Simvastatin

Dosage and Administration Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products-removal (2.7) 03/2019 Warnings and Precautions Myopathy/Rhabdomyolisis ( 5.1 ) 03/2019

1 INDICATIONS AND USAGE Simvastatin tablets USP are an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: • Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. ( 1.1 ) • Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. ( 1.2 ) • Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbetalipoproteinemia. ( 1.2 ) • Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. ( 1.2 ) • Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. ( 1.2 , 1.3 ) Limitations of Use Simvastatin tablets USP has not been studied in Fredrickson Types I and V dyslipidemias. ( 1.4 ) 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. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin tablets USP can be started simultaneously with diet. 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin tablets USP are indicated to: • Reduce the risk of total mortality by reducing CHD deaths. • Reduce the risk of non-fatal myocardial infarction and stroke. • Reduce the need for coronary and non-coronary revascularization procedures. 1.2 Hyperlipidemia Simvastatin tablets USP are indicated to: • Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb). • Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia). • Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia). • Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) Simvastatin tablets USP are indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: 1. LDL cholesterol remains ≥190 mg/dL; or 2. LDL cholesterol remains ≥160 mg/dL and 3. There is a positive family history of premature cardiovascular disease (CVD) or 4. Two or more other CVD risk factors are present in the adolescent patient. The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined. 1.4 Limitations of Use Simvastatin tablets USP have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

2 DOSAGE AND ADMINISTRATION Dose range is 5 to 40 mg/day. ( 2.1 ) Recommended usual starting dose is 10 or 20 mg once a day in the evening. ( 2.1 ) Recommended starting dose for patients at high risk of CHD is 40 mg/day. ( 2.1 ) Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80-mg dose of simvastatin tablets USP should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. ( 2.2 ) Patients who are currently tolerating the 80-mg dose of simvastatin tablets USP 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 with less potential for the drug-drug interaction. ( 2.2 ) Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets USP, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets USP should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. ( 2.2 ) Adolescents (10 to 17 years of age) with HeFH: starting dose is 10 mg/day; maximum recommended dose is 40 mg/day. ( 2.5 ) 2.1 Recommended Dosing The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, simvastatin tablets USP can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter. 2.2 Restricted Dosing for 80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of simvastatin tablets USP should be restricted to patients who have been taking simvastatin 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 80-mg dose of simvastatin tablets USP 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 with less potential for the drug-drug interaction. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets USP, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets USP should not be titrated to the 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 simvastatin tablets USP should not exceed 10 mg/day [see WARNINGS AND PRECAUTIONS ( 5.1 ), DRUG INTERACTIONS ( 7.3 ), and CLINICAL PHARMACOLOGY ( 12.3 )]. Patients taking Amiodarone, Amlodipine or Ranolazine The dose of simvastatin tablets USP should not exceed 20 mg/day [see WARNINGS AND PRECAUTIONS ( 5.1 ), DRUG INTERACTIONS ( 7.3 ), and CLINICAL PHARMACOLOGY ( 12.3 )] . 2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage is 40 mg/day in the evening Simvastatin tablets USP should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. The recommended dosage is 40 mg/day in the evening [see DOSAGE AND ADMINISTRATION, Restricted Dosing for 80 mg ( 2.2 )]. Simvastatin tablets USP 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 …

3 DOSAGE FORMS AND STRENGTHS Simvastatin tablets, USP 5 mg are white to off white, oval, biconvex, film-coated tablets with the logo “B300” debossed on one side and “5”on the other side. Simvastatin tablets, USP 10 mg are peach to dark peach, oval, biconvex, film-coated tablets with the logo “B301” debossed on one side and “10” on the other side. Simvastatin tablets, USP 20 mg are orange to dark orange, oval, biconvex, film-coated tablets with the logo “B302” debossed on one side and “20” on the other side. Simvastatin tablets, USP 40 mg are light pink to pink, oval, biconvex, film-coated tablets with the logo “B303” debossed on one side and “40” on the other side. Simvastatin tablets, USP 80 mg are pink to dark pink, capsule-shaped, film-coated tablets with the logo “B304” debossed on one side and “80” on the other side. Tablets: 5 mg; 10 mg; 20 mg; 40 mg; 80 mg ( 3 )

4 CONTRAINDICATIONS 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 , 6.2 ) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. ( 4 , 5.2 ) Women who are pregnant or may become pregnant. ( 4 , 8.1 ) Nursing mothers. ( 4 , 8.3 ) Simvastatin is contraindicated in the following conditions:Simvastatin is 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 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 ( 6.2 )] . Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see WARNINGS AND PRECAUTIONS ( 5.2 )] . 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) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, 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 use with simvastatin 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. 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, 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 treatment with simvastatin should not breastfeed their infants [see USE IN SPECIFIC POPULATIONS ( 8.3 )] .

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 Accord Healthcare Inc. at 1-866-941-7875 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 simvastatin tablets with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these simvastatin clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued simvastatin tablets 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 to 71 years, 19% women, 100% Caucasians) were treated with 20 to 40 mg per day of simvastatin 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 Simvastatin Tablets and Greater than Placebo in Study 4S % Placebo (N = 2,223) % S imvastatin Tablets (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 simvastatin tablets, 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 simvastatin tablets 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 simvastatin (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 simvastatin 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 simvastatin 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 simvastatin 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was 3xULN was 0.7% in patients taking simvastatin tablets compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking simvastatin tablets and 0.2% of patients taking placebo. The majority of elevated transaminases leading to …

