No drug interaction studies were conducted with SIMCOR. However, the following interactions have been noted with the individual components of SIMCOR:
Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate 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 include:
Itraconazole, ketoconazole, and other antifungal azoles,
Macrolide antibiotics erythromycin, clarithromycin, and telithromycin,
HIV protease inhibitors,
Grapefruit juice in large quantities (> 1 quart daily).
Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Hence when simvastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions ]
Serious skeletal muscle disorder, e.g., rhabdomyolysis, have been reported during concomitant therapy of simvastatin or other HMG-CoA reductase inhibitors with cyclosporine, danazol, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, telithromycin, nefazodone or HIV protease inhibitors.
Concomitant use of drugs labeled as potent inhibitors of CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with SIMCOR should be suspended during the course of treatment.
Cyclosporine or Danazol
Although the mechanism is not fully understood, cyclosporine has been shown to increase the area under the curve (AUC) of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin. [See Warnings and Precautions ]
Amiodarone or Verapamil
The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin. [See Warnings and Precautions ]
Gemfibrozil and other Fibrates
Coadministration of gemfibrozil (600 mg twice daily for 3 days) with simvastatin (40 mg daily) resulted in clinically significant increases in simvastatin acid AUC (185%) and peak plasma concentration (Cmax,112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil. The increase in simvastatin exposure increases the risk of myopathy when coadministred with gemfibrozil. The combined use of SIMCOR with gemfibrozil should be avoided [See Warnings and Precautions ]. The risk of myopathy also increases to a lesser extent when simvastatin is used in combination with other fibrates. Coadministration of 160 mg fenofibrate daily with 80 mg simvastatin daily for 7 days had no effect on plasma AUC (and Cmax) of either total HMG-CoA reductase inhibitory activity or fenofibric acid; there was a modest reduction (approximately 35%) of simvastatin acid which was not considered clinically significant.
In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.
Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when SIMCOR is initiated.
In normal volunteers and hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants since the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteers and patients, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting SIMCOR and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of SIMCOR is changed or discontinued, the same procedure should be repeated.
Concomitant use of aspirin may decrease the metabolic clearance of niacin. The clinical relevance of this finding is unclear.
Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.
Bile Acid Sequestrants
An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. About 98% of available niacin was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of SIMCOR.
Nutritional supplements containing large doses of niacin or related compounds may potentiate the adverse effects of SIMCOR.