SIMVASTATIN

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. Simvastatin tablets USP are available for oral administration in strength of 5 mg, 10 mg, 20 mg, 40 mg or 80 mg. Each tablet contains following inactive ingredients: ascorbic acid, citric acid, hydroxy propyl cellulose, hypromellose, iron oxides, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch, talc and titanium dioxide. Butylated hydroxyanisole is added as a preservative. Image

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.

Important Dosage and Administration Information : ( 1 ) Take simvastatin tablets USP orally once daily in the evening. Maximum recommended dosage is simvastatin tablets USP 40 mg once daily. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 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 simvastatin tablets USP 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 simvastatin tablets USP dosage modifications due to drug interactions. ( 2.5 ) 2.1 Important Dosage and Administration Information Take simvastatin tablets USP orally once daily in the evening. The maximum recommended dosage is simvastatin tablets USP 40 mg once daily [see DOSAGE AND ADMINISTRATION ( 2.2 , 2.3 )]. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 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 simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating simvastatin tablets USP, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended dosage range of simvastatin tablets USP 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 simvastatin tablets USP 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 simvastatin tablets USP with the following drugs requires dosage modification of simvastatin tablets USP [see WARNINGS AND PRECAUTIONS ( 5.1 ) AND DRUG INTERACTIONS ( 7.1 )]. Patients taking Lomitapide Reduce the dosage of simvastatin tablets USP by 50%. Do not exceed simvastatin tablets USP 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of simvastatin tablets USP chronically while taking lomitapide) [see DOSAGE AND ADMINISTRATION (2.1)]. Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed simvastatin tablets USP 10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed simvastatin tablets USP 20 mg once daily.

Simvastatin 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 simvastatin tablets USP. 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 simvastatin tablets USP ( 4 , 6.2 )

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 <0.1% in patients treated with simvastatin. Elevations in Liver Enzyme Tests Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of simvastatin. 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 occurred with simvastatin. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. In Study 4S, with a median follow-up of 5.4 years, 1,986 adult patients were treated with simvastatin 20 mg once daily, of whom 37% titrated to 40 mg once daily. The percentage of patients with one or more occurrences of transaminase elevations to >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

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.