7 DRUG INTERACTIONS • See full prescribing information for details regarding concomitant use of simvastatin with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) • Coumarin Anticoagulants: Obtain INR before simvastatin initiation and monitor INR during simvastatin dosage initiation or adjustment. ( Error! Hyperlink reference not valid. ) • Digoxin: During simvastatin initiation, monitor digoxin levels. ( Error! Hyperlink reference not valid. ) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Simvastatin is a substrate of CYP3A4 and of the transport protein OATP1B1. Simvastatin 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 simvastatin and instructions for preventing or managing them [see WARNINGS AND PRECAUTIONS ( Error! Hyperlink reference not valid. ) AND CLINICAL PHARMACOLOGY ( Error! Hyperlink reference not valid. )] . Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with simvastatin increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher simvastatin dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with Simvastatin is contraindicated [see CONTRAINDICATIONS ( Error! Hyperlink reference not valid. )] . If treatment with a CYP3A4 inhibitor is unavoidable, suspend simvastatin 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 simvastatin. Gemfibrozil may cause myopathy when given alone. Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin is contraindicated [see CONTRAINDICATIONS ( Error! Hyperlink reference not valid. )] . 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 simvastatin. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed simvastatin 10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed simvastatin 20 mg daily [see DOSAGE AND ADMINISTRATION ( Error! Hyperlink reference not valid. )] . 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 simvastatin by 50% if initiating lomitapide. Do not exceed simvastatin 20 mg daily (or simvastatin 40 mg daily for patients who have previously taken simvastatin 80 mg daily chronically) while taking lomitapide [see DOSAGE AND ADMINISTRATION ( 2.1 , Error! Hyperlink reference not valid. )] . Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin 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 tempo …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 4 , 8.1 ) Lactation: Breastfeeding not recommended during treatment with simvastatin tablets. ( 4 , 8.2 ) 8.1 Pregnancy Risk Summary Discontinue simvastatin tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Simvastatin tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin tablets 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 simvastatin tablets 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 to 17 and to pregnant rabbits from gestation days 6 to 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, …

12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

11 DESCRIPTION Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus . After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. 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 molecular formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57. Its structural formula is: Simvastatin USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin tablets USP for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin USP and the following inactive ingredients: ascorbic acid, lactose monohydrate, microcrystalline cellulose, pregelatinized starch (maize), hydroxypropyl cellulose, hypromellose, titanium dioxide, talc, citric acid monohydrate, isopropyl alcohol, magnesium stearate and butylated hydroxyanisole. Simvastatin 5 mg also contains ferric oxide yellow, simvastatin 10 mg and simvastatin 20 mg also contains ferric oxide red and ferric oxide yellow, simvastatin 40 mg and simvastatin 80 mg also contains ferric oxide red. Chemical Structure

10. OVERDOSAGE Significant lethality was observed in mice after a single oral dose of 9 g/m 2 . No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m 2 , respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools. A few cases of overdosage with simvastatin tablets have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

16 HOW SUPPLIED/STORAGE AND HANDLING Simvastatin Tablets USP, 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side. They are supplied as follows: Bottles of 30 NDC 65862-050-30 (Child Resistant Closure) Bottles of 45 NDC 65862-050-45 (Child Resistant Closure) Bottles of 90 NDC 65862-050-90 (Child Resistant Closure) Bottles of 100 NDC 65862-050-01 (Child Resistant Closure) Bottles of 100 NDC 65862-050-00 (Non-Child Resistant Closure) Bottles of 1,000 NDC 65862-050-99 (Non-Child Resistant Closure) Bottles of 2,500 NDC 65862-050-26 (Non-Child Resistant Closure) Simvastatin Tablets USP, 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side. They are supplied as follows: Bottles of 30 NDC 65862-051-30 (Child Resistant Closure) Bottles of 45 NDC 65862-051-45 (Child Resistant Closure) Bottles of 90 NDC 65862-051-90 (Child Resistant Closure) Bottles of 100 NDC 65862-051-01 (Child Resistant Closure) Bottles of 100 NDC 65862-051-00 (Non-Child Resistant Closure) Bottles of 1,000 NDC 65862-051-99 (Non-Child Resistant Closure) Bottles of 2,500 NDC 65862-051-26 (Non-Child Resistant Closure) Simvastatin Tablets USP, 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side. They are supplied as follows: Bottles of 30 NDC 65862-052-30 (Child Resistant Closure) Bottles of 45 NDC 65862-052-45 (Child Resistant Closure) Bottles of 90 NDC 65862-052-90 (Child Resistant Closure) Bottles of 100 NDC 65862-052-01 (Child Resistant Closure) Bottles of 100 NDC 65862-052-00 (Non-Child Resistant Closure) Bottles of 1,000 NDC 65862-052-99 (Non-Child Resistant Closure) Bottles of 2,500 NDC 65862-052-26 (Non-Child Resistant Closure) Simvastatin Tablets USP, 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side. They are supplied as follows: Bottles of 30 NDC 65862-053-30 (Child Resistant Closure) Bottles of 45 NDC 65862-053-45 (Child Resistant Closure) Bottles of 90 NDC 65862-053-90 (Child Resistant Closure) Bottles of 100 NDC 65862-053-01 (Child Resistant Closure) Bottles of 100 NDC 65862-053-00 (Non-Child Resistant Closure) Bottles of 1,000 NDC 65862-053-99 (Non-Child Resistant Closure) Bottles of 2,000 NDC 65862-053-22 (Non-Child Resistant Closure) Simvastatin Tablets USP, 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side. They are supplied as follows: Bottles of 30 NDC 65862-054-30 (Child Resistant Closure) Bottles of 45 NDC 65862-054-45 (Child Resistant Closure) Bottles of 90 NDC 65862-054-90 (Child Resistant Closure) Bottles of 100 NDC 65862-054-00 (Non-Child Resistant Closure) Bottles of 1,000 NDC 65862-054-99 (Non-Child Resistant Closure) Bottles of 3,000 NDC 65862-054-39 (Non-Child Resistant Closure) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].