SIMVASTATIN tablet

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Active ingredient:
SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)
Available from:
Micro Labs Limited
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. Simva
Product summary:
Simvastatin Tablets, USP 5 mg are Light yellow colored, oblong shaped, biconvex, film-coated tablets, engraved with ‘5’ on one face and ‘SVT’ on the other. They are supplied as follows: NDC 42571-005-30 unit of use bottles of 30 NDC 42571-005-60 unit of use bottles of 60 NDC 42571-005-90 unit of use bottles of 90 NDC 42571-005-05 unit of use bottles of 500 NDC 42571-005-10 bottles of 1000. Simvastatin Tablets, USP 10 mg are White to off white oblong shaped, biconvex, film-coated tablets, engraved with ‘10’ on one face and ‘SVT’ on the other. They are supplied as follows: NDC 42571-010-30 unit of use bottles of 30 NDC 42571-010-60 unit of use bottles of 60 NDC 42571-010-90 unit of use bottles of 90 NDC 42571-010-05 unit of use bottles of 500 NDC 42571-010-10 bottles of 1000. Simvastatin Tablets, USP 20 mg are White to off white oblong shaped, biconvex, film-coated tablets, engraved with ‘20’ on one face and ‘SVT’ on the other. They are supplied as follows: NDC 42571-020-30 unit of use bottles of 30 NDC 42571-020-60 unit of use bottles of 60 NDC 42571-020-90 unit of use bottles of 90 NDC 42571-020-05 unit of use bottles of 500 NDC 42571-020-10 bottles of 1000. Simvastatin Tablets, USP 40 mg are White to off white oblong shaped, biconvex, film-coated tablets, engraved with ‘40’ on one face and ‘SVT’ on the other. They are supplied as follows: NDC 42571-040-30 unit of use bottles of 30 NDC 42571-040-60 unit of use bottles of 60 NDC 42571-040-90 unit of use bottles of 90 NDC 42571-040-05 unit of use bottles of 500 NDC 42571-040-10 bottles of 1000. Simvastatin Tablets, USP 80 mg are White to off white oblong shaped, biconvex, film-coated tablets, engraved with ‘80’ on one face and ‘SVT’ on the other. They are supplied as follows: NDC 42571-080-30 unit of use bottles of 30 NDC 42571-080-60 unit of use bottles of 60 NDC 42571-080-90 unit of use bottles of 90 NDC 42571-080-05 unit of use bottles of 500 NDC 42571-080-10 bottles of 1000.   Storage   Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) [see USP Controlled Room Temperature]   Dispense in tightly-closed container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
42571-005-05, 42571-005-10, 42571-005-30, 42571-005-60, 42571-005-90, 42571-010-05, 42571-010-10, 42571-010-30, 42571-010-60, 42571-010-90, 42571-020-05, 42571-020-10, 42571-020-30, 42571-020-60, 42571-020-90, 42571-040-05, 42571-040-10, 42571-040-30, 42571-040-60, 42571-040-90, 42571-080-05, 42571-080-10, 42571-080-30, 42571-080-60, 42571-080-90

SIMVASTATIN- simvastatin tablet

Micro Labs Limited

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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) 3/2019

Warnings and Precautions Myopathy/Rhabdomyolisis (

5.1) 3/2019

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%) are: upper respiratory infection, headache, abdominal pain, constipation,

and nausea. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 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,

e rythromycin,

clarithromycin,

telithromycin,

protease

inhibitors ,

boceprevir,

telaprevir,

nefazodone,

cobicistat-containing

products), gemfibrozil, cyclosporine, danazol

Contraindicated with simvastatin

Niacin(≥1g/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*

Grapefruit juice

Avoid grapefruit juice

* 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.

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 prolongs INR. Achieve stable INR prior to starting

simvastatin. Monitor INR frequently until stable upon initiation or alteration of simvastatin 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: 9/2019

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

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

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 IV 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:

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

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 should be reduced by 50% if initiating lomitapide. Simvastatin dosage should not exceed

20 mg/day (or 40 mg/day for patients who have previously taken simvastatin 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 1

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

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

Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.

2.6 Patients with Renal Impairment

Because simvastatin tablet does 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 tablet is 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

Tablets simvastatin 5 mg are Light yellow colored, oblong shaped, biconvex, film-coated tablets,

engraved with ‘5’ on one face and ‘SVT’ on the other.

