title: Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, CL299, Indianapolis, IN 46202, USA. mfarlow@iupui.edu
authors: Martin
authors: M
authors: Farlow
authors: Felix
authors: F
authors: Veloso
authors: Margaret
authors: M
authors: Moline
authors: Jane
authors: J
authors: Yardley
authors: Elimor
authors: E
authors: Brand-Schieber
authors: Francesco
authors: F
authors: Bibbiani
authors: Heng
authors: H
authors: Zou
authors: Timothy
authors: T
authors: Hsu
authors: Andrew
authors: A
authors: Satlin
references: PLoS Med. 2009 Sep;6(9):e1000157
references: 19787032
references: Dement Geriatr Cogn Disord. 2006;21(5-6):353-63
references: 16508298
references: Arch Intern Med. 2009 May 11;169(9):867-73
references: 19433698
references: Clin Ther. 2010 Jul;32(7):1234-51
references: 20678673
references: Psychogeriatrics. 2009 Jun;9(2):50-5
references: 19604325
references: Dement Geriatr Cogn Disord. 1999 May-Jun;10(3):237-44
references: 10325453
references: Int J Clin Pract Suppl. 2002 Jun;(127):45-63
references: 12139367
references: Neurology. 1998 Jan;50(1):136-45
references: 9443470
references: BMJ. 1999 Mar 6;318(7184):633-8
references: 10066203
references: Curr Med Res Opin. 2002;18(6):347-54
references: 12442882
references: Int J Geriatr Psychiatry. 2004 Jul;19(7):624-33
references: 15254918
references: Curr Med Res Opin. 2010 Feb;26(2):263-9
references: 19929593