Is 23 mg nightly donepezil a high dose?
Yes, 23 mg once daily is the maximum approved dose of donepezil and is specifically indicated only for moderate-to-severe Alzheimer's disease in patients who have already been stabilized on 10 mg daily for at least 3 months. 1
FDA-Approved Dosing Framework
The FDA label establishes a clear dose ceiling based on disease severity:
- Mild to moderate AD: Maximum dose is 10 mg/day 1
- Moderate to severe AD: Maximum dose is 23 mg/day 1
- The 23 mg dose should never be administered until patients have been on 10 mg daily for at least 3 months 1
Why 23 mg Is Considered a High Dose
Substantially increased cholinergic adverse events: In the pivotal controlled trial, patients escalated to 23 mg experienced markedly higher rates of nausea (11.8% vs. 3.4%), vomiting (9.2% vs. 2.5%), and treatment discontinuation due to vomiting (2.9% vs. 0.4%) compared to those continuing 10 mg 1, 2
Dose-response relationship for harms: Six studies documented that adverse event frequency increases with escalating donepezil doses, with gastrointestinal effects (diarrhea RR 2.57, nausea RR 2.54, anorexia RR 3.21) becoming progressively more common 3
Limited additional efficacy: The 23 mg dose provides modest incremental cognitive benefit over 10 mg—approximately 1.2 additional points on the Severe Impairment Battery—but does not improve global function (CIBIC-plus) 4
Clinical Context and Safety Profile
The 23 mg formulation was developed specifically for patients with advancing disease who continue to decline on 10 mg, not as a routine escalation strategy 4. Common adverse events at this dose include:
- Nausea, vomiting, diarrhea (most frequent) 2
- Anorexia and weight loss 5, 2
- Dizziness (leading to discontinuation in 1.1% of patients) 2
These effects typically emerge within the first 1–3 weeks after dose escalation and may resolve with continued use, but close monitoring is essential 1
Practical Prescribing Caveats
Titration reduces adverse events: Intermediate dose titration (using 15 mg for 4 weeks or alternating 10 mg/23 mg before full escalation) significantly decreases nausea and other cholinergic symptoms compared to direct escalation from 10 mg to 23 mg 6
The 23 mg tablet must not be split, crushed, or chewed because it is a sustained-release formulation 1
Population-specific considerations: A Japanese trial in severe AD found that 23 mg was not superior to 10 mg on either cognitive (SIB) or global (CIBIC-plus) measures, suggesting 10 mg may be optimal for some populations 7
When 23 mg Is Appropriate
Reserve the 23 mg dose for patients who meet all of the following criteria:
- Moderate-to-severe Alzheimer's disease (not mild-to-moderate) 1
- Already receiving donepezil 10 mg daily for ≥3 months 1
- Continued cognitive or functional decline despite stable 10 mg therapy 8, 4
- Absence of significant gastrointestinal comorbidities or cardiac conduction abnormalities 1
Do not use 23 mg as first-line therapy or in mild-to-moderate disease, where the maximum recommended dose remains 10 mg 1