Tablets simvastatin 10 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘10’ on one face and ‘SVT’ on the other.

Tablets simvastatin 20 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘20’ on one face and ‘SVT’ on the other.

Tablets simvastatin 40 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘40’ on one face and ‘SVT’ on the other.

Tablets simvastatin 80 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘80’ on one face and ‘SVT’ on the other.

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 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 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 [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), Drug Interactions (7.3)] .

Cases of 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)].

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 (

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

Table 1:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

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*

Grapefruit juice

Avoid grapefruit juice

* 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. *

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.

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

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 HbA

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%), 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 and Greater than Placebo in 4S

Simvastatin

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

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

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 (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

rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1) and

Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on

CYP3A4 is contraindicated [see Contraindications (4)] . If treatment with itraconazole, ketoconazole,

posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with

simvastatin must be suspended during the course of treatment.

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant

administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated

[see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4)and Warnings and Precautions

(5.1)].

Other fibrates: Caution should be used when prescribing with simvastatin [see Warnings and Precautions

(5.1)].

7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of

amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or

amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1), and Table 3 in

Clinical Pharmacology (12.3)] .

7.4 Niacin

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-

modifying doses (≥1 g/day niacin) of niacin-containing products. The risk of myopathy is greater in

Chinese patients. In a clinical trial (median follow-up 3.9 years) involving patients at high risk of

cardiovascular disease 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 (≥1 g/day) of niacin. Coadministration of simvastatin tablets with

lipid-modifying doses (≥1 g/day) of niacin is not recommended in Chinese patients. It is unknown if this

risk applies to other Asian patients [see Warnings and Precautions (5.1) and Use in Specific Populations

(8.8)].

7.5 Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in

digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when

simvastatin is initiated [see Clinical Pharmacology (12.3)].

7.6 Coumarin Anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients,

simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin

time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from

2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident

bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin

anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting

simvastatin and frequently enough during early therapy to ensure that no significant alteration of

prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can

be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose

of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy

has not been associated with bleeding or with changes in prothrombin time in patients not taking

anticoagulants.

7.7 Colchicine

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

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category X [ See Contraindications (4).]

Simvastatin is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer

no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal

no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal

fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs

during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia

therapy. There are no adequate and well-controlled studies of use with simvastatin during pregnancy;

however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal

reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum

cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol

derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and

possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin

may cause fetal harm when administered to a pregnant woman. If simvastatin is used during pregnancy or

if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential

hazard to the fetus. There are rare reports of congenital anomalies following intrauterine exposure to

statins. In a review

of approximately 100 prospectively followed pregnancies in women exposed to

simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous

abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However,

the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the

background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was

discontinued during the first trimester when pregnancy was identified.

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted

in 3 times the human exposure based on mg/m

surface area. However, in studies with another

structurally-related statin, skeletal malformations were observed in rats and mice.

Women of childbearing potential, who require treatment with simvastatin for a lipid disorder, should be

advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin

should be considered. If pregnancy occurs, simvastatin should be immediately discontinued.

Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of

Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446,

1996.

8.3 Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in

this class is excreted in human milk and because of the potential for serious adverse reactions in nursing

infants, women taking simvastatin should not nurse their infants. A decision should be made whether to

discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother

[see Contraindications (4)] .

8.4 Pediatric Use

Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial

hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls

who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile

similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in

this population. In this limited controlled study, there was no significant effect on growth or sexual

maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and

Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).] Adolescent females should be

counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4)

and Use in Specific Populations (8.1)] . Simvastatin has not been studied in patients younger than 10 years

of age, nor in pre-menarchal girls.

8.5 Geriatric Use

Of the 2,423 patients who received simvastatin in Phase III clinical studies and the 10,269 patients in the

Heart Protection Study who received simvastatin, 363 (15%) and 5,366 (52%), respectively were ≥65

years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness

were observed between these subjects and younger subjects, and other reported clinical experience has

not identified differences in responses between the elderly and younger patients, but greater sensitivity

of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor

for myopathy, simvastatin should be prescribed with caution in the elderly. [See Clinical Pharmacology

(12.3).]

A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be

approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients

between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering

efficacy was at least as great in elderly patients compared with younger patients, and simvastatin

significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In

HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806

patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-

coronary revascularization procedures, and stroke were similar in older and younger patients [see

Clinical Studies ( 14.1)] . In HPS, among 32,145 patients entering the active run-in period, there were 2

cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of

myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at

baseline), of whom one was over 75. There were no overall differences in safety between older and

younger patients in either 4S or HPS.

Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis,

simvastatin should be prescribed with caution in the elderly. In a clinical trial of patients treated with

simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including

rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1) and

Clinical Pharmacology (12.3).]

8.6 Renal Impairment

Caution should be exercised when simvastatin is administered to patients with severe renal impairment.

[See Dosage and Administration (2.6).]

8.7 Hepatic Impairment

Simvastatin is contraindicated in patients with active liver disease which may include unexplained

persistent elevations in hepatic transaminase levels [see Contraindications (4) and Warnings and

Precautions (5.2)] .

8.8 Chinese Patients

In a clinical trial in which patients at high risk of cardiovascular disease were treated with simvastatin

40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-

Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). The incidence of

myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day

coadministered with extended-release niacin 2 g/day was 1.24%.

Chinese patients may be at higher risk for myopathy, monitor patients appropriately. Coadministration of

simvastatin with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products is not

recommended in Chinese patients [see Warnings and Precautions (5.1), Drug Interactions (7.4)].

10 OVERDOSAGE

Significant lethality was observed in mice after a single oral dose of 9 g/m

. No evidence of lethality

was observed in rats or dogs treated with doses of 30 and 100 g/m

, respectively. No specific

diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and

mucoid stools.

A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All

patients recovered without sequelae. Supportive measures should be taken in the event of an overdose.

The dialyzability of simvastatin and its metabolites in man is not known at present.

11 DESCRIPTION

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-4-

hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The

molecular formula of simvastatin is C

and its molecular weight is 418.57. Its structural

formula is:

Simvastatin USP is a white to off-white, nonhygroscopic, crystalline powder that is practically

insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Tablets simvastatin for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of

simvastatin USP and the following inactive ingredients: ascorbic acid, citric acid monohydrate,

hydroxypropyl cellulose, hypromellose, iron oxide yellow (5 mg), lactose monohydrate, magnesium

stearate, microcrystalline cellulose, pregelatinized maize starch, talc, and titanium dioxide. Butylated

hydroxyanisole is added as a preservative.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after

administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-

CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate

limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG

and increases HDL-C.

12.2 Pharmacodynamics

Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as

decreased levels of HDL-C are associated with the development of atherosclerosis and increased

cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising

HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been

determined.

12.3 Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzed in vivoto the corresponding β hydroxyacid, a potent

inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in

pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base

hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of

simvastatin.

Following an oral dose of

C-labeled simvastatin in man, 13% of the dose was excreted in urine and

60% in feces. Plasma concentrations of total radioactivity (simvastatin plus

C-metabolites) peaked at 4

hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes

extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low

(<5%).

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human

plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-

derived radioactivity crossed the blood-brain barrier.

The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of

simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. Peak plasma

concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While

the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from

linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg.

Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was

administered immediately before an American Heart Association recommended low-fat meal.

In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40

mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately

45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly

(n=1522), suggests that there were no overall differences in safety between elderly and younger patients

[see Use in Specific Populations (8.5)] .

Kinetic studies with another statin, having a similar principal route of elimination, have suggested that

for a given dose level higher systemic exposure may be achieved in patients with severe renal

insufficiency (as measured by creatinine clearance).

Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of

medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma

concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has

been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase

in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and

increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1)] .

