Safety and tolerability of donepezil 23mg with or without intermediate dose titration in patients with Alzheimer's disease taking donepezil 10mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial

Abstract

BackgroundHigh-dose donepezil is currently prescribed for patients with Alzheimer's disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23mg is preferred. We investigated safety and tolerability of donepezil 23mg during the first 12weeks of dose escalation in patients with moderate to severe AD.MethodsThis study was a 12-week, multicenter, randomized, open-label prospective trial. We included patients with moderate to severe AD who were treated with a stable dose of donepezil 10mg/day. Patients were randomized into 3 groups according to the dose escalation method: 15mg of donepezil for 4weeks before escalating to 23mg (group 1), 10mg and 23mg on alternate days for 4weeks prior to escalation (group 2), and direct escalation to 23mg (group 3). Safety analyses included incidence, severity, timing of AEs, relationship to the study drug, and premature study discontinuation due to AEs between the groups.ResultsAmong 175 enrolled, 110 patients completed the study. Baseline characteristics were similar among the groups. Using safety population (N=160), cholinergic gastrointestinal symptoms including anorexia and nausea were the most common AEs and titration groups showed significantly fewer cases of nausea as compared with those in no-titration group.ConclusionsIn this study, dose titration before escalating to donepezil 23mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4weeks can be recommended for patients with moderate to severe AD.