Objective  To mine and analyze adverse drug event (ADE) signals related to donepezil, and to elucidate its potential medication risk characteristics and promote safe clinical medication.

Methods  ADE reports associated with donepezil were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database from first quarter of 2004 to first quarter of 2025. The reporting odds ratio (ROR) method, proportional reporting ratio (PRR) method, Bayesian confidence propagation neural network method (BCPNN), and multi-item gamma-Poisson shrinker (MGPS) method were used for signal dectection. Sex-specific subgroup analysis and time-to-onset (TTO) evaluation of ADEs were conducted, and sensitivity analyses were performed to assess the robustness of the findings.

Results  A total of 9,489 ADE reports with donepezil as the primary suspected drug were included, with the majority of patients being female (51.27%) and aged ≥65 years (66.88%). A total of 310 ADE signals were dectected involving 27 system organ classes (SOCs), including common ADEs such as bradycardia, vomiting, syncope, and altered consciousness, as well as 21 potential new signals not previously listed in the drug label, such as opisthotonus, haemophilus bacteraemia, and visuospatial impairment. Sex-stratified analysis showed 201 ADE signals reported in males and 264 in females; gastrointestinal ulcer, mucosal hemorrhage and neurotoxicity were more common in males, while gastric emptying disorder, decompensated hypothyroidism, and QT interval prolongation posed greater risks in females. The median TTO for all ADEs was 48 days, with most events in both sexes occurring within one month of initiation, though some persisted for over a year. Sensitivity analysis demonstrated high stability and reliability of the ADE signals associated with donepezil.

Conclusion  Based on large-scale real-world data, this study systematically identified both established and novel ADE profiles associated with donepezil therapy. The findings elucidated sex-specific and temporal characteristics, providing a basis for the identification of high-risk populations and the development of individualized pharmacovigilance strategies.

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