Table 3:

Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Coadminis tered

Drug

or Grapefruit

Juice

Dosing of

Coadministered

Drug or Grapefruit

Juice

Dosing of

Simvastatin

Geometric Mean Ratio

(Ratio * with / without

coadministered drug)

No Effect = 1.00

AUC

C

Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]

Telithromycin

200 mg QD for 4 days

80 mg

simvastatin acid

simvastatin

Nelfinavir

1250 mg BID for 14

days

20 mg QD for 28

days

simvastatin acid

simvastatin

Itraconazole

200 mg QD for 4 days

80 mg

simvastatin acid

simvastatin

13.1

13.1

Posaconazole

100 mg (oral

suspension) QD for 13

days

200 mg (oral

suspension) QD for 13

days

40 mg

40 mg

simvastatin acid

simvastatin

simvastatin acid

simvastatin

10.3

10.6

11.4

Gemfibrozil

600 mg BID for 3 days

40 mg

simvastatin acid

simvastatin

2.85

1.35

2.18

0.91

Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]

Grapefruit

Juice

(high dose)

200 mL

double-

strength

60 mg single dose

simvastatin acid

simvastatin

Grapefruit

Juice

(low dose)

8 oz

(about

237mL) of

single-

strength

20 mg single dose

simvastatin acid

simvastatin

Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see

Warnings and Precautions (5.1)]

Verapamil SR

240 mg

QD Days

1 to 7 then

240 mg

BID on

Days 8 to

80 mg on Day 10

simvastatin acid

simvastatin

Diltiazem

120 mg

BID for

10 days

80 mg on Day 10

simvastatin acid

simvastatin

2.69

3.10

2.69

2.88

max

Diltiazem

120 mg

BID for

14 days

20 mg on Day 14

simvastatin

Dronedarone

400 mg

BID for

14 days

40 mg QD for 14 days simvastatin acid

simvastatin

1.96

3.90

2.14

3.75

Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see

Warnings and Precautions (5.1)]

Amiodarone

400 mg

QD for 3

days

40 mg on Day 3

simvastatin acid

simvastatin

1.75

1.76

1.72

1.79

Amlodipine

10 mg QD

x 10 days

80 mg on Day 10

simvastatin acid

simvastatin

1.58

1.77

1.56

1.47

Ranolazine SR

1000 mg

BID for 7

days

80 mg on Day 1 and

Days 6 to 9

simvastatin acid

simvastatin

2.26

1.86

2.28

1.75

Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg

simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based

on clinical experience

Lomitapide

60 mg

QD for 7

days

40 mg single dose

simvastatin acid

simvastatin

Lomitapide

10 mg QD

for 7 days

20 mg single dose

simvastatin acid

simvastatin

No dosing adjustments required for the following:

Fenofibrate

160 mg

QD X 14

days

80 mg QD on Days 8

to 14

simvastatin acid

simvastatin

0.64

0.89

0.89

0.83

Niacin

extended-

release

2 g single

dose

20 mg single dose

simvastatin acid

simvastatin

1.84

1.08

Propranolol

80 mg

single

dose

80 mg single dose

total inhibitor

active inhibitor

0.79

0.79

↓ from 33.6 to

21.1 ng·eq/mL

↓ from 7 to

4.7 ng·eq/mL

Results based on a chemical assay except results with propranolol as indicated.

Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin,

clarithromycin, HIV protease inhibitors, and nefazodone.

Simvastatin acid refers to the β-hydroxyacid of simvastatin.

The effect of amounts of grapefruit juice between those used in these two studies on simvastatin

pharmacokinetics has not been studied.

Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was

administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes

following single dose simvastatin on Day 3.

Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was

administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.

In a study of 12 healthy volunteers, simvastatin at the 80 mg dose had no effect on the metabolism of the

probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates

that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels

of other drugs metabolized by CYP3A4.

Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean

levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and

400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times

higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC)

after an 80 mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid-

and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the

liver was significantly increased in mid- and high-dose females. Drug treatment also significantly

increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the

Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in

controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a

tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80

mg simvastatin as measured by AUC).

In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence

of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of

simvastatin than in humans given 80 mg simvastatin (as measured by AUC).

A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced

hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day).

Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular

cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid

neoplasms appears to be consistent with findings from other statins. These treatment levels represented

plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the

mean human plasma drug exposure after an 80 milligram daily dose.

No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat

or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in

an in vitroalkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an

in vitrochromosome aberration study in CHO cells, or an in vivochromosomal aberration assay in mouse

bone marrow.

There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body

weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day);

however, this effect was not observed during a subsequent fertility study in which simvastatin was

administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis

including epididymal maturation). No microscopic changes were observed in the testes of rats from

either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans

taking 80 mg/day based on surface area, mg/m

), seminiferous tubule degeneration (necrosis and loss

of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy,

decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day,

(approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of

these findings is unclear.

13.2 Animal Toxicology and/or Pharmacology

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at

180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean

plasma drug level in humans taking 80 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration

of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60

mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma

drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory

activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal

ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a

mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell

infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen

in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug

levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day.

Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25

times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19

times) and at two years at 50 mg/kg/day (5 times).

14 CLINICAL STUDIES

14.1 Clinical Studies in Adults

Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD

and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8 mmol/L). In this multicenter, randomized,

double-blind, placebo-controlled study, patients were treated with standard care, including diet, and

either simvastatin 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years.

Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and

TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. 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 vs 189 deaths). There was no statistically significant difference between groups in

non-cardiovascular mortality. Simvastatin significantly decreased the risk of having major coronary

events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34%

(p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-

fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial

revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary

angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of

fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28%

(p=0.033, 75 vs 102 patients). Simvastatin reduced the risk of major coronary events to a similar extent

across the range of baseline total and LDL cholesterol levels. Because there were only 53 female

deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However,

simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women

with one or more event). The randomization was stratified by angina alone (21% of each treatment

group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at

baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed.

However, trends in reduced coronary mortality, major coronary events and revascularization procedures

were consistent between this group and the total study cohort. Additionally, simvastatin resulted in

similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in

elderly patients (≥65 years), compared with younger patients.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study

with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267

on placebo). Patients were allocated to treatment using a covariate adaptive method

which took into

account the distribution of 10 important baseline characteristics of patients already enrolled and

minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years

(range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event

because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other

cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years

(6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had

LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and

10,047 patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; non-

fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).

Table 4:

Summary of Heart Protection Study Results

Endpoint

simvastatin

(N=10,269)

n (%)

Placebo

(N=10,267)

n (%)

Risk Reduction

(%) (95% CI)

p-Value

Primary

Mortality

CHD mortality

1,328 (12.9)

587 (5.7)

1,507 (14.7)

707 (6.9)

13 (6 to 19)

18 (8 to 26)

p=0.0003

p=0.0005

Secondary

Non-fatal MI

Stroke

357 (3.5)

444 (4.3)

574 (5.6)

585 (5.7)

38 (30 to 46)

25 (15 to 34)

p<0.0001

p<0.0001

Tertiary

Coronary revascularization

Peripheral and other non-coronary

revascularization

513 (5)

450 (4.4)

725 (7.1)

532 (5.2)

30 (22 to 38)

16 (5 to 26)

p<0.0001

p=0.006

n = number of patients with indicated event

Two composite endpoints were defined in order to have sufficient events to assess relative risk

reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary

events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898

patients treated with simvastatin had events and 1,212 patients on placebo had events). A composite of

major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures

including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event;

2,033 patients treated with simvastatin had events and 2,585 patients on placebo had events). Significant

relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE,

p<0.0001). Treatment with simvastatin produced significant relative risk reductions for all components

of the composite endpoints.

D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin.

Pharmacol. Ther. 15 (1974), pp. 443-453

The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent

regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or

peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without

CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C,

HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta

blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed

risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or

obesity with the greatest effects seen for diabetics without CHD

Figure 1

The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS

N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk,

with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the

number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE,

respectively, in the entire study population. The vertical solid line represents a relative risk of one. The

vertical dashed line represents the point estimate of relative risk in the entire study population.

Angiographic Studies

In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by

quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized,

double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo.

Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean

change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease,

respectively. Simvastatin significantly slowed the progression of lesions as measured in the Year 4

angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin

significantly decreased the proportion of patients with new lesions and with new total occlusions.

Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type IIa and IIb)

Simvastatin has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and

non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is

generally achieved within 4 to 6 weeks and maintained during chronic therapy. Simvastatin significantly

decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin also decreased

TG and increased HDL-C (see Table 5).

Table 5:

Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia

(Mean Percent Change from Baseline After 6 to 24 Weeks)

TREATMENT

TOTAL-C

LDL-C

HDL-C

Lower Dose Comparative Study

(Mean % Change at Week 6)

Simvastatin 5 mg q.p.m.

Simvastatin 10 mg q.p.m.

