Drug Interaction Report

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of ranolazine, which is primarily metabolized by the isoenzyme. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In pharmacokinetic studies, plasma levels of ranolazine (1000 mg twice a day) were increased 3.2-fold by the potent CYP450 3A4 inhibitor, ketoconazole (200 mg twice a day), and 1.8- to 2.3-fold by the moderately potent inhibitor diltiazem (180 to 360 mg/day). Plasma levels of ranolazine (750 mg twice a day) were increased about 2-fold by the CYP450 3A4 and P-glycoprotein inhibitor, verapamil (120 mg three times a day).

MANAGEMENT: The dosage of ranolazine should not exceed 500 mg twice a day when coadministered with moderate inhibitors of CYP450 3A4, including but not limited to diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of orally administered ranolazine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

MANAGEMENT: Patients treated with ranolazine should avoid consumption of grapefruit juice and other grapefruit products if possible. Otherwise, the dosage of ranolazine should be limited to 500 mg twice a day.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.