Drug Interaction Report

GENERALLY AVOID: Ranolazine can cause dose-related prolongation of the QT interval. In addition, limited data suggest that pitolisant may produce mild to moderate QT interval prolongation (10 to 13 milliseconds) at doses 3 to 6 times the standard therapeutic dose. Theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. At Tmax following repeat dosing of 1000 mg twice a day, the mean effect of ranolazine on QTc is approximately 6 milliseconds. However, in 5% of the population with the highest plasma concentrations, the prolongation of QTc is 15 milliseconds or more. The relationship between ranolazine plasma level and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by a dosage of 1000 mg twice a day. However, the apparent linear relationship is much steeper in cirrhotic subjects with mild or moderate hepatic impairment. There have been no reported cases of torsade de pointes in clinical studies of ranolazine comprising 3,669 patient-years of treatment. In fact, ranolazine was found to be antiarrhythmic in Study CVT 3036 (MERLIN-TIMI 36). No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 acute coronary syndromes (ACS) patients treated with ranolazine. There was a significantly lower incidence of arrhythmias in patients treated with ranolazine (80%) versus placebo (87%), including ventricular tachycardia greater than or equal to 3 beats (52% versus 61%). The risk of an individual agent or a combination of these agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drugs.

MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase plasma concentrations of pitolisant. The proposed mechanism is decreased clearance of pitolisant due to inhibition of its metabolism via this isoenzyme. Coadministration with the CYP450 2D6 inhibitor paroxetine was reported to increase the mean peak plasma concentration (Cmax) of pitolisant by approximately 47% and result in a 2-fold increase in its systemic exposure. Clinical data are not available.

MANAGEMENT: Concomitant use of multiple agents associated with QT interval prolongation should generally be avoided. If these drugs are coadministered, the manufacturer advises that a dosage adjustment may be considered. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of ranolazine, the maximum recommended dosage of 1000 mg twice a day should not be exceeded. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, 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.