SIMVASTATIN tablet, film coated

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Active ingredient:
SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)
Available from:
Proficient Rx LP
INN (International Name):
SIMVASTATIN
Composition:
SIMVASTATIN 20 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: Simvastatin tablets are indicated to: 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 thera
Product summary:
Simvastatin Tablets 20 mg are brick red coloured oval shaped, biconvex, film-coated tablets, debossed "S 5" on one side and plain on other side. Simvastatin tablets USP 10 mg are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed "S 4" on one side and plain on other side. Bottles of 90 Tablets NDC 63187-191-90 Simvastatin Tablets 40 mg are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed "S 6" on one side and plain on other side. Bottles of 30 Tablets (NDC 63187-449-30) Bottles of 60 Tablets (NDC 63187-449-90) Storage Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. "Dispense in tight containers as defined in the USP"
Authorization status:
Abbreviated New Drug Application
Authorization number:
63187-075-30, 63187-075-60, 63187-075-90, 63187-191-30, 63187-191-60, 63187-191-90, 63187-449-30, 63187-449-60, 63187-449-90

SIMVASTATIN- simvastatin tablet, film coated

Proficient Rx LP

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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 USP for oral use

Initial U.S. Approval:1991

RECENT MAJOR CHANGES

Dosage and Administration

Coadministration with Other Drugs (2.3)

10/2012

Contraindications (4) 10/2012

Warnings and Precautions

INDICATIONS AND USAGE

Simvastatin tablets are an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

Myopathy/Rhabdomyolysis

(5.1) 10/2012

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 tablet has not been studied in Fredrickson Types I and V dyslipidemias. (1.4)

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)

Tablets: 5 mg; Tablets: 10 mg; 20 mg; 40 mg; 80 mg ( 3 )

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥5.0%) are: upper respiratory infection, headache, abdominal pain,

constipation, and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

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

Interacting Agents

Prescribing Recommendations

Contraindicated with simvastatin

Verapamil, diltiazem, dronedarone

Do not exceed 10 mg simvastatin daily

Amiodarone, amlodipine, ranolazine

Do not exceed 20 mg simvastatin daily

Grapefruit juice

Avoid grapefruit juice

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 1/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE

1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events

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 )

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. (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)

Strong CYP3A4 inhibitors (e.g. itraconazole,

ketoconazole, posaconazole, voriconazole,

erythromycin, clarithromycin, telithromycin, HIV

protease inhibitors, boceprevir, telaprevir,

nefazodone), gemfibrozil, cyclosporine, danazol

Other Lipid-lowering Medications: Use with other fibrate products or lipid-modifying doses (≥1 g/day) of niacin

increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with simvastatin. (5.1,

7.2, 7.4)

Coumarin anticoagulants: Concomitant use with simvastatin tablets prolongs INR. Achieve stable INR prior to starting

simvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of simvastatin tablets therapy.

(7.6)

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

1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events

1.2 Hyperlipidemia

1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)

1.4 Limitations of Use

2. DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Restricted Dosing for 80 mg

2.3 Coadministration with Other Drugs

2.4 Patients with Homozygous Familial Hypercholesterolemia

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

2.6 Patients with Renal Impairment

2.7 Chinese Patients Taking Lipid-Modifying Doses ( ≥ 1 g/day Niacin) of Niacin-Containing

Products

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

5. WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

5.2 Liver Dysfunction

5.3 Endocrine Function

6. ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7. DRUG INTERACTIONS

7.1 Strong CYP3A4 Inhibitors, cyclosporine, or danazol

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

7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers

7.4 Niacin

7.5 Digoxin

7.6 Coumarin Anticoagulants

7.7 Colchicine

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10. OVERDOSAGE

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14. CLINICAL STUDIES

14.1 Clinical Studies in Adults

14.2 Clinical Studies in Adolescents

16. HOW SUPPLIED/STORAGE AND HANDLING

17. PATIENT COUNSELING INFORMATION

17.1 Muscle Pain

17.2 Liver Enzymes

17.3 Pregnancy

17.4 Breastfeeding

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:

1.2 Hyperlipidemia

Simvastatin tablets are indicated to:

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:

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C

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

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.

Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C),

apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein

cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous

familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).

Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson

type III hyperlipidemia).

Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an

adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are

unavailable.

LDL cholesterol remains ≥190 mg/dL; or

LDL cholesterol remains ≥160 mg/dL and

There is a positive family history of premature cardiovascular disease (CVD) or

Two or more other CVD risk factors are present in the adolescent patient.

<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 tablet has 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

Patients taking Amiodarone, Amlodipine or Ranolazine

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.

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

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)]. .

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)].

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

2.6 Patients with Renal Impairment

2.7 Chinese Patients Taking Lipid-Modifying Doses ( ≥ 1 g/day Niacin) of Niacin-Containing

Products

Because of an increased risk for myopathy, in Chinese patients taking simvastatin 40 mg coadministered

with lipid-modifying doses ( ≥ 1 g/day niacin) of niacin-containing products, caution should be used

when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-

modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese

patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-

containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the

risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing

products observed in Chinese patients applies to other Asian patients. [see Warnings and Precautions

(5.1)]

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

Simvastatin tablets are contraindicated in the following conditions:

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

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

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 tablets are administered to patients with severe renal

impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings

and Precautions (5.1) and Clinical Pharmacology (12.3) ].

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

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

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

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

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

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

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

tablets,debossed “S 6” on one side and plain on the other side

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

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

Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,

posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin,

clarithromycin, telithromycin and nefazodone) [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)] .

5. WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

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

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

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

fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma.

Predisposing factors for myopathy include advanced age (≥65 years),female gender, uncontrolled

hypothyroidism, and renal impairment.

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.

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

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)] .

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).]

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.

Drug Interactions

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 co-administered [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 [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 (other fibrates or ≥1 g/day of

niacin), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions

(7.3) and Table 3 in Clinical Pharmacology (12.3)].

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.

The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma.

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, 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)

.]

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

with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind,

randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that

the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin

40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be

used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with

lipid- modifying doses of niacin-containing products. Because the risk for myopathy is dose-related,

Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of

niacin- containing products. It is unknown if the risk for myopathy with coadministration of simvastatin

with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other

Asian patients [see Drug Interactions (7.4)] .

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

Administration (2.3), 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

Gemfibrozil

Cyclosporine

Danazol

Contraindicated with simvastatin

Verapamil

Diltiazem

Dronedarone

Do not exceed 10 mg simvastatin daily

Amiodarone

Amlodipine

Ranolazine

Do not exceed 20 mg simvastatin daily

Grapefruit juice

Avoid grapefruit juice

5.2 Liver Dysfunction

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

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

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

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

no evidence of hypersensitivity.

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

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

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

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

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

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

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

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

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

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

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

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

6 months of treatment at a given dose.

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

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.

As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases

have been reported following therapy with simvastatin. These changes appeared soon after initiation of

therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not

require interruption of treatment.

5.3 Endocrine Function

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

inhibitors, including simvastatin.

6. ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice.

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

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

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

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

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

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

Scandinavian Simvastatin Survival Study

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

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

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

TABLE 2: Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with

Simvastatin Tablets and Greater than Placebo in 4S

Simvastatin Tablets

(N = 2,221)

Placebo

(N = 2,223)

%

%

Body as a Whole

Edema/swelling

Abdominal pain

Cardiovascular System Disorders

Atrial fibrillation

Digestive System Disorders

Constipation

Gastritis

Endocrine Disorders

Diabetes mellitus

Musculoskeletal Disorders

Myalgia

Nervous System / Psychiatric Disorders

Headache

Insomnia

Vertigo

Respiratory System Disorders

Bronchitis

Sinusitis

Skin / Skin Appendage Disorders

Eczema

Urogenital System Disorders

Infection, urinary tract

Heart Protection Study

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

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

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

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

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

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

Other Clinical Studies

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with

simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle

weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients

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

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

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

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

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

medicinal products were excluded.

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

asthenia.

Laboratory Tests

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

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

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

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

Adolescent Patients (ages 10 to 17 years)

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

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

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

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

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

(14.2)] .

