Rivastigmine (Exelon):
Another Anticholinesterase for People With Dementia
by: Firoz Munshi, MD
Rashid Anjum, MD
Mohammad Safi, MD
Amanpreet Kaur, MD
Yasser Morgan, MD
Djenita, Butulija, MD
Fayez, Romman, MD
Steven Lippmann, MD

Department of Psychiatry and Behavioral Science
University of Louisville School of Medicine
Louisville, KY

Introduction:
In 1906, German psychiatrist Alois Alzheimer first described Alzheimer's disease (AD), the most common form of dementia among elderly people. AD impairs both cognition and behavior with pathogenesis linked to cholinergic neuronal loss and deposition of amyloid plaques in the brain. Approximately 4 million Americans are affected. This amounts to one in five people between the ages of 75 to 84 and nearly half of those 85 and older. The prevalence is expected to soar as the large population of "baby boomers" age enters their senior years. AD results in an expensive health care burden on society, costing up to $100 billion annually. (1)

Pharmacotherapy:
Cholinesterase inhibitors (ChEI) are the most widely studied medications for the treatment of AD. Tacrine, the first of the ChEIs to be marketed for this purpose, was associated with significant hepatotoxicity. Several other ChEIs, such as donepezil, galantamine, and rivastigmine are approved by the Food and Drug Administration (FDA). (1-2) These drugs are cholinomimetic. Donepezil is a reversible ChEI and highly selective for acetylcholinesterase (AChE) in the central nervous system. Its long half-life (70 hours) supports once-daily administration. (3) Galantamine acts as a competitive, reversible inhibitor of AChE, and its nicotinic agonist properties may provide an additional therapeutic mechanism for AChE inhibition. (4) Rivastigmine is marketed in 60 countries, including all members of the European Union and the USA since 2000.

Rivastigmine:
Rivastigmine is a pseudo-irreversible, selective AChE subtype inhibitor offered as a pharmacotherapy in mild to moderate Alzheimer's dementia. Novartis Pharmaceuticals provides this medication in both capsules and liquid form, under the trade name, Exelon. (4)

Indication:
The primary indication for rivastigmine is patients with cognitive impairment from Alzheimer's disease. It is also considered in AD cases with a vascular component to the dementia. (1,5-7) In addition, rivastigmine may be helpful for people with dementia associated pathologically with Lewy Bodies. (8)

Pharmacology:
Rivastigmine has regional selectivity for the hippocampus and cerebral cortex, and exerts its therapeutic effect by enhancing cholinergic function in the central synapses. It binds to AChE for up to 10 hours, providing a long duration of action, due to slow hydroxylation. (2,5-7) It is also reported to affect butylcholinesterase, which theoretically may have therapeutic advantages in people with AD.

Pharmacokinetics:
Rivastigmine is well absorbed and is widely distributed throughout the body tissues, including the brain. It is converted to a metabolite at the site of action, thus bypassing the liver. There is, however, some hepatic metabolism, followed by renal elimination. The drug has a half-life of about 1.5 hours. Since rivastigmine is gradually titrated to individual tolerability, little adjustment for hepatic or renal disease should be required clinically.

Efficacy:
Patients with rapid rates of disease progression manifest a better response to this pharmaceutical than do those with a slow rate of cognitive decline. (9) The benefits of rivastigmine are yet to be fully evaluated, but past ChEI therapies have been somewhat disappointing in efficacy.

Clinical Trials:
Two randomized, double blind, controlled studies using similar methodology have been completed. In both, patients fulfilled criteria for dementia of the Alzheimer's type as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer's Disease and Related Disorders Association criteria. (7,8) Participants had a baseline Mini-Mental State Examination score between 10 and 26, consistent with mild to moderately severe impairment.

One investigation involved 699 subjects at 22 sites in the USA. (8) Participants were randomized into one of three groups: treatment with 1-4 mg/day rivastigmine (low dose), 6-12 mg/day rivastigmine (high dose), and placebo. An initial fixed dose phase (up to 2 months) was followed by a flexible dose period (weeks 8-26). Results revealed more significant progress on the Alzheimer's Disease Assessment Scale in the high dose group than for those taking placebo. Using the Clinician's Interview Based Impression of Change Scale, a global function measure, high dose rivastigmine induced more significant improvement than did placebo (p<0.01). Differences in outcome between low dose rivastigmine and placebo did not reach statistical significance.

The other research involved 725 subjects and was conducted at 45 centers in Europe and North America in mild to moderately severe Alzheimer's disease cases. (7) Patients received either 1-4 mg/day rivastigmine (low dose), 6-12 mg/day rivastigmine (high dose), or placebo. Dosages were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over three months, with a subsequent assessment period of 14 weeks. At the end of the investigation, intellectual function deteriorated more among those in the placebo group. Scores of cognition improved more in patients on the higher dose therapy, as compared to controls (p<0.5). Global function as rated by the Clinician Interview Scale also revealed more significant improvement among those in the higher dose group, in comparison to individuals taking placebo (p<0.001). Mean scores on the Progressive Deterioration Scale improved the baseline function in the higher dose subjects, but did not do so in control cases.

