simvastatin and fluconazole

Fluconazole inhibits the hepatic cytochrome P450 enzyme CYP3A4, which is the primary enzyme responsible for the metabolism of simvastatin. Inhibition of CYP3A4 reduces simvastatin clearance, leading to increased plasma concentrations of simvastatin and its active metabolites.

Elevated simvastatin concentrations increase the risk of dose-related myopathy and rhabdomyolysis. Patients may present with muscle pain, weakness, tenderness, and dark urine, which can progress to acute kidney injury, particularly in high-dose simvastatin therapy.

Avoid concurrent use of simvastatin and fluconazole. If necessary, consider alternative antifungal agents that do not inhibit CYP3A4, or use a statin that is not metabolised by CYP3A4, such as pravastatin or rosuvastatin. If co-administration is unavoidable, reduce the simvastatin dose and monitor creatine kinase levels and symptoms of myopathy.

The interaction is well established through pharmacokinetic studies and clinical case reports. Fluconazole is a moderate CYP3A4 inhibitor; the increase in simvastatin exposure may be clinically significant, especially at higher fluconazole doses.