Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer’s disease

Abstract

BackgroundDonepezil (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.MethodsPatients 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.Results915 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.ConclusionThis 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.

Donepezil 23 mg: A Brief Insight on Efficacy and Safety Concerns

“…two subgroups were defined in the study: patients who had received donepezil 10 mg (10 mg/23 mg subgroup) and those who had received donepezil 23 mg (23 mg/23 mg subgroup) in Farlow's double-blind study. 9 For the purposes of this extension study, all participants would be placed on donepezil 23 mg. When compared with the 23 mg/23 mg subgroup, the 10 mg/23 mg subgroup had higher rates of cholinergic AEs during the first four weeks of the trial.…”

“…Consequently, 17.5% versus 11.4% of patients discontinued therapy as a result of AEs in the 10 mg/23 mg and 23 mg/23 mg subgroups, respectively. 9 The investigators concluded that the difference in discontinuations between groups was a result of the transient increase in cholinergic-related AEs that occur with titrating from a lower-to a higher-dose regimen. 9 onset of new AEs was limited to the initial weeks of the study and declined thereafter.…”

“…The study demonstrated that long-term treatment of AD with high-dose donepezil 23 mg is not associated with new safety findings and is a tolerable treatment option. 9 Additionally, a post hoc analysis of Farlow and colleagues' study was performed to provide an assessment of both safety and efficacy of donepezil 23 mg versus donepezil 10 mg in patients with moderate-to-severe AD, with respect to concomitant use of memantine. 10 The analysis concluded that concomitant use of memantine had no substantial impact on the cognitive benefits of donepezil 23 mg compared with donepezil 10 mg. 10 The study further suggests that donepezil 23 mg is safe and tolerable for patients irrespective of whether or not they are concomitantly using memantine for treatment of AD.…”

Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer’s disease

“…Different classes of AchE inhibitors, including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues, have been developed for the treatment of AD. Among them, donepezil hydrochloride (DPH) is the second FDA-approved anti-AD drug and is considered a safe and well-tolerated drug for AD patients [7,8]. DPH has a very long half-life, indicating that it is ideal for convenient once-daily dosage [3,[8][9][10].…”

High‐Dose Donepezil (23 mg/day) for the Treatment of Moderate and Severe Alzheimer's Disease: Drug Profile and Clinical Guidelines

“…A subsequent 12-month, open-label extension study, in which all participants received donepezil 23 mg/day, has also been conducted. Several articless and presentations have detailed either the primary outcomes from these trials or outcomes from post hoc analyses of trial data [26][27][28][29][30][31][32].…”