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By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
Rivastigmine was recently approved by the FDA for the treatment of mild to moderate dementia of the Alzheimer’s type. It is a cholinesterase inhibitor similar to tacrine and donepezil. Rivastigmine is marketed as capsules and an oral solution by Novartis as Exelon.
Rivastigmine is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.
The recommended starting dose is 1.5 mg twice a day with food. If the drug is tolerated after a minimum of two weeks, the dose may be increased to 3 mg twice daily, then increased again, if tolerated, to a maximal dose of 6 mg twice daily. If side effects such as nausea, vomiting, abdominal pain, or loss of appetite occur, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose.1 The solution may be administered directly from the dosing syringe or mixed with a small glass of water, cold fruit juice, or soda.
Rivastigmine is supplied as capsules (1.5 mg, 3.0 mg, 4.5 mg, 6 mg) and an oral solution (2 mg/mL, 120 mL). An oral syringe is provided to measure the appropriate dose.
Cytochrome P450 isoenzymes are minimally involved in the metabolism of rivastigmine.1 Drug-drug interactions involving rivastigmine and drugs metabolism by the cytochrome P450 system are not expected. Tacrine and donepezil are metabolized by the P450 system.
Rivastigmine’s side effects are similar to other cholinesterase inhibitors and include nausea, vomiting, anorexia, and weight loss. In the controlled trials, 47% of patients taking 6-12 mg/d developed nausea compared to 12% for placebo. Other side effects compared to placebo: 31% had one episode of vomiting vs. 6%, 26% weight loss (³ 7% of baseline weight) vs. 6%, and 17% anorexia vs. 3%.1 These side effects generally occur during the titration period and tend to be less severe during the maintenance phase.
In the 26-week trials, 65-67% of patients completed the study at the high dose compared to 84% for placebo and 85% for the low dose (1-4 mg/d).
Fifteen percent of patients discontinued due to side effects.1
Rivastigmine requires twice daily dosing compared to once daily for donepezil.
Rivastigmine is the third cholinesterase inhibitor to be approved for the treatment of Alzheimer’s disease (AD). In contrast to tacrine and donepezil, which are reversible shorting-acting drugs, rivastigmine is a "pseudo irreversible intermediate-acting" drug and can inhibit the enzyme up to 10 hours even though it has an elimination half-life of about 1.5 hours.1,9 Donepezil has an elimination half-life of 70 hours permitting once-daily dosing compared to twice daily for rivastigmine.
The safety and efficacy were assessed in 26-week trials, one in the United States (n = 699) and the other in Europe and North America (n = 725).2-4 In these trials, patients with probably mild to moderately severe AD were randomized to receive 6-12 mg/d or 1-4 mg/d of rivastigmine or placebo. There was a 12-week forced titration phase and a 14-week maintenance phase. Efficacy was assessed using the cognitive subscale of the AD assessment scale (ADAS-Cog) and the Clinician Interview Based Impression of Change Scale (CIBIC-Plus), and progressive deterioration scale. The ADAS-Cog is a 70-point scale that assesses memory language, orientation, and praxis. The CIBIC-Plus is a 7-point scale incorporating caregiver information and measuring global assessment of behavior, general psychopathology, cognition, and activities of daily living. The progressive deterioration scale, which is not an indicator of efficacy recognized by the FDA, assesses activities of daily living including dressing, eating independently, social interaction, participation in housework and hobbies, awareness of time, and handling financial matters. Results showed a modest improvement in cognitive testing and clinical impression of change and participation in daily living. The change in ADAS-Cog was 2.6-4.9 U and 0.35-0.41 in CIBIC-Plus for the 6-12 mg dose compared to placebo. The mean score in the progressive deterioration scale improved from baseline in the high-dose group. The 1-4 mg/d dose was generally not effective. The magnitude of effect appears similar to that reported for donepezil.4,5 In terms of side effects, the 5 mg dose of donepezil may be better tolerated than the 6-12 mg dose of rivastigmine. The two products are priced identically, $4.35 per day, with each strength having the same price. A comparative trial between rivastigmine and donepezil is expected to be initiated by the end of the year.6
It is estimated that one in 10 persons older than the age of 65 and nearly half of those older than 85, or about 4 million persons in the United States, have AD.7 There are currently no treatments that stop or reverse the progression of the disease. Rivastigmine, as with donepezil, produces modest benefit in cognitive testing and clinical impression of change. Their effect on improved functional ability is less clear.8
1. Exelon Product Information.
2. Rosler M, et al. BMJ 1999;318:633-638.
3. Corey-Bloom J, et al. Int J Ger Psychopharmacol 1998; 1:55-65.
4. Aricept Product Information. Pfizer Pharmaceuticals. December 1996.
5. Greenberg SM, et al. Arch Neurol 2000;57:94-99.
6. FDC Report. The Pink Sheet 2000;62(17):3.
7. Statistics from the Alzheimer’s Association. March 2000.
8. Bentham P, et al. BMJ 1999;319:640-641.
9. Jann MW. Pharmacotherapy 2000;20(1):1-12.