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Uses

Alzheimer's Disease

Donepezil hydrochloride is used for the palliative treatment of mild to moderate dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia). The rationale for use of donepezil in this condition is to potentially increase CNS acetylcholine concentrations, which can be deficient in patients with Alzheimer's disease (see Description). The current indication is based principally on 2 short-term (15 or 30 weeks), double-blind, placebo-controlled studies in patients with a diagnosis of Alzheimer's disease of mild to moderate severity. Both studies demonstrated clinically important but modest and variable improvement in cognitive function and clinician-rated global assessment of observed clinical change. However, as with tacrine (no longer available in the US), improvement associated with donepezil therapy was not maintained following discontinuance of the drug, suggesting that donepezil does not alter the underlying disease process of dementia.

The specific role of donepezil in the management of Alzheimer's disease, particularly long-term or in patients with severe disease, remains to be fully elucidated. In patients who received therapy with donepezil for at least 2 years in uncontrolled studies following their participation in placebo-controlled studies of the drug, improvement in cognitive function was maintained for an average of at least 40 weeks, with some benefit still evident after 2 years of follow-up. However, the cognitive abilities of patients receiving donepezil decline over time, although apparently to a lesser degree than in untreated patients.

The American Psychiatric Association (APA) and other experts (e.g., the American Geriatrics Society, the American Academy of Neurology) state that because anticholinesterase agents produce apparently modest improvement in some patients and because other established effective therapies are lacking, the use of an anticholinesterase agent (e.g., donepezil, galantamine, rivastigmine, tacrine [no longer available in the US]) to treat cognitive symptoms should be considered in the management of Alzheimer's disease in patients who are mildly or moderately impaired. Anticholinesterase therapy potentially may improve cognitive functioning or delay decline and also may enhance clinician and family assessments and activities of daily living in such patients, albeit modestly. Although comparative studies have not been performed to date, donepezil does not share the hepatotoxic potential of tacrine and may be preferable to tacrine as a first-line treatment because it can be administered once daily and does not require regular monitoring of liver function. The APA states that the limited potential benefits and the costs of therapy with anticholinesterase agents should be discussed with patients and their families. As the efficacy of such therapy is modest, therapeutic alternatives such as other drug therapy (e.g., vitamin E, selegiline), psychosocial interventions, participation in a study of investigational treatment, and/or no treatment, may be considered. Further study and clinical experience are needed to more fully elucidate the efficacy and safety of donepezil in the management of Alzheimer's disease.

In the 15- and 30-week, placebo-controlled studies upon which the current indication principally is based, donepezil therapy was associated with improvements in cognitive and overall functioning (e.g., as assessed by results of neuropsychological tests and clinicians' impression of change, respectively). Age, race, or gender did not predict response to donepezil therapy in these studies. Cognitive function was evaluated with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog), a multiple-item instrument that has been extensively validated in longitudinal cohorts of patients with Alzheimer's disease. ADAS cog measures elements of memory, orientation, attention, reasoning, language, and praxis. Scores on the ADAS cog range from 0-70, with increasing scores being indicative of increasing cognitive impairment. Although normal geriatric adults may have scores of 0 or 1, slightly higher scores are not unusual in adults without dementia. Patients recruited into the 2 controlled studies of donepezil had initial scores of approximately 26 (range: 4-61) on the ADAS cog. Longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggest that scores on the ADAS cog will increase (i.e., indicating a decline in cognitive function) by 6-12 points each year in such patients. A smaller annual change in scores is observed in patients with either very mild or very advanced Alzheimer's disease because the ADAS cog does not uniformly reflect cognitive change over the course of the disease. In clinical trials of donepezil, ADAS cog scores increased by approximately 2-4 points per year in patients who received placebo.

Overall clinical change in patients receiving donepezil or placebo was evaluated with a Clinician's Interview Based Impression of Change (CIBIC) that required use of information from caregivers (CIBIC plus). A variety of CIBIC formats have been used in clinical studies, and the various CIBIC formats may differ in terms of depth and structure. The CIBIC plus used in the studies of donepezil was a subjective, semistructured instrument intended to measure the patient's ability to function generally, cognitively, behaviorally, and in activities of daily living. Scores of 1, 4, or 7 on the CIBIC plus denote marked improvement, no change, or markedly worse, respectively.

In the 15- and 30-week controlled studies of donepezil, the treatments were administered for 12 or 24 weeks, respectively, followed by placebo washout periods of 3 or 6 weeks, respectively, to determine whether rebound effects would occur following discontinuance of the drug. Patients received 5 or 10 mg of donepezil hydrochloride or placebo once daily in these studies; patients who were assigned to receive the 10-mg dosage of donepezil hydrochloride initially received 5 mg daily for 7 days to minimize the likelihood of adverse cholinergic effects. In the 15-week study, the improvement from baseline in the ADAS cog score with donepezil compared with placebo averaged 2.7 or 3 points after 12 weeks of treatment with donepezil hydrochloride 5 or 10 mg daily, respectively; the difference in ADAS cog scores for the 2 dosages was not statistically significant. In this study, an improvement of 7 points in the ADAS cog score was attained at 12 weeks by a cumulative 14, 21, or 36% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively, while an improvement of 4 points was attained at 12 weeks by a cumulative 30, 49, or 57% of patients in these respective groups. Cognitive function was maintained (i.e., no change in ADAS cog score from baseline) at 12 weeks in a cumulative 72, 83, or 87% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. In the 30-week study, improvement from baseline in ADAS cog score with donepezil compared with placebo averaged 2.8 or 3.1 points after 24 weeks of treatment with 5 or 10 mg daily, respectively, of donepezil hydrochloride; the difference in ADAS cog scores for the 2 dosages was not statistically significant. An improvement of 7 points from baseline in the ADAS cog score was attained at 24 weeks by a cumulative 8, 15, or 26% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. Improvement of 4 points from baseline in the ADAS cog score was attained at 24 weeks by a cumulative 28, 40, or 58% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. Cognitive function was maintained (i.e., no change in ADAS cog score from baseline) at 24 weeks in a cumulative 59, 83, or 82% of patients who received placebo, donepezil hydrochloride 5 mg, or donepezil hydrochloride 10 mg once daily, respectively.

Overall clinical improvement (as determined by the CIBIC plus assessment) also was observed in patients treated with donepezil in these 2 controlled studies. CIBIC plus scores attained in patients receiving 5 or 10 mg of donepezil hydrochloride once daily differed from placebo by 0.36 or 0.38 points, respectively, after 12 weeks of treatment in the 15-week study and by 0.35 or 0.39 points, respectively, after 24 weeks of treatment in the 30-week study. As with the ADAS cog scores, a dose-related effect of donepezil on overall clinical change in these studies was not established.

Following the 6-week placebo washout period in the 30-week study, scores on the ADAS cog for patients treated with donepezil or placebo were indistinguishable, indicating no evidence of an effect of donepezil on the underlying disease process in dementia. Results of neuropsychologic tests (i.e., ADAS cog, CIBIC plus, Mini-Mental State Examination [MMSE], and Clinical Dementia Rating [CDR]) performed 6 weeks after discontinuance of donepezil therapy did not show evidence of a rebound deterioration in cognitive symptoms.

Dosage and Administration

Administration

Donepezil hydrochloride is administered orally as conventional or orally disintegrating tablets. The drug is administered once daily, usually in the evening at bedtime.Donepezil hydrochloride orally disintegrating tablets should be allowed to dissolve on the tongue and followed with water. Donepezil hydrochloride orally disintegrating and conventional film-coated tablets are bioequivalent. Because food does not affect the rate or extent of absorption of donepezil when administered as conventional film-coated tablets, the drug can be administered with or without food. The effect of food on absorption of donepezil after administration as orally disintegrating tablets has not been studied. However, the manufacturer states that any effects are expected to be minimal, and orally disintegrating tablets may be taken without regard to meals.

Donepezil should not be used in patients with known hypersensitivity to the drug or to piperidine derivatives.

As a cholinesterase inhibitor, donepezil hydrochloride may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia. Cholinesterase inhibitors such as donepezil may increase gastric acid secretion as a result of increased cholinergic activity. Therefore, although placebo-controlled studies have shown no increase in the incidence of peptic ulcer disease or GI bleeding with donepezil, the manufacturer states that patients receiving the drug, especially those at increased risk for developing ulcers (e.g., those with a history of peptic ulcer disease, those taking concurrent nonsteroidal anti-inflammatory agents), should be monitored carefully for symptoms of active or occult GI bleeding.

Cholinesterase inhibitors may produce vagotonic effects on the sinoatrial or atrioventricular nodes. These effects may be manifested as bradycardia or heart block in patients with or without known cardiac conduction abnormalities. In clinical trials, syncopal episodes were reported in 2 or 1% of patients receiving donepezil or placebo, respectively.

Cholinesterase inhibitors such as donepezil, because of their cholinomimetic actions, should be prescribed with caution in patients with a history of asthma or obstructive pulmonary disease.

Although not reported in clinical studies with donepezil, cholinomimetic agents may cause bladder outflow obstruction; urinary frequency was reported more often (in 2% more patients) with donepezil therapy than with placebo in clinical trials. In addition, these agents may have the potential to cause generalized seizures; however, seizure activity also may be a manifestation of Alzheimer's disease.

Dosage

The manufacturer states that safety and efficacy of donepezil hydrochloride for any use in children have not been established. Dementia of the Alzheimer's type occurs principally in patients more than 55 years of age. The mean age of patients receiving donepezil in clinical studies was 73 years of age. For most adverse effects, there were no clinically important differences reported in patients 65 years of age or older compared with those younger than 65 years of age.

Alzheimer's Disease

For the palliative treatment of mild to moderate dementia of the Alzheimer's type (Alzheimer's disease), the recommended initial dosage of donepezil hydrochloride is 5 mg daily. Donepezil hydrochloride dosages of 5 or 10 mg daily are both effective, but additional clinical benefit with the 10-mg dosage has not been demonstrated in controlled clinical studies. However, based on the ordering of treatment group mean ADAS cog scores and dose trend analyses from these studies, there is the possibility of additional benefit with the higher (10 mg) dosage in some patients.

The manufacturer states that use of the 10-mg daily dosage of donepezil hydrochloride depends on prescriber and patient preference. In controlled studies, the occurrence of adverse cholinergic effects was more likely in patients receiving 10 mg of donepezil hydrochloride daily following titration from 5 mg daily over a 1-week period, than in those who received 5 mg daily. However, adverse cholinergic effects with the 10-mg daily dosage of donepezil hydrochloride were no more frequent than with the 5-mg daily dosage when the dosage of donepezil hydrochloride increased from 5 to 10 mg over a 6-week period in uncontrolled studies. Therefore, because plasma concentrations of donepezil do not reach steady state for 15 days, and the occurrence of adverse effects may be influenced by the rate of increase in dosage, the daily administration of 10 mg of donepezil hydrochloride should not be considered until after the patient has received 5 mg daily for 4-6 weeks.

Dosage in Renal and Hepatic Impairment

Limited data in a few patients with moderate to severe renal impairment (creatinine clearance less than 22 mL/minute per 1.73 m) indicate no difference in the clearance of donepezil compared with that in healthy individuals matched for age and gender, and the manufacturer makes no specific recommendation for dosage adjustment in patients with renal impairment.

Clearance of donepezil in a limited number of patients with stable alcoholic cirrhosis was reduced by 20% compared with that in healthy age- and gender-matched individuals; however, the manufacturer makes no specific recommendation for dosage adjustment in patients with hepatic disease.