Donepezil Treatment Protocol for Mild to Moderate Alzheimer's Disease

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

Initial Dosing Strategy

Begin with 5 mg once daily taken in the evening, just prior to retiring 1, 2
Maintain this starting dose for a minimum of 4-6 weeks before considering dose escalation 1, 2
Taking donepezil at bedtime rather than in the morning reduces sleep disturbances 1
The 70-hour half-life supports once-daily dosing 1

Increase to 10 mg once daily after 4-6 weeks if the patient tolerates the initial dose well 1, 2
The 10 mg dose provides superior cognitive and functional benefits compared to 5 mg, though the difference is modest 1, 3
While 10 mg did not achieve statistically significantly greater clinical benefit than 5 mg in all studies, dose trend analyses suggest some patients derive additional benefit from the higher dose 3
Do not escalate to 23 mg daily—this higher dose shows no greater efficacy than 10 mg but causes significantly more adverse events and withdrawals 4

Cognitive improvements appear as early as 3 weeks but require 6-12 months to properly assess the full therapeutic response 2, 5
Donepezil produces statistically significant improvements in cognition (ADAS-Cog) and global function (CIBIC-plus), though the average improvement does not reach the 4-point ADAS-Cog threshold considered clinically significant 6, 1
Benefits are maintained for approximately 21-81 weeks with the 10 mg dose 1, 5
A subset of patients will achieve clinically meaningful improvement even though average improvements are modest 6, 1
All patients continue to decline over time despite treatment—donepezil slows but does not stop disease progression 2

The most common adverse effects are gastrointestinal: nausea, vomiting, diarrhea, and anorexia 6, 7
These effects are dose-related, with the 10 mg dose carrying 2.5-3.2 times higher risk than 5 mg 1
Minimize side effects by taking donepezil with food and using gradual dose titration over 4-6 weeks rather than rapid escalation 1, 7
Most cholinergic side effects are mild, transient, and typically subside after a few weeks 6, 7
Unlike tacrine, donepezil does not cause hepatotoxicity and does not require liver function monitoring 6, 7, 5

Major contraindications include uncontrolled asthma, angle-closure glaucoma, sick sinus syndrome, and left bundle-branch block 2
Do not prescribe donepezil for mild cognitive impairment—evidence shows no significant benefit in this population 6, 1
Monitor for bradycardia, though clinically significant ECG changes are uncommon 8
Be aware of potential drug interactions with strong CYP3A4 inhibitors (ketoconazole increases donepezil levels by 36%) and CYP2D6 inhibitors (increase donepezil levels by 17-23%) 3

If donepezil is not tolerated or proves ineffective:

Switch to rivastigmine: start 1.5 mg twice daily with food, increase by 1.5 mg twice daily every 4 weeks as tolerated to maximum 6 mg twice daily 6, 2
Switch to galantamine: start 4 mg twice daily with meals, increase to 8 mg twice daily after 4 weeks, with possible further increase to 12 mg twice daily based on benefit and tolerability 6, 2
Tacrine is no longer considered first-line treatment due to hepatotoxicity requiring biweekly liver monitoring for 16 weeks 6

Stop donepezil if:

Side effects develop and do not resolve despite management strategies 2
Poor medication adherence occurs 2
Continued deterioration at the pre-treatment rate persists after 6-12 months of therapy 2
Disease progresses to severe or end-stage dementia 2

Implement these strategies alongside medication:

Establish predictable daily routines for exercise, meals, and bedtime 6, 2
Simplify all tasks by breaking complex activities into steps with instructions for each 6, 2
Use calendars, clocks, color-coded labels, and graphic cues for orientation 6
Ensure optimal treatment of comorbid conditions 6, 2
Install safety features: grab bars, safety locks on doors/gates, remove hazards like throw rugs 6
Control vascular risk factors and modify lifestyle (smoking cessation, regular exercise, healthy diet) 2