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

摘要

High-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 23?mg is preferred. We investigated safety and tolerability of donepezil 23?mg during the first 12?weeks of dose escalation in patients with moderate to severe AD. This 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 10?mg/day. Patients were randomized into 3 groups according to the dose escalation method: 15?mg of donepezil for 4?weeks before escalating to 23?mg (group 1), 10?mg and 23?mg on alternate days for 4?weeks prior to escalation (group 2), and direct escalation to 23?mg (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. Among 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. In this study, dose titration before escalating to donepezil 23?mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4?weeks can be recommended for patients with moderate to severe AD. Clinicaltrials.gov , NCT02550665. Retrospectively registered on 15 Sep 2015.