ZOCOR

Dosage and Administration ( 2.1 ) 3/2023

1 INDICATIONS AND USAGE 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: ( 1 ) 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.

2 DOSAGE AND ADMINISTRATION Important Dosage and Administration Information: ( 2.1 ) 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. ( 2.2 ) Pediatric Patients Aged 10 Years and Older with HeFH: Recommended dosage is 10 mg to 40 mg once daily. ( 2.3 ) Patients with Severe Renal Impairment: Recommended starting dosage is simvastatin 5 mg once daily. ( 2.4 , 8.6 ) See full prescribing information for ZOCOR dosage modifications due to drug interactions. ( 2.5 ) 2.1 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 [see Dosage and Administration (2.2 , 2.3) ] . 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 [see Warnings and Precautions (5.1) ] . 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. 2.2 Recommended Dosage in Adult Patients The recommended dosage range of ZOCOR is 20 mg to 40 mg once daily. 2.3 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. 2.4 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ] . Use another simvastatin product to initiate dosing in such patients [see Dosage and Administration (2.1) ] . There are no dosage adjustment recommendations for patients with mild or moderate renal impairment. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of ZOCOR with the following drugs requires dosage modification of ZOCOR [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . 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) [see Dosage and Administration (2.1) ] . 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.

3 DOSAGE FORMS AND STRENGTHS 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 ( 3 ) The 5 mg and 80 mg strengths of ZOCOR are no longer marketed.

4 CONTRAINDICATIONS ZOCOR is contraindicated in the following conditions: Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see Drug Interactions (7.1) ] . Concomitant use of cyclosporine, danazol or gemfibrozil [see Drug Interactions (7.1) ] . Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] . Hypersensitivity to simvastatin or any excipients in ZOCOR. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see Adverse Reactions (6.2) ] . Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) ( 4 , 7.1 ) Concomitant use of cyclosporine, danazol or gemfibrozil ( 4 , 7.1 ) Acute liver failure or decompensated cirrhosis ( 4 , 5.3 ) Hypersensitivity to simvastatin or any excipient in ZOCOR ( 4 , 6.2 )

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] Hepatic Dysfunction [see Warnings and Precautions (5.3) ] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥5%) are upper respiratory infection, headache, abdominal pain, constipation, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies, 2,423 adult patients were exposed to ZOCOR with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these ZOCOR clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued ZOCOR due to adverse reactions. The most common adverse reactions that led to discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). In a Cardiovascular Outcomes Study (the Scandinavian Simvastatin Survival Study [Study 4S]), adult patients (age range 35-71 years, 19% women, 100% Caucasians) were treated with 20-40 mg per day of ZOCOR or placebo over a median of 5.4 years [see Clinical Studies (14) ] ; adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 1 . Table 1: Adverse Reactions Reported ≥2% of Patients Treated with ZOCOR and Greater than Placebo in Study 4S % Placebo (N = 2,223) % ZOCOR (N = 2,221) Bronchitis 6.3 6.6 Abdominal pain 5.8 5.9 Atrial fibrillation 5.1 5.7 Gastritis 3.9 4.9 Eczema 3.0 4.5 Vertigo 4.2 4.5 Diabetes mellitus 3.6 4.2 Insomnia 3.8 4.0 Myalgia 3.2 3.7 Urinary tract infection 3.1 3.2 Edema/swelling 2.3 2.7 Headache 2.1 2.5 Sinusitis 1.8 2.3 Constipation 1.6 2.2 Myopathy/Rhabdomyolysis In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received ZOCOR , the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the ZOCOR 20 mg, 40 mg, and 80 mg daily groups, respectively. In a clinical outcomes study in which 12,064 adult patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10x [1200 U/L] ULN) in patients taking ZOCOR 20 mg and 80 mg daily was approximately 0.02% and 0.9%, respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients on ZOCOR 20 mg and 80 mg daily was approximately 0% and 0.4%, respectively. The incidence of myopathy and rhabdomyolysis were highest during the first year and then decreased during the subsequent years of treatment. In another clinical outcomes study in which 10,269 adult patients were treated with ZOCOR 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was 3xULN was 0.7% in patients taking ZOCOR compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking ZOCOR and 0.2% of patients taking placebo. The majority of elevated transaminases leading to treatment discontinuation occurred within in the first year. Adverse Reactions in Pediatric Patients with Heterozygous Familial Hypercholeste …

7 DRUG INTERACTIONS 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. ( 2.5 , 7.1 ) Coumarin Anticoagulants: Obtain INR before ZOCOR initiation and monitor INR during ZOCOR dosage initiation or adjustment. ( 7.2 ) Digoxin: During ZOCOR initiation, monitor digoxin levels. ( 7.2 ) 7.1 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 [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 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 [see Contraindications (4) ] . 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 [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 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 [see Dosage and Administration (2.5) ] . 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 [see Dosage and Administration (2.1 , 2.5) ] . 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 …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended during treatment with ZOCOR. ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue ZOCOR when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. ZOCOR decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, ZOCOR 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 ZOCOR 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 ) (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 A Medicaid cohort linkage study 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 mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum …

12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.

11 DESCRIPTION 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

10 OVERDOSAGE No specific antidotes for ZOCOR are known. Contact Poison Control (1-800-222-1222) for latest recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING ZOCOR tablets are supplied as follows: Strength The 5 mg and 80 mg strengths of ZOCOR are no longer marketed. How Supplied NDC Tablet Description 10 mg unit of use bottles of 30 78206-180-01 peach, oval, marked MSD 735 on one side and plain on the other unit of use bottles of 90 78206-180-02 20 mg unit of use bottles of 30 78206-181-01 tan, oval, marked MSD 740 on one side and plain on the other unit of use bottles of 90 78206-181-02 40 mg unit of use bottles of 30 78206-182-01 brick red, oval, marked MSD 749 on one side and plain on the other unit of use bottles of 90 78206-182-02 Storage Store between 41°F to 86°F (5°C to 30°C).