Open Access Highly Accessed Open Badges Research article

Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease

Martin Farlow1*, Felix Veloso2, Margaret Moline3, Jane Yardley4, Elimor Brand-Schieber3, Francesco Bibbiani3, Heng Zou3, Timothy Hsu3 and Andrew Satlin3

Author Affiliations

1 Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, CL299, Indianapolis, IN, 46202, USA

2 Centre for Clinical Cognitive Research, Pasqua Hospital, 4101 Dewdney Avenue, Regina, Saskatchewan, S4T 1A5, Canada

3 Eisai Inc, Neuroscience Product Creation Unit, 100 Tice Blvd., Woodcliff Lake, NJ 07677, USA

4 Eisai Ltd, Neuroscience, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, UK

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BMC Neurology 2011, 11:57  doi:10.1186/1471-2377-11-57

Published: 25 May 2011



Donepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d.


Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed.


The safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%).


The 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d.


The good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.

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