Scandinavian Simvastatin Survival Study

(Mean % Change at Week 6)

Placebo

2223

Simvastatin 20 mg q.p.m.

2221

Upper Dose Comparative Study

(Mean % Change Averaged at Weeks 18 and 24)

Simvastatin 40 mg q.p.m.

Simvastatin 80 mg q.p.m.

Multi-Center Combined Hyperlipidemia Study

(Mean % Change at Week 6)

Placebo

Simvastatin 40 mg q.p.m.

Simvastatin 80 mg q.p.m.

median percent change

mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL

mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL

mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL

21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL,

respectively. Patients with TG >350 mg/dL were excluded

mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.

Hypertriglyceridemia (Fredrickson type IV)

The results of a subgroup analysis in 74 patients with type IV hyperlipidemia from a 130-patient,

double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.

Table 6:

Six-week, Lipid-lowering Effects of Simvastatin in Type IV Hyperlipidemia Median Percent

Change (25

and 75

percentile) from Baseline

th

th

*

TREATMENT

Total-C

LDL-C

HDL-C

VLDL-C

Non-HDL-C

Placebo

(-7, +7)

(-8, +14)

(-3, +10)

(-25, +13)

(-25, +11)

(-9, +8)

Simvastatin 40

mg/day

(-34, -19)

(-40, -17)

(+5, +23)

(-43, -16)

(-54, -23)

(-42, -23)

Simvastatin 80

mg/day

(-38, -24)

(-46, -26)

(+5, +23)

(-45, -18)

(-57, -28)

(-49, -32)

The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135,

HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215. Dysbetalipoproteinemia (Fredrickson

type III)

The results of a subgroup analysis in 7 patients with type III hyperlipidemia (dysbetalipoproteinemia)

(apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period

crossover study are presented in Table 7.

Table 7:

Six-week, Lipid-lowering Effects of Simvastatin in Type III Hyperlipidemia Median Percent

Change (min, max) from Baseline

TREATMENT

Total-C

LDL-C +

HDL-C

VLDL-

C+IDL

Non-HDL-C

Placebo

(-24, +34)

(-27, +23)

(-21, +16)

(-22, +90)

(-28, +78)

(-26, -39)

Simvastatin

40 mg/day

(-66, -39)

(-60, -31)

(-8, +23)

(-74, -16)

(-90, -37)

(-72, -44)

Simvastatin

80 mg/day

(-55, -41)

(-57, -28)

(-5, +29)

(-58, +2)

(-72, -39)

(-61, -46)

The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411,

VLDL-C = 170, and non-HDL-C = 291.

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial

hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80

mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40

and 80 mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median

29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C

receptor function had an LDL-C reduction of 41% with the 80 mg dose.

Endocrine Function

In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma

cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were

observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid

sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-

controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma

*

*

testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20 to 40

mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to

simvastatin 20 to 40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual

adverse events in the two treatment groups was not significantly different. Because of these factors, the

small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the

pituitary-gonadal axis in pre-menopausal women are unknown.

14.2 Clinical Studies in Adolescents

In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal

girls) 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia

(HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion

in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with

an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the

first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients

elected to continue therapy with simvastatin 40 mg or placebo.

Simvastatin significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results

from the extension at 48 weeks were comparable to those observed in the base study.

Table 8:

Lipid-Lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial

Hypercholesterolemia (Mean Percent Change from Baseline)

Dosage

Duration

Total-C

LDL-C

HDL-C

Apo B

Placebo

24 Weeks

% Change from

Baseline (95% CI)

(-2.2, 5.3)

(-3.4, 5.5)

(-0.7, 8)

-3.2

(-11.8,

5.4)

-0.5

(-4.7, 3.6)

Mean baseline,

mg/dL (SD)

278.6

(51.8)

211.9

(49)

46.9

(11.9)

(50.7)

186.3

(38.1)

Simvastatin

24 Weeks

% Change from

Baseline (95% CI)

-26.5

(-29.6, -

23.3)

-36.8

(-40.5, -

(4.6, 11.9)

-7.9

(-15.8, 0)

-32.4

(-35.9,-29)

Mean baseline,

mg/dL (SD)

270.2

(44)

203.8

(41.5)

47.7

78.3

(46)

179.9

(33.8)

median percent change

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64 to 289

mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128 to 334 mg/dL) in the

placebo group.

