Page 40 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

B. Summary of the evidence

The overall grade of the evidence on comparative tolerability is poor to fair. Evidence of the comparative
incidence of adverse events and tolerability comes from three open-label trials comparing donepezil with
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galantamine and rivastigmine. One 52-week trial and one 12-week trial compared donepezil to
galantamine. Although the number of adverse events and loss to follow-up differed between trials,
withdrawals and withdrawals because of adverse events were not significantly different in the 52-week

trial and only minor differences favoring donepezil were observed in the 12-week trial. In one trial that
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compared donepezil to rivastigmine, total withdrawals and withdrawals because of adverse events were
significantly greater among rivastigmine-treated patients. Gastrointestinal-related events were most

commonly reported among rivastigmine-treated patients. Indirect comparison of the pooled mean
incidence of adverse events from placebo-controlled trials also suggests a higher rate of gastrointestinal-

related events among rivastigmine-treated patients. However, this comparison is limited by the
tremendous variability observed among placebo-controlled evidence.

Evidence of hepatotoxicity and cardiovascular events comes from comparative trials, meta-analyses, and
indirect comparison of placebo controlled evidence. Evidence from one meta-analysis and four placebo-

controlled trials indicate substantially higher rates of hepatotoxicity for tacrine. 67, 80 Donepezil,
galantamine, rivastigmine, and memantine did not present hepatotoxic effects in placebo controlled trials.
Two open-label comparative trials reported no difference in cardiovascular events between donepezil and
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galantamine and rivastigmine. Placebo-controlled trials revealed no other significant differences in
cardiovascular events.

Alzheimer's Drugs Page 40 of 205