Drug Interactions between ivacaftor / lumacaftor and ranolazine

CONTRAINDICATED: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ranolazine, which is primarily metabolized by the isoenzyme. In pharmacokinetic studies, the potent inducer rifampin (600 mg once a day) has been shown to reduce the plasma concentrations of ranolazine (1000 mg twice a day) by approximately 95%. No data are available for other CYP450 3A4 inducers.

MANAGEMENT: The manufacturer considers the use of ranolazine to be contraindicated in patients taking potent CYP450 3A4 inducers such as carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, primidone (partially metabolized to phenobarbital), rifamycins, and St. John's wort. The extent to which other, less potent CYP450 3A4 inducers may interact with ranolazine is unknown. Caution is advised if they are used with ranolazine.

MONITOR: Coadministration with inhibitors of the P-glycoprotein (P-gp) efflux transporter may increase the oral bioavailability of ranolazine, which has been shown in vitro to be a substrate of P-gp. Ranolazine can prolong the QT interval in a dose-dependent manner, thus increased plasma levels may potentiate the risk of ventricular arrhythmias including ventricular fibrillation and torsade de pointes. However, the interaction has not been evaluated in pharmacokinetic studies. Plasma levels of ranolazine (750 mg twice a day) were increased about 2-fold by the CYP450 3A4 and P-gp inhibitor, verapamil (120 mg three times a day), although the extent to which P-gp inhibition actually contributes to the overall interaction is unknown.

MANAGEMENT: Caution is advised if ranolazine is prescribed in combination with P-gp inhibitors. Pharmacologic response to ranolazine should be monitored more closely whenever a P-gp inhibitor is added to or withdrawn from therapy, and the ranolazine dosage adjusted as necessary. 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.