Drug Interactions between Evotaz and nebivolol

MONITOR CLOSELY: Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers, digoxin, lacosamide, mefloquine, verapamil) may result in elevated risk of conduction disturbances and atrioventricular block. In a pharmacokinetic study, no substantial additive effect on the PR interval was observed during coadministration of atazanavir (400 mg once a day) and atenolol (50 mg once a day). However, an additive effect cannot be excluded because data are limited and atazanavir has not been studied in combination with other agents that prolong the PR interval.

MANAGEMENT: Caution is advised if atazanavir is used concomitantly with other agents that prolong the PR interval, particularly those that are metabolized by CYP450 3A4 (e.g., verapamil), since atazanavir is an inhibitor of that isoenzyme.

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.