Drug Interaction Report

MONITOR: Coadministration with fluconazole may significantly increase the plasma concentrations of fluvastatin. The mechanism is fluconazole inhibition of CYP450 2C9, the isoenzyme primarily responsible for the metabolic clearance of fluvastatin. In 12 healthy volunteers, fluconazole (400 mg orally on day 1 and 200 mg on days 2 to 4) increased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and elimination half-life (t1/2) of fluvastatin (40 mg single oral dose) by 44%, 84% and 80%, respectively, compared to placebo.

MANAGEMENT: Because of the increased risk of musculoskeletal toxicity (e.g., severe myopathy, rhabdomyolysis) associated with high levels of HMG-CoA reductase inhibitory activity in plasma, fluconazole should preferably not be given with fluvastatin. It may be advisable to temporarily discontinue fluvastatin during and for a few days after fluconazole therapy, or consider using another azole antifungal agent such as ketoconazole or itraconazole that is less likely to interfere with CYP450 2C9 metabolism. Alternatively, pravastatin has been shown to lack significant interaction with fluconazole and may be a reasonable substitute for fluvastatin. If fluconazole is used with fluvastatin, patients should be closely monitored for early signs and symptoms of myopathy. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.