Drug Interactions between dronedarone and ivabradine

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ivabradine, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of ivabradine with moderate CYP450 3A4 inhibitors (e.g., diltiazem, verapamil, grapefruit juice) has been shown to increase ivabradine systemic exposure (AUC) by approximately 2- to 3-fold. Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

GENERALLY AVOID: Due to its bradycardic effects, the risk of QT prolongation and torsade de pointes arrhythmia may be increased when ivabradine is used with drugs that can prolong the QT interval. In clinical studies, the rate of bradycardia was 6.0% versus 1.3% per patient-year for ivabradine compared to placebo. At recommended dosages of ivabradine, heart rate reduction is approximately 10 beats per minute at rest and during exercise. 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: Concomitant use of ivabradine with moderate CYP450 3A4 inhibitors that can also prolong the QT interval such as crizotinib, dronedarone, fluconazole, lefamulin (when administered orally), and mifepristone should generally be avoided. If coadministration is required, a dosage reduction of ivabradine should be considered. Some authorities recommend initiating ivabradine at a dosage of 2.5 mg twice daily when used with moderate CYP450 3A4 inhibitors, provided the resting heart rate is at or above 70 beats per minute and frequent cardiac monitoring is performed. 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.