Pharmacology Update

Donepezil: A New Alzheimer’s Drug

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

A new anticholinesterase has been approved by the FDA for the treatment of Alzheimer’s disease. Donepezil (Aricept; Pfizer) follows tacrine (Cognex) as the second drug available for this indication. Donepezil (a piperidine derivative) is a reversible acetylcholinesterase inhibitor similar to tacrine. The drug is indicated for the treatment of mild-to-moderate dementia of the Alzheimer type.

The use of these drugs is predicated on the finding that cholinergic pathways are compromised in the brains of Alzheimer’s patients, and that cholinergic deficiency may contribute to cognitive deficits in these patients.1 Anticholinesterase drugs have been tested for years in Alzheimer’s disease but have been limited by systemic side effects or liver toxicity. Donepezil is somewhat selective for acetylcholinesterase in the CNS, thus reducing peripheral side effects such as nausea.

Potential Advantages

Patients treated with donepezil in a 30-week trial showed about a three unit difference in ADAS-Cog score compared to patients on placebo. The ADAS-Cog examines cognitive performance including memory, orientation, attention, reasoning, language, and praxis. The mean baseline score of patients was 26 (range, 4-61).2,3

In addition, there was about a 0.37 unit difference on a Clinician’s Interview Based Impression of Change (CIBIC plus). This non-standardized instrument examines four areas of patient function: general, cognitive, behavioral, and activities of daily living. CIBIC plus represents the combined assessment of a skilled clinician and information supplied by a caregiver. About 20% of the patients treated with donepezil were judged to be minimally improved compared to about 7% for the placebo-treated patients.3

Unlike tacrine, donepezil appears to be generally well-tolerated and does not require periodic liver function tests. It is conveniently dosed once daily.

Potential Disadvantages

Donepezil does not appear to affect the progression of the disease process. Preliminary data, in abstract form, suggest that the difference in ADAS-Cog scores between donepezil and placebo could be sustained for at least two years.4 Six weeks after discontinuation of the drug, the ADAS-Cog scores for those treated with donepezil and placebo were indistinguishable.

While donepezil produced statistically significant differences in ADAS-Cog scores, the difference represents about an 11% change from baseline mean score. It is not established whether this represents a clinically meaningful difference. In a 14-week study comparing donepezil 5 mg and placebo, patient quality of life scores (i.e., well-being) as assessed by the caregiver showed no statistical evidence of improvement over placebo, although those assessed by the patients did show a statistical difference.5

Dosage Information

Donepezil is supplied in 5 mg and 10 mg tablets. Patients should be started on 5 mg once daily in the evening. After steady state has been achieved, at 4-6 weeks, a dose of 10 mg may be considered. The higher dose may provide additional benefit to some patients, although in the clinical trials, there was no significant difference in the ADAS-Cog or CIBIC scores between 5 mg and 10 mg daily. The higher dose is associated with higher incidence of side effects. For example, the incidence of nausea is 5% with the 5 mg dose and 19% with the 10 mg dose.


Donepezil is the second acetylcholinesterase inhibitor to be marketed, the other being tacrine. Compared to tacrine, donepezil is longer acting and much better tolerated. In clinical trials, 28% of patients discontinued tacrine due to liver transaminase elevation and 16% due to GI complaints. In contrast, the discontinuation rate with donepezil was 5% in the 5 mg group and 13% in the 10 mg group, primarily due to GI symptoms.3,6

There are no comparative studies between donepezil and tacrine. In studies of similar design and duration, donepezil 5 mg and 10 mg and tacrine 120 mg and 160 mg produced similar and statistically significant improvements in ADAS-Cog scores compared to placebo. In patients who tolerated tacrine 160 mg per day, the drug-placebo difference was greater than with donepezil (5.3 vs 3.1). With both drugs, however, the clinical benefit appears to be marginal.3,6

Clinical Implications

Alzheimer’s disease is a common form of dementia related to old age. It is estimated to affect 2-4 million person in the United States alone.7 The disease places tremendous emotional and financial burden on the family members as well as the cost of care to society. While the effect of the acetylcholinesterase inhibitors is marginal in Alzheimer’s disease, they are the only drugs available for this indication. Donepezil is better tolerated than tacrine, although tacrine may be somewhat more effective in patients who are able to tolerate it. Both drugs are priced at about $3.40 per day.


1. Bartus RT, et al. Science 1982;217:408-414.

2. Rogers SL, et al. Neurology 1996;46:A217 (S14.001).

3. Aricept Product Information. Roerig. December 1996.

4. Rogers SL, et al. Eur Neuropsychopharmacol 1995;5: 386 (P-8-21).

5. Rogers SL, et al. Dementia 1996;7:293-303.

6. Knapp MJ, et al. JAMA 1994;271:85-91.

7. Growdon JH. JAMA 1992;327:1306-1308.