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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
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.

Table 1
Recommended Adult Dosages for ACIs
Drug Name Maximum Recommended Dosage
Donepezil (Aricept®, Aricept® ODT)
tablets (5 mg, 10 mg) 10 mg/day, as a single dose
oral solution (1 mg/ml)
orally disintegrating tablets (5 mg, 10 mg)
Galantamine (Razadyne®)
immediate-release: immediate-release: 24 mg/day, in 2 divided doses
tablets (4 mg, 8 mg, 12 mg)
oral solution (4 mg/ml)
extended-release: extended-release: 24 mg/day once daily
capsules, extended-release (8 mg, 16 mg, 24 mg)
Rivastigmine (Exelon®)
immediate-release: immediate-release: 12 mg/day, in 2 divided doses
capsules (1.5 mg, 3 mg, 4.5 mg, 6 mg)
oral solution (2 mg/ml)
transdermal (extended-release): extended-release: 9.5 mg/24 h
transdermal patch (4.6 mg/24 h, 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.

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.
Table 2
Drug-Drug Interactions for ACIs
tacrine fluvoxamine potential for increased tacrine monitor for enhanced moderate (DrugReax)
concentrations and enhanced cholinergic/ adverse effects, 2 (DIF)
pharmacologic/ adverse effects due to especially hepatotoxicity; may 3-moderate (Clinical Pharmacology)
fluvoxamine inhibition of CYP1A2, substitute other SSRIs not 2 (Hansten & Horn)
the enzyme responsible for tacrine metabolized by CYP1A2 (e.g.,
metabolism fluoxetine, sertraline)
tacrine theophyllines potential for increased theophylline observe for increased serum moderate (DrugReax)
concentrations and toxicity due to theophylline levels; reduce 4 (DIF)
tacrine inhibition of CYP1A2, an initial theophylline dose by 3-moderate (Clinical Pharmacology)
enzyme responsible for theophylline 25-50% to avoid toxicity 3 (Hansten & Horn)
tacrine, cimetidine increased tacrine bioavailability, monitor for increased tacrine
galantamine serum concentrations due to and galantamine cholinergic tacrine: 4 (DIF)
cimetidine inhibition of adverse effects; may 3-moderate (Clinical Pharmacology)
CYP1A2increased galantamine substitute an H2 receptor 3 (Hansten & Horn)
bioavailability and potential for antagonist less likely to
increased cholinergic effects due to interfere with tacrine and
cimetidine inhibition of CYP2D6 galantamine metabolism
ACIs NSAIDs potential for additive gastrointestinal monitor for gastrointestinal 3-moderate (Clinical Pharmacology)
effects intolerance and/or bleeding
donepezil, CYP3A4 and CYP2D6 potential for increased donepezil and monitor for increased moderate (DrugReax)
galantamine inhibitors galantamine serum concentrations cholinergic effects 3-moderate (Clinical Pharmacology)
4 (Hansten & Horn)
donepezil CYP3A4 and CYP2D6 potential for reduced donepezil monitor for reduced 3-moderate (Clinical Pharmacology)
inducers serum concentrations and decreased donepezil efficacy
ACIs cholinergic agents and enhanced cholinergic/ adverse effects avoid combination, if minor (DrugReax)
other cholinesterase possible; if combination 2-major (Clinical Pharmacology)
inhibitors necessary, monitor for
enhanced cholinergic effects;
may adjust doses to achieve
tolerable clinical effects
ACIs anticholinergics potential for reduced cholinergic monitor for diminished moderate (DrugReax)
activity with centrally acting cholinergic effects; choose 3- moderate (Clinical Pharmacology)
anticholinergics, which may manifest agents with less centrally 3 (Hansten & Horn)
as reduced activities of daily living acting anticholinergic activity
but not cognitive function;
peripherally acting anticholinergics
less likely to attenuate ACI
therapeutic effects
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4. Galantamine extended-release capsules, tablets and oral solution (Razadyne® ER, Razadyne®)
package insert. Ortho-McNeil Neurologics, April 2008.
5. Rivastigmine capsules and oral solution (Exelon®) package insert. Novartis Pharmaceuticals
Corporation, June 2006.
6. Rivastigmine transdermal system (Exelon® Patch) package insert. Novartis Pharmaceuticals
Corporation, July 2007.
7. Donepezil tablets, orally disintegrating tablets (Aricept®, Aricept® ODT) package insert. Eisai
Inc., November 2006.
8. Tacrine capsule (Cognex®) package insert. Sciele Pharm, Inc., August 2008.
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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.