Criteria for Outpatient Use Guidelines
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Acetylcholinesterase Inhibitors
[Developed, April 2006; Revised, January 2010]
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].
1.* Dosage
Adults
All available acetylcholinesterase inhibitors (ACIs) are FDA-approved in adults for the management of mild to moderate Alzheimer’s dementia, while donepezil is also FDA-approved for management of severe Alzheimer’s disease. Additionally, rivastigmine (Exelon®) is FDA-approved for use in mild to moderate dementia associated with Parkinson’s disease. Alzheimer’s disease is associated with significant losses in cholinergic neurons and decreased concentrations of acetylcholine, a neurotransmitter significantly involved in learning and memory processes. ACIs exert pharmacologic effects by increasing availability of intrasynaptic acetylcholine in the presence of intact cholinergic neurons. Recommended adult dosages are summarized in Table 1.
| Drug Name | Maximum Recommended Dosage |
|---|---|
| Donepezil (Aricept®, Aricept® ODT) tablets (5 mg, 10 mg); oral solution (1 mg/ml); orally disintegrating tablets (5 mg, 10 mg) |
10 mg/day, as a single dose |
| Galantamine (Razadyne®) immediate-release: tablets (4 mg, 8 mg, 12 mg) oral solution (4 mg/ml) extended-release: capsules, extended-release (8 mg, 16 mg, 24 mg) |
immediate-release: 24 mg/day, in 2 divided doses extended-release: 24 mg/day once daily |
| Rivastigmine (Exelon®) immediate-release: capsules (1.5 mg, 3 mg, 4.5 mg, 6 mg) oral solution (2 mg/ml) transdermal (extended-release): transdermal patch (4.6 mg/24 h, 9.5 mg/24 h) |
immediate-release: 12 mg/day, in 2 divided doses extended-release: 9.5 mg/24 h |
| Tacrine (Cognex®)** capsules (10 mg, 20 mg, 30 mg, 40 mg) |
160 mg/day, in 4 divided doses |
**This agent has largely been replaced with other available acetylcholinesterase inhibitors with more favorable dosage regimens and adverse event profiles.
Although not FDA-approved, ACIs have also been evaluated for use in vascular dementia, dementia with Lewy bodies, post stroke aphasia, and memory improvement in multiple sclerosis patients.
Pediatrics
ACIs are not recommended for use in children, as adequate, well-controlled clinical trials have not documented safety and efficacy of these agents for any disease state in the pediatric population.
2. Duration of Therapy
ACIs do not alter the long-term progressive decline of Alzheimer’s disease, but have been shown to delay time to institutionalization, which may be cost-effective. ACI may be prescribed to stabilize dementia in Alzheimer’s patients, as determined by periodic assessment of functional and cognitive ability. ACIs should be discontinued when dementia becomes unresponsive to therapy and progressively severe, as the efficacy of these agents diminishes due to loss of intact cholinergic neurons.
3.* Duplicative Therapy
Combined use of two or more ACIs does not provide enhanced therapeutic benefit and may result in additive adverse effects. Concurrent administration of two or more ACIs is not recommended and will be reviewed.
4.* Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.
