Background
Efficacy and safety of once-daily donepezil 23 mg, an acetylcholinesterase inhibitor (AChEI), were investigated in a recent clinical trial involving 1467 randomized patients with moderate to severe Alzheimer's disease (AD) (NCT00478205) [
1]. Compared with patients who continued taking donepezil 10 mg/d, those whose dose was increased to donepezil 23 mg/d demonstrated a significantly greater cognitive benefit on the Severe Impairment Battery (SIB) after 6 months of treatment.
AChEIs as a class may cause cholinergic adverse events (AEs). The most frequently occurring treatment-related AEs are nausea, vomiting, and diarrhea, and the frequency and severity of these effects are related to dose [
2,
3]. Less common class-related AEs include vagotonic (eg, bradycardia, syncope), central nervous system (eg, aggression, sleep disturbance), and parasympathetically mediated (eg, urinary incontinence) AEs [
4,
5]. Gastrointestinal (GI) AEs typically increase after dose initiation or upward dose titration, after which the frequency declines within a few weeks [
3,
4].
This report is a detailed presentation and analysis of the safety and tolerability data from the previously published clinical trial [
1] comparing an increase in the daily dose of donepezil from 10 mg/d to 23 mg/d with continuation on 10 mg/d. These analyses substantively extend the presentation of safety and tolerability findings previously published. In addition, this paper includes an analysis of pooled data from 2 previous double-blind, placebo-controlled, 24-week trials in which donepezil was initiated at 5 mg/d and titrated to 10 mg/d [
6,
7] in order to further clarify the relationship between dose transitions and AEs. The primary objective is to help guide clinicians who are treating patients with moderate to severe AD at this new dosage.
Discussion
Both the 23 mg/d and 10 mg/d doses of donepezil used in the study reported by Farlow et al. were generally safe and well tolerated. A transient increase in cholinergic-related GI AEs was observed in the first 2-4 weeks after starting 23 mg/d, after which the incidence of AEs was similar in both treatment groups. AEs usually associated with more advanced disease, such as neuropsychiatric symptoms [
8], were not clinically significantly different between the 10 and 23 mg/d groups. There were no differences between groups in the incidence of clinically notable abnormal laboratory parameters or vital signs.
The 23 mg/d dose of donepezil was associated with a higher rate of AEs, particularly GI-related AEs (nausea, vomiting, diarrhea, and anorexia), than the 10 mg/d dose. The transient increase in these cholinergic AEs observed with initiation of the higher dose is consistent with the pattern previously seen in studies with a dose increase from 5 mg/d to 10 mg/d [
9]. These results are in accord with other studies showing that AChEIs as a class are associated with cholinergic AEs and that the incidence and severity of these AEs increase when patients are titrated from a lower to a higher dose regimen [
2,
3]. However, previous studies did not specifically examine the temporal relationship between dose initiation and AEs.
During the first 2 weeks following upward dose titration, approximately 20% of patients reported a first episode of a GI-related AE. A less pronounced rise in GI-related AEs was also seen during this period in patients who continued treatment with donepezil 10 mg/d. This finding of early and transient increases in GI-related AEs following upward dose titration is consistent with those of previous studies in which GI AEs were associated with both treatment initiation and transitions from low-dose to higher dose treatment [
3,
4,
7,
9,
10]. These events declined in frequency after 1 month of treatment, or about 2 weeks after steady-state donepezil levels had been reached [
4,
9,
11]. Indeed, after 1 month, the proportion of patients reporting new occurrences of GI-related AEs in this trial fell to roughly 3% in both groups, and then remained low, steady, and similar between groups through Week 24. Discontinuations due to AEs also peaked during the first 2 weeks of the study in both treatment groups, with a higher incidence in the 23 mg/d group, and then the rate of discontinuations declined steadily thereafter. After 2 months of treatment, the rate of discontinuations remained low, steady, and similar between groups through Week 24.
Analysis of pooled data from 2 similarly conducted trials in mild to moderate AD [
6,
7] demonstrated that increasing donepezil dose from 5 mg/d to 10 mg/d led to a temporal pattern of AEs and discontinuations due to AEs similar to that observed with increasing from 10 mg/d to 23 mg/d. These data suggest that physicians and other prescribers may anticipate the same overall timing, type, and severity of AEs when changing patients' dose from 10 mg/d to 23 mg/d as has already been encountered when switching patients from 5 mg/d to 10 mg/d. No data are currently available to support an interim dose titration when increasing from donepezil 10 mg/d to 23 mg/d.
Rates of non-GI AEs with the 23 mg/d dose of donepezil were generally low but were greater than those seen with the 10 mg/d dose. Cardiac AEs were infrequent with both the 23 mg/d and 10 mg/d doses. Some studies have shown an increased risk of bradycardia and syncope in patients treated with AChEIs [
12,
13]. In the current study, the overall incidence of bradycardia was greater in the higher-dose group, and all 8 patients who discontinued the study due to bradycardia were taking 23 mg/d. However, bradycardia occurred in fewer than 3% of patients in the 23 mg/d group and was not commonly associated with other sequelae. Weight decrease as an AE was more common in the 23 mg/d group, though it occurred in fewer than 5% of patients, being mild to moderate in 45 patients and severe in only 1 patient.
Post hoc analyses to explore additional demographic factors showed that more women than men who increased dose to 23 mg/d had anorexia and weight loss. With respect to age, increased dose to 23 mg/d was associated with a higher incidence of fatigue, somnolence, and urinary incontinence in successively higher age groups. The higher rates of some common AEs observed in Asian/Pacific patients in both treatment groups may be related to lower mean weight in this patient subpopulation, as was found for the lower weight compared with the higher weight patients in general. A higher rate of AEs was observed in patients receiving memantine regardless of treatment group assignment, consistent with their more advanced stage of AD.
The study in which these data were obtained was a rigorously conducted global clinical trial involving a large number of patients with moderate to severe AD, of whom about one third were receiving concomitant memantine. Strengths of this study include the detailed temporal analysis, stratification by concomitant memantine use, and high completion rate in both groups. Limitations include lack of sufficient representation of Hispanic and black populations to assess potential race-related safety or tolerability issues, and a 24 week study duration.
Competing interests
Dr. Farlow is a paid consultant for Accera, Astellas, Bayer Bristol-Myers Squibb, Eisai Medical Research, GE Healthcare, Helicon, Medavante, Medivation, Inc., Merck and Co., Inc. Novartis Pharma, Pfizer, Prana Biotech, QR Pharma, Sanofi-aventis Groupe and Toyama Pharm.; is paid speaker for Eisai, Forest, Novartis, and Pfizer; and receives research support from Bristol-Myers Squibb, Elan, Eli Lilly and Co., Novartis Pharm., Pfizer, Octapharma, and Sonexa.
Dr. Felix Veloso has conducted clinical drug trials for and is in the speaker bureau of several pharmaceutical companies, including Pfizer, Lundbeck, Novartis, Janssen Ortho, Johnson & Johnson, Biogen Idec, sanofi aventis, Boehringer Ingelheim, Glaxo Smith Kline.
M. Moline, J. Yardley, E. Brand-Schieber, F. Bibbiani, H. Zou, T. Hsu, and A. Satlin are employees of Eisai Inc.
Authors' contributions
MF participated in designing and conducting the study, and helped draft the manuscript. FV participated in monitoring the study and helped draft the manuscript. MM and TH conceived and designed the study, analyzed and interpreted the data, and helped draft the manuscript. JY, EB-S, FB, HZ, and AS analyzed and interpreted study data and helped to draft the manuscript. All authors read and approved the final manuscript.