Page 35 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

KEY QUESTION 3

What are the comparative incidence and severity of complications of donepezil,
galantamine, rivastigmine, tacrine, and memantine?

In general, adverse events depend on dose and mechanism of action for individual AD drugs. In most
trials assessing a range of doses specific adverse events were reported more frequently among patients
randomized to higher doses of study drugs. 43, 44, 50, 52-55, 57, 58 In some trials the speed of dose titration also

was believed to be related to greater reporting of adverse events. 55, 57

Based on three open-label head-to-head trials, 27-29 evidence suggests some differences between compared

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drugs. In one 12-week trial comparing donepezil with rivastigmine, gastrointestinal-related adverse
events were significantly more common among rivastigmine-treated patients; nausea and vomiting were
reported by 41.8% and 23.6% of rivastigmine-treated patients compared to 10.7% and 7.1% of donepezil-

treated patients, respectively (P = NR). Two trials compared donepezil to galantamine; the evidence is
mixed. The incidence of gastrointestinal-related adverse events was not different in a 52-week trial
27
comparing donepezil and galantamine. In one 12-week trial gastrointestinal-related events were
reported by 46.4% of patients in the galantamine group compared to 25% of patients in the donepezil
28
group.

Indirect comparisons based on evidence from placebo-controlled trials are difficult to make given
differences in trial design, study populations, and assessment and reporting of specific events. Overall,

adverse events were reported by 40% to 96% of randomized patients. In general ChEI- and memantine-
treated patients appear to report a similar number of adverse events, although evidence is insufficient to
compare the incidence of specific adverse events across drugs. Overall discontinuation rates are similar

among memantine and ChEIs except for tacrine.

Table 5 presents the mean incidence of specific adverse events based on data provided by placebo-
controlled trials of ChEIs and memantine. Statistics are descriptive only. Comparisons across different
drugs are limited and should be made with caution. Large confidence intervals for some estimates indicate

lack of precision due to a small number of component studies for some medications.

Alzheimer's Drugs Page 35 of 205