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.