Donepezil hydrochloride and/or any of its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine or digoxin in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin or cimetidine.
In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil hydrochloride. Drug interaction studies performed in vitro show that ketoconazole and guanidine, inhibitors of CYP3A4 and 2D6 respectively, inhibit donepezil hydrochloride metabolism. Therefore, these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil hydrochloride. In a study in healthy volunteers, ketoconazole increased mean donepezil hydrochloride concentrations by about 30%. Moreover, CYP-450 3A4 and 2D6 inducers such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil hydrochloride. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care.
Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity such as atropine. There is also the potential for synergistic activity with concomitant treatment involving medications such as succinylcholine, other neuro-muscular blocking agents, cholinergic agonists such as bethanechol, beta blocking agents which have effects on cardiac condition or aspirin/ NSAIDs such as ibuprofen, or naproxen may increase the risk of developing stomach ulcers.