Major
diltiazem × Simvastatin
Calcium channel blocker, non-DHP (benzothiazepine derivative)×HMG-CoA reductase inhibitors (statins)
Mechanism
Diltiazem moderately inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise 3- to 5-fold. FDA Zocor caps simvastatin at 10 mg/day with diltiazem.
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 1–4 weeks of co-administration.
Management
Cap simvastatin at 10 mg/day when combined. If LDL targets are missed, switch to pravastatin or rosuvastatin (no CYP3A4 dependence). Alternative to diltiazem: amlodipine (with simvastatin capped at 20 mg/day) or a beta-blocker.