The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The

long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood

has not been established.

16 HOW SUPPLIED/STORAGE AND HANDLING

Simvastatin Tablets, USP 5 mg are Light yellow colored, oblong shaped, biconvex, film-coated tablets,

engraved with ‘5’ on one face and ‘SVT’ on the other. They are supplied as follows:

*

*

engraved with ‘5’ on one face and ‘SVT’ on the other. They are supplied as follows:

NDC 42571-005-30 unit of use bottles of 30

NDC 42571-005-60 unit of use bottles of 60

NDC 42571-005-90 unit of use bottles of 90

NDC 42571-005-05 unit of use bottles of 500

NDC 42571-005-10 bottles of 1000.

Simvastatin Tablets, USP 10 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘10’ on one face and ‘SVT’ on the other. They are supplied as follows:

NDC 42571-010-30 unit of use bottles of 30

NDC 42571-010-60 unit of use bottles of 60

NDC 42571-010-90 unit of use bottles of 90

NDC 42571-010-05 unit of use bottles of 500

NDC 42571-010-10 bottles of 1000.

Simvastatin Tablets, USP 20 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘20’ on one face and ‘SVT’ on the other. They are supplied as follows:

NDC 42571-020-30 unit of use bottles of 30

NDC 42571-020-60 unit of use bottles of 60

NDC 42571-020-90 unit of use bottles of 90

NDC 42571-020-05 unit of use bottles of 500

NDC 42571-020-10 bottles of 1000.

Simvastatin Tablets, USP 40 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘40’ on one face and ‘SVT’ on the other. They are supplied as follows:

NDC 42571-040-30 unit of use bottles of 30

NDC 42571-040-60 unit of use bottles of 60

NDC 42571-040-90 unit of use bottles of 90

NDC 42571-040-05 unit of use bottles of 500

NDC 42571-040-10 bottles of 1000.

Simvastatin Tablets, USP 80 mg are White to off white oblong shaped, biconvex, film-coated tablets,

engraved with ‘80’ on one face and ‘SVT’ on the other. They are supplied as follows:

NDC 42571-080-30 unit of use bottles of 30

NDC 42571-080-60 unit of use bottles of 60

NDC 42571-080-90 unit of use bottles of 90

NDC 42571-080-05 unit of use bottles of 500

NDC 42571-080-10 bottles of 1000.

Storage

Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) [see USP

Controlled Room Temperature]

Dispense in tightly-closed container.

17 PATIENT COUNSELING INFORMATION

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-

recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

Patients should be advised about substances they should not take concomitantly with simvastatin

[see Contraindications (4) and Warnings and Precautions (5.1)] . Patients should also be advised to

inform other healthcare professionals prescribing a new medication or increasing the dose of an

existing medication that they are taking simvastatin.

17.1 Muscle Pain

All patients starting therapy with simvastatin 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 these muscle signs or symptoms persist after

discontinuing simvastatin. Patients using the 80 mg dose should be informed that the risk of

myopathy, including rhabdomyolysis, is increased with use of the 80 mg dose. The risk of

myopathy, including rhabdomyolysis, occurring with use of simvastatin is increased when taking certain

types of medication or consuming grapefruit juice. Patients should discuss all medication, both

prescription and over the counter, with their healthcare professional.

17.2 Liver Enzymes

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

thereafter when clinically indicated. All patients treated with simvastatin should be advised to report

promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal

discomfort, dark urine or jaundice.

17.3 Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent

pregnancy while using simvastatin. Discuss future pregnancy plans with your patients, and discuss when

to stop taking simvastatin if they are trying to conceive. Patients should be advised that if they become

pregnant they should stop taking simvastatin and call their healthcare professional.

17.4 Breastfeeding

Women who are breastfeeding should not use simvastatin. Patients who have a lipid disorder and are

breastfeeding should be advised to discuss the options with their healthcare professional.

Manufactured by:

Micro Labs Limited

Goa-403 722, INDIA.

Manufactured for:

Micro Labs USA Inc.

