Amiodarone × Simvastatin

Amiodarone moderately inhibits hepatic CYP3A4 – the primary clearance route for simvastatin. Simvastatin plasma levels rise 2- to 3-fold. The effect is weaker than with clarithromycin, but at simvastatin doses of 40 mg and above the risk becomes clinically significant. The FDA caps simvastatin at 20 mg/day when used with amiodarone.

Pain and weakness in thigh, shoulder, and calf muscles. Dark urine, elevated creatine kinase on lab work. Symptoms typically emerge 2–4 weeks after starting or increasing the dose. Acute rhabdomyolysis is less common than with clarithromycin pairs.

When amiodarone is required, prescribe simvastatin at no more than 20 mg/day. If the patient is already established on 40–80 mg, switch to pravastatin or rosuvastatin, which do not use CYP3A4. Check creatine kinase 4–6 weeks after the combination starts and whenever muscle symptoms appear.