SIMVASTATIN tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)
Available from:
Accord Healthcare, Inc.
INN (International Name):
SIMVASTATIN
Composition:
SIMVASTATIN 5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. 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. Simvastatin tablets are indicated to: - Reduce elevated total cholesterol (to
Product summary:
Simvastatin tablets USP 5 mg are brick red coloured, round shaped, biconvex, film coated tablet debossed “SI” on one side and plain on other side. Bottles of 30 Tablets with child-resistant closure (NDC 16729-156-10) Bottles of 90 Tablets with child-resistant closure (NDC 16729-156-15) Bottles of 1000 Tablets (NDC 16729-156-17) Simvastatin tablets USP 10 mg are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed "S 4" on one side and plain on other side. Bottles of 30 Tablets with child-resistant closure (NDC 16729-004-10) Bottles of 60 Tablets with child-resistant closure (NDC 16729-004-12) Bottles of 90 Tablets with child-resistant closure (NDC 16729-004-15) Bottles of 1000 Tablets with child-resistant closure (NDC 16729-004-17) Simvastatin tablets USP 20 mg are brick red coloured oval shaped, biconvex, film-coated tablets, debossed "S 5" on one side and plain on other side. Bottles of 30 Tablets with child-resistant closure (NDC 16729-005-10) Bottles of 60 Tablets with child-resistant closure (NDC 16729-005-12) Bottles of 90 Tablets with child-resistant closure (NDC 16729-005-15) Bottles of 1000 Tablets with child-resistant closure (NDC 16729-005-17) Simvastatin tablets USP 40 mg are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed "S 6" on one side and plain on other side. Bottles of 30 Tablets with child-resistant closure (NDC 16729-006-10) Bottles of 60 Tablets with child-resistant closure (NDC 16729-006-12) Bottles of 90 Tablets with child-resistant closure (NDC 16729-006-15) Bottles of 1000 Tablets with child-resistant closure (NDC 16729-006-17) Simvastatin tablets USP 80 mg are brick red coloured,capsule-shaped, biconvex, film-coated tablets, debossed with "SMV" on one side and "80" on the other side. Bottles of 30 Tablets with child-resistant closure (NDC 16729-007-10) Bottles of 60 Tablets with child-resistant closure (NDC 16729-007-12) Bottles of 90 Tablets with child-resistant closure (NDC 16729-007-15) Bottles of 1000 Tablets with child-resistant closure (NDC 16729-007-17) Storage Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. "Dispense in tight containers as defined in the USP"
Authorization status:
Abbreviated New Drug Application
Authorization number:
16729-004-10, 16729-004-12, 16729-004-15, 16729-004-17, 16729-005-10, 16729-005-12, 16729-005-15, 16729-005-17, 16729-006-10, 16729-006-12, 16729-006-15, 16729-006-17, 16729-007-10, 16729-007-12, 16729-007-15, 16729-007-17, 16729-156-10, 16729-156-15, 16729-156-17

SIMVASTATIN- simvastatin tablet, film coated

Accord Healthcare, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

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, for oral use

Initial U.S. Approval:1991

RECENT MAJOR CHANGES

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)

10/2020

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 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

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

Niacin (≥1 g/day)

For Chinese patients, not recommended 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

Daptomycin

Temporarily suspend simvastatin

Grapefruit juice

Avoid grapefruit juice

Other Lipid-lowering Medications: Use with other fibrate products increases the risk of adverse skeletal muscle effects.

Caution should be used when prescribing with simvastatin. ( 5.1, 7.2)

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)

Chinese patients: May be at higher risk of myopathy; monitor appropriately. ( 5.1, 8.8)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 1/2020

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

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

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.

7.7 Colchicine

7.8 Daptomycin

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

8.8 Chinese Patients

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

FULL PRESCRIBING INFORMATION

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)

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

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:

1. LDL cholesterol remains ≥190 mg/dL; or

2. 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).

2. DOSAGE AND ADMINISTRATION

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 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 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 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, 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.

2.3 Coadministration with Other Drugs

Patients taking Verapamil, Diltiazem, or Dronedarone

The dose of simvastatin tablets 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 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 [see Dosage and Administration, Restricted Dosing

for 80 mg (2.2)] . Simvastatin tablets 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 of lomitapide; therefore, the dose

of simvastatin tablets should be reduced by 50% if initiating lomitapide. Simvastatin tablets dosage

should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken simvastatin tablets

80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking

lomitapide.

2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia

The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing

range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be

individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines

and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more.

2.6 Patients with Renal Impairment

Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should

not be necessary in patients with mild to moderate renal impairment. However, caution should be

exercised when simvastatin tablets are administered to patients with severe renal impairment; such

patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and

Clinical Pharmacology (12.3)].

3. DOSAGE FORMS AND STRENGTHS

Simvastatin tablets 5 mg are brick red colored, round shaped, biconvex, film coated tablet debossed

“SI” on one side and plain on other side.

Simvastatin tablets 10 mg are brick red colored,oval shaped, biconvex,film-coated tablets, debossed

“S 4” on one side and plain on the other side

Simvastatin tablets 20 mg are brick red colored,oval shaped, biconvex,film-coated tablets, debossed

“S 5” on one side and plain on the other side.

