Drug-Drug Interactions (see Clinical Pharmacology: Clinical Pharmacokinetics:
Drug-drug Interactions)
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.
Whether ARICEPT® has any potential for enzyme induction
is not known.
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.
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.
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.
Use with Anticholinergics: Because of their mechanism of action, cholinesterase
inhibitors have the potential to interfere with the activity of anticholinergic
medications.
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.
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 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).
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.
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).
Pregnancy
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.
Nursing Mothers
It is not known whether donepezil is excreted in human breast milk. ARICEPT®
has no indication for use in nursing mothers.
Pediatric Use
There are no adequate and well-controlled trials to document the safety and efficacy
of ARICEPT® in any illness occurring in children.
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.