Page 46 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

The potential for other drug-drug interactions with donepezil, galantamine, rivastigmine, tacrine, and
memantine should be evaluated on an individual basis. Pharmacokinetic parameters and information

submitted to the FDA for approval provide useful information.

Donepezil

Donepezil is metabolized by CYP450 isoenzymes 2D6 and 3A4. Because other drugs may compete for
or inhibit these metabolic enzymes, a potential for interaction exists with drugs metabolized by the same
isoenzymes. Although to our knowledge no in vivo studies have been conducted, in vitro evidence

suggests that donepezil has little effect on the metabolism of other drugs (e.g., theophylline, cimetidine,
warfarin, digoxin, etc.). Drugs that inhibit 2D6 and 3A4 (e.g., ketoconazole, miconazole, quinidine,
ritonavir, selective serotonin reuptake inhibitors [SSRIs], etc.) have been shown to inhibit donepezil

metabolism but clinically significant interactions are rare. Patients taking donepezil in combination with
other drugs metabolized by CYP450 isoenzymes 2D6 and 3A4 should be monitored closely.

Although donepezil is highly protein bound (96%) drug displacement studies performed in vitro have
shown little effect of other highly bound drugs on the binding of donepezil to human albumin. Similarly,

donepezil did not affect binding of other drugs to human albumin.

Galantamine

Like donepezil, galantamine is metabolized by CYP450 isoenzymes 2D6 and 3A4. In vivo studies have
shown increased bioavailability of galantamine when it is administered together with inhibitors of these
isoenzymes (e.g., cimetidine, ranitidine, ketoconazole, erythromycin, paroxetine). By contrast,

galantamine is believed to have little effect on other drugs metabolized by the CYP system.

Rivastigmine

Because rivastigmine is metabolized primarily through hydrolysis by esterases, minimal interaction with
drugs metabolized by CYP450 enzymes is anticipated. No other drug-drug interactions have been
demonstrated.

In a subgroup analysis of nicotine users randomized to rivastigmine, a statistically significant relationship
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in the dose-response relationship was reported; this analysis suggests that nicotine attenuates the
benefits of rivastigmine. Another post-hoc analysis of 2,459 patients from 4 placebo-controlled
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rivastigmine trials evaluated drug interactions with 22 classes of medications. This analysis did not
reveal any significant pattern of increase in adverse events that would indicate a drug-drug interaction.

Alzheimer's Drugs Page 46 of 205