ZOCOR (simvastatin) is a prodrug of 3-hydoroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is derived synthetically from a fermentation product of Aspergillus terreus . 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. Its structural formula is: Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. ZOCOR tablets (simvastatin) are available for oral administration in strength of 10 mg, 20 mg, or 40 mg. Each tablet contains following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and titanium dioxide. Butylated hydroxyanisole is added as a preservative. The 5 mg and 80 mg strengths of ZOCOR are no longer marketed. Chemical Structure

ZOCOR ® 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. As an adjunct to diet to reduce 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). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. ZOCOR is an HMG-CoA reductase inhibitor 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. As an adjunct to diet to reduce 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). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia.

ZOCOR tablets: 10 mg: peach, oval tablets, marked MSD 735 on one side and plain on the other 20 mg: tan, oval tablets, marked MSD 740 on one side and plain on the other 40 mg: brick red, oval tablets, marked MSD 749 on one side and plain on the other The 5 mg and 80 mg strengths of ZOCOR are no longer marketed. Tablets: 10 mg; 20 mg; 40 mg The 5 mg and 80 mg strengths of ZOCOR are no longer marketed.

Important Dosage and Administration Information: ZOCOR is no longer marketed in the 5 mg and 80 mg strengths. For dosing with the 5 mg strength, use another simvastatin product. Take ZOCOR orally once daily in the evening. Maximum recommended dosage is ZOCOR 40 mg once daily. An 80 mg daily dosage of ZOCOR is restricted to patients who have been taking simvastatin 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 ZOCOR 40 mg daily, prescribe alternative LDL-C lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating, and adjust the dosage if necessary. Adults: Recommended dosage is 20 mg to 40 mg once daily. Pediatric Patients Aged 10 Years and Older with HeFH: Recommended dosage is 10 mg to 40 mg once daily. Patients with Severe Renal Impairment: Recommended starting dosage is simvastatin 5 mg once daily. See full prescribing information for ZOCOR dosage modifications due to drug interactions

Important Dosage and Administration Information ZOCOR is no longer marketed in the 5 mg and 80 mg strengths. For dosing with the 5 mg strength, use another simvastatin product. Take ZOCOR orally once daily in the evening. The maximum recommended dosage is ZOCOR 40 mg once daily . An 80 mg daily dosage of ZOCOR is restricted to patients who have been taking simvastatin 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity . If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ZOCOR 40 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ZOCOR, and adjust the dosage if necessary

Recommended Dosage in Adult Patients The recommended dosage range of ZOCOR is 20 mg to 40 mg once daily

Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended dosage range of ZOCOR is 10 mg to 40 mg daily

Recommended Dosage in Patients with Renal Impairment For patients with severe renal impairment [creatinine clearance (CLcr) 15 – 29 mL/min], the recommended starting dosage of simvastatin is 5 mg once daily . Use another simvastatin product to initiate dosing in such patients . There are no dosage adjustment recommendations for patients with mild or moderate renal impairment

Dosage Modifications Due to Drug Interactions Concomitant use of ZOCOR with the following drugs requires dosage modification of ZOCOR . Patients taking Lomitapide Reduce the dosage of ZOCOR by 50%. Do not exceed ZOCOR 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of ZOCOR chronically while taking lomitapide) . Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed ZOCOR 10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed ZOCOR 20 mg once daily.

Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher ZOCOR dosage. Chinese patients may be at higher risk for myopathy. Discontinue ZOCOR if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue ZOCOR 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 ZOCOR dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 , 7.1 , 8.5 , 8.6 , 8.8 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue ZOCOR 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 ZOCOR. ( 4 , 5.3 , 8.7 ) 5.1 Myopathy and Rhabdomyolysis ZOCOR 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 ZOCOR. In clinical studies of 24,747 ZOCOR-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 (10xULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with ZOCOR 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical study of 12,064 ZOCOR-treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking ZOCOR 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively. The incidences of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients taking ZOCOR 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively . 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 ZOCOR dosage; Chinese patients on ZOCOR 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 an 80 mg daily dosage of ZOCOR compared with patients taking lower ZOCOR 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 ZOCOR is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend ZOCOR during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of ZOCOR with gemfibrozil, cyclosporine, or danazol is also contraindicated . ZOCOR dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine . ZOCOR 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 ZOCOR only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity . If patients treated with an 80 mg daily dosage of ZOCOR are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin . Discontinue ZOCOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if ZOCOR is discontinued. Temporarily discontinue ZOCOR 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 ZOCOR dosage and advise patients receiving an 80 mg daily dosage of ZOCOR 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 ZOCOR if IMNM is suspected

Hepatic Dysfunction Increases in serum transaminases have been reported with use of ZOCOR . 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. Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving ZOCOR in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with ZOCOR. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including ZOCOR. 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 ZOCOR initiation and when clinically indicated thereafter. ZOCOR 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 ZOCOR

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

See full prescribing information for details regarding concomitant use of ZOCOR with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. Coumarin Anticoagulants: Obtain INR before ZOCOR initiation and monitor INR during ZOCOR dosage initiation or adjustment. Digoxin: During ZOCOR initiation, monitor digoxin levels

Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with ZOCOR ZOCOR is a substrate of CYP3A4 and of the transport protein OATP1B1. ZOCOR exposure 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 ZOCOR and instructions for preventing or managing them . Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with ZOCOR Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with ZOCOR increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher ZOCOR dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with ZOCOR is contraindicated . If treatment with a CYP3A4 inhibitor is unavoidable, suspend ZOCOR 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), 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 ZOCOR. Gemfibrozil may cause myopathy when given alone. Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with ZOCOR 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 ZOCOR. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed ZOCOR 10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed ZOCOR 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 ZOCOR by 50% if initiating lomitapide. Do not exceed ZOCOR 20 mg daily (or ZOCOR 40 mg daily for patients who have previously taken an 80 mg daily dosage of ZOCOR chronically) while taking lomitapide . Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both ZOCOR 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 ZOCOR 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 ZOCOR. The risk of myopathy is greater in Chinese patients. In a clinical study (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 ZOCOR 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 ZOCOR 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 ZOCOR. Intervention: Consider if the benefit of using fibrates concomitantly with ZOCOR 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 ZOCOR. Intervention: Consider if the benefit of using colchicine concomitantly with ZOCOR 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 ZOCOR

ZOCOR Effects on Other Drugs Table 3 presents ZOCOR’s effect on other drugs and instructions for preventing or managing them. Table 3: ZOCOR Effects on Other Drugs Coumarin Anticoagulants Clinical Impact: ZOCOR may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of ZOCOR (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 and warfarin. Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting ZOCOR 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 ZOCOR may result in elevated plasma digoxin concentrations . Intervention: Monitor digoxin levels in patients taking digoxin when ZOCOR is initiated.