Which drug can be recommended as a substitute for Exelon (rivastigmine) 4.5mg x2 daily?

Fråga: Which drug can be recommended as a substitute for Exelon (rivastigmine) 4.5mg x2 daily?

Sammanfattning: Although there are no comparative clinical studies between tacrine and donepezil, at maximal doses, the two drugs seem to have similar benefit over placebo. However, donepezil is not subject to as large variations in oral availability as tacrine. During treatment with tacrine, more than 50 per cent of the patients may drop out of the treatment due to adverse reactions as compared to about 20 per cent for those who receive donepezil but this comparison is done on separate trials and using fixed doses. Donepezil is given once-daily compared to the four-times daily for tacrine the absorption of which is influenced by concomitant food intake. Donepezil is somewhat more expensive in the retail price, but there are no studies comparing the overall cost during long-term therapy. Thus, donepezil given at a single dose of 5-10 mg daily at bedtime seems to be the best substitute.

Svar: In Sweden there are three cholinesterase inhibitors approved for the treatment of Alzheimer´s disease, of which rivastigmine is one of them. The other two drugs are tacrine (Cognex) and donepezil (Aricept) (FASS 99).

Tacrine (tetrahydroaminoacridine) is a reversible inhibitor of both acetyl- and pseudocholinesterase. Its absolute bioavailability is about 20 per cent, but can vary between 2-65 per cent. Concomitant intake with food reduces its absorption by 30-40 per cent. The drug is largely eliminated by metabolism through CYP 1A2 and only one per cent is excreted in the urine as tacrine. The main metabolite, 1-hydroxytacrine has pharmacological activity. The plasma half-life is about three hours, necessitating four-times daily dosing (2). In a 30-week randomised placebo controlled study of 663 patients, those assigned to receive 160 mg of tacrine per day had around 6 per cent decrease in both the score on the cognitive subscale of the Alzheimer´s Disease Assessment Scale and the score on the Clinician´s Interview-based Impression of Change Scale. Fifty five percent of the tacrine-treated patients dropped out of the study because of adverse reactions. The most common adverse drug reaction (ADR) was elevated serum aminotransferase (29 per cent) (3).

Donepezil is a reversible inhibitor of acetylcholinesterase. Donepezil has 100 per cent bioavailability. Concomitant food intake does not influence its rate or extent of absorption. Its elimination half-life is about 70 hours allowing once-daily dosing. Donepezil is both excreted in the urine intact and extensively metabolised to four major metabolites, of which one 6-O-desmethyldonepezil has similar activity as the parent drug. Donepezil is metabolised via CYP450 probably by CYP2D6 and CYP3A4 (2). Two 24-week clinical trials of donepezil including a total of 1291 patients with Alzheimer´s disease who received either 5 mg or 10 mg of donepezil per day resulted in up to a 4 per cent decrease in the score on the cognitive subscale of the Alzheimer´s Disease Assessment Scale and a 6 per cent decrease in the score on the Clinician´s Interview-based Impression of Change Scale. Approximately 80 per cent of the patients completed the studies. The most common side effects were nausea, diarrhoea, vomiting and insomnia (3).

There are no comparative clinical studies between rivastigmine, tacrine and donepezil. Neither are there any studies on switching from rivastigmine to either tacrine or donepezill. 1 FASS 1999 (The Swedish catalogue of approved medical products) 2 Reynolds JEF, editor. Martindale, The extra pharmacopoeia. 31st ed. London: Royal Pharmaceutical Society; 1996 3 Mayeux R and Sano M. Treatment of Alzheimer´s Disease. New Engl J Med 1999; 341: 1670-1678