Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer's disease.
BACKGROUND
Donepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD.


METHODS
Patients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs.


RESULTS
915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study.


CONCLUSIONS
This study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.
Banner Alzheimer's Institute, 901 E. Willetta Street, Third Floor, Phoenix, AZ 85006, USA.
Pierre
P
Tariot
Steven
S
Salloway
Jane
J
Yardley
Joan
J
Mackell
Margaret
M
Moline
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000553:Ambulatory Care; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D054316:Biomarkers, Pharmacological; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil