Simvastatin

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Simvastatin tablets 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.

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

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.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Simvastatin tablets are 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. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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)]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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

11 DESCRIPTION

DESCRIPTION SECTION

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-4­hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),-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 for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: alcohol, anhydrous citric acid, ascorbic acid, colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch (maize), purified water, talc, titanium dioxide, triethyl citrate, and butylated hydroxyanisole is added as a preservative. Simvastatin 10mg, 20mg, and 40 mg contains red and yellow ferric oxide. Simvastatin 80 mg contains red ferric oxide.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

Adults at High Risk of Coronary Heart Disease Events In a randomized, double-blind, placebo-controlled, multi-centered study [the Scandinavian Simvastatin Survival Study (Study 4S)], the effect of therapy with simvastatin on total mortality was assessed in 4,444 adult patients with CHD (history of angina and/or a previous myocardial infarction) and baseline total cholesterol (total-C) between 212 and 309 mg/dL who were on a lipid-lowering diet. In Study 4S, patients were treated with standard care, including lipid-lowering diet, and randomized to either simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 deaths in the simvastatin group vs 189 deaths in the placebo group). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly reduced the risk for the secondary composite endpoint (time to first occurrence of CHD death, definite or probable hospital verified non-fatal MI, silent MI verified by ECG, or resuscitated cardiac arrest) by 34% (p

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

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. They are supplied as follows: NDC 51655-448-52 bottles of 30 NDC 51655-448-26 bottles of 90 Storage Store between 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature]. Dispense in a tightly-closed container as defined in the USP.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that simvastatin tablets may cause myopathy and rhabdomyolysis. Inform patients taking an 80 mg daily dose of simvastatin tablets that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin tablets. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Contraindications (4) , Warnings and Precautions (5.1) , and Drug Interactions (7.1) ] . Hepatic Dysfunction Inform patients that simvastatin tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3) ]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with simvastatin tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)]. Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if simvastatin tablets should be discontinued [see Use in Specific Populations (8.1) ]. Lactation Advise patients that breastfeeding is not recommended during treatment with simvastatin tablets [see Use in Specific Populations (8.2)] . Missed Dose Instruct patients to take simvastatin tablets only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose. Manufactured for: Biocon Pharma Inc., Iselin, New Jersey, 08830-3009 United States of America Manufactured by: Pura Cap Caribe Dorado, PR 00646 USA Revised: 09/2023 BP0141 BPCM0017/07

PATIENT INFORMATION

SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION simvastatin (sim-va-STAT-in) tablets, for oral use Read this Patient Information before you start taking simvastatin tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are simvastatin tablets? Simvastatin tablets is a prescription medicine that contains the cholesterol lowering medicine, simvastatin. Simvastatin tablets is used to lower: the risk of death by lowering the risk of heart disease death. the risk of heart attacks and strokes. the need for certain types of heart and blood vessel procedures to improve blood flow called arterial revascularization in people with known heart, cerebrovascular disease (conditions that affect blood flow and the blood vessels in the brain), peripheral vascular disease (a blood circulation disorder that causes the blood vessels outside of your heart and brain to narrow, block, or spasm), and diabetes, who are at high risk for heart disease problems. Simvastatin tablets are used along with diet to: lower the level of low-density lipoprotein (LDL) cholesterol or “bad” cholesterol in adults with hyperlipidemia (high levels of fat in the blood), and in adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL). treat adults with a type of high cholesterol called primary dysbetalipoproteinemia. lower the level of triglycerides (type of fat in the blood) in adults. Simvastatin tablets are used along with other cholesterol lowering treatments to lower the level of low-density lipoprotein (LDL) in adults with a type of high cholesterol called homozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL). The safety and effectiveness of simvastatin tablets has not been established in children younger than 10 years of age with heterozygous familial hypercholesterolemia (HeFH) or other types of hyperlipidemia (high levels of fat in the blood). Do not take simvastatin tablets if you: take certain medicines called CYP3A4 inhibitors such as: certain antifungal medicines (such as itraconazole, ketoconazole, posaconazole, voriconazole). certain antibiotics (including erythromycin, clarithromycin). HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and darunavir/ritonavir) and cobicistatcontaining products such as (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate). certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir). the antidepressant nefazodone. take medicines called cyclosporine, danazol, or gemfibrozil. have liver problems. are allergic to simvastatin or any of the ingredients in simvastatin tablets. See the end of this Patient Information leaflet for a complete list of ingredients in simvastatin tablets. Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above. Before you take simvastatin tablets, tell your healthcare provider about all of your medical conditions, including if you: have unexplained muscle aches or weakness. have or have had myasthenia gravis (a disease causing general muscle weakness including in some cases muscles used for breathing), ocular myasthenia (a disease causing eye muscle weakness). have kidney problems. have liver problems or drink more than 2 glasses of alcohol daily. have thyroid problems. are 65 years of age or older. are of Chinese descent. are pregnant or plan to become pregnant. If you become pregnant while taking simvastatin tablets, call your healthcare provider right away to discuss stopping simvastatin tablets. are breastfeeding or plan to breastfeed. It is not known if simvastatin passes into your breast milk. Do not breastfeed while taking simvastatin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines. Tell your healthcare provider who prescribes simvastatin tablets if another healthcare provider increases the dose of another medicine you are taking. Simvastatin tablets may affect the way other medicines work, and other medicines may affect how simvastatin tablets works. Especially tell your healthcare provider if you take: digoxin (a drug used to treat irregular heartbeat). coumarin anticoagulants (drugs that prevent blood clots, such as warfarin). Taking simvastatin tablets with certain substances can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: amiodarone or dronedarone (medicines used to treat an irregular heartbeat). verapamil, diltiazem, amlodipine, or ranolazine (medicines used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions). lomitapide (a medicine used to treat a serious and rare genetic cholesterol condition). daptomycin (a drug used to treat complicated skin and bloodstream infections). large doses of niacin or nicotinic acid, especially if you are of Chinese descent. fibric acid derivatives (such as fenofibrate). colchicine (a medicine used to treat gout). grapefruit juice. Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take Simvastatin tablets? Take simvastatin tablets exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking simvastatin tablets without talking to your healthcare provider. Take simvastatin tablets 1 time each day in the evening. If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take 2 doses of simvastatin tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose. While taking simvastatin tablets, continue to follow your cholesterol-lowering diet and to exercise as your healthcare provider told you to. Your healthcare provider may do blood tests to check your cholesterol while you take simvastatin tablets. Your healthcare provider may change your dose of simvastatin tablets if needed. In case of overdose, get medical help or contact a live Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org What are the possible side effects of simvastatin tablets? Simvastatin tablets may cause serious side effects including: Muscle pain, tenderness, and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death. Tell your healthcare provider right away if: you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take simvastatin tablets. you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking simvastatin tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: are taking certain other medicines while you take simvastatin tablets. are 65 years of age or older. are female. have thyroid problems (hypothyroidism) that are not controlled. have kidney problems. are taking higher doses of simvastatin tablets. are Chinese. Liver problems. Your healthcare provider should do blood tests to check your liver before you start taking simvastatin tablets and if you have any symptoms of liver problems while you take simvastatin tablets. Call your healthcare provider right away if you have the following symptoms of liver problems: feeling tired or weak los...

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NDC: 51655-448-26