Donepezil precautions

List of precautions
Effect of Aricept® on the metabolism of other drugs Effect of other drugs on the metabolism of Aricept® Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Pediatric use Geriatric use
 * Potential for enzyme induction
 * Theophylline, cimetidine, warfarin, digoxin, ketoconazole
 * Effect of drugs on rate of elimination
 * Use with anticholinergics
 * Use with cholinomimetics and other cholinesterase inhibitors
 * Pregnancy Category C
 * Nursing mothers

Effect of Aricept® on the metabolism of other drugs
No in vivo clinical trials have investigated the effect of Aricept® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Return to top

Potential for enzyme induction
Whether Aricept® has any potential for enzyme induction is not known.

Theophylline, cimetidine, warfarin, digoxin, ketoconazole
Formal pharmacokinetic studies evaluated the potential of Aricept® for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of Aricept® on the pharmacokinetics of these drugs were observed. Return to top

Effect of other drugs on the metabolism of Aricept®
Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown. Return to top

Effect of drugs on rate of elimination
Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of Aricept®. Formal pharmacokinetic studies demonstrated that the metabolism of Aricept® is not significantly affected by concurrent administration of digoxin or cimetidine. Return to top

Use with anticholinergics
Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Return to top

Use with cholinomimetics and other cholinesterase inhibitors
A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. Return to top

Carcinogenesis
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 90 times the maximum recommended human dose on a mg/m2 basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30mg/kg/day (approximately 30 times the maximum recommended human dose on a mg/m2 basis). Return to top

Mutagenesis
Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouse lymphoma forward mutation assay in vitro. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed. Donepezil was not clastogenic in the in vivo mouse micronucleus test and was not genotoxic in an in vivo unscheduled DNA synthesis assay in rats. Return to top

Impairment of fertility
Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis). Return to top

Pregnancy Category C
Teratology studies conducted in pregnant rats at doses up to 16 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2 basis) and in pregnant rabbits at doses up to 10 mg/kg/day (approximately 16 times the maximum recommended human dose on a mg/m2 basis) did not disclose any evidence for a teratogenic potential of donepezil. However, in a study in which pregnant rats were given up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis) from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and a slight decrease in pup survival through day 4 postpartum at this dose; the next lower dose tested was 3 mg/kg/day. There are no adequate or well-controlled studies in pregnant women. Aricept® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Return to top

Nursing mothers
It is not known whether donepezil is excreted in human breast milk. Aricept® has no indication for use in nursing mothers. Return to top

Pediatric use
There are no adequate and well-controlled trials to document the safety and efficacy of Aricept® in any illness occurring in children. Return to top

Geriatric use
Alzheimer's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with Aricept® was 73 years; 80% of these patients were between 65 and 84 years old and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old. Return to top