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Safety and Tolerability of Donepezil at Doses up to 20 mg/day

Results from a Pilot Study in Patients with Alzheimer’s Disease

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Abstract

Background: Donepezil is licensed for the treatment of mild-to-moderate Alzheimer’s disease (AD) at doses of 5–10 mg/day and has recently been approved in the US for severe AD. Multiple studies have suggested that donepezil 10 mg/day provides additional cognitive and functional benefits over the 5 mg/day dose. Higher doses of donepezil, if safe and well tolerated, might provide further benefits for patients with AD.

Objective: To evaluate the safety and tolerability of donepezil at doses of 15 and 20 mg/day.

Method: A 24-week, randomized, double-blind, placebo-controlled, pilot study conducted at two investigational sites in the US. Enrolled patients (male and female; aged 50–86 years) had a diagnosis of probable AD at the mild-to-moderate stage (Mini-Mental State Examination [MMSE] score 10–26). All patients had been treated with donepezil 10 mg/day for 12–30 months prior to enrolment. Patients (n = 31) were randomized 1 : 1 to receive either a standard dose of donepezil (donepezil 10 mg/day plus placebo 5 mg/day for weeks 1–12; donepezil 10 mg/day plus placebo 10 mg/day for weeks 13–24) or a higher dose of donepezil (donepezil 15 mg/day for weeks 1–12; donepezil 20 mg/day for weeks 13–24). Primary outcome measures were tolerability (as determined by monitoring of discontinuations, dose modifications and adverse events) and safety (as determined by adverse event monitoring, physical examinations, clinical laboratory tests and ECGs). Psychometric measures (Alzheimer’s Disease Assessment Scale-Cognitive Subscale [ADAS-cog], MMSE and Clinician’s Interview-Based Impression of Change with caregiver information [CIBIC+]) and pharmacokinetic/pharmacodynamic parameters were secondary outcomes.

Results: No patients withdrew from the study and there were no serious adverse events or deaths. By week 24, 15 of 16 patients in the higher-dose group tolerated the maximum 20 mg/day dose; one patient had a permanent dose reduction to donepezil 15 mg/day. In the standard-dose group, 14 of 15 patients tolerated donepezil 10 mg/day plus placebo 10 mg/day by the end of the study; one patient had a permanent dose reduction to donepezil 10 mg/day plus placebo 5 mg/day. Temporary dose reductions occurred in two patients (one from each group). Adverse events reported were as expected for donepezil and were all mild to moderate in intensity. Adverse events considered to be possibly or probably related to treatment were reported for three patients in the standard-dose group and six patients in the higher-dose group. One patient in the higher-dose group had weight loss reported as possibly or probably treatment related. Mean changes on ECGs were not clinically significant in either group, and the incidence of bradycardia was comparable. No treatment difference on any of the psychometric measures was observed between the groups. Pharmacokinetic analyses showed that an increased donepezil dose was associated with an increase in donepezil plasma concentrations from baseline.

Conclusion: In this small pilot study of patients with mild-to-moderate AD already stabilized on donepezil 10 mg/day, doses of 15 and 20 mg/day of donepezil appeared safe and well tolerated. These results justify initiation of larger clinical trials designed to investigate the efficacy and safety of doses of donepezil higher than 10 mg/day in patients with AD.

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Notes

  1. Use of donepezil 15 and 20 mg/day for treatment of AD in this pilot study is up to twice the dosage approved by the US FDA and publication of this study does not imply endorsement of use of this dose as ‘usual care’.

  2. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

Activities related to study design, data collection and data analysis were funded by Eisai and Pfizer. Editorial support was provided by R. Daniel, PhD, of PAREXEL and was funded by Pfizer. The help of Nisith Kumar and Mindy Sovel throughout the trial is also gratefully acknowledged.

Honglan Li and John Ieni are employees of Eisai. Richard Zhang and Rachel Schindler are employees and stock owners of Pfizer. Rachelle Doody has received honoraria from Eisai, Pfizer, Janssen, Novartis, Merz, Forest and Lundbeck for consulting and/or lecturing, and has been a principal investigator on multiple clinical drug trials sponsored by various pharmaceutical companies, including Eisai and Pfizer. Jody Corey-Bloom has been a principal investigator on multiple clinical drug trials sponsored by various pharmaceutical companies, including Eisai and Pfizer, and received compensation through her institution to conduct the current study.

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Authors and Affiliations

  1. Alzheimer’s Disease and Memory Disorders Center, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, Texas, 77030, USA

    Rachelle S. Doody

  2. Department of Neurosciences, UCSD School of Medicine, San Diego, California, USA

    Jody Corey-Bloom

  3. Pfizer Inc., New York, New York, USA

    Richard Zhang & Rachel Schindler

  4. Eisai Inc., Teaneck, New Jersey, USA

    Honglan Li & John Ieni

Authors
  1. Rachelle S. Doody
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  2. Jody Corey-Bloom
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  6. Rachel Schindler
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Doody, R.S., Corey-Bloom, J., Zhang, R. et al. Safety and Tolerability of Donepezil at Doses up to 20 mg/day. Drugs Aging 25, 163–174 (2008). https://doi.org/10.2165/00002512-200825020-00008

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