EZETIMIBE AND SIMVASTATIN

Ezetimibe and Simvastatin Tablets contain ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, an HMG-CoA reductase inhibitor. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The molecular formula is C 24 H 21 F 2 NO 3 and its molecular weight is 409.44 g/mol. Ezetimibe is a white, crystalline powder that is freely soluble in ethanol, methanol and acetone and practically insoluble in water. Its structural formula is: Simvastatin, an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7α,8α(2 S* ,4 S* ),-8aβ]]. The molecular formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57 g/mol. Simvastatin is a white to off-white, nonhygroscopic powder that is freely soluble in chloroform, methanol and alcohol, sparingly soluble in propylene glycol, very slightly soluble in hexane and practically insoluble in water. Its structural formula is: Ezetimibe and Simvastatin Tablets are available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/10 mg), 20 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/20 mg), 40 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/40 mg), or 80 mg of simvastatin (Ezetimibe and Simvastatin Tablets 10 mg/80 mg). Each tablet contains the following inactive ingredients: butylated hydroxyanisole, citric acid monohydrate, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propyl gallate, and sodium lauryl sulfate. ezetimibe-structure simva-structure

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Ezetimibe and simvastatin tablets, which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy to diet to: • reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. ( 1.1 ) • reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments. ( 1.2 ) Limitations of Use ( 1.3 ) • No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. • Ezetimibe and simvastatin tablets have not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. 1.1 Primary Hyperlipidemia Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. 1.2 Homozygous Familial Hypercholesterolemia (HoFH) Ezetimibe and simvastatin tablets are indicated for the reduction of elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Limitations of Use No incremental benefit of ezetimibe and simvastatin tablets on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Ezetimibe and simvastatin tablets have not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

• Dose range is 10/10 mg/day to 10/40 mg/day. ( 2.1 ) • Recommended usual starting dose is 10/10 or 10/20 mg/day. ( 2.1 ) • Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. ( 2.2 ) • Patients who are currently tolerating the 10/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. ( 2.2 ) • Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. ( 2.2 ) • Dosing of ezetimibe and simvastatin tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ( 2.3 , Error! Hyperlink reference not valid. ) 2.1 Recommended Dosing The usual dosage range is 10/10 mg/day to 10/40 mg/day. The recommended usual starting dose is 10/10 mg/day or 10/20 mg/day. Ezetimibe and simvastatin tablets should be taken as a single daily dose in the evening, with or without food. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 ). After initiation or titration of ezetimibe and simvastatin tablets, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed. 2.2 Restricted Dosing for 10/80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 10/80 mg dose of ezetimibe and simvastatin tablets should be restricted to patients who have been taking ezetimibe and simvastatin tablets 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions ( 5.1 )] . Patients who are currently tolerating the 10/80 mg dose of ezetimibe and simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80 mg dose of ezetimibe and simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 10/40 mg dose of ezetimibe and simvastatin tablets should not be titrated to the 10/80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. 2.3 Coadministration with Other Drugs Patients taking Verapamil, Diltiazem, or Dronedarone • The dose of ezetimibe and simvastatin tablets should not exceed 10/10 mg/day [see Warnings and Precautions ( 5.1 ), Drug Interactions ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( 12.3 )]. Patients taking Amiodarone, Amlodipine or Ranolazine • The dose of ezetimibe and simvastatin tablets should not exceed 10/20 mg/day [see Warnings and Precautions ( 5.1 ), Drug Interactions ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( 12.3 )]. Patients taking Bile Acid Sequestrants • Dosing of ezetimibe and simvastatin tablets should occur either greater than or equal to 2 hours before or greater than or equal to 4 hours after administration of a bile acid sequestrant [see Drug Interactions ( Error! Hyperlink reference not valid. )]. 2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage for patients with homozygous familial hypercholesterolemia is ezetimibe and simvastatin tablets 10/40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 10/80 mg ( 2.2 )] . Ezetimibe and simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of ezetimibe and simvastatin tablets should be reduced by 50% if initiating lomitapide. Ezetimibe and simvastatin tablets dosage should not exceed 10/20 mg/day (or 10/40 mg/day for patients who have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide. 2.5 Patients with Renal Impairment/Chronic Kidney Disease In patients with mild renal impairment (estimated GFR greater than or equal to 60 mL/min/1.73 m 2 ), no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 , the dose of ezetimibe and simvastatin tablets is 10/20 mg/day in the evening. In such patients, higher doses should be used with caution and close monitoring [see Warnings and Precautions ( 5.1 ); Clinical Pharmacology ( 12.3 )]. 2.6 Geriatric Patients No dosage adjustment is necessary in geriatric patients [see Clinical Pharmacology ( 12.3 )].

