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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Posted by Dr. Jim Joyner
Extensive federal Hospice Conditions of Participation (CoP's) were published in the Federal Register June 5, 2008. These regulations became effective on December 2, 2008. A documented comprehensive assessment of each patient is required which must identify patient needs across the entire spectrum of hospice related care. Part of this assessment entails a review of each patient's drugs both prescription and OTC drugs, including herbal remedies. The review should address at least the following:
1) Effectiveness of drug therapy
2) Drug side effects
3) Actual or potential drug interactions
4) Duplicate drug therapy
5) Drug therapy currently associated with lab monitoring
With regard to the drug regimen review, the hospice is required to ensure that the interdisciplinary group confers with an individual with education and training in drug therapy management . This individual may be an employee of the hospice or under contract with the hospice to ensure that drugs and biologicals meet the patient's individual needs. In most cases this individual would be a clinical pharmacist.
Outcome Resources offers a service to provide Comprehensive Medication Reviews. Our team of PharmD's can provide these for all patients, just complex patients, or as needed if the qualified person the hospice employs is unavailable. Turnaround time is 24-48 hours, well within the 5 day timeframe established by the CoP's. If you are interested in learning more about the services we can offer to your hospice, Contact Us for more information.