Drug Interaction Report

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.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of ivabradine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. According to the product labeling, administration with grapefruit juice (quantity unknown) resulted in an approximately twofold increase in ivabradine systemic exposure (AUC). Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

ADJUST DOSING INTERVAL: Food delays the absorption of ivabradine by approximately 1 hour and increases plasma exposure by 20% to 40% compared to fasting conditions.

MANAGEMENT: Patients treated with ivabradine should avoid or limit consumption of grapefruit or grapefruit juice. The manufacturer recommends taking ivabradine with meals to reduce variability in exposure.

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.