Ezetimibe and simvastatin tablets are contraindicated in the following conditions: • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions ( 5.1 )]. • Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions ( 5.1 )]. • Hypersensitivity to any component of this medication [see Adverse Reactions ( Error! Hyperlink reference not valid. )]. • Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions ( 5.3 )]. • Women who are pregnant or may become pregnant . Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered to a pregnant woman. 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 hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and simvastatin use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Ezetimibe and simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )]. • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin treatment should not breastfeed their infants [see Use in Specific Populations ( Error! Hyperlink reference not valid. )]. • Concomitant administration of strong CYP3A4 inhibitors. ( 4 , 5.1 ) • Concomitant administration of gemfibrozil, cyclosporine, or danazol. ( 4 , 5.1 ) • Hypersensitivity to any component of this medication ( 4 , Error! Hyperlink reference not valid. ) • Active liver disease or unexplained persistent elevations of hepatic transaminase levels ( 4 , 5.3 ) • Women who are pregnant or may become pregnant ( 4 , 8.1 ) • Nursing mothers ( 4 , Error! Hyperlink reference not valid. )

The following serious adverse reactions are discussed in greater detail in other sections of the label: • Rhabdomyolysis and myopathy [see Warnings and Precautions ( 5.1 )] • Liver enzyme abnormalities [see Warnings and Precautions ( 5.3 )] • Common (incidence ≥2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. ( Error! Hyperlink reference not valid. ) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Ezetimibe and Simvastatin Tablets Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the ezetimibe and simvastatin tablets placebo-controlled clinical trials database of 1420 patients (age range 20 to 83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin tablets and 2.2% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group treated with ezetimibe and simvastatin tablets that led to treatment discontinuation and occurred at a rate greater than placebo were: • Increased ALT (0.9%) • Myalgia (0.6%) • Increased AST (0.4%) • Back pain (0.4%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). Ezetimibe and simvastatin tablets have been evaluated for safety in more than 10,189 patients in clinical trials. Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with ezetimibe and simvastatin tablets (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials. Table 2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Ezetimibe and Simvastatin Tablets and at an Incidence Greater than Placebo, Regardless of Causality Body System/Organ Class Adverse Reaction Placebo (%) n=371 Ezetimibe 10 mg (%) n=302 Simvastatin † (%) n=1234 Ezetimibe and Simvastatin Tablets † (%) n=1420 Body as a whole – general disorders Headache 5.4 6 5.9 5.8 Gastrointestinal system disorders Diarrhea 2.2 5 3.7 2.8 Infections and infestations Influenza 0.8 1 1.9 2.3 Upper respiratory tract infection 2.7 5 5 3.6 Musculoskeletal and connective tissue disorders Myalgia 2.4 2.3 2.6 3.6 Pain in extremity 1.3 3 2 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin tablets were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin tablets was administered. † All doses. Study of Heart and Renal Protection In SHARP , 9270 patients were allocated to ezetimibe and simvastatin tablets 10/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued study treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin tablets and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin tablets vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (>3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each study visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin tablets and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin tablets and placebo, respectively. Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue. Simvastatin In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported with simvastatin in placebo-controlled clinical studies, regardless of causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia, edema/swelling; Psychiatric disorders: insomnia. Laboratory Tests Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions ( 5.3 )] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions ( 5.1 )] . 6.2 Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported in postmarketing experience for ezetimibe and simvastatin tablets or ezetimibe or simvastatin: pruritus; alopecia; erythema multiforme; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps; myalgia; arthralgia; pancreatitis; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis [see Warnings and Precautions ( 5.1 )] ; hepatitis/jaundice; fatal and non-fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions ( 5.1 )] . Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria have been reported. In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

[See Clinical Pharmacology ( 12.3 )]. Ezetimibe and simvastatin tablets Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , Error! Hyperlink reference not valid., Error! Hyperlink reference not valid., Error! Hyperlink reference not valid., Error! Hyperlink reference not valid., 12.3 ) 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 10/10 mg ezetimibe and simvastatin tablets daily Amiodarone, amlodipine, ranolazine Do not exceed 10/20 mg ezetimibe and simvastatin tablets daily Lomitapide For patients with HoFH, do not exceed 10/20 mg ezetimibe and simvastatin tablets daily * Daptomycin Temporarily suspend ezetimibe and simvastatin Grapefruit juice Avoid grapefruit juice * 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 10/40 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 tablets therapy. ( Error! Hyperlink reference not valid. ) • Cholestyramine: Combination decreases exposure of ezetimibe. ( 2.3 , Error! Hyperlink reference not valid. ) • Other Lipid-lowering Medications: Use with fenofibrates increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with ezetimibe and simvastatin tablets. ( 5.1 , 7.2 ) • 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. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , 12.3 ) 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 [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications ( 4 )]. 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone Gemfibrozil: Contraindicated with ezetimibe and simvastatin tablets [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Fenofibrates (e.g., fenofibrate and fenofibric acid): Caution should be used when prescribing with ezetimibe and simvastatin tablets [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( Error! Hyperlink reference not valid. )]. 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 [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.1 ) and Table 6 in Clinical Pharmacology ( 12.3 )]. 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 (≥1 g/day) of niacin is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.8 )] . 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 [see Warnings and Precautions ( 5.1 )]. Fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Animal Toxicology and/or Pharmacology ( 13.2 )] . 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 [see the product labeling for fenofibrate and fenofibric acid] . 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 administered with daptomycin. Both ezetimibe and simvastatin 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 in patients taking daptomycin [see Warnings and Precautions ( 5.1 )].