Drug Interactions between atazanavir / cobicistat and levamlodipine

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 CYP450 3A4 inhibitors may increase the plasma concentrations of amlodipine, which is a substrate of the isoenzyme. In 8 elderly hypertensive patients, administration of a single 5 mg dose of amlodipine in combination with the moderate CYP450 3A4 inhibitor diltiazem (180 mg orally daily for 3 days) resulted in a nearly 60% increase in amlodipine peak plasma concentration (Cmax) and systemic exposure (AUC). Associated systolic, diastolic, and standing blood pressures decreased compared to those obtained with amlodipine alone. Erythromycin, another moderate inhibitor, did not significantly alter amlodipine systemic exposure in healthy volunteers. However, pharmacokinetic changes may be more pronounced in elderly patients.

MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if amlodipine is prescribed with potent or moderate CYP450 3A4 inhibitors. Dosage reduction may be required for amlodipine. 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.