Drug Interactions between ranolazine and vardenafil

MONITOR: Ranolazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death, although there is little experience in this setting. At Tmax following repeat dosing of 1000 mg twice daily, the mean effect of ranolazine on QTc is approximately 6 msec. However, in 5% of the population with the highest plasma concentrations, the prolongation of QTc is 15 msec 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, and this relationship is not significantly affected by age, weight, gender, race, heart rate, congestive heart failure, diabetes, or renal impairment. However, the apparent linear relationship is much steeper in cirrhotic subjects with mild or moderate hepatic impairment. Ranolazine did not induce torsade de pointes or other arrhythmias in several in vitro and animal models. There have also 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), which was a Phase 3, randomized, double-blind, parallel-group, placebo-controlled clinical trial designed to evaluate the efficacy and safety of ranolazine as chronic therapy in patients with non-ST elevation acute coronary syndromes (ACS) treated with other standard therapy. No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 ACS patients treated with ranolazine. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with ranolazine (80%) versus placebo (87%), including ventricular tachycardia >= 3 beats (52% versus 61%). In general, the risk of an individual agent or a combination of 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). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if ranolazine is used in combination with other drugs that can prolong the QT interval. Since the magnitude of QTc prolongation increases with increasing plasma concentrations of ranolazine, the maximum recommended dosage of 1000 mg twice daily 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. Ranolazine is contraindicated in patients with liver cirrhosis because of the profound effect on QT prolongation in this population.

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