Drug Interaction Report

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 prolong the QT interval. In clinical studies in adult patients, the rate of bradycardia was 6.0% versus 1.3% per patient-year for ivabradine compared to placebo. Asymptomatic and symptomatic bradycardia were observed in 6.8% and 4.1% of the pediatric patients treated with ivabradine compared to 2.4% and 0% in the placebo treatment group, respectively. 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: Coadministration of ivabradine with drugs that can prolong the QT interval should generally be avoided. Caution and cardiac monitoring are recommended if concomitant use is required. 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.

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: The oral bioavailability of quinolone and tetracycline antibiotics may be reduced by concurrent administration of preparations containing polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc. Therapeutic failure may result. The proposed mechanism is chelation of quinolone and tetracycline antibiotics by di- and trivalent cations, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. Reduced gastrointestinal absorption of the cations should also be considered.

MANAGEMENT: Concomitant administration of oral quinolone and tetracycline antibiotics with preparations containing aluminum, calcium, iron, magnesium, and/or zinc salts should generally be avoided. Otherwise, the times of administration should be staggered by as much as possible to minimize the potential for interaction. Quinolones should typically be dosed either 2 to 4 hours before or 4 to 6 hours after polyvalent cation preparations, depending on the quinolone and formulation. Likewise, tetracyclines and polyvalent cation preparations should typically be administered 2 to 4 hours apart. The prescribing information for the antibiotic should be consulted for more specific dosing recommendations.