Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase the plasma concentrations of nebivolol, which is primarily metabolized by the isoenzyme The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity. Several studies have shown that coadministration of CYP450 2D6 inhibitors increases the peak plasma concentration (Cmax) and systemic exposure (AUC) of nebivolol. When the potent CYP450 2D6 inhibitor paroxetine (20-40 mg daily) was coadministered with nebivolol (5 mg) in 23 healthy subjects, nebivolol's Cmax and AUC increased by 5.7-fold and 6.1-fold, respectively. Similarly, when bupropion (300 mg), a potent CYP450 2D6 inhibitor, was coadministered with nebivolol in 18 healthy volunteers, the Cmax and AUC increased by 2.3-fold and 7.2-fold, respectively. Fluoxetine (20 mg daily), a potent CYP450 2D6 inhibitor, increased nebivolol's Cmax and AUC by approximately 2.3-fold and 6-fold in 10 patients. Fluvoxamine, a mild CYP450 2D6 inhibitor, increased Cmax and AUC by 1.41-fold and 1.44-fold in 18 healthy volunteers. However, no data resulted in significant changes to heart rate or blood pressure.

MANAGEMENT: Caution is advised when nebivolol is used concomitantly with CYP450 2D6 inhibitors. Additional caution and monitoring are advised if the coadministered CYP450 2D6 inhibitor may potentiate the blood pressure lowering effects of nebivolol (e.g., phenothiazines, tricyclic antidepressants (TCAs), and some antipsychotic (neuroleptic) agents). Patients should be monitored closely for adverse effects such as bradycardia, diarrhea, nausea, fatigue, chest pain, peripheral edema, headache, dizziness, insomnia, dyspnea and rash, and the nebivolol dose should be adjusted according to blood pressure response.

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of orally administered ranolazine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

MANAGEMENT: Patients treated with ranolazine should avoid consumption of grapefruit juice and other grapefruit products if possible. Otherwise, the dosage of ranolazine should be limited to 500 mg twice a day.