Page 38 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

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studies from the efficacy analysis on grounds of quality because of high overall 67, 68 or differential loss
to follow-up. In all three trials the high drop-out rate was attributable to a high rate of elevated liver

function tests in tacrine-treated patients. The differential loss to follow-up because of adverse events in
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the fourth study was 18 percentage points (placebo: 7%; tacrine: 25%). Hepatotoxicity has not been
reported for donepezil, galantamine, rivastigmine, or memantine.

Gastrointestinal adverse events and loss of body weight

ChEI trials commonly reported nausea and vomiting by more than 10% of patients (and as many as 50%

of patients) randomized to active treatment. In the only memantine trial the incidence of nausea and
vomiting did not differ between the active drug and placebo. Nausea, vomiting, and diarrhea are thought
to reflect excessive activation of intestinal muscarinic cholinergic receptors and tend to be dose related.

Anorexia and loss of body weight are associated gastrointestinal adverse events.

We did not find any trials directly comparing the incidence of gastrointestinal adverse events among
ChEIs and memantine.

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In a systematic review of donepezil, galantamine, and rivastigmine trials, nausea and vomiting were 3 to
5 times more common in patients randomized to active treatment compared to placebo (P < 0.0001). The

odds of having nausea or vomiting with rivastigmine compared to placebo (OR 5.28; 95% CI 4.19-6.65)
were consistently higher than with donepezil or galantamine compared to placebo (donepezil OR 2.73;
95% CI 1.86-4.00; galantamine OR 3.01; 95% CI 2.15-4.21), although this finding could likely be

attributed, at least in part, to the faster than recommended dose titration used in rivastigmine trials. 55, 57

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Diarrhea was also common in the pooled analysis, although the pooled odds ratio was significant for
donepezil and rivastigmine (donepezil OR 2.83; 95% CI 2.01-4.00; rivastigmine OR 1.77; 95% CI 1.38-
2.28) but not for galantamine (OR 1.37; 95% CI 0.91-2.05). The higher incidence of gastrointestinal
events may be related to the significant loss of body weight commonly reported for donepezil-,

galantamine-, and rivastigmine-treated patients. Pooled analysis suggests a 2- to 4-fold increase in the
risk of anorexia for active treatment compared to placebo. Although tacrine was not included in this

analysis, relative trends in gastrointestinal adverse events and loss of body weight reported in tacrine trials
are consistent with those seen in donepezil, galantamine, and rivastigmine trials. 58, 67-69

A retrospective data review of the mean incidence rates of gastrointestinal adverse events of some RCTs
shows that the following percentages of patients suffered nausea: donepezil, 11%; rivastigmine, 35%;

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