Simvastatin tablets 40 mg are brick red colored,oval shaped, biconvex,film-coated tablets,debossed

“S 6” on one side and plain on the other side

Simvastatin tablets 80 mg are brick red colored, capsule-shaped, biconvex, film-coated tablets,

debossed with “SMV” on one side and “80” on the other side

4. CONTRAINDICATIONS

Simvastatin tablets are 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 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

tablets 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 tablets 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 tablets

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 tablets

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 tablets

should not breastfeed their infants [see Use in Specific Populations (8.3)] .

5. WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with

creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the

form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare

fatalities have occurred. The risk of myopathy is increased by elevated plasma levels of simvastatin and

simvastatin acid. Predisposing factors for myopathy include advanced age (≥65 years), female gender,

uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for

National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood

Cholesterol Levels in Children and Adolescents. Pediatrics 89(3):4 95-501. 1992.

myopathy [See Use in Specific Populations (8.8)] .

In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately

60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of

myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of

myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In

these trials, patients were carefully monitored and some interacting medicinal products were excluded

The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in

which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were

enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was

approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80

mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients

were carefully monitored and some interacting medicinal products were excluded

In a clinical trial in which 12,064 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 creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients

on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence

of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was

approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy,

including rhabdomyolysis, was highest during the first year and then notably decreased during the

subsequent years of treatment. In this trial, patients were carefully monitored and some interacting

medicinal products were excluded.In a clinical trial in which 12,064 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 creatine kinase [CK] >10 times

upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02%

for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times

ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day.

The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then

notably decreased during the subsequent years of treatment. In this trial, patients were carefully

monitored and some interacting medicinal products were excluded.

The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared

with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower

doses of simvastatin. Therefore, the 80-mg dose of simvastatin should be used only in patients who

have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of

muscle toxicity . If, however, a patient who is currently tolerating the 80-mg dose of simvastatin needs

to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for

simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug

interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and

to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment

should be discontinued immediately . The risk of myopathy, including rhabdomyolysis, is greater in

patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-

lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of

simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for

12 months or more) without evidence of muscle toxicity [See Dosage and Administration, Restricted

Dosing for 80 mg (2.2)] . If, however, a patient who is currently tolerating the 80-mg dose of simvastatin

needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for

simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug

interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and

to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment

should be discontinued immediately [See Warnings and Precautions (5.2)] .

There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune

myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and

elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy

showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive

agents.There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune

myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and

elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy

showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive

agents.

In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued.

Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose

dose is being increased, but there is no assurance that such monitoring will prevent myopathy. All

patients starting therapy with simvastatin, or whose dose of simvastatin is being increased,

should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly

any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or

fever or if muscle signs and symptoms persist after discontinuing simvastatin. Simvastatin

therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases,

muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK

determinations may be considered in patients starting therapy with simvastatin or whose dose is being

increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had

complicated medical histories, including renal insufficiency usually as a consequence of long-standing

diabetes mellitus. Such patients merit closer monitoring. Simvastatin therapy should be discontinued if

markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Simvastatin therapy should

also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to

the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;

trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.Many of the

patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical

histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus.

Such patients merit closer monitoring. Simvastatin therapy should be discontinued if markedly elevated

CPK levels occur or myopathy is diagnosed or suspected. Simvastatin therapy should also be

temporarily withheld in any patient experiencing an acute or serious condition predisposing to the

development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;

trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and

simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which

inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of

myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide

antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease

inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or

grapefruit juice . Combination of these drugs with simvastatin is contraindicated. If short-term treatment

with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the

course of treatment . The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels

of simvastatin and simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4.

Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may

increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole,

the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV

protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing

products, or grapefruit juice [See Clinical Pharmacology (12.3)] . Combination of these drugs with

simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable,

therapy with simvastatin must be suspended during the course of treatment [See Contraindications (4) and

Drug Interactions (7.1)] .

The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated . The

combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [See

Contraindications (4) and Drug Interactions (7.1 and 7.2)] .

Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause

myopathy when given alone and the risk is increased when they are coadministered . Caution should be

used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given

alone and the risk is increased when they are coadministered [see Drug Interactions (7.2)] .

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with

colchicine, and caution should be exercised when prescribing simvastatin with colchicine . Cases of

myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with

colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug

Interactions (7.7)] .

The benefits of the combined use of simvastatin with the following drugs should be carefully weighed

against the potential risks of combinations: other lipid-lowering drugs (fibrates or, for patients with

HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine . The

benefits of the combined use of simvastatin with the following drugs should be carefully weighed

against the potential risks of combinations: other lipid-lowering drugs (fibrates or, for patients with

HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see

Dosage and Administration (2.4) and Drug Interactions (7.3)] .

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered

with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. [see Drug Interactions (7.4)]

Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin.

Temporarily suspend simvastatin in patients taking daptomycin [see Drug Interactions (7.8)] .

Prescribing recommendations for interacting agents are summarized in Table 1 . Prescribing

recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration

recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration

(2.3, 2.4), Drug Interactions (7), Clinical Pharmacology (12.3)] .