Drug-drug interactions considered clinically relevant for ACIs are summarized in Table 2. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
| TARGET DRUG | INTERACTING DRUG | INTERACTION | RECOMMENDATIONS | CLINICAL SIGNIFICANCE |
|---|---|---|---|---|
| tacrine | fluvoxamine | potential for increased tacrine concentrations and enhanced pharmacologic/ adverse effects due to fluvoxamine inhibition of CYP1A2, the enzyme responsible for tacrine metabolism | monitor for enhanced cholinergic/ adverse effects, especially hepatotoxicity; may substitute other SSRIs not metabolized by CYP1A2 (e.g., fluoxetine, sertraline) | moderate (DrugReax) 2 (DIF) 3-moderate (Clinical Pharmacology) 2 (Hansten & Horn) |
| tacrine | theophyllines | potential for increased theophylline concentrations and toxicity due to tacrine inhibition of CYP1A2, an enzyme responsible for theophylline metabolism | observe for increased serum theophylline levels; reduce initial theophylline dose by 25-50% to avoid toxicity | moderate (DrugReax) 4 (DIF) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| tacrine, galantamine | cimetidine | increased tacrine bioavailability, serum concentrations due to cimetidine inhibition of CYP1A2increased galantamine bioavailability and potential for increased cholinergic effects due to cimetidine inhibition of CYP2D6 | monitor for increased tacrine and galantamine cholinergic adverse effects; may substitute an H2 receptor antagonist less likely to interfere with tacrine and galantamine metabolism | tacrine: 4 (DIF) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| ACIs | NSAIDs | potential for additive gastrointestinal effects | monitor for gastrointestinal intolerance and/or bleeding | 3-moderate (Clinical Pharmacology) |
| donepezil, galantamine | CYP3A4 and CYP2D6 inhibitors | potential for increased donepezil and galantamine serum concentrations | monitor for increased cholinergic effects | moderate (DrugReax) 3-moderate (Clinical Pharmacology) 4 (Hansten & Horn) |
| donepezil | CYP3A4 and CYP2D6 inducers | potential for reduced donepezil serum concentrations and decreased efficacy | monitor for reduced donepezil efficacy | 3-moderate (Clinical Pharmacology) |
| ACIs | cholinergic agents and other cholinesterase inhibitors | enhanced cholinergic/ adverse effects | avoid combination, if possible; if combination necessary, monitor for enhanced cholinergic effects; may adjust doses to achieve tolerable clinical effects | minor (DrugReax) 2-major (Clinical Pharmacology) |
| ACIs | anticholinergics | potential for reduced cholinergic activity with centrally acting anticholinergics, which may manifest as reduced activities of daily living but not cognitive function; peripherally acting anticholinergics less likely to attenuate ACI therapeutic effects | monitor for diminished cholinergic effects; choose agents with less centrally acting anticholinergic activity | moderate (DrugReax) 3- moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
References
- AHFS Drug Information 2009 [book online]. Jackson, WY: Teton Data Systems, Version 6.3.1, 2009. Based on: McEvoy GK, editor. AHFS drug information 2009. Bethesda (MD): American Society of Health-System Pharmacists; 2009. Stat!Ref Electronic Medical Library.
- Drug Facts and Comparisons. Clin-eguide [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; 2010. Available at: http://clineguide.com. Accessed January 14th, 2010.
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2010. Available at: http://www.clinicalpharmacology.com. Accessed January 14th, 2010.
- Galantamine extended-release capsules, tablets and oral solution (Razadyne® ER, Razadyne®) package insert. Ortho-McNeil Neurologics, April 2008.
- Rivastigmine capsules and oral solution (Exelon®) package insert. Novartis Pharmaceuticals Corporation, June 2006.
- Rivastigmine transdermal system (Exelon® Patch) package insert. Novartis Pharmaceuticals Corporation, July 2007.
- Donepezil tablets, orally disintegrating tablets (Aricept®, Aricept® ODT) package insert. Eisai Inc., November 2006.
- Tacrine capsule (Cognex®) package insert. Sciele Pharm, Inc., August 2008.
- Drug Interaction Facts. Clin-eguide [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; 2010. Available at: http://clineguide.com. Accessed January 15th, 2010.
- Klasco RK (Ed): DRUG-REAX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu. Accessed January 15th, 2010.
- Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer’s disease. Am J Med. 2007;120:388-97.
- Blennow K, deLeon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387-403.
- Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006, Issue 1. Art. No.: CD005593. DOI: 10.1002/14651858.CD005593.
- Hansten PD, Horn JR, eds. Hansten and Horn's Drug Interactions Analysis and Management. St. Louis, MO: Wolters Kluwer Health, Inc.; 2010.
- Masterman D. Cholinesterase inhibitors in the treatment of Alzheimer’s disease and related dementias. Clin Geriatr Med. 2004;20:59-68.
Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.