RiteMED Simvastatin Drug Interactions

Coumarin Derivatives: Simvastatin appeared to slightly enhance the anticoagulant effect of warfarin (mean changes in prothrombin time less than 2 s) in normal volunteers maintained in a state of low therapeutic anticoagulation. The clinical importance of these findings for fully anticoagulated patients receiving concomitant chronic therapy with simvastatin is unknown. In patients taking anticoagulants, prothrombin time should be determined prior to starting therapy with simvastatin and then monitored at the intervals usually recommended for patients on coumarin anticoagulants once a stable prothrombin time has been reached.
Digoxin: Concomitant administration of digoxin and simvastatin results in a slight increase (less than 0.3 micrograms per liter) in plasma digoxin levels.
Protease Inhibitors (Lopinavir/Nelfinavir) and Selected Azole Antifungals (Itraconazole/Ketoconazole): These group of drugs are known to inhibit the metabolism of some HMG-CoA reductase inhibitors at the cytochrome P450-3A4 isozyme. Concurrent administration may result in an increased levels of simvastatin, which may result in an increased risk of rhabdomyolysis.
Fibrates, Lipid-Lowering Doses of Niacin, Cyclosporine: Concurrent administration of simvastatin with these drugs has been associated with severe myopathy, rhabdomyolysis and acute renal failure.
Erythromycin: Erythromycin may inhibit the metabolism of HMG-CoA reductase inhibitors and concurrent administration may result in increased levels of simvastatin which may produce rhabdomyolysis. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels and reddish-brown, hemepositive urine.
Verapamil/Diltiazem: Verapamil and diltiazem may increase the serum concentrations of simvastatin, a CYP3A4 substrate. The interaction is presumed to be due to increased simvastatin bioavailability via inhibition of CYP3A4 metabolism and reduction of first-pass metabolism. In a drug interaction study with simvastatin, verapamil was reported to increase serum concentrations and the AUC.
Grapefruit Juice: Clinicians should be aware that some food products may interact with some HMG-CoA reductase inhibitors. Grapefruit juice contains an unknown compound that inhibits cytochrome P450 3A4 isozymes in the gut wall. Co-administration with grapefruit juice increases the peak serum concentrations and the AUC of simvastatin. Grapefruit juice should be avoided in patients taking these agents to avoid the potential for drug accumulation and toxicity (ie, myopathy and rhabdomyolysis).
Other Significant Interactions: In clinical studies, simvastatin was used concomitantly with beta-blockers, ACE inhibitors, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.