Generic Name: donepezil hydrochloride
Dosage Form: tablet, film coated, extended release
Aricept 23 is an acetylcholinesterase inhibitor indicated for the treatment of moderate to severe dementia of the Alzheimer's type. In this population, the efficacy of Aricept 23 has been demonstrated in comparison to donepezil hydrochloride 10 mg immediate release tablets.
DOSAGE AND ADMINISTRATION
Aricept 23 can be taken in the morning or evening and can be taken with or without food. Aricept 23 should not be split or crushed and should be swallowed whole with water.
Initiation of Treatment: Patients who have been established on 10 mg of donepezil hydrochloride daily with good tolerability can be administered one Aricept 23 tablet once daily (14).
Maintenance Dose: 23 mg administered once daily
Aricept 23 can be taken with or without memantine.
DOSAGE FORMS AND STRENGTHS
Aricept 23 is supplied as reddish, round, film-coated, extended-release, matrix-type tablets containing 23 mg of donepezil hydrochloride. The strength in mg (23) is debossed on one side, and "Aricept" is debossed on the other side.
WARNINGS AND PRECAUTIONS
Initiation of Treatment
Because donepezil steady state is achieved about 15 days after dosing is started, and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of Aricept 23 should not be administered until patients have been on a daily dose of 10 mg donepezil hydrochloride for 4 to 6 weeks.
Aricept 23, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of Aricept 23.
Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS). Results of a controlled clinical study of Aricept 23 showed an increase relative to donepezil hydrochloride 10 mg/day, in the incidence of peptic ulcer disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%).
Aricept 23 has been shown to produce diarrhea, nausea and vomiting as a result of its pharmacological properties. In most cases, these effects have been mild to moderate and transient, sometimes lasting one to three weeks, and have resolved during continued use of Aricept 23.
Weight loss was reported as an adverse event in 4.7% of patients assigned to Aricept 23 compared to 2.5% of patients assigned to 10 mg donepezil hydrochloride. Compared to their baseline weights, 8.4% of patients in the Aricept 23 group were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of the group taking 10 mg donepezil hydrochloride was found to have weight loss. Therefore, consideration should be given when prescribing Aricept 23 to patients of lower weight.
Although not observed in clinical trials of Aricept 23, cholinomimetics may cause bladder outflow obstruction.
Neurological Conditions: Seizures
Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease.
Clinical Studies Experience
Aricept 23 has been administered to over 1300 individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950 patients have been treated for at least six months. The range of patient exposure was from 1 to over 500 days.
Adverse Events Leading to Discontinuation
The rate of discontinuation from a controlled clinical trial of Aricept 23 due to adverse events was higher (18.6%) than for the donepezil 10 mg/day treatment group (7.9%).
The most common adverse events leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with donepezil 10 mg/day doses, are shown in Table 1.
|Dose Group||Aricept |
The majority of discontinuations due to adverse events in the Aricept 23 group occurred during the first month of treatment.
Most Frequent Adverse Clinical Events Seen in Association with the Use of Aricept 23
The most common adverse events, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. These adverse events were often of mild to moderate intensity and transient, resolving during continued Aricept 23 treatment.
Adverse Events Reported in Controlled Trials
The events cited reflect experience gained under closely monitored conditions of a controlled clinical trial in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 2 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in a controlled trial who received Aricept 23 or 10 mg donepezil hydrochloride.
|Body System/Adverse Event||Aricept |
|Percent of Patients with any Adverse Event||73.7||63.7|
|General disorders and administration site conditions|
|Infections and infestations|
|Urinary tract infection||4.4||4.0|
|Injury, poisoning and procedural complications|
|Metabolism and nutrition disorders|
|Renal and urinary disorders|
Postmarketing Experience with 5 and 10 mg Donepezil Hydrochloride Tablets
The following adverse reactions have been identified during post approval use of donepezil hydrochloride 5 and 10 mg tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include the following: abdominal pain, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.
Effects of Donepezil Hydrochloride and Aricept 23 on the Metabolism of Other Drugs
No in vivo clinical trials have investigated the effect of donepezil hydrochloride 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 23 has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of donepezil for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of donepezil on the pharmacokinetics of these drugs were observed.
