Critical
Ketoconazole × Simvastatin
Systemic antimycotics. Imidazole derivatives×HMG-CoA reductase inhibitors (statins)
Mechanism
Simvastatin clearance is 98% via hepatic CYP3A4. Ketoconazole is one of the strongest CYP3A4 inhibitors. Simvastatin plasma levels rise 10-fold or more. The FDA lists the combination as an absolute contraindication.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–2 weeks of co-prescription.
Management
The combination is not prescribed. Hold simvastatin during ketoconazole therapy or switch to pravastatin or rosuvastatin (no CYP3A4 use). Alternative antifungals: terbinafine or echinocandins.