Ezetimibe and simvastatin

See full prescribing information for details regarding concomitant use of VYTORIN with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. ( 2.3 , 7.1 ) Cholestyramine: Combination decreases exposure of ezetimibe. ( 2.3 , 7.2 ) Coumarin Anticoagulants: Obtain INR before VYTORIN initiation and monitor INR during VYTORIN dosage initiation or adjustment. ( 7.3 ) Digoxin : During VYTORIN initiation, monitor digoxin levels. ( 7.3 ) 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. ( 7.3 , 12.3 )

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with VYTORIN VYTORIN is a substrate of CYP3A4 and of the transport protein OATP1B1. VYTORIN plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1. Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with VYTORIN and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .

Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with VYTORIN Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with VYTORIN increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher VYTORIN dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with VYTORIN is contraindicated [see Contraindications (4) ] . If treatment with a CYP3A4 inhibitor is unavoidable, suspend VYTORIN during the course of strong CYP3A4 inhibitor treatment.

Examples: Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin, telithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., boceprevir and telaprevir), cobicistat-containing products, and nefazodone. Cyclosporine, Danazol, or Gemfibrozil Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with VYTORIN. Gemfibrozil may cause myopathy when given alone.

Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with VYTORIN is contraindicated [see Contraindications (4) ] . Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with VYTORIN. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed VYTORIN 10/10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed VYTORIN 10/20 mg daily [see Dosage and Administration (2.3) ] .

Lomitapide Clinical Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased. Intervention: Reduce the dose of VYTORIN by 50% if initiating lomitapide. Do not exceed VYTORIN 10/20 mg daily (or VYTORIN 10/40 mg daily for patients who have previously taken VYTORIN 10/80 mg daily chronically) while taking lomitapide [see Dosage and Administration (2.1 , 2.3) ] . Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin.

Both VYTORIN and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Intervention: If treatment with daptomycin is required, consider temporarily suspending VYTORIN during the course of daptomycin treatment. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (≥1 gram/day niacin) with VYTORIN. The risk of myopathy is greater in Chinese patients.

In a clinical trial (median follow-up 3.9 years) of patients at high risk of CVD 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 of niacin Intervention: Concomitant use of VYTORIN with lipid-modifying dosages of niacin is not recommended in Chinese patients [see Use in Specific Populations (8.8) ] . For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with VYTORIN outweighs the increased risk of myopathy and rhabdomyolysis.

If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with VYTORIN. Intervention: Consider if the benefit of using fibrates concomitantly with VYTORIN outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with VYTORIN. Intervention: Consider if the benefit of using colchicine concomitantly with VYTORIN outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid grapefruit juice when taking VYTORIN.

7.2 Drug Interactions that Decrease the Efficacy of VYTORIN Table 3 presents drug interactions that may decrease the efficacy of VYTORIN and instructions for preventing or managing them. Table 3: Drug Interactions that Decrease the Efficacy of VYTORIN Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be reduced by this interaction [see Clinical Pharmacology (12.3) ] .

Intervention: In patients taking a bile acid sequestrant, administer VYTORIN at least 2 hours before or at least 4 hours after cholestyramine [see Dosage and Administration (2.3) ] .

7.3 VYTORIN’s Effect on Other Drugs Table 4 presents VYTORIN’s effect on other drugs and instructions for preventing or managing them. Table 4: VYTORIN Effects on Other Drugs Coumarin Anticoagulants Clinical Impact: VYTORIN may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins (with or without ezetimibe) and coumarin anticoagulants.

Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting VYTORIN and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. Digoxin Clinical Impact: Concomitant use of digoxin with VYTORIN may result in elevated plasma digoxin concentrations [see Clinical Pharmacology (12.3) ] . Intervention: Monitor digoxin levels in patients taking digoxin when VYTORIN is initiated. Fenofibrates Clinical Impact: Both ezetimibe and fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.

Intervention: If cholelithiasis is suspected in a patient receiving VYTORIN and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid] .

8.1 Pregnancy VYTORIN Risk Summary Discontinue VYTORIN when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. VYTORIN decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, VYTORIN may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy.

Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with VYTORIN use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data ) .

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m 2 ). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits orally administered ezetimibe during the period of organogenesis at doses that resulted in up to 10 and 150 times, respectively, the human exposure at the MRHD, based on AUC (see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Ezetimibe There are insufficient data on ezetimibe use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Simvastatin A Medicaid cohort linkage trial of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes…