Drug Interaction Report

CONTRAINDICATED: Coadministration with darunavir, a moderate CYP450 3A4 inhibitor, may significantly increase the plasma concentrations of ivabradine, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of ivabradine with the moderate CYP450 3A4 inhibitor diltiazem (120 mg twice daily) resulted in approximately 3-fold increases in ivabradine peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration of ivabradine alone. Likewise, administration with verapamil (120 mg twice daily) increased the Cmax and AUC of ivabradine by approximately 2-fold. Grapefruit juice, another moderate CYP450 3A4 inhibitor, increased ivabradine AUC by a little over 2-fold. Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

MANAGEMENT: Concomitant use of ivabradine with darunavir, including boosted darunavir, is considered contraindicated.

CONTRAINDICATED: Coadministration with potent 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 the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) resulted in approximately 3.5- and 7-fold increases in ivabradine peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of ivabradine alone. Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

MANAGEMENT: Concomitant use of ivabradine with potent CYP450 3A4 inhibitors is considered contraindicated. Some authorities consider concomitant administration of ivabradine and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole.

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.

ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir. The mechanism is unknown. When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state. Darunavir exposure was similar for the range of meals studied. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food. The type of food is not important.