation of alcohol or benzodiazepines, and uncontrolled hypertension. 1, 2

Ongoing Monitoring

• Reassess renal function at least annually, and more frequently (every 3–6 months) if eGFR <60 mL/min or if clinical status changes (e.g., dehydration, acute illness, nephrotoxic medications). 1, 6
• Monitor for dose-dependent adverse effects, including dizziness, somnolence, agitation, and neuropsychiatric symptoms. 1
• Monitor blood pressure and heart rate periodically, especially in the first 12 weeks, as bupropion can elevate both parameters. 1

Seizure Risk Minimization

• Never exceed 300 mg/day in patients with any degree of renal impairment, as seizure risk increases markedly above this threshold. 1, 2
• The seizure risk with bupropion at 300 mg/day is approximately 0.1% (1 in 1,000), but this risk is higher in renal impairment due to metabolite accumulation. 1
• Avoid concomitant use of medications that lower seizure threshold (e.g., antipsychotics, tramadol, systemic corticosteroids). 1, 2

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Practical Dosing Algorithm

1. Calculate creatinine clearance using the Cockcroft-Gault equation. 1, 5
2. If eGFR ≥90 mL/min: Use standard dosing (150–300 mg/day). 1, 2
3. If eGFR 30–89 mL/min: Reduce dose by 50% (e.g., 150 mg/day instead of 300 mg/day). 1
4. If eGFR <30 mL/min or on hemodialysis: Avoid bupropion entirely; if unavoidable, use 150 mg every 3 days with close monitoring. 1, 3
5. Reassess renal function every 3–6 months if eGFR <60 mL/min and adjust dose accordingly. 1, 6

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Alternative Considerations in Renal Impairment

Preferred Opioid Analgesics

• Methadone is preferred for patients requiring opioid therapy with renal impairment, as it is eliminated primarily via fecal excretion rather than renal pathways. 1
• Avoid morphine, meperidine, codeine, and tramadol in renal impairment, as their neurotoxic metabolites accumulate and increase the risk of adverse neurologic effects. 1

Buprenorphine as an Alternative

• Buprenorphine can be administered at normal doses in patients with renal dysfunction, as it is mainly excreted through the liver and its pharmacokinetics are unchanged in hemodialysis patients. 7
• Unlike morphine, buprenorphine does not produce active metabolites that accumulate in renal failure, making it a safer choice for chronic pain management in this population. 7

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Common Pitfalls

• Do not rely on eGFR alone for dosing decisions; always calculate creatinine clearance using the Cockcroft-Gault equation, as this method was used in pharmacokinetic studies and FDA labeling. 1, 5
• Do not prescribe bupropion without first calculating creatinine clearance, as this is the most common prescribing error leading to toxicity, particularly in elderly patients. 6, 5
• Do not assume that standard dosing is safe in mild renal impairment (eGFR 60–89 mL/min); even mild impairment requires dose reduction due to metabolite accumulation. 1, 4
• Do not combine bupropion with naltrexone in patients with renal impairment, as the naltrexone-bupropion ER formulation is limited to one tablet twice daily (instead of two tablets twice daily) in moderate to severe renal impairment. 1