What is the recommended treatment approach for an older adult patient with Alzheimer's disease or dementia using Aricept (donepezil)?

Donepezil (Aricept) Treatment for Alzheimer's Disease

Initial Dosing and Titration

Start donepezil at 5 mg once daily at bedtime, then increase to 10 mg once daily after 4-6 weeks if the patient tolerates the initial dose well. 1, 2

• The 5 mg starting dose minimizes gastrointestinal side effects (nausea, vomiting, diarrhea) which are the most common adverse events. 1
• Taking donepezil with food further reduces these cholinergic side effects. 1, 2
• The 10 mg dose provides marginally greater cognitive benefit than 5 mg, though the difference is modest. 3, 4
• Higher doses (23 mg) show no additional efficacy over 10 mg but significantly increase adverse events and treatment discontinuation. 2, 4

Expected Therapeutic Response

Assess treatment response at 3 months initially, but allow 6-12 months for full evaluation of benefit. 1, 2

• Cognitive improvements typically appear within 3 weeks of starting treatment. 5
• Beneficial response is defined as stabilization or delayed deterioration, not reversal of symptoms. 1, 2
• On the ADAS-Cog scale (0-70 points), expect approximately 2-3 point improvement compared to placebo. 1, 4
• On the MMSE, expect approximately 1 point improvement. 4
• Brief mental status tests are relatively insensitive measures; use comprehensive assessments including caregiver reports and functional observations. 1, 2

When Initial Treatment is Insufficient

If the patient continues to decline after 3 months on donepezil 10 mg, add memantine 20 mg/day while continuing donepezil. 6, 2

• Combination therapy with donepezil plus memantine is evidence-based and "rational and safe" for patients with moderate to severe disease who decline on monotherapy. 2
• Start memantine at 5 mg daily and increase by 5 mg weekly in divided doses to reach the target of 20 mg/day (10 mg twice daily). 2
• Do not discontinue donepezil when adding memantine, as continuing the cholinesterase inhibitor provides proven therapeutic benefit. 2
• Switching between different cholinesterase inhibitors (donepezil, rivastigmine, galantamine) is not supported as a first-line strategy, though patients who cannot tolerate one may respond to another. 1, 7

Dose Adjustments for Special Populations

For patients with severe renal impairment (creatinine clearance ≈30 mL/min), reduce memantine to 5 mg twice daily (10 mg/day total) when using combination therapy. 2

• Donepezil dosing does not require adjustment for renal or hepatic impairment. 3
• No hepatotoxicity monitoring is required with donepezil, unlike tacrine. 1, 5

Monitoring and Duration of Treatment

Continue treatment as long as the patient shows stabilization or slower decline compared to pre-treatment progression. 1, 2

• Discontinue if side effects persist despite dose adjustment, adherence is poor, or deterioration continues at the pre-treatment rate after 6-12 months. 1, 2
• Approximately 29% of patients discontinue due to adverse events versus 18% on placebo. 7
• Most adverse events are mild, transient, and cholinergic in nature (gastrointestinal and nervous system effects). 5

Drug Interactions and Precautions

Monitor patients taking CYP2D6 or CYP3A4 inhibitors, as these can increase donepezil levels by 17-36%. 3, 8

• Ketoconazole (strong CYP3A4 inhibitor) increases donepezil concentrations by 36%. 3
• CYP2D6 inhibitors increase donepezil AUC by approximately 17-20%. 3
• Approximately 15-20% of AD patients may exhibit abnormal metabolism requiring dose adjustments. 8
• Donepezil does not significantly interact with digoxin, warfarin, cimetidine, or theophylline. 1, 3

Critical Caveats

Avoid premature discontinuation—many patients require the full 6-12 month assessment period to demonstrate benefit. 1, 2

• Set realistic expectations: donepezil slows decline but does not reverse Alzheimer's disease or alter the underlying pathology. 1, 2
• The medication provides modest benefits—average improvements are statistically significant but clinically small. 1, 4
• All symptomatic therapies for Alzheimer's disease do not alter disease progression; patients continue to decline over time despite treatment. 6
• Gradual dose titration over 4-6 weeks (not 7 days) minimizes gastrointestinal side effects. 1, 5