Pre-clinical Studies

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in CD-1 mice at doses up to 180 mg/kg/day (approximately 40 times the maximum recommended human dose of 23 mg/day on a mg/m2 basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/ m2 basis). 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 vitro mouse micronucleus). Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 4 times the maximum recommended human dose on a mg/ m2 basis) when administered to males and females prior to and during mating and continuing in females through implantation.

Animal Toxicology

In a published study, female rats were given single doses of donepezil and memantine by intraperitoneal injection, each alone or in combination. When given in combination with memantine, donepezil increased the incidence and severity of memantine-induced neurodegeneration. The relevance of this finding to humans is unknown.