Dosage and Administration:
The initial oral dosage is 1.5 mg BID. This can be increased to 3 mg twice a day, after two weeks. Further escalations are titrated gradually on an individualized basis. This medicine should be taken with food. The maximum recommended quantity is 6 mg, twice daily. (10-11) If therapy is discontinued for more than few days, it is recommended that rivastigmine be restarted at a lower quantity and then clinically titrated in an individualized manner. An average daily dose of about 9 mg is reportedly associated with the best efficacy. (9-11)

How Supplied:
Rivastigmine capsules are available in four different strengths. Capsule identification, by color, is noted in the table. The liquid solution contains rivastigmine equivalent to 2 mg/ml. (11)
Dose Color
1.5 mg Yellow
3 mg Orange
4.5 mg Red
6 mg Orange and Red

Side Effects:
Somatic discomforts are most often associated with dose initiation and titration. The following table lists the frequency and types of patient complaints. Less such problems are observed during maintenance therapy. Sleep quality is reportedly not affected, although rivastigmine does induce a 50% increase in rapid eye movement (REM) sleep density. (5-7) Erythematous maculopapular eruptions, caused by rivastigmine, are cited in the literature. (1,5,10) Adverse effects may lead to withdrawal from the drug in 20-30 % of patients prescribed the higher doses (i.e., 6-12 mg per day). (8)

Adverse Event 6-12 mg/day Placebo
Nausea 50 % 10 %
Vomiting 34 % 6 %
Weight Loss 24 % 7 %
Dizziness 20 % 7 %
Headache 19 % 8 %
Diarrhea 17 % 9 %
Anorexia 14 % 2 %
Abdominal Pain 12 % 3 %
Malaise 10 % 3 %
Fatigue 10 % 3 %

Drug Interactions:
Since pharmaceuticals with anticholinergic properties (e.g., diphenhydramine) have the potential to interfere with the action of rivastigmine, co-utilization should be avoided. A synergistic effect is possible when used concurrently with neuromuscular blocking agents (e.g., succinylcholine) or cholinergic agonists (e.g., bethanecol). Otherwise, rivastigmine has not been associated with other known, significant drug interactions, possibly due to its minimal hepatic microsomal cytochrome P-450 involvement and low protein binding. (7,11)

Comment:
Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease impairment of cognition. Whether this cholinesterase inhibitor will demonstrate greater efficacy, with safety, than previous pharmacotherapies might be learned after longer experience with its use. It is administered in a divided regimen, with maximum doses between 6-12mg daily. In comparison with placebo, improvements in the severity of dementia were seen clinically in better intellectual function and more competence in the activities of daily living. Adverse events were consistent with the cholinergic actions of the drug. Further research is desirable and clinical application over time will provide better understanding of its side effects and true risk to benefit ratio. (12)

REFERENCES:
(1) Lon S: Alzheimer's Disease and Dementia: Treatment of Alzheimer's disease with cholinesterase inhibitors. Clinics in Geriatric Medicine 2001;17(2):337-358
(2) Birks J, Evans JG, Iakovidou V, et al: Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev 2000;4:CD001191
(3) Feldman H, Gauthier S, Hecker J, et al: A 24 week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Am Acad Neuro 2001;57(4):613-620
(4) Raskind M, Peskind E, Wessel T, et al: Galantamine in Alzheimer's disease: A 6 month, randomized, placebo-controlled trial with a 6 month extension. Neurology 2000;54:2261-2268
(5) Schneider L: Treatment of Alzheimer's disease with cholinesterase inhibitors. Clin Geriatr Med 2001;17(2):337-358
(6) Kumar V, Anand R, Messina J, et al: An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. Eur J Neurol 2000;7(2):159-169
(7) Rosler M, Anand R, Cicin-Sain A, et al: Efficacy and safety of rivastigmine in patients with Alzheimer's disease: International randomized controlled trial.Bt Med J 1999;318(7184):633-638
(8) Patterson C, Hogan D: Brief Review: Rivastigmine, A second cholinesterase inhibitor. Can J Neurol Sci 2001;28(1):S122-S123
(9) Farlow M, Hake A, Anand R, et al: Response of patients with Alzheimer disease to Rivastigmine Treatment is Predicted by the Rate of Disease Progression: Arch Neurol 2001;58(3):417-422
(10) Grutzendler J, Morris J: Cholinesterase Inhibitors for Alzheimer's Disease. Drugs 2001;61(1):41-52
(11) Mosby's Drug Consult; Mosby, Inc.
(12) Schneider L, Farlow M: Severity of Alzheimer's disease and response to cholinergic therapy. Eur J Neurol 1996; 3(5):238-243

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