Immunosuppressive drugs, Itraconazole, Gemfibrozil, Nicotinic acid, Erythromycin: Rhabdomyolysis has been associated when used with HMG-Co A reductase inhibitors.
Digoxin: Slight increase in digoxin concentration is seen in patients receiving digoxin and simvastatin.
Warfarin: Simvastatin modestly potentiated the effect of coumarin anticoagulants resulting in increased prothrombin time. Prothrombin time should be determined before starting treatment and frequently during early therapy to ensure that no significant alteration of prothrombin time occurs.
Simvastatin is metaboliosed by cytochrome P450 isoform 3A4.
Inhibitors of C4P3A4 like Ketoconazole, Erythromycin, Clarithromycin, HIV protease inhibitors, antidepressant nefazodone raise plasma levels of Simvastatin and can increase risk of myopathy.
Use of drugs that may increase risk of myopathy CKP3A4 inhibitors - Itraconazole, Ketoconazole, Erythromycin, Clarithromycin, Protease inhibitor, Nefazodore, Cyclosporin.
Gemfibrozil (fibrates), Niacin, Amiodarone, Verapamil.
Contraindicated drugs: Concomitant use of the following drugs is contraindicated: Potent Inhibitors of CYP3A4: Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity. Therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin.
Concomitant use of drugs labeled as having a potent inhibitory effect on CYP3A4 (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone) is contraindicated.
Other drug interactions: Other Fibrates: The risk of myopathy is increased by gemfibrozil and other fibrates (except fenofibrate); these lipid-lowering drugs can cause myopathy when given alone. When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid.
Amiodarone: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin.
Calcium channel blockers: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine.
Moderate Inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, particularly higher simvastatin doses, may have an increased risk of myopathy.
Niacin (nicotinic acid) (≥1g/day): Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1g/day) of niacin.
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.
Other interactions: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250ml glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, because large quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during simvastatin therapy.