In a patient with Alzheimer‑type dementia and impaired renal function, how should donepezil be dosed and monitored, including adjustments for creatinine clearance ≥30 mL/min versus <30 mL/min and in patients on chronic hemodialysis?

Donepezil Dosing in Renal Impairment

No dose adjustment of donepezil is required for any degree of renal impairment, including patients with creatinine clearance <30 mL/min or those on chronic hemodialysis, because donepezil is primarily metabolized hepatically rather than renally excreted.

Pharmacokinetic Rationale

• Donepezil undergoes extensive hepatic metabolism via CYP2D6 and CYP3A4, with minimal renal elimination of the parent compound 1, 2.
• The drug exhibits high bioavailability (>90%) and a very long elimination half-life (approximately 70 hours), which is not significantly altered by renal dysfunction 1.
• Pharmacokinetic studies demonstrate that renal impairment does not meaningfully affect donepezil plasma concentrations or clearance 2.

Standard Dosing Across All Renal Function Levels

For patients with any degree of renal impairment (CrCl ≥30 mL/min, CrCl <30 mL/min, or on dialysis):

• Initial dose: 5 mg once daily 2.
• Maintenance dose: After 4-6 weeks at 5 mg/day, increase to 10 mg once daily if tolerated 2.
• Timing: Administer once daily, preferably in the evening before bedtime 2.

This standard dosing schedule applies regardless of creatinine clearance level.

Evidence in Dialysis Patients

The most relevant clinical evidence comes from case reports of chronic hemodialysis patients successfully treated with donepezil:

• A case series of 5 chronic hemodialysis patients with moderate Alzheimer's disease were initiated on donepezil 2.5 mg/day, then increased to 5 mg/day after 1 month 3.
• All patients showed improvement in behavioral symptoms and cognitive function without adverse events over 6 months, with stable condition maintained for up to 10 years of follow-up 3.
• A single case report documented a 72-year-old hemodialysis patient treated with donepezil 3 mg/day who achieved therapeutic plasma concentrations (11.1-18.2 ng/mL) without toxicity 4.
• Plasma concentrations remained stable over 3 months, and the patient experienced no adverse effects or drug accumulation 4.

Practical Dosing Strategy for Dialysis Patients

Conservative initiation approach:

• Start with 2.5-3 mg once daily in hemodialysis patients to assess tolerability 3, 4.
• After 1 month without adverse effects, increase to 5 mg once daily 3.
• If further dose escalation is needed after 4-6 weeks at 5 mg/day, increase to 10 mg once daily 3.

Timing relative to dialysis:

• Donepezil is not significantly removed by hemodialysis due to high protein binding (96%), large volume of distribution, and hepatic metabolism 4, 1.
• No supplemental dosing is required after dialysis sessions 4.
• Administer at a consistent time each day, independent of dialysis schedule 4.

Monitoring Parameters

In patients with renal impairment or on dialysis, monitor for:

• Cholinergic adverse effects: Nausea, diarrhea, vomiting, anorexia, muscle cramps (most common in first 4-6 weeks) 2.
• Cardiac effects: Bradycardia, syncope (particularly in patients with pre-existing cardiac conduction abnormalities) 2.
• Weight loss: Monitor body weight monthly, especially in dialysis patients who may have marginal nutritional status 5.
• Behavioral changes: Assess for improvement in cognitive function and behavioral symptoms at 4-6 week intervals 3.

Higher Doses (15-23 mg/day)

• Donepezil doses up to 20 mg/day have been studied in patients with normal renal function and appear safe and well-tolerated 5.
• However, no data exist for doses >10 mg/day in patients with severe renal impairment or on dialysis 3, 4.
• The 23 mg formulation is approved for moderate to severe Alzheimer's disease but should be used with extreme caution (if at all) in dialysis patients given the lack of safety data 1.

Critical Pitfalls to Avoid

Do not assume renal dose adjustment is needed: Unlike many medications, donepezil does not require dose reduction based on creatinine clearance because hepatic metabolism is the primary elimination pathway 1, 2.

Do not withhold treatment in dialysis patients: The evidence, though limited to case reports, demonstrates that donepezil can be safely used in chronic hemodialysis patients with appropriate monitoring 3, 4.

Do not administer supplemental doses after dialysis: Donepezil is not dialyzable and does not require post-dialysis supplementation 4.

Do not escalate doses too rapidly in dialysis patients: Use a more conservative titration schedule (starting at 2.5-3 mg/day) compared to patients with normal renal function to minimize risk of cholinergic adverse effects 3, 4.