Drug Interactions between atazanavir / cobicistat and mibefradil

MONITOR: Coadministration with atazanavir may increase the plasma concentrations and pharmacologic effects of calcium channel blockers, especially the dihydropyridines (e.g., amlodipine, felodipine, nicardipine, nifedipine, nisoldipine). The mechanism involves atazanavir inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of most calcium channel blockers. In a pharmacokinetic study, coadministration of atazanavir (400 mg once a day) and diltiazem (180 mg once a day) resulted in a 2-fold increase in diltiazem plasma concentration, and an additive prolonging effect on the PR interval was observed.

MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if calcium channel blockers are used in combination with atazanavir. Dosage reduction may be required for the calcium channel blocker, particularly if it is a dihydropyridine. ECG monitoring may be appropriate due to potential additive effects on the PR interval. Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

MONITOR: Coadministration with cobicistat may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 or 2D6 isoenzymes and/or P-glycoprotein (P-gp) efflux transporter.

MANAGEMENT: Caution is advised if cobicistat is used concomitantly with medications that undergo metabolism primarily by CYP450 3A4 and/or 2D6 or are substrates of P-glycoprotein, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever cobicistat is added to or withdrawn from therapy.