Donepezil Titration Protocol
Start donepezil at 5 mg once daily and increase to 10 mg once daily after 4 weeks (or 4-6 weeks if tolerability is a concern). 1
Initial Dosing
- Begin with 5 mg once daily 1
- Administer in the morning rather than at bedtime to minimize sleep disturbances 2
- Take with food to reduce gastrointestinal side effects 1
Dose Escalation Timeline
- Increase to 10 mg once daily after 4 weeks if the initial dose is well tolerated 1
- If tolerability concerns exist, consider waiting 4-6 weeks before escalating 1
- The 10 mg dose is the standard maximum for mild-to-moderate Alzheimer's disease 1
Managing Side Effects During Titration
Gastrointestinal symptoms are the primary concern:
- 70-80% of GI adverse effects occur within the first 2 weeks, and 60-65% resolve within the first month 2
- Common side effects include nausea (relative risk 2.54), vomiting, diarrhea (relative risk 2.57), and anorexia (relative risk 3.21) 3
- These effects are dose-dependent, with higher incidence at 10 mg compared to 5 mg 1, 3
- Taking donepezil with food significantly reduces these symptoms 1
Other adverse effects to monitor:
- Initial increase in agitation typically subsides after the first few weeks 1, 3
- Muscle cramps, particularly leg cramps 3
- Dizziness (relative risk 1.47) 3
Special Considerations for Higher Doses
If considering escalation beyond 10 mg (for moderate-to-severe disease):
- Use intermediate dose titration (15 mg for 4 weeks) before escalating to 23 mg 4
- Direct escalation to 23 mg without titration results in significantly more nausea compared to gradual titration 4
- Higher doses (15-20 mg) appear safe and well tolerated in patients already stabilized on 10 mg 5
Assessment of Response
- Wait 6-12 months to fully assess treatment benefit, as brief mental status tests are relatively insensitive to donepezil's cognitive effects 1
- Response is defined as stabilization or delayed deterioration of cognitive or behavioral problems 1
- Discontinue if side effects persist, adherence is poor, or deterioration continues at the pretreatment rate after 6-12 months 1
Key Advantages of Donepezil
- Once-daily dosing improves adherence 1, 2
- No hepatotoxicity and no liver function monitoring required 1, 3
- No dose adjustment needed for mild-to-moderate hepatic or renal disease at the 5 mg dose 6
Common Pitfalls to Avoid
- Do not escalate too quickly (faster than every 4 weeks), as this increases cholinergic side effects 1
- Do not administer at bedtime if sleep disturbances occur; switch to morning dosing 2
- Do not discontinue prematurely for mild GI symptoms, as most resolve within the first month 2
- Be aware of potential interactions with cimetidine, theophylline, warfarin, and digoxin 1, 3