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In October 2006, the FDA approved donepezil HCl (Aricept) for patients diagnosed with severe Alzheimer's disease (AD).1 Donepezil, a cholinesterase inhibitor, was approved for mild-to-moderate AD in 1996.2 It is only the second drug, after memantine, approved for severe dementia.
The approval was based on the results of 2 clinical trials submitted by the sponsor, Eisai Inc. Together, the 2 studies showed that patients with severe dementia who received donepezil performed better on cognitive functions, such as memory, language, orientation, and attention.1 Decreases in acetylcholine are thought to be associated with the loss of cognitive functions, including memory. Therefore, inhibiting the breakdown of this neurotransmitter is an important pharmacologic therapy for AD.3
A 6-month, double-blind, placebo-controlled study enrolled 248 patients diagnosed with severe dementia from various Swedish nursing homes.4,5 The patients were randomized to receive either active donepezil or placebo. In the active arm, the patients received donepezil 5 mg once daily for 30 days; then the dose was titrated to 10 mg daily. Ninety-five patients assigned to donepezil and 99 patients assigned to placebo completed the study.5
The primary outcomes were measured using the Severe Impairment Battery (SIB) and the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe AD (ADCSADL-severe).4 The SIB scale is a validated instrument that measures the severity of cognitive dysfunction in advanced AD in terms of memory, language, orientation, attention, praxis, visuospatial construction, ability to name people and objects, and social interaction. The ADCS-ADLsevere is a 19-item scale used to measure basic activities of daily living, such as eating and bathing, and complex abilities, such as opening water taps and switching on lights, with scores ranging from zero to 54.4 Severe dementia was defined using the Mini-Mental State Examination scores of 1 to 10.4,5 At 6 months, the donepezil-treated group had higher SIB scores by a mean of 5.7 points (P = .008) and higher ADCS-ADL-severe scores by a mean of 1.7 points (P = .03), compared with placebo.4,5
The second 6-month study, which was conducted in Japan, included 325 patients diagnosed with AD. Patients were randomized to receive 5 mg/day, 10 mg/day, or matching placebo for 6 months. Improvement was measured using the SIB and the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus).4,5 On the SIB scale, the donepezil 10-mg group improved by a mean of 4.7 points; the donepezil 5-mg group improved by a mean of 2.5 points; and the patients who received placebo demonstrated a decline of 4.2 points. At both doses, the difference between the treatment groups and placebo was statistically significant. Only the donepezil 10-mg group was statistically favorable on the CIBIC-Plus scale.4,5
Donepezil was titrated in both studies to minimize cholinergic side effects. The most common side effects included diarrhea, nausea, vomiting, insomnia, muscle cramp, fatigue, and anorexia.4 The side effects generally subsided with continued donepezil therapy. The patient's response should be monitored with the 5-mg/day dose for 4 to 6 weeks before titrating up to 10 mg, because the rate of the common adverse events may be affected by the rate of titration.4
Donepezil reaches peak plasma concentrations in 3 to 4 hours and has an elimination half-life of 70 hours.4 It is metabolized by the isoenzymes CYP2D6 and CYP3A4 and undergoes glucuronidation.4 No dosage adjustment is necessary in patients with renal disease, and the clearance of donepezil was decreased by 20% in patients with stable alcohol cirrhosis.4
More clinical trials are needed to study the AD patients who are not naive to cholinesterase inhibition therapy. Aricept is available in 5-and 10-g tablets. Aricept Orally Disintegrating Tablets (ODT) also are available in 5-and 10-mg strengths, for patients who have difficulty swallowing tablets. Aricept ODT is bioequivalent to Aricept tablets and may be taken with or without food.
Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Mass. Mr. Exter is a sixth-year PharmD candidate from Northeastern University School of Pharmacy currently on clinical clerkship in the Investigational Drug Service at Brigham and Women's Hospital.
1. www.eisai.com/view_press_release.asp?ID=147&press=150. Accessed February 20, 2007.
2. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed February 20, 2007.
3. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. The Cochrane Library, Copyright 2006, The Cochrane Collaboration Volume (4), 2006.
4. Teaneck, NJ: Eisai Inc. Aricept Package Insert. Revised October 2006.
5. Teaneck, NJ: Eisai Inc. Health Professional Letter.