What are the recommended dosing, titration schedule, contraindications, monitoring parameters, and common adverse effects of donepezil for an older adult with mild‑to‑moderate Alzheimer disease?

Donepezil for Mild-to-Moderate Alzheimer Disease

Start donepezil 5 mg once daily in the evening, just before bedtime, and increase to 10 mg daily after 4–6 weeks if tolerated; the 10 mg dose provides additional cognitive and functional benefit over 5 mg. 1, 2

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Dosing and Titration Schedule

• Initial dose: 5 mg once daily in the evening, just prior to retiring. 1, 2
• Titration: After 4–6 weeks on 5 mg daily, increase to 10 mg once daily if the patient tolerates the lower dose. 1, 2
• Maximum dose for mild-to-moderate disease: 10 mg once daily. 1
• Administration: Take in the evening, just before bedtime; can be taken with or without food, though taking with food reduces gastrointestinal side effects. 1, 3
• Morning dosing alternative: If insomnia or vivid dreams occur, consider switching to morning administration. 3

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Contraindications

• Known hypersensitivity to donepezil hydrochloride or piperidine derivatives. 1

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Warnings and Precautions

Cardiovascular Effects

• Bradycardia and heart block: Cholinesterase inhibitors exert vagotonic effects on the sinoatrial and atrioventricular nodes, which may manifest as bradycardia, heart block, or syncope in patients with or without underlying cardiac conduction abnormalities. 1
• Action: Assess for sick-sinus syndrome, significant bradycardia, or other conduction defects before initiating therapy. 2

Anesthesia Risk

• Exaggerated muscle relaxation: Donepezil may prolong succinylcholine-type neuromuscular blockade during anesthesia. 1

Gastrointestinal Effects

• Peptic ulcer risk: Monitor patients closely for symptoms of active or occult gastrointestinal bleeding, especially those with a history of peptic ulcer disease or severe gastroesophageal reflux. 1, 2

Respiratory Conditions

• Asthma and COPD: Prescribe with caution in patients with a history of asthma or obstructive pulmonary disease, as cholinomimetics may exacerbate bronchospasm. 1

Genitourinary Effects

• Bladder outflow obstruction: Cholinomimetics may worsen urinary retention. 1

Seizure Risk

• Generalized convulsions: Cholinomimetics have the potential to cause seizures, though the risk is low. 1

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Monitoring Parameters

No Routine Laboratory Monitoring Required

• Unlike tacrine, donepezil is not hepatotoxic and does not require liver function monitoring. 3, 2

Clinical Assessment Timeline

• Baseline: Document cognitive function (MMSE, MoCA, or ADAS-Cog), functional ability (ADL/IADL scales), and obtain caregiver input on behavioral symptoms. 2
• 4–6 weeks: Assess tolerability and titrate to 10 mg if no significant adverse effects. 1, 2
• 6–12 months: Full efficacy evaluation using physician global assessment, caregiver reports of functional and behavioral changes, and cognitive testing. 2, 3
  • Do not rely solely on brief mental-status tests (e.g., MMSE), as they are relatively insensitive to drug effects; comprehensive caregiver-reported functional data are essential. 2

Criteria for Discontinuation

• Persistent adverse effects that do not resolve despite dose adjustment or taking with food. 2, 3
• Poor medication adherence. 2
• Continued disease progression at the pre-treatment rate after a 6–12-month trial. 2, 3

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Common Adverse Effects

Gastrointestinal (Most Common)

• Nausea, vomiting, diarrhea, and anorexia are dose-dependent and occur more frequently with 10 mg than 5 mg. 1, 3
• Mitigation strategy: Take donepezil with food and use gradual dose titration (4–6 weeks at 5 mg before increasing). 3, 2
• These effects are typically mild, transient, and resolve within a few weeks. 3, 4

Musculoskeletal

• Muscle cramps, particularly leg cramps. 3

Neuropsychiatric

• Insomnia, vivid dreams, or agitation may occur, especially with evening dosing. 3
  • If sleep disturbances develop, switch to morning administration. 3
• Early increase in agitation generally resolves within a few weeks. 2

Other

• Fatigue, dizziness, and anorexia. 3

Serious Adverse Events

• No statistically significant difference between donepezil and placebo for serious adverse events, aside from expected cholinergic side effects. 2
• Withdrawal due to adverse events ranges from 0–20%, comparable to placebo rates. 2

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Expected Clinical Benefits

• Modest symptomatic improvement: Approximately 20–35% of patients show a clinically meaningful improvement on neuropsychological tests, equivalent to delaying cognitive decline by about one year. 3, 5
• Stabilization or slowing of decline: Donepezil does not cure or reverse Alzheimer disease; it may temporarily stabilize cognition or modestly slow the rate of decline. 2, 3
• Functional benefits: The 10 mg dose significantly delays deterioration in activities of daily living and improves patients' abilities to perform complex tasks. 2, 6
• Duration of benefit: Improvements in cognition, global function, and ADL are maintained for approximately 21–81 weeks (about 1 year) with donepezil 10 mg/day. 6, 3

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Key Clinical Pitfalls to Avoid

• Unrealistic expectations: Communicate to patients and families before initiating treatment that donepezil provides modest symptom management, not disease cure or reversal. 3, 5
• Premature discontinuation: Some patients require up to 12 months to demonstrate benefit; avoid stopping therapy before a full 6–12-month trial. 2
• Inadequate dose titration: The 10 mg dose provides additional cognitive and functional benefit over 5 mg; ensure patients reach the higher dose unless side effects prevent titration. 2, 7
• Relying solely on MMSE: Use comprehensive assessments including caregiver reports and functional scales, as brief mental-status tests are relatively insensitive to drug effects. 2