Page 37 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

significantly higher discontinuation rates for tacrine than for placebo patients. 58, 67-69 The high withdrawal
rates were mainly attributable to elevated serum alanine aminotransferase (ALT; a feature of liver

toxicity).

Withdrawals because of adverse events in donepezil, galantamine, rivastigmine, and memantine trials

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varied. Evidence from one open-label head-to-head comparison of donepezil and rivastigmine suggests
a higher number of withdrawals due to adverse events among rivastigmine-treated compared to

donepezil-treated patients (21.8% vs. 10.7%, respectively; P = NR). Based on two open-label trials
comparing donepezil and galantamine, withdrawals due to adverse events were higher among
galantamine-treated patients than among donepezil-treated patients in one 12-week trial (21.4% vs. 9.4%,

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respectively; P = NR), but not in a 52-week trial (13.4% vs. 13.2%, respectively; P not significant).
From placebo-controlled evidence, no obvious trend favored one drug over another. Patients treated with
higher doses were more likely to discontinue because of an adverse event. A meta-analysis of
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discontinuation rates did not find a statistically significant difference between donepezil and placebo,
even though the incidence of anorexia, diarrhea, dizziness, fatigue, insomnia, muscle cramps, nausea,

vomiting, tremor, vertigo, and weight loss were statistically significantly more common in the donepezil
than in the placebo group.

We did not identify any study that assessed temporary or permanent adverse events due to discontinuation
of donepezil, galantamine, rivastigmine, tacrine or memantine.

A. Specific adverse events

Hepatotoxicity

A major safety concern of tacrine treatment is hepatotoxic effects. A retrospective review of tacrine-trials

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involving 2,446 AD patients reported that 49% of tacrine-treated patients had elevated ALT levels.
Among all patients, 25% presented an ALT elevation three times the upper normal limit; 2% had ALT
levels 20 times higher than normal. Patients with elevated ALT levels were generally asymptomatic,

although sometimes they experienced eosinophilia, rash, and fever. Few patients developed signs of
severe hepatocellular injury (e.g., jaundice); no death attributable to liver toxicity was reported.

Results of this retrospective analysis are consistent with individual trials included in this review. All four
placebo-controlled RCTs of tacrine reported high elevations of ALT. 58, 67-69 We excluded three of these

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