Interactions with Other Medicaments and Other Forms of Interaction: Gemfibrozil and Other Fibrates, Lipid-Lowering Dose (1g/day) of Niacin (nicotinic acid): These drugs increase the risk of myopathy when given concomitantly with simvastatin, probably because they can produce myopathy when given alone (see Muscle Effect under Precautions).
CYP3A4 Interactions: Simvastatin has no CYP3A4 inhibitory activity; therefore, it is not expected to affect plasma levels of the drugs metabolised by CYP3A4. However, simvastatin itself is a substrate for CYP3A4. Potent inhibitors of CYP3A4 may increase the risk of myopathy by increasing the plasma levels of HMG-CoA reductase activity during simvastatin therapy. These include cyclosporin, itraconazole, ketoconazole erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone (see Muscle Effects under Precautions).
Grape fruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolised by CYP3A4. The effect of typical consumption (one 240 mL glass daily) is minimal (13% increase in the active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-curve) and of no clinical relevance. However, very large quantities (over 1 L daily) significantly increase the plasma levels of HMG-CoA reductase inhibitory activity during simvastatin therapy and should be avoided. Amounts of grapefruit juice between 240 mL and 1 L have not been studied.
Propranolol: In normal volunteers, there was no clinically significant pharmacokinetic or pharmacodynamic interaction with concomitant administration of single doses of Corstat and propranolol.
Digoxin: Concomitant administration of Corstat and digoxin resulted in a slight elevation (>0.3 ng/mL) in drug concentration (as measured by a digoxin radio immunoassay) in plasma compared to concomitant administration of placebo and digoxin.
Coumarin Derivatives: In 2 clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: The prothrombin time, reported as International Normalised Ratio (INR), increased from patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin occurs. Once a stable prothrombin time has been documented, prothrombin time can be monitored at the intervals usually recommended for patients on coumarin anticoagulants.
Other Concomitant Therapy: In clinical studies, Corstat was used concomitantly with ACE inhibitors β-blockers, calcium antagonists, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.
Incompatibilities: None known.