Ezetimibeinteractions

Ezetimibe and Simvastatin Tablets Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets Niacin (≥1 g/day) For Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil, diltiazem, dronedarone Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Amiodarone, amlodipine, ranolazine Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets 1 Daptomycin Temporally suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1. For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin tablets when taking lomitapide.

Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to starting ezetimibe and simvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of ezetimibe and simvastatin tablet therapy.

Cholestyramine: Combination decreases exposure of ezetimibe.

Other Lipid-lowering Medications: Use with fenofibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with ezetimibe and simvastatin tablets.

Fenofibrates: Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

7.1 Strong CYP3A4

Inhibitors, Cyclosporine, or Danazol Strong CYP3A4 inhibitors: The risk of myopathy is increased by reducing the elimination of the simvastatin component of ezetimibe and simvastatin tablets. Hence when ezetimibe and simvastatin tablets are used with an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of ezetimibe and simvastatin tablets. Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with ezetimibe and simvastatin tablets must be suspended during the course of treatment.

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated.

7.2 Lipid-Lowering

Drugs That Can Cause Myopathy When Given Alone Gemfibrozil: Contraindicated with ezetimibe and simvastatin tablets. Fenofibrates (e.g., fenofibrate and fenofibric acid): Caution should be used when prescribing with ezetimibe and simvastatin tablets.

7.3 Amiodarone,

Dronedarone, Ranolazine, or Calcium Channel Blockers The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem or amlodipine. 7.4 Niacin Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of cardiovascular disease and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses (≥1 g/day) of niacin. Coadministration of ezetimibe and simvastatin tablets with lipid-modifying doses (≥1g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients.

7.5 Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe and simvastatin tablets to cholestyramine may be reduced by this interaction.

7.6 Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately when ezetimibe and simvastatin tablets are initiated. 7.7 Fenofibrates (e.g., fenofibrate and fenofibric acid) The safety and effectiveness of ezetimibe and simvastatin tablets administered with fibrates have not been established. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fenofibrates, ezetimibe and simvastatin tablets should be administered with caution when used concomitantly with a fenofibrate. Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. If cholelithiasis is suspected in a patient receiving ezetimibe and simvastatin tablets and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

7.8 Coumarin

Anticoagulants Simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: 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 a normal volunteer study and in a hypercholesterolemic patient study, respectively. With other statins, 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 ezetimibe and simvastatin tablets 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 ezetimibe and simvastatin tablets is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been postmarketing reports of increased INR in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications. The effect of ezetimibe and simvastatin tablets on the prothrombin time has not been studied.

7.9 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing ezetimibe and simvastatin tablets with colchicine.

7.10 Daptomycin

Cases of rhabdomyolysis have been reported with ezetimibe and simvastatin tablets administered with daptomycin. Both ezetimibe and simvastatin tablets and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Temporarily suspend ezetimibe and simvastatin tablets in patients taking daptomycin

7.10 Daptomycin

Cases of rhabdomyolysis have been reported with ezetimibe and simvastatin tablets administered with daptomycin. Both ezetimibe and simvastatin tablets and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Temporarily suspend ezetimibe and simvastatin tablets in patients taking daptomycin