Simvastatin

SIMVASTATIN- simvastatin tablet, film coated
RedPharm Drug, Inc.


These highlights do not include all the information needed to use simvastatin tablets safely and effectively. See full prescribing information for simvastatin tablets.
SIMVASTATIN Tablets USP for oral use
Initial U.S. Approval: 1991

RECENT MAJOR CHANGES

Contraindication ( 4) 02/2014

Warnings and Precautions

Myopathy/Rhabdomyolysis ( 5.1) 02/2014

INDICATIONS AND USAGE

Simvastatin tablets 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 dysbeta-lipoproteinemia. ( 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 have not been studied in Fredrickson Types I and V dyslipidemias. ( 1.4)

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 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 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, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets 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)

DOSAGE FORMS AND STRENGTHS

Tablets: 5 mg; 10 mg; 20 mg; 40.0#160;mg; 80 mg ( 3)

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 )

WARNINGS AND PRECAUTIONS

Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80-mg dose. ( 5.1)
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 4, 5.1, 8.5, 8.6)
Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. ( 5.1)
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.2)

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥5.0%) 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

DRUG INTERACTIONS

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations

*
For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.

Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily *
Grapefruit juice Avoid grapefruit juice

Other Lipid-lowering Medications: Use with other fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with simvastatin. ( 5.1, 7.2, 7.4)
Coumarin anticoagulants: Concomitant use with simvastatin tablets prolongs INR. Achieve stable INR prior to starting simvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of simvastatin tablets therapy. ( 7.6)

USE IN SPECIFIC POPULATIONS

Severe renal impairment: patients should be started at 5 mg/day and be closely monitored. ( 2.6, 8.6)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 7/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE
1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events
1.2 Hyperlipidemia
1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)
1.4 Limitations of Use
2. DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
2.2 Restricted Dosing for 80 mg
2.3 Coadministration with Other Drugs
2.4 Patients with Homozygous Familial Hypercholesterolemia
2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia
2.6 Patients with Renal Impairment
2.7 Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products
3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS
5.1 Myopathy/Rhabdomyolysis
5.2 Liver Dysfunction
5.3 Endocrine Function
6. ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7. DRUG INTERACTIONS
7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol
7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers
7.4 Niacin
7.5 Digoxin
7.6 Coumarin Anticoagulants
7.7 Colchicine
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10. OVERDOSAGE
11. DESCRIPTION
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14. CLINICAL STUDIES
14.1 Clinical Studies in Adults
14.2 Clinical Studies in Adolescents
16. HOW SUPPLIED/STORAGE AND HANDLING
17. PATIENT COUNSELING INFORMATION
17.1 Muscle Pain
17.2 Liver Enzymes
17.3 Pregnancy
17.4 Breastfeeding

*
Sections or subsections omitted from the full prescribing information are not listed.

1. INDICATIONS AND USAGE

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 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 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 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 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:

LDL cholesterol remains ≥190 mg/dL; or
LDL cholesterol remains ≥160 mg/dL and

There is a positive family history of premature cardiovascular disease (CVD) or
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 have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

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