Drug Interaction Report

MONITOR: Coadministration with azole agents may increase the plasma concentrations of calcium channel blockers (CCBs), especially the dihydropyridines (e.g., amlodipine, felodipine, nicardipine, nifedipine, nisoldipine). The mechanism involves inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of most CCBs. In a pharmacokinetic study, nisoldipine mean peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 11- and 24-fold, respectively, during concomitant treatment with ketoconazole. Significant increases of severalfold in felodipine and nifedipine plasma concentrations have also been observed during coadministration with itraconazole. Theoretically, the interaction may potentiate the risk of ventricular dysfunction, congestive heart failure, and peripheral and pulmonary edema, particularly in patients with preexisting risk factors (e.g., a history of congestive heart failure; cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disorder; edematous disorders such as renal failure). There have been case reports of leg and ankle edema in patients treated with various itraconazole-dihydropyridine combinations.

MANAGEMENT: Close monitoring of clinical response and tolerance is recommended if calcium channel blockers are used in combination with azole agents. Dosage reduction may be required for the calcium channel blocker, particularly if it is a dihydropyridine. 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.