DailyMed Label: Donepezil Hydrochloride

DailyMed Label: donepezil hydrochloride

2007

DailyMed Prescription

donepezil hydrochloride

donepezil hydrochloride

Eisai Inc.

NDC: 62856-851

ARICEPT® (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C 24 H 29 NO 3 HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane. Each 1mL of ARICEPT® Oral Solution contains 1 mg of donepezil hydrochloride. ARICEPT® Oral Solution also contains sorbitol solution 70%, povidone K-30, citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, methylparaben, propylene glycol, sodium metabisulfite, purified water and strawberry flavor.

ARICEPT® is indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild to moderate Alzheimer's Disease, as well as in patients with severe Alzheimer's Disease.

The dosages of ARICEPT® shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day. The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of ARICEPT® might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference. Evidence from the controlled trials indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events than the 5 mg dose. In open label trials using a 6 week titration, the frequency of these same adverse events was similar between the 5 mg and 10 mg dose groups. Therefore, because steady state is not achieved for 15 days and because the incidence of untoward effects may be influenced by the rate of dose escalation, treatment with a dose of 10 mg should not be contemplated until patients have been on a daily dose of 5 mg for 4 to 6 weeks. Each teaspoon (5 mL) of ARICEPT® Oral Solution contains a 5 mg dose. Patients should be instructed as to how to measure their dose of ARICEPT® Oral Solution in teaspoons. ARICEPT® Oral Solution should be taken in the evening, just prior to retiring. ARICEPT® Oral Solution can be taken with or without food.

ARICEPT® is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.

(see Clinical Pharmacology: Clinical Pharmacokinetics: Drug-drug Interactions ) 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 and digoxin. No significant effects on the pharmacokinetics of these drugs were observed.. Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro . Whether there is a clinical effect of these inhibitors is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC 0-24 and C max ) 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. Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. 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/m 2 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/m 2 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/m 2 basis). 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/m 2 basis) and in pregnant rabbits at doses up to 10 mg/kg/day (approximately 16 times the maximum recommended human dose on a mg/m 2 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/m 2 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. It is not known whether donepezil is excreted in human breast milk. ARICEPT® has no indication for use in nursing mothers. There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT® in any illness occurring in children. 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.

The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® 5 mg/day treatment groups were comparable to those of placebo-treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day, was higher at 13%.

(see Clinical Pharmacology: Clinical Pharmacokinetics: Drug-drug Interactions ) 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 and digoxin. No significant effects on the pharmacokinetics of these drugs were observed.. Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro . Whether there is a clinical effect of these inhibitors is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC 0-24 and C max ) 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.

ARICEPT® Oral Solution is a clear, colorless to light yellow solution containing 1 mg of donepezil hydrochloride in each mL (1 mg/mL). Each teaspoon (5mL) contains 5 mg of donepezil hydrochloride. NDC#62856-851-30          300 mL HDPE Bottles Storage: Store at controlled room temperature, 15°C to 30°C (59°F to 86°F). R X only ARICEPT® is a registered trademark of Eisai Co., Ltd. Manufactured and Marketed by Eisai Inc., Teaneck, NJ 07666 Marketed by Pfizer Inc, New York, NY 10017 © 2006 Eisai Inc. Printed in U.S.A. Revised October 2006

Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's Disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.