Table 1: Drug Interactions Associated with Increased Risk of

Myopathy/Rhabdomyolys is

Interacting Agents

Prescribing Recommendations

Strong

CYP3A4

Inhibitors,

e.g.:Strong

CYP3A4

Inhibitors, e.g.:

ItraconazoleItraconazole

KetoconazoleKetoconazole

PosaconazolePosaconazole

VoriconazoleVoriconazole

ErythromycinErythromycin

ClarithromycinClarithromycin

TelithromycinTelithromycin

protease

inhibitorsHIV

protease inhibitors

BoceprevirBoceprevir

TelaprevirTelaprevir

NefazodoneNefazodone

Cobicistat-containing

productsCobicistat-containing

products

GemfibrozilGemfibrozil

CyclosporineCyclosporine

DanazolDanazol

Contraindicated with simvastatin

Niacin

(≥1

g/day)Niacin

(≥1

g/day)

For Chinese patients, not recommended with

simvastatin

VerapamilVerapamil

DiltiazemDiltiazem

DronedaroneDronedarone

Do not exceed 10 mg simvastatin daily

AmiodaroneAmiodarone

AmlodipineAmlodipine

RanolazineRanolazine

Do not exceed 20 mg simvastatin daily

LomitapideLomitapide

For patients with HoFH, do not exceed 20

mg simvastatin daily

DaptomycinDaptomycin

Temporarily suspend simvastatin

Grapefruit

juiceGrapefruit

juice

Avoid grapefruit juice

5.2 Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in

approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was

interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment

levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was

no evidence of hypersensitivity.

In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)] , the number of patients

with more than one transaminase elevation to > 3X ULN, over the course of the study, was not

significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated

transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group

(n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with

normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to > 3X

ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up)

of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All

of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic

transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg

dose, respectively. No patients developed persistent liver function abnormalities following the initial

6 months of treatment at a given dose.

It is recommended that liver function tests be performed before the initiation of treatment, and

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 4 0 mg

simvastatin when taking lomitapide.

thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal

hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical

symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, promptly

interrupt therapy. If an alternate etiology is not found do not restart simvastatin. Note that ALT may

emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and

Precautions (5.1)] .

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or

have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are

contraindications to the use of simvastatin.

Moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy

with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often

transient, were not accompanied by any symptoms and did not require interruption of treatment.

5.3 Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase

inhibitors, including simvastatin.

6. ADVERSE REACTIONS

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 the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median

duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse

reactions. The most common adverse reactions that led to treatment discontinuation were:

gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported

adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory

infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).

Scandinavian Simvastatin Survival Study

In 4S involving 4,444 (age range 35 to 71 years, 19% women, 100% Caucasians) treated with 20 to

40 mg/day of simvastatin (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions

reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

Table 2: Adverse Reactions Reported Regardless of Causality by ≥2% of

Patients Treated with Simvastatin Tablets and Greater than Placebo in 4S

Simvastatin Tablets

(N = 2,221)

%

Placebo

(N = 2,223)

%

Body as a Whole

Edema/swelling

Abdominal pain

Cardiovascular System Disorders

Atrial fibrillation

Digestive System Disorders

Constipation

Gastritis

Endocrine Disorders

Diabetes mellitus

Musculoskeletal Disorders

Myalgia

Nervous System / Psychiatric Disorders

Headache

Insomnia

Vertigo

Respiratory System Disorders

Bronchitis

Sinusitis

Skin / Skin Appendage Disorders

Eczema

Urogenital System Disorders

Infection, urinary tract

Heart Protection Study

In the Heart Protection Study (HPS), involving 20,536 patients (age range 40 to 80 years, 25% women,

97% Caucasians, 3% other races) treated with simvastatin tablets 40 mg/day (n=10,269) or placebo

(n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any

adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients

treated with simvastatin tablets compared with 5.1% in patients treated with placebo. The incidence of

myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin tablets.

Other Clinical Studies

In a clinical trial in which 12,064 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 creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients

on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence

of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was

approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy,

including rhabdomyolysis, was highest during the first year and then notably decreased during the

subsequent years of treatment. In this trial, patients were carefully monitored and some interacting

medicinal products were excluded.

Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and

asthenia.

Laboratory Tests

Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions

(5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5%

of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions.

This was attributable to the noncardiac fraction of CK. [See Warnings and Precautions (5.1).]

Adolescent Patients (ages 10 to 17 years)

In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10

to 17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with

heterozygous familial hypercholesterolemia (n=175), treated with placebo or simvastatin tablets (10 to

40 mg daily), the most common adverse reactions observed in both groups were upper respiratory

infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies

(14.2)] .

6.2 Postmarketing Experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generally

not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during postapproval use of simvastatin:

pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous

membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia,

peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis,

hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [See

Warnings and Precautions (5.1)]

An apparent hypersensitivity syndrome has been reported rarely which has included some of the

following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia

rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia,

positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity,

fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including

Stevens-Johnson syndrome.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness,

amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been

reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation,

with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

7. DRUG INTERACTIONS

7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol

Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a

substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity;

therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and

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