Simvastatin

1 INDICATIONS AND USAGE Simvastatin tablets USP are 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. Simvastatin tablets USP are 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.

5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher simvastatin dosage. Chinese patients may be at higher risk for myopathy. Discontinue simvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue simvastatin 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 simvastatin 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 simvastatin if IMNM is suspected. ( 5.2 ) 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 simvastatin. ( 4 , 5.3 , 8.7 ) 5.1 Myopathy and Rhabdomyolysis Simvastatin 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 simvastatin. In clinical studies 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 (10xULN), 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 study 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 >40xULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively [see ADVERSE REACTIONS ( 6.1 )]. 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 simvastatin dosage; Chinese patients on simvastatin may be at higher risk for myopathy [see CONTRAINDICATIONS ( 4 ), DRUG INTERACTIONS ( 7.1 ), AND USE IN SPECIFIC POPULATIONS ( 8.8 )]. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking simvastatin 80 mg daily compared with patients taking lower simvastatin dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [see ADVERSE REACTIONS ( 6.1 )]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend simvastatin during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of simvastatin with gemfibrozil, cyclosporine, or danazol is also contraindicated [see CONTRAINDICATIONS ( 4 ) AND DRUG INTERACTIONS ( 7.1 )]. Simvastatin dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see DOSAGE AND ADMINISTRATION ( 2.5 )]. Simvastatin 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 [see DRUG INTERACTIONS ( 7.1 )]. Use the 80 mg daily dosage of simvastatin only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see DOSAGE AND ADMINISTRATION ( 2.1 )] . If patients treated with an 80 mg daily dosage of simvastatin tablet USP are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [SEE DRUG INTERACTIONS ( 7.1 )]. Discontinue simvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if simvastatin is discontinued. Temporarily discontinue simvastatin 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 simvastatin dosage and advise patients receiving an 80 mg daily dosage of simvastatin tablet USP 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. 5.2 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 simvastatin if IMNM is suspected 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of simvastatin [see ADVERSE REACTIONS ( 6.1 )] . 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 simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with simvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. 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 simvastatin initiation and when clinically indicated thereafter. Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS ( 4 )] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue simvastatin. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 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 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 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 and Greater than Placebo in Study 4S % Placebo (N = 2,223) % Simvastatin (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, 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 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 compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking simvastatin 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 Hypercholesterolemia In a 48-week clinical study in pediatric patients 10 years of age and older (43% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with HeFH (n=175), treated with placebo or simvastatin (10 – 40 mg daily), the most common adverse reactions were upper respiratory infection, headache, abdominal pain, and nausea [see USE IN SPECIFIC POPULATIONS (8.4) AND CLINICAL STUDIES ( 14 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of simvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as whole fever, chills, malaise, asthenia Blood and Lymphatic System Disorders anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders pancreatitis, vomiting Hepatic and Pancreatic Disorders hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders muscle cramps, immune-mediated necrotizing myopathy, polymyalgia rheumatica, arthritis Nervous System Disorders dizziness, depression, paresthesia, peripheral neuropathy. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Skin and Subcutaneous Tissue Disorders pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome Respiratory and Thoracic interstitial lung disease, dyspnea Reproductive System Disorders erectile dysfunction

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. ( 2.5 , 7.1 ) Coumarin Anticoagulants: Obtain INR before simvastatin initiation and monitor INR during simvastatin dosage initiation or adjustment. ( 7.2 ) Digoxin: During simvastatin initiation, monitor digoxin levels. ( 7.2 ) 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 ( 5.1 ) AND CLINICAL PHARMACOLOGY ( 12.3 )] . 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 ( 4 )] . 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 ( 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 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 ( 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 simvastatin by 50% if initiating lomitapide. Do not exceed simvastatin 20 mg daily (or simvastatin 40 mg daily for patients who have previously taken an 80 mg daily dosage of simvastatin 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 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 temporarily suspending simvastatin 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 simvastatin. 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 simvastatin with lipid-modifying dosages of niacin is not recommended in Chinese patients [see USE IN SPECIFIC POPULATIONS ( 8.8 )]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with simvastatin 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 simvastatin. Intervention : Consider if the benefit of using fibrates concomitantly with simvastatin 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 simvastatin. Intervention: Consider if the benefit of using colchicine concomitantly with simvastatin 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 simvastatin. 7.2 Simvastatin Effects on Other Drugs Table 3 presents Simvastatin’s effect on other drugs and instructions for preventing or managing them. Table 3: Simvastatin Effects on Other Drugs Coumarin Anticoagulants Clinical Impact: Simvastatin 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 and warfarin. Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting simvastatin 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 simvastatin may result in elevated plasma digoxin concentrations [ see CLINICAL PHARMACOLOGY ( 12.3 ) ]. Intervention: Monitor digoxin levels in patients taking digoxin when simvastatin is initiated.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended during treatment with simvastatin. ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin 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 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 recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta. 8.2 Lactation Risk Summary There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with simvastatin [see USE IN SPECIFIC POPULATIONS (8.1), CLINICAL PHARMACOLOGY ( 12.1 )]. 8.4 Pediatric Use The safety and effectiveness of simvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of simvastatin for this indication is based on a double-blind, placebo-controlled clinical study in 175 pediatric patients (99 boys and 76 girls at least 1 year post-menarche) 10 years of age and older with HeFH. In this limited controlled study, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of simvastatin have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). 8.5 Geriatric Use Of the total number of simvastatin-treated patients in clinical studies 1,021 (23%) patients, 5,366 (52%) patients, and 363 (15%) patients were ≥65 years old, respectively. In Study HPS, 615 (6%) patients were ≥75 years old [see CLINICAL STUDIES ( 14 )] . In a clinical study of patients treated with simvastatin 80 mg daily, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. A pharmacokinetic study with simvastatin use showed the mean plasma level of total inhibitors to be approximately 45% higher in geriatric patients between 70-78 years of age compared with patients between 18-30 years of age [see CLINICAL PHARMACOLOGY ( 12.3 )] . 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment (CLcr 15 – 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see DOSAGE AND ADMINISTRATION ( 2.4 ), WARNINGS AND PRECAUTIONS ( 5.1 )] . Simvastatin is not available in a 5 mg strength. Use another simvastatin product to initiate dosing in such patients. 8.7 Hepatic Impairment Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS ( 4 ), WARNINGS AND PRECAUTIONS ( 5.3 )] . 8.8 Chinese Patients In a clinical study in which patients at high risk of CVD were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). In this study, the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%. Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of simvastatin with lipid-modifying doses of niacin-containing products (≥1 g/day niacin) is not recommended in Chinese patients [see WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS ( 7.1 )].

8.1 Pregnancy Risk Summary Discontinue simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin 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 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 recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta.