How should Wellbutrin (bupropion) be dosed in patients with impaired renal function (estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² versus <30 mL/min/1.73 m²) and is it appropriate for patients on chronic dialysis?

Bupropion (Wellbutrin) Dosing in Renal Impairment

Patients with impaired renal function require significant dose reduction of bupropion, with the most conservative approach being 150 mg every other day for moderate impairment (eGFR 30-60 mL/min/1.73 m²) and 150 mg every 3 days for severe impairment (eGFR <30 mL/min/1.73 m²) or dialysis patients, due to marked accumulation of both parent drug and active metabolites.

Pharmacokinetic Rationale for Dose Reduction

Bupropion exhibits dramatically altered pharmacokinetics in renal impairment:

• In patients with kidney disease, bupropion AUC increases by 126%, Cmax by 86%, clearance decreases by 63%, and half-life prolongs by 140% compared to those with normal renal function 1
• The parent compound bupropion accumulates substantially, with elimination half-life more than doubling in renally impaired patients 1
• Active metabolites hydroxybupropion and threohydrobupropion demonstrate even more pronounced accumulation, with significantly increased areas under the curve in end-stage renal disease 2

Specific Dosing Recommendations by Renal Function

eGFR ≥60 mL/min/1.73 m² (Normal to Mild Impairment)

• Standard dosing may be used: 150 mg once or twice daily, or 300 mg extended-release once daily 1
• No dose adjustment required for mild impairment 3

eGFR 30-60 mL/min/1.73 m² (Moderate Impairment)

• Reduce to 150 mg every other day (every 48 hours) 1
• This represents a 50% reduction in total weekly dose compared to standard dosing 1
• Monitor closely for adverse effects including seizures, as metabolite accumulation still occurs 1

eGFR <30 mL/min/1.73 m² (Severe Impairment)

• Reduce to 150 mg every 3 days (every 72 hours) 2
• This dosing interval is more appropriate than the manufacturer's recommendation of 150 mg daily, which leads to excessive accumulation 2
• The 63% reduction in clearance necessitates this extended dosing interval 1

End-Stage Renal Disease (ESRD) on Hemodialysis

• Use 150 mg every 3 days 2
• Hemodialysis does not effectively remove bupropion or its metabolites, particularly hydroxybupropion 2
• Dialysis clearance is negligible, so timing doses around dialysis sessions is unnecessary 2
• Multi-dose studies suggest significant metabolite accumulation occurs even with this conservative regimen 2

Peritoneal Dialysis

• Apply the same dosing as hemodialysis: 150 mg every 3 days 2, 3
• Peritoneal dialysis removes even less drug than hemodialysis due to the characteristics of the peritoneal membrane 3

Critical Safety Considerations

The accumulation of active metabolites poses unique challenges:

• Hydroxybupropion and threohydrobupropion possess similar pharmacological activity to bupropion itself 1
• The hydroxybupropion:bupropion AUC ratio decreases by 66% and hydrobupropion:bupropion ratio by 69% in renal impairment, indicating disproportionate parent drug accumulation 1
• Despite reduced metabolite ratios, absolute metabolite concentrations remain elevated due to impaired renal clearance 2
• The clinical significance of metabolite accumulation and toxic plasma levels remains incompletely defined 2

Seizure risk is the primary safety concern:

• Bupropion lowers the seizure threshold in a dose-dependent manner 4
• Accumulation of both parent drug and active metabolites in renal impairment substantially increases seizure risk 1
• Never exceed 150 mg per dose in any patient with renal impairment 2, 1
• Avoid use entirely in patients with seizure disorders, eating disorders, or abrupt alcohol/benzodiazepine withdrawal 4

Monitoring Protocol

Establish baseline renal function before initiating therapy:

• Calculate eGFR using the Cockcroft-Gault formula or CKD-EPI equation 3, 5
• Recognize that serum creatinine alone is insufficient, particularly in elderly patients with reduced muscle mass 5
• Document any fluctuations in renal function, as acute kidney injury will require immediate dose adjustment 3

Ongoing monitoring requirements:

• Reassess renal function every 3-6 months in patients with eGFR <60 mL/min/1.73 m² 5
• Monitor for signs of drug accumulation: tremor, agitation, insomnia, seizures 4
• If renal function declines, immediately extend the dosing interval rather than continuing the current regimen 3
• Consider therapeutic drug monitoring if available, though reference ranges for renal impairment are not well established 2

Common Pitfalls and How to Avoid Them

Do not rely on manufacturer labeling alone:

• The current manufacturer recommendation of 150 mg daily in renal impairment leads to excessive accumulation 2
• Pharmacokinetic data support more conservative dosing (every 2-3 days) than package insert recommendations 2, 1

Do not assume dialysis removes bupropion:

• Unlike many renally cleared drugs, bupropion and its metabolites are poorly dialyzed 2
• Supplemental post-dialysis doses are not indicated and will cause accumulation 2

Do not overlook non-renal factors affecting drug metabolism:

• Renal impairment may affect hepatic CYP2B6 activity, though this remains incompletely characterized 1
• Plasma protein binding decreases in uremia, potentially increasing free drug concentrations 3
• Drug transporters may be impaired in chronic kidney disease, affecting both distribution and elimination 3

Do not initiate standard doses and titrate down:

• Start with the reduced dose appropriate for the patient's eGFR from the outset 5
• Loading doses are not necessary for bupropion, as immediate therapeutic efficacy is not required for smoking cessation or depression 4

Alternative Considerations

When bupropion is contraindicated or poorly tolerated in renal impairment:

• For smoking cessation: varenicline requires dose reduction to 0.5 mg twice daily when eGFR <30 mL/min/1.73 m² but may be better tolerated 5
• For depression: SSRIs such as citalopram or sertraline undergo hepatic metabolism and require minimal renal dose adjustment 4
• Behavioral interventions and nicotine replacement therapy do not require dose modification for renal function 5

Special Populations

Elderly patients with renal impairment:

• Age-related decline in renal function may not be reflected in serum creatinine due to reduced muscle mass 5
• Calculate creatinine clearance using actual body weight in the Cockcroft-Gault formula 5
• Use the most conservative dosing interval (every 3 days) if uncertainty exists about true renal function 2

Patients with fluctuating renal function:

• Acute kidney injury superimposed on chronic kidney disease requires immediate dose reduction or discontinuation 3
• Resume therapy only after renal function stabilizes, using the dosing interval appropriate for the new baseline eGFR 3