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

Abstract

BackgroundDonepezil 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.MethodSafety 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.ResultsThe 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%).DiscussionThe 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.ConclusionThe good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.Trial RegistrationNCT00478205

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

“…This difference in rates of discontinuation appears to be attributed primarily to the transient increase in cholinergic-related gastrointestinal AEs (nausea, vomiting, diarrhea, and anorexia) in the 10–23 subgroup due to titration to the higher dose. This pattern was documented in the initial double-blind study, where 18.8% and 7.9% of patients discontinued in the donepezil 23 mg/day and 10 mg/day subgroups, respectively [9,19], and is consistent with other studies with a dose increase from donepezil 5 mg/day to 10 mg/day [8]. An increase in cholinergic AEs has been widely observed with acetylcholinesterase inhibitors when patients are titrated from a lower to a higher dose regimen [20,21].…”

Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau

“…Donepezil was first developed for mild to moderate (5~10 mg/d) AD patients, but larger dose (23 mg/d) was recently approved in the U.S. for treatment of moderate to severe AD. The good safety and predictable tolerability profile in a phase 3 trial for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with advanced AD [1]. Rivastigmine is effective in improving the cognitive and global functioning in AD patients, but the incidence of nausea and vomiting make it difficult to maintain high therapeutic doses in clinical practice.…”

The ethanolic extract of the Eclipta prostrata L. ameliorates the cognitive impairment in mice induced by scopolamine

“…The drugs that are currently available for AD patients are donepezil, galantamine, and rivastigmine, which act by inhibiting acetylcholinesterase (AChE) and increasing the level of acetylcholine (ACh) in the brain. These drugs improve the cognitive functions of AD patients symptomatically, but they produce several adverse effects such as nausea, diarrhea, anorexia, or vomiting (Farlow et al, 2011;Shintani and Uchida, 1997). We are working on the development of anti-amnesic or anti-dementia agents using an in vivo screening of herbal materials due to their safety and cost-effectiveness although quality assurance issues could be raised (Chan, 2003;Myers and Cheras, 2004).…”