Drug Interactions between ivabradine and ivacaftor / lumacaftor

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of ivabradine and its active N-desmethylated metabolite, both of which are primarily metabolized by the isoenzyme. In 12 healthy volunteers, administration of a single 10 mg dose of ivabradine following pretreatment with the potent CYP450 3A4 inducer St. John's wort (300 mg three times daily for 14 days) decreased mean ivabradine peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 53% and 62%, respectively, compared to administration of ivabradine alone. Mean Cmax and AUC of the N-desmethylated metabolite, which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine, decreased by 25% and 32%, respectively. No significant changes in pharmacodynamic effects of ivabradine were observed in the study. However, reduced therapeutic efficacy may occur based on the magnitude of pharmacokinetic changes. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Concomitant use of ivabradine with potent CYP450 3A4 inducers should generally be avoided. If coadministration is required, the possibility of diminished therapeutic response to ivabradine should be considered. Pharmacologic response to ivabradine should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for the concomitant potent CYP450 3A4 inducers should be consulted for specific recommendations.

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of ivabradine, which is primarily metabolized by the isoenzyme. According to the product labeling, potent CYP450 3A4 inhibitors such as ketoconazole and josamycin have been shown to increase ivabradine systemic exposure (AUC) by approximately 7- to 8-fold, and moderate CYP450 3A4 inhibitors such as diltiazem, verapamil and grapefruit juice have been shown to increase ivabradine systemic AUC by approximately 2- to 3-fold. Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

MANAGEMENT: Caution is advised when ivabradine is prescribed with CYP450 3A4 inhibitors. Patients should be monitored for adverse effects such as bradycardia and atrial fibrillation, and the dosage of ivabradine adjusted as necessary in accordance with the product labeling.