Basking Ridge, NJ 07920

Revised: 4/2019

PRINCIPAL DISPLAY PANEL

NDC 42571-005-90

Simvastatin

Tablets, USP

5 mg

Rx Only

90 Tablets

MICRO LABS

NDC 42571-010-90

Simvastatin

Tablets, USP

10 mg

Rx Only

90 Tablets

MICRO LABS

NDC 42571-020-90

Simvastatin

Tablets, USP

20 mg

Rx Only

90 Tablets

MICRO LABS

NDC 42571-040-90

Simvastatin

Tablets, USP

40 mg

Rx Only

90 Tablets

MICRO LABS

NDC 42571-080-90

Simvastatin

Tablets, USP

80 mg

Rx Only

90 Tablets

MICRO LABS

SIMVASTATIN

simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:42571-0 0 5

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

CITRIC ACID MO NO HYDRATE (UNII: 29 6 8 PHW8 QP)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

Product Characteristics

Color

yello w (Light Yello w)

S core

no sco re

S hap e

OVAL (Oblo ng, bico nvex)

S iz e

9 mm

Flavor

Imprint Code

5;SVT

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:42571-0 0 5-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

2

NDC:42571-0 0 5-6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

3

NDC:42571-0 0 5-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

4

NDC:42571-0 0 5-0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

5

NDC:42571-0 0 5-10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 38 3

0 6 /13/20 13

SIMVASTATIN

simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:42571-0 10

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

CITRIC ACID MO NO HYDRATE (UNII: 29 6 8 PHW8 QP)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

Product Characteristics

Color

white (white to o ff white)

S core

no sco re

S hap e

OVAL (Oblo ng, bico nvex)

S iz e

9 mm

Flavor

Imprint Code

10 ;SVT

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:42571-0 10 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

2

NDC:42571-0 10 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

3

NDC:42571-0 10 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

4

NDC:42571-0 10 -0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

5

NDC:42571-0 10 -10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 38 3

0 6 /13/20 13

SIMVASTATIN

simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:42571-0 20

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

CITRIC ACID MO NO HYDRATE (UNII: 29 6 8 PHW8 QP)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

Product Characteristics

Color

white (white to o ff white)

S core

no sco re

S hap e

OVAL (Oblo ng, bico nvex)

S iz e

11mm

Flavor

Imprint Code

20 ;SVT

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:42571-0 20 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

2

NDC:42571-0 20 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

3

NDC:42571-0 20 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

4

NDC:42571-0 20 -0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

5

NDC:42571-0 20 -10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 38 3

0 6 /13/20 13

SIMVASTATIN

simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:42571-0 40

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

CITRIC ACID MO NO HYDRATE (UNII: 29 6 8 PHW8 QP)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

Product Characteristics

Color

white (white to o ff white)

S core

no sco re

S hap e

OVAL (Oblo ng, bico nvex)

S iz e

14mm

Flavor

Imprint Code

40 ;SVT

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:42571-0 40 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

2

NDC:42571-0 40 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

3

NDC:42571-0 40 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

4

NDC:42571-0 40 -0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

5

NDC:42571-0 40 -10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 38 3

0 6 /13/20 13

SIMVASTATIN

simvastatin tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:42571-0 8 0

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SIMVASTATIN (UNII: AGG2FN16 EV) (SIMVASTATIN - UNII:AGG2FN16 EV)

SIMVASTATIN

8 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

CITRIC ACID MO NO HYDRATE (UNII: 29 6 8 PHW8 QP)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

BUTYLATED HYDRO XYANISO LE (UNII: REK49 6 0 K2U)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

Product Characteristics

Color

white (white to o ff white)

S core

no sco re

S hap e

OVAL (Oblo ng, bico nvex)

S iz e

17mm

Flavor

Imprint Code

8 0 ;SVT

Contains

Packag ing

Micro Labs Limited

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:42571-0 8 0 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

2

NDC:42571-0 8 0 -6 0

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

3

NDC:42571-0 8 0 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

4

NDC:42571-0 8 0 -0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

5

NDC:42571-0 8 0 -10

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /13/20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 38 3

0 6 /13/20 13

Labeler -

Micro Labs Limited (862174955)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Micro Labs Limited

9 1579 36 58

manufacture(42571-0 0 5, 42571-0 10 , 42571-0 20 , 42571-0 40 , 42571-0 8 0 )

Revised: 10/2019

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