Pre-clinical Studies


Extensive testing in experimental animals has demonstrated that this compound causes few effects other than the intended pharmacological effects consistent with its action as a cholinesterase inhibitor.


Donepezil hydrochloride is not genotoxic in bacterial reverse mutation and mouse lymphoma tk assays. In chromosomal aberration assays in vitro, some clastogenic effects were observed in vitro at concentrations overtly toxic to the cells and more than 3000 times the steady-state plasma concentrations produces by 10 mg/day. However, no clastogenic potential was observed in the in vivo mouse micronucleus model and DNA damage was not observed in vivo/in vitro UDS assay. In summary, donepezil was negative in a battery of genotoxicity assays (in vitro bacterial reverse mutation, in vitro mouse lymphoma tk, in vitro chromosomal aberration, and in vivo mouse micronucleus).


No evidence of a carcinogenic potential was obtained in an 88 week carcinogenicity study of donepezil hydrochloride conduced in CD-1 mice at doses of up to 180 mg/kg/day (approximately 39 times the maximum recommended human dose (23mg/day) on a mg/m2 basis), or in a 104 week carcinogenicity study in Sprague-Dawley rats at doses of up to 30 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2 basis).


Donepezil hydrochloride had no effect on fertility at dosages up to 10 mg/kg/day (approximately 4 times the maximum recommended human dose [23 mg/day] on a mg/ m2 basis) when administered to males and females prior to and during mating and continuing in females through implantation. Donepezil hydrochloride was not teratogenic in rats or rabbits. Donepezil hydrochloride was not teratogenic in rats/rabbits. Donepezil hydrochloride had a slight effect on stillbirths and early pup survival when administered to pregnant rats at doses up to 10 mg/kg/day.