Common Side Effects of Donepezil

Gastrointestinal Side Effects

Nausea, vomiting, and diarrhea are the most frequently reported adverse effects, with diarrhea (relative risk 2.57) and nausea (relative risk 2.54) occurring significantly more often than with placebo, according to the American Academy of Family Physicians and the American College of Physicians 1, 2, 3
Anorexia has the largest effect size among gastrointestinal symptoms (relative risk 3.21), as reported by the American College of Physicians 2
Gastrointestinal effects are dose-related, with higher incidence at 10mg compared to 5mg dosing, as noted by the American College of Physicians 2, 3

Initial increase in agitation that typically subsides after the first few weeks of therapy, as reported by the American Academy of Family Physicians and other guideline societies 1, 4
Muscle cramps, particularly leg cramps, occur with a very high relative risk in vascular dementia patients, according to the American College of Physicians 2
Dizziness (relative risk 1.47) is also a common side effect, as reported by the American College of Physicians 2

Adverse effects can be minimized by starting at 5mg daily and gradually increasing to 10mg after 4 weeks, as recommended by the American Academy of Family Physicians and other guideline societies 1, 4
Unlike tacrine (another cholinesterase inhibitor), donepezil does not cause hepatotoxicity and does not require liver function monitoring, as noted by the American Academy of Family Physicians 1

Potential interactions with cimetidine, theophylline, warfarin, and digoxin should be considered, as reported by guideline societies such as the American College of Physicians and others 4

Withdrawal rates due to adverse events ranged from 0% to 57% in treatment groups compared to 0% to 20% in placebo groups, as reported by the American College of Physicians 2

Donepezil, a cholinesterase inhibitor, increases acetylcholine availability at cholinergic synapses by reversibly inhibiting acetylcholinesterase, leading to increased secretions through muscarinic receptor stimulation, as reported by the British Medical Journal 5, 6

Taking donepezil with food reduces gastrointestinal adverse effects, as suggested by the American Academy of Family Physicians 7

Nausea occurs with a relative risk of approximately 2.5 compared with placebo, making it one of the most frequent gastrointestinal side‑effects of donepezil. 8
Diarrhea shows a relative risk of about 2.6 versus placebo, indicating a markedly increased incidence in treated patients. 8
Anorexia demonstrates the largest effect size among gastrointestinal symptoms, with a relative risk near 3.2 compared with placebo. 8
Vomiting is commonly reported, especially during the initial dose‑escalation period. 8
The FDA label indicates that nausea, diarrhea, and vomiting each occur in ≥5 % of patients receiving the standard 10 mg daily dose and at roughly twice the rate observed with placebo; these events are dose‑related, occurring more often at 10 mg than at 5 mg daily. 8

Bradyarrhythmia (including sinus bradycardia) is listed as a serious and common adverse effect of donepezil in the Mayo Clinic Proceedings guideline. 8
Cases of complete atrioventricular block and ventricular tachyarrhythmia have been documented in patients using donepezil. 8
Caution is advised when prescribing donepezil to patients with pre‑existing bradycardia, due to the risk of exacerbating conduction abnormalities. 8

Anxiety is not identified as a common adverse effect of donepezil in any guideline or FDA labeling. 8
Sedation is also not a characteristic adverse effect; instead, insomnia occurs in roughly 9 % of patients on donepezil versus 6 % on placebo. 8
Somnolence is reported in about 2 % of treated patients and is not considered a major adverse effect. 8