Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2C9 may increase the plasma concentrations of fluvastatin. According to the prescribing information, fluvastatin is primarily metabolized by CYP450 2C9 (approximately 75%) and, to a much lesser extent, by CYP450 2C8 and 3A4 (approximately 5% and 20%, respectively). When a single 40 mg oral dose of fluvastatin was administered on day 4 of treatment with the moderate CYP450 2C9 inhibitor fluconazole (400 mg orally on day 1 and 200 mg on days 2 to 4) in 12 healthy study subjects, mean fluvastatin peak plasma concentration (Cmax), systemic exposure (AUC) and elimination half-life (t1/2) increased by 44%, 84% and 80%, respectively, compared to administration with placebo. Fluconazole is also a moderate CYP450 3A4 inhibitor, which may have contributed to the interaction. In a similar study conducted by the same investigators, fluconazole had no significant effect on the pharmacokinetics of a single 40 mg oral dose of pravastatin.

MANAGEMENT: Caution is advised when fluvastatin is prescribed with CYP450 2C9 inhibitors. The lowest starting dosage of fluvastatin is recommended, then titrated as needed based on clinical response and tolerance. Alternatively, pravastatin is not metabolized by CYP450 2C9 and may be a reasonable substitute for fluvastatin. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.