Effects of Other Drugs on the Metabolism of Aricept 23
Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. In a 7 day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.) increased mean donepezil (5 mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.
The relative influence of CYP2D6 on the metabolism of donepezil was assessed in drug-drug interaction studies. The effect of co-administered risperidone on donepezil metabolism was evaluated in two studies. Concurrent administration of 5 mg donepezil and risperidone (administered at 0.5 mg twice daily) to healthy subjects showed that steady state concentrations of donepezil were unaffected by co-administration of risperidone. Similarly, in a second study, 5 mg donepezil hydrochloride tablets were concurrently administered to patients taking physician-optimized doses of risperidone (1-4 mg). The results indicated that steady state donepezil concentrations were unaffected by co-administration of risperidone.
A drug interaction study that evaluated the effect of sertraline, a CYP2D6 inhibitor, on donepezil disposition indicated that steady state concentrations of donepezil were unaffected by concurrent administration of sertraline.
Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of Aricept 23.
Formal pharmacokinetic studies demonstrated that the metabolism of donepezil 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.
USE IN SPECIFIC POPULATIONS
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 23 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 23 has no indication for use in nursing mothers.
There are no adequate and well-controlled trials to document the safety and efficacy of Aricept 23 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 study with Aricept 23 was 73.8 years; and 50% 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.
Lower Weight Individuals
In the controlled clinical trial, among patients in the Aricept 23 treatment group, those patients weighing < 55 kg reported more nausea, vomiting, and decreased weight than patients weighing 55 kg or more. There were more withdrawals due to adverse events as well. This finding may be related to higher plasma exposure associated with lower weight (12.3).
Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.
As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for Aricept 23 overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether donepezil and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature.
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]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl 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.
Aricept 23 is available for oral administration in reddish film-coated tablets containing 23 mg of donepezil hydrochloride. Inactive ingredients include ethylcellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and methacrylic acid copolymer, Type C. The film coating includes ferric oxide, hypromellose 2910, polyethylene glycol 8000, talc and titanium dioxide.
Mechanism of Action
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.
Aricept 23 is an extended-release, matrix-type tablet with a delivery system that allows for gradual release of donepezil. Following oral dosing, Aricept 23 achieves peak plasma concentrations in approximately 6-9 hours, compared with 3-4 hours for donepezil hydrochloride 10 mg tablets. The peak plasma concentrations observed for Aricept 23 are lower than would be expected for an equivalent dose of the immediate release formulation. In healthy volunteers and in Alzheimer's disease patients, Aricept 23 was found to be well-absorbed, with plasma exposures averaging 3015 ng*h/mL for the Aricept 23 group and 1388 ng*h/mL for the donepezil 10 mg group compared with 10 mg immediate release tablets. Food does not influence the rate or extent of absorption of Aricept 23 Tablets. Aricept 23 can be taken without regard to meals or time of day.
The elimination half life of donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold, and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL.
Metabolism and Excretion. Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug. Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance. These results suggest CYP2D6 has a minor role in the metabolism of donepezil.
Hepatic Disease: In a study of 10 patients with stable alcoholic cirrhosis, the clearance of donepezil was decreased by 20% relative to 10 healthy age- and sex-matched subjects.
Renal Disease: In a study of 11 patients with moderate to severe renal impairment (ClC < 18 mL/min/1.73 m2) the clearance of donepezil did not differ from 11 age- and sex-matched healthy subjects.
Age: No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of Aricept 23. However, mean plasma donepezil concentrations measured during therapeutic drug monitoring of patients with Alzheimer's disease (45 - 90 years old) do not show important differences due to age.
Gender and Race: No formal pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of Aricept 23. However, mean plasma donepezil concentrations measured during therapeutic drug monitoring of patients with Alzheimer's disease did not show important differences due to gender or race on the clearance of donepezil.
Body weight: There was a relationship noted between body weight and clearance. Over the range of weights from 50 kg to 110 kg, clearance increased from 7.77 L/h to 14.04 L/h.
Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil at concentrations of 0.3-10 μg/mL did not affect the binding of furosemide
(5 μg/mL), digoxin (2 ng/mL), and warfarin (3 μg/mL) to human albumin. Similarly, the binding of donepezil to human albumin was not affected by furosemide, digoxin and warfarin.
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 30 mg/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).
The effectiveness of Aricept 23 as a treatment for moderate to severe Alzheimer's disease compared to donepezil hydrochloride 10 mg has been demonstrated by the results of a randomized, double-blind, controlled clinical investigation in patients with moderate to severe Alzheimer's disease. The controlled clinical study was conducted globally in patients with probable Alzheimer's disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 0-20. 1434 patients with moderate to severe Alzheimer's disease were randomized to Aricept 23 or donepezil hydrochloride 10 mg (Safety Population). The mean age of patients was 73.8 years, with a range of 47 to 90. Approximately 62.8% of patients were women, and 37.2% were men. Approximately 36.3% of the patients were taking memantine throughout the study. Patients were required to have been on a stable dose of donepezil hydrochloride 10 mg/day for at least 3 months prior to Screening.
Study Outcome Measures: The effectiveness of treatment with Aricept 23 was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on Aricept 23 experienced important clinical benefit on both measures compared to donepezil hydrochloride 10 mg/day.
The ability of Aricept 23 to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
The ability of Aricept 23 to produce an overall clinical effect was assessed using a Clinician's Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "markedly worse."
Effects on the SIB:
Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the LS mean difference in the SIB change scores for Aricept 23 treated patients compared to patients treated with 10 mg donepezil was 2.2 units (p <0.0001). Aricept 23 was statistically significantly superior to 10 mg donepezil.
Figure 1. Time-course of the Change from Baseline in SIB Score for Patients Completing 24 Weeks of Treatment.
Figure 2 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to Aricept 23 and to donepezil hydrochloride 10 mg tablets have a wide range of responses, the curves show that the Aricept 23 group is more likely to show a greater improvement in cognitive performance. When such curves are shifted to the left, this indicates a greater percentage of patients responding to treatment on the SIB.
Figure 2. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with Specified Changes from Baseline SIB Scores
Effects on the CIBIC-plus: Figure 3 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients at the end of 24 weeks of treatment. The mean difference between Aricept 23 and donepezil hydrochloride 10 mg tablets was 0.06 units. This difference was not statistically significant.
Figure 3. Frequency Distribution of CIBIC plus Scores at Week 24
Patients who entered the clinical trial with more severe symptoms, defined by scores on the Mini Mental State Examination of 0 - 16 points (MMSE 0 - 20 for the entire patient population), showed statistically significant benefit on the CIBIC-plus with Aricept 23 compared to donepezil hydrochloride 10 mg tablets. The treatment difference was 0.11 units (p = 0.0279). These patients also showed statistically significant benefit on the SIB with Aricept 23 compared to donepezil hydrochloride 10 mg tablets. The treatment difference was 3.1 units (p < 0.0001).
HOW SUPPLIED/STORAGE AND HANDLING
Aricept 23 Tablets
Supplied as round, film-coated, extended-release, matrix-type tablets containing 23 mg of donepezil hydrochloride.
The 23 mg tablets are reddish in color. The strength, in mg (23), is debossed on one side and "Aricept" is debossed on the other side.
Bottles of 30 (NDC# 62856-247-30)
Bottles of 90 (NDC# 62856-247-90)
Storage: Aricept 23 Tablets should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]
Aricept 23™ is a trademark of
Eisai Co., Ltd.
Manufactured by Eisai Co. Ltd, Kawashima, Japan
Marketed by Eisai Inc., Woodcliff Lake, NJ 07677
Marketed by Pfizer Inc, New York, NY 10017
© 2009 Eisai Inc.
donepezil hydrochloride tablet, film coated, extended release
|Labeler - Eisai Inc. (831600833)|
|Registrant - Eisai Inc. (831600833)|
|Eisai Co., Ltd.||690549845||MANUFACTURE|
More Aricept resources
- Aricept Monograph (AHFS DI)
- Aricept Advanced Consumer (Micromedex) - Includes Dosage Information
- Aricept Consumer Overview
- Aricept MedFacts Consumer Leaflet (Wolters Kluwer)
- Donepezil Professional Patient Advice (Wolters Kluwer)
- Aricept ODT orally disintegrating tablets MedFacts Consumer Leaflet (Wolters Kluwer)