Drug Interaction Report

MONITOR CLOSELY: Coadministration with azole antifungal agents may increase the plasma concentrations and toxicities of tretinoin. The proposed mechanism is inhibition of CYP450 2C9 and/or 3A4, two of the isoenzymes responsible for the metabolic clearance of tretinoin. All azole antifungal agents can inhibit CYP450 3A4, with itraconazole and ketoconazole considered particularly potent inhibitors. Fluconazole and voriconazole also inhibit CYP450 2C9, which may increase the likelihood of a significant interaction with tretinoin compared to agents that inhibit just CYP450 3A4. There have been isolated reports of pseudotumor cerebri, hypercalcemia, and acute renal failure in patients receiving tretinoin with concomitant azole antifungal therapy, primarily fluconazole or voriconazole. The conditions resolved following interruption of tretinoin therapy and/or discontinuation of the azole antifungal agent. As tretinoin is thought to undergo autoinduction of its own metabolism, CYP450 inhibitors have been investigated for use to boost plasma tretinoin concentrations and to overcome treatment resistance that often occurs with continued tretinoin therapy. In a study of two patients with acute promyelocytic leukemia, tretinoin systemic exposure (AUC) was found to be reduced significantly from baseline after one week of treatment. Following two daily doses of fluconazole administered 1 hour before tretinoin, the AUC of tretinoin increased by about 2- to 4-fold compared to day eight of tretinoin treatment alone, but similar to AUCs reported at baseline. In 13 patients who had received tretinoin daily for 4 consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour before the tretinoin dose on day 29 led to a 72% increase in tretinoin mean plasma AUC. Likewise, in 6 patients with lung cancer, a single 400 mg dose of ketoconazole (but not a 200 mg dose) one hour before tretinoin on day 29 increased tretinoin AUC by 115% compared to day 28 when tretinoin was given alone. No effect was observed when ketoconazole was given on day 2 relative to tretinoin alone on day one. By contrast, one study showed that prolonged ketoconazole administration (400 mg initially, then 200 mg daily for 14 days) in patients receiving tretinoin (45 mg/m2 twice daily for 14 days) had no effect on tretinoin auto-induction, but was associated with more vomiting.

MANAGEMENT: Caution is advised when tretinoin is prescribed in combination with azole antifungal agents such as fluconazole, itraconazole, ketoconazole, and voriconazole. Patients should be closely monitored and advised to seek medical attention immediately if they develop early symptoms of pseudotumour cerebri such as headache, nausea, vomiting, visual disturbances, photosensitivity, and tinnitus.