Drug Interaction Report

MONITOR: Coadministration of ivabradine with other drugs that can slow the heart rate such as beta-blockers, calcium channel blockers, and digitalis may increase the risk of excessive bradycardia or other conduction disturbances. Non-cardiac drugs that may also cause bradycardia include atazanavir, fingolimod, lacosamide, lithium, mefloquine, succinylcholine, thalidomide, H2-receptor antagonists, tricyclic antidepressants, and anticholinesterase or cholinergic agents.

MANAGEMENT: Caution is advised when ivabradine is prescribed with other bradycardic drugs. Heart rate should be closely monitored, and the dosage of ivabradine adjusted accordingly. Patients should be advised to report significant decreases in heart rate or symptoms such as dizziness, lightheadedness, fatigue, and hypotension.

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.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.