Drug Interaction Report

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of galantamine, which is primarily metabolized by the isoenzyme. In multiple-dose pharmacokinetic studies, a potent inhibitor such as paroxetine has been shown to increase the area under the plasma concentration-time curve (AUC) of galantamine by 40%. Data from a population pharmacokinetic analysis of 852 patients demonstrated that amitriptyline, fluoxetine, fluvoxamine, and quinidine decreased the clearance of galantamine by about 25% to 33%.

MANAGEMENT: During concomitant therapy with drugs that inhibit CYP450 2D6 activity, the possibility of prolonged and/or increased pharmacologic effects of galantamine should be considered. Patients should be advised to notify their physician if they experience nausea, vomiting, sweating, weakness, salivation, or slower respirations.

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Coadministration with grapefruit juice does not appear to affect the pharmacokinetics of quinine in a clinically relevant manner. Although grapefruit juice is an inhibitor of CYP450 3A4 and quinine is metabolized by this pathway to its major metabolite, 3-hydroxyquinine, a study of ten healthy volunteers found no significant differences in quinine peak plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination half-life, systemic exposure (AUC), or apparent oral clearance (Cl/F) when a single 600 mg oral dose of quinine sulfate was administered in combination with 200 mL of orange juice (control), half-strength grapefruit juice, and full-strength grapefruit juice twice daily for 6 days each, separated by a 2-week washout period. Relative to the control period, the apparent renal clearance of quinine was markedly increased by 81% during treatment with half-strength grapefruit juice. However, since renal clearance accounts for approximately 6% of the total clearance of quinine, this change would likely have minimal clinical impact. The lack of a significant interaction is probably due to the fact that grapefruit juice primarily inhibits intestinal rather than hepatic CYP450 3A4, and quinine is not known to undergo significant presystemic metabolism as evidenced by its relatively high oral bioavailability (76% to 88%). Nevertheless, excessive consumption of grapefruit juice and tonic water (which contains quinine) was suspected as the cause of torsade de pointes arrhythmia in a patient with a history of asymptomatic long QT syndrome. Treatment with magnesium sulfate and metoprolol had no effect, but the arrhythmia resolved spontaneously 48 hours after discontinuation of the drinks. Based on current data, moderate grapefruit juice consumption is probably safe for the majority of patients taking quinine.

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