Safety Comparison of Acetylcholinesterase Inhibitors Using FAERS Spontaneous-Reporting Data: Drug-Specific Reporting Signals and Time-to-Onset Dynamics
Yidan Du, Jia Li, Fei Han, Jianjun Li, Hong Lin, Fangfang GeIntroduction/Objective:
Acetylcholinesterase Inhibitors (AChEIs) are widely used for symptomatic treatment of Alzheimer’s disease, but their post-marketing reporting profiles may differ. This study compared FAERS disproportional reporting signals and Time-To-Onset (TTO) patterns for donepezil, galantamine, and rivastigmine.
Methods:
FAERS reports from Q1 2004 to Q2 2025 were analyzed. Reports listing donepezil, galantamine, or rivastigmine as the primary suspect drug were retained. Unique case–drug–Preferred Term (PT) triplets were constructed after case-level and drug–event-level de-duplication. Positive signals were defined conservatively by the intersection of ROR, PRR, BCPNN, and MGPS/EBGM criteria. TTO was evaluated using cumulative onset-distribution curves, Weibull models, and Accelerated Failure-Time (AFT) models
Results:
The analysis included 9,474 donepezil reports, 3,042 galantamine reports, and 14,666 rivastigmine reports. The four-method intersection identified 286 positive PT reporting signals for donepezil, 143 for galantamine, and 259 for rivastigmine. Donepezil showed prominent cardiac reporting signals, including sinus bradycardia (ROR = 49.0) and electrocardiogram QT prolongation (ROR = 16.75). Rivastigmine showed application-site signals, including application-site erythema (ROR = 21.36) and application-site pruritus (ROR = 18.07). Galantamine showed signals including bradycardia (ROR = 15.37), fall (ROR = 3.44), and decreased appetite (ROR = 3.57). Median TTOs were 38, 44, and 64 days for donepezil, galantamine, and rivastigmine, respectively. Rivastigmine showed a later reported onset than donepezil in the AFT model (TR = 1.08; p = 0.008).
Discussion:
The findings suggest shared cholinergic reporting patterns and drug-specific signal profiles. Because FAERS lacks exposure denominators, these results indicate disproportional reporting rather than incidence, causality, or comparative clinical risk.
Conclusion:
Donepezil, galantamine, and rivastigmine showed distinct FAERS reporting profiles and early post-initiation TTO patterns. These findings are hypothesis-generating and require confirmation in independent pharmacovigilance or clinical datasets.