VYTORIN contains ezetimibe, a dietary cholesterol absorption inhibitor, 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 empirical formula is C 24 H 21 F 2 NO 3 and its molecular weight is 409.4. Ezetimibe is a white, crystalline powder that is freely to very 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,7β,8β(2 S *,4 S *),-8aβ]]. The empirical formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57. Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol and ethanol. Its structural formula is: VYTORIN is available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of simvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or 80 mg of simvastatin (VYTORIN 10/80). Each tablet contains the following inactive ingredients: butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF. Chemical Structure Chemical Structure

VYTORIN VYTORIN ® is a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of VYTORIN, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. VYTORIN is a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of VYTORIN, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.

VYTORIN tablets: 10/10, (ezetimibe 10 mg and simvastatin 10 mg tablets) are white to off-white capsule-shaped and debossed with “311” on one side. 10/20, (ezetimibe 10 mg and simvastatin 20 mg tablets) are white to off-white capsule-shaped and debossed with “312” on one side. 10/40, (ezetimibe 10 mg and simvastatin 40 mg tablets) are white to off-white capsule-shaped and debossed with “313” on one side. 10/80, (ezetimibe 10 mg and simvastatin 80 mg tablets) are white to off-white capsule-shaped and debossed with “315” on one side. Tablets (ezetimibe mg/simvastatin mg): 10/10, 10/20, 10/40, 10/80

Important Dosage and Administration Information: Take VYTORIN orally once daily in the evening with or without food. Maximum recommended dosage is VYTORIN 10/40 mg once daily. VYTORIN 10/80 mg daily dosage is restricted to patients who have been taking VYTORIN 10/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving VYTORIN 10/40 mg daily, prescribe alternative LDL-C-lowering treatment. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 2 weeks after initiating VYTORIN, and adjust the dosage if necessary. Adults: Recommended dosage range of 10/10 mg to 10/40 mg once daily. See full prescribing information for VYTORIN dosage modifications due to drug interactions. Patients with Renal Impairment: Doses exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment

Important Dosage and Administration Information Take VYTORIN orally once daily in the evening with or without food. The maximum recommended dosage is VYTORIN 10/40 mg once daily. The VYTORIN 10/80 mg daily dosage is restricted to adult patients who have been taking VYTORIN 10/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity . For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving VYTORIN 10/40 mg daily, prescribe alternative LDL-C-lowering treatment. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating VYTORIN, and adjust the dosage if necessary

Recommended Dosage in Adult Patients The recommended dosage range of VYTORIN 10/10 mg to 10/40 mg once a day

Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended dosage range of VYTORIN 10/10 mg to 10/40 mg once a day

Recommended Dosage in Patients with Renal Impairment Renal impairment is a risk factor for statin-associated myopathy. Doses of VYTORIN exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment . There are no dosage adjustment recommendations for patients with mild renal impairment

Dosage Modifications Due to Drug Interactions Concomitant use of VYTORIN with the following drugs requires dosage modification of VYTORIN . Patients taking Lomitapide Reduce the dosage of VYTORIN by 50%. Do not exceed VYTORIN 10/20 mg once daily (or 10/40 mg once daily for patients who have previously taken VYTORIN 10/80 mg daily chronically while taking lomitapide) . Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed VYTORIN 10/10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed VYTORIN 10/20 mg once daily. Patients taking Bile Acid Sequestrants In patients taking a bile acid sequestrant, administer VYTORIN at least 2 hours before or 4 hours after the bile acid sequestrant.

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher VYTORIN dosage. Chinese patients may be at higher risk for myopathy. Discontinue VYTORIN if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue VYTORIN in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing VYTORIN dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue VYTORIN if IMNM is suspected. Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue VYTORIN. 5.1 Myopathy and Rhabdomyolysis VYTORIN may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including VYTORIN. In clinical trials of 24,747 simvastatin-treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10 X ULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with simvastatin 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical trial of 12,064 simvastatin-treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively. The incidences of rhabdomyolysis (defined as myopathy with a CK >40 X ULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively . In the Trial of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated to receive VYTORIN 10/20 mg daily (n=4650) or placebo (n=4620). During a median follow-up period of 4.9 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]) was 0.2% for VYTORIN and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for VYTORIN and 0.02% for placebo. In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives. VYTORIN and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher VYTORIN dosage; Chinese patients on VYTORIN may be at higher risk for myopathy . The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking VYTORIN 80 mg daily compared with patients taking lower VYTORIN dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of strong CYP3A4 inhibitors with VYTORIN is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend VYTORIN during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of VYTORIN with gemfibrozil, cyclosporine, or danazol is also contraindicated . VYTORIN dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine . VYTORIN use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis . Use the 80 mg daily dosage of VYTORIN only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity . If patients treated with VYTORIN 80 mg are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin . Discontinue VYTORIN if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if VYTORIN is discontinued. Temporarily discontinue VYTORIN in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the VYTORIN dosage and advise patients receiving VYTORIN 80 mg of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever

Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue VYTORIN if IMNM is suspected

Hepatic Dysfunction Increases in serum transaminases have been reported with use of VYTORIN . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Marked persistent increases of hepatic transaminases have also occurred with VYTORIN. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including VYTORIN. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose-related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with VYTORIN 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. In SHARP, 9270 patients with chronic kidney disease were allocated to receive VYTORIN 10/20 mg daily (n=4650), or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of consecutive elevations of transaminases (>3 X ULN) was 0.7% for VYTORIN and 0.6% for placebo. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before VYTORIN initiation and when clinically indicated thereafter. VYTORIN is contraindicated in patients with acute liver failure or decompensated cirrhosis . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue VYTORIN

Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including VYTORIN. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

VYTORIN 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. Cholestyramine: Combination decreases exposure of ezetimibe. Coumarin Anticoagulants: Obtain INR before VYTORIN initiation and monitor INR during VYTORIN dosage initiation or adjustment. Digoxin : During VYTORIN initiation, monitor digoxin levels. 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 . 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 . 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 . 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 . 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 . 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 . 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

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 . Intervention: In patients taking a bile acid sequestrant, administer VYTORIN at least 2 hours before or at least 4 hours after cholestyramine

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 . 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 .