Objective: To assess the safety and tolerability of donepezil in patients with mild to moderate Alzheimers disease (AD) over a 3-year period.
Design: 286 patients were randomized to either 52 weeks of donepezil treatment (5 mg/day for 4 weeks followed by 10 mg/day, where possible) or placebo. Patients who completed the double-blind study entered into a 2-year, open-label extension study. All patients in the open-label study received donepezil 5 mg/day for 4 weeks followed by 10 mg/day, where possible.
Methods: Safety and tolerability were assessed at Weeks 12, 24, 52 and every 6 months thereafter. Assessments included discontinuation rate, compliance and adverse events (AEs).
Results: Of the 157 patients who completed the 1-year double-blind study and enrolled into the 2-year extension, 81 received continuous donepezil treatment for 3 years and 76 had a delayed treatment start (ie placebo for 1 year then donepezil for 2 years). Baseline characteristics between the two groups were similar, with a mean patient age of 71 years and females comprising 63% of the population. During the 2-year extension 31% of patients continuously treated with donepezil and 24% of patients in the delayed-start cohort withdrew from the study. The annualized discontinuation rate of 13% during this period was lower than the 30% discontinuation rate that occurred during the 1-year double-blind study. Compliance rates over the 2-year extension were greater than 90% in both cohorts. For those who discontinued, 10 (12.3%) continuously treated with donepezil and 6 (7.9%) in the delayed-start cohort withdrew due to AEs. Over the 3-year study, treatment-emergent AEs were recorded for the majority of patients in both treatment groups; 96.3% continuously treated- compared with 97.4% delayed-start- patients. Commonly reported AEs included typical cholinergic side effects such as nausea, diarrhea, headache, and vomiting, rated as mild or moderate in severity. In both cohorts the first occurrence of these AEs were observed more frequently during the double-blind period than during the 2-year extension.
Conclusions: Donepezil has an excellent long-term safety profile and is well tolerated over time in AD patients, with the first occurrence of treatment-emergent AEs being reported less frequently as therapy continues. The relatively low rate of discontinuation and high rate of compliance of this elderly population suggests that these patients are able to tolerate and persist with donepezil treatment in the long term.
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