Drug Interactions between fluconazole and nateglinide

MONITOR: Coadministration with certain azole antifungal agents such as fluconazole, miconazole, and voriconazole may increase the plasma concentrations of nateglinide. The interaction stems from simultaneous inhibition of CYP450 2C9 and 3A4, the isoenzymes responsible for the metabolic clearance of nateglinide. In 10 healthy volunteers, administration of a single 30 mg dose of nateglinide following pretreatment with fluconazole (400 mg orally on day 1, then 200 mg/day for 3 days) increased nateglinide systemic exposure (AUC) by an average of 48% and prolonged its half-life from 1.6 to 1.9 hours compared to administration after placebo. Similarly, in nine healthy volunteers, pretreatment with the CYP450 2C9 inhibitor gemfibrozil (600 mg) plus the potent CYP450 3A4 inhibitor itraconazole (200 mg first dose, then 100 mg) twice daily for 3 days increased the mean Cmax and AUC of a single 30 mg dose of nateglinide by an average of 30% and 47%, respectively, compared to administration after placebo. No significant differences in blood glucose levels or adverse events were observed in these studies between nateglinide alone and in combination with the CYP inhibitors. However, clinical significance of the interaction in diabetics cannot be precluded due to potentially reduced counter-regulatory response to hypoglycemia in these patients.

MANAGEMENT: Caution is advised if nateglinide is used in combination with azole antifungal agents that inhibit both CYP450 2C9 and 3A4. Blood glucose should be closely monitored, and the nateglinide dosage adjusted as necessary. Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitations.