High-Dose Donepezil Approved for Moderate to Severe Alzheimer's Disease
Posted by Dr. Julia Harder
The FDA has approved donepezil (Aricept) 23 mg once daily for the treatment of patients with moderate to severe Alzheimer’s disease who have been using 10 mg daily for at least 3 months. This approval comes at an opportune moment for the manufacturers of Aricept (Eisai Inc. and Pfizer Inc.), as the 5 mg and 10 mg strengths of Aricept go off patent in November of this year. The new 23 mg strength is expected to be available this month and the manufacturers will have 3 years of market exclusivity.
The FDA’s approval was based on the results of a clinical trial (Ref.1) comparing the 23 mg and 10 mg strengths. The randomized, double-blind, multicenter study enrolled 1467 patients age 45-90 with probable AD and a Mini Mental Status Exam score of 0 – 20 (indicating moderate to severe cognitive impairment) who had been receiving donepezil 10 mg daily for at least 12 weeks. Patients were randomized to 24 weeks of treatment with either high-dose donepezil (23 mg daily) or continued treatment with standard-dose donepezil (10 mg daily).
The two primary effectiveness measures were cognition and global functioning. Cognition was measured using the Severe Impairment Battery (SIB), a validated clinical instrument used to rate 9 aspects of cognition, including social interaction skills, memory, orientation, language, attention, praxis, visuospatial ability, construction and orientation to name. Scores on the SIB range from 0 to 100, where lower scores indicate greater impairment. There was a statistically significant difference between the two groups in the change from baseline SIB score: +2.6 in the 23 mg group vs. +0.4 in the 10 mg group (P = 0.0001). However, the study did not address the clinical significance of these changes.
Global functioning, the second primary outcome measure, was assessed using the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (the CIBIC-Plus). The CIBIC-Plus examines four major areas of patient function: general, cognitive, behavioral and activities of daily living. It combines the assessment of a skilled clinician based upon his/her observations of the patient with information supplied by a caregiver familiar with the patient’s behavior. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change,” to a score of 7, indicating “markedly worse.” The between-treatment difference in CIBIC-Plus score was not statistically significant (4.23 vs. 4.29, P = 0.1789).
Study discontinuation due to medication adverse effects were far more common in the high-dose donepezil group (18.6% vs. 7.9%). The most common adverse effects leading to study discontinuation, in order of prevalence, were vomiting, diarrhea, nausea and dizziness. The following table compares the percentage of patients in each group experiencing adverse effects:
| ADVERSE EFFECT |
23 mg/day
(% of patients)
|
10 mg/day
(% of patients)
|
| Nausea |
12 |
3 |
| Vomiting |
9 |
3 |
| Diarrhea |
8 |
5 |
| Weight Loss |
5 |
3 |
| Anorexia |
5 |
2 |
| Dizziness |
5 |
3 |
The Aricept package insert (Ref. 2) claims that, in most cases, side effects were mild and transient, tending to resolve during the first month of continued donepezil use.
In the past, the FDA has warned that cholinesterase inhibitors such as donepezil may have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia or heart block in patients with and without underlying cardiac conduction abnormalities. Syncopal episodes have been reported. The percentage of patients experiencing syncope was not reported in this trial, but it may be expected that the higher donepezil dose would increase the risk of cardiovascular side effects. Caution is warranted when prescribing high-dose donepezil to patients with a history of bradycardia, heart block or syncope, or who are taking other medications that slow transmission through the sinoatrial or atrioventricular nodes (such as beta blockers, calcium channel blockers, or digoxin).
The role of high-dose donepezil in the management of advanced Alzheimer’s disease will remain to be seen. Given the questionable clinical benefit and the increased side effects, the use of high-dose donepezil should, for now, be reserved for select patients in whom the benefit outweighs the risk. Further research is needed to demonstrate the efficacy of high-dose donepezil in this patient population before its use can be routinely recommended.
(Ref. 1) Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer's disease: A 24-week, randomized, double-blind study. Clin Ther 2010;32:1234-1251.
(Ref. 2) Aricept® (donepezil hydrochloride) tablets. Package insert, revised July 2010. Eisai, Inc and Pfizer, Inc. Available online at http://www.aricept.com.
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