What is the recommended dose and timing of donepezil (cholinesterase inhibitor) for Alzheimer's disease treatment?

Donepezil Dosing and Timing for Alzheimer's Disease

Start donepezil at 5 mg once daily in the evening just prior to retiring, then increase to 10 mg daily after 4-6 weeks if well tolerated. 1, 2, 3

Initial Dosing

• The FDA-approved starting dose is 5 mg once daily, taken in the evening just before bedtime. 3
• Donepezil can be taken with or without food, though taking it with food may reduce gastrointestinal side effects. 4, 1
• The evening timing is important—administering donepezil at bedtime rather than morning increases the risk of sleep disturbances. 2

Dose Escalation for Mild to Moderate Alzheimer's Disease

• Increase to 10 mg once daily after 4-6 weeks on the 5 mg dose. 1, 3
• The 10 mg dose provides additional cognitive and functional benefits over 5 mg, with higher efficacy particularly for activities of daily living. 2, 5, 6
• Do not rush the dose increase—the gradual 4-6 week titration period significantly improves tolerability and reduces gastrointestinal side effects compared to faster escalation schedules. 5, 7

Dose Escalation for Moderate to Severe Alzheimer's Disease

• After at least 3 months on 10 mg daily, consider increasing to 23 mg once daily for moderate to severe disease. 3, 8
• The 23 mg tablet must not be split, crushed, or chewed as it is a sustained-release formulation. 3
• However, the 23 mg dose shows no greater efficacy than 10 mg but has higher rates of adverse events (particularly nausea at 11.8% vs 3.9%) and treatment withdrawals. 3, 6
• Most patients will achieve adequate benefit on 10 mg daily without needing the 23 mg dose. 6

Expected Timeline for Assessment

• An assessment period of 6-12 months is necessary to adequately evaluate treatment benefit. 1
• Cognitive benefits can be observed as early as 3 weeks after starting treatment. 5
• Benefits on cognition, activities of daily living, and behavior can be maintained for approximately 21-81 weeks with donepezil 10 mg daily. 2, 5

Side Effect Management

• Monitor for dose-dependent gastrointestinal effects: nausea (relative risk 2.54), diarrhea (relative risk 2.57), and anorexia (relative risk 3.21). 2, 9
• These effects are more common at 10 mg versus 5 mg, and dramatically more common at 23 mg versus 10 mg. 9, 3
• Initial agitation may occur but typically subsides after the first few weeks. 4, 9
• Unlike tacrine, donepezil does not cause hepatotoxicity and requires no liver function monitoring. 9

Common Pitfalls to Avoid

• Do not prescribe donepezil for mild cognitive impairment—evidence shows no significant benefit in this population. 2
• Do not escalate the dose too quickly—the 4-6 week interval between 5 mg and 10 mg is critical for tolerability. 3, 5
• Do not administer in the morning—evening dosing reduces sleep disturbances. 2
• Do not expect dramatic improvement—realistic expectations include slowing decline rather than reversing it, with effects that are statistically significant but modest in magnitude. 1, 2
• Do not discontinue prematurely—some patients require up to 12 months to demonstrate benefit. 1
• Be aware of potential interactions with cimetidine, theophylline, warfarin, and digoxin. 4, 9