6.2 Post-Marketing 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.

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

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

[See Warnings and Precautions (5.1) ]

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

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. In particular, caution should be used

when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-

modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese

patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-

containing products. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .

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

Pregnancy Category X

[See Contraindications (4).]

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) ].

Simvastatin tablets are contraindicated in women who are or may become pregnant. Lipid lowering

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 tablets for a lipid disorder,

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

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

discontinued.

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.

Simvastatin tablets are 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 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 tablets 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 tablets may cause fetal harm when

administered to a pregnant woman. If simvastatin tablets are 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.

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

Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):4 39-4 4 6, 1996.

8.5 Geriatric Use

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

patients in the Heart Protection Study who received simvastatin tablets, 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 tablets 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 tablets

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 tablets 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

8.7 Hepatic Impairment

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 tablets 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

Caution should be exercised when simvastatin tablets are administered to patients with severe

renal impairment. [See Dosage and Administration (2.6) .]

Simvastatin tablets are 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) ] .

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

empirical formula of simvastatin is C

H O and its molecular weight is 418.57. Its structural formula

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

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

Simvastatin tablets for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of

simvastatin and the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose,

hypromellose E5, croscarmellose sodium, ferric oxide red, lactose monohydrate, magnesium stearate,

maize starch, talc, titanium dioxide, butylated hydroxyanisole , ascorbic acid, citric acid monohydrate,

and triethyl citrate.

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 vivo to 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 tablets

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).

Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of

statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

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

Expos ure

Coadminis tered

Drug

or Grapefruit

Juice

Dosing of

Coadminis tered

Drug or

Grapefruit Juice

Dosing of

Simvas tatin

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

80 mg

simvastatin acid

13.1

*

max

days

simvastatin

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 of

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 post-marketing experience [see

Warnings and Precautions (5.1)]

Verapamil SR

240 mg QD Days

1 to 7 then

240 mg BID on

Days 8 to 10

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

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

3.90

3.75

Avoid taking with >20 mg simvastatin, based on clinical and/or post-marketing 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

No dosing adjustments required for the following:

Fenofibrate

160 mg QD X 14

days

80 mg QD

on Days 8 to

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 7.0 to 4.7

ng·eq/mL

simvastatin

acid

1.96

2.14

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

in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal 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

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

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 tablets on total mortality was assessed in 4,444 patients with

CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8.0 mmol/L). In this multicenter,

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

diet, and either simvastatin tablets 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 tablets 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 tablets significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the

simvastatin tablets 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 tablets 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 tablets 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 tablets 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

tablets 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 tablets

on mortality in women could not be adequately assessed. However, simvastatin tablets 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 tablets 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 tablets 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 tablets 40 mg and

10,267 on placebos). 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 tablets 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

Simvas tatin

Tablets

(N=10,269)

n (%)

Placebo

(N=10,267)

n (%)

Risk Reduction

(%) (95% CI)

p-Value

Primary

Mortality

1,328 (12.9)

1,507 (14.7)

13 (6 to 19)

p=0.0003

CHD mortality

587 (5.7)

707 (6.9)

18 (8 to 26)

p=0.0005

Secondary

Non-fatal MI

357 (3.5)

574 (5.6)

38 (30 to 46)

p<0.0001

Stroke

444 (4.3)

585 (5.7)

25 (15 to 34)

p<0.0001

Tertiary

Coronary revascularization

513 (5)

725 (7.1)

30 (22 to 38)

p<0.0001

Peripheral and other non-

coronary revascularization

450 (4.4)

532 (5.2)

16 (5 to 26)

p=0.006

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 tablets 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 tablets 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 tablets produced significant relative risk

reductions for all components of the composite endpoints. The risk reductions produced by simvastatin

tablets 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

*

*

n = number of patients with indicated event

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 tablets treatment regardless of baseline HbA1c levels or obesity with the greatest effects

seen for diabetics without CHD.

Fig ure 1: The Effects of Treatment with Simvastatin Tablets on Major Vascular Events and Major

Coronary Events in HPS

Figure 1: The Effects of Treatment with Simvastatin Tablets on Major Vascular Events and Major

Coronary Events in HPS

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 tablets 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 lla and llb)

Simvastatin tablet 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

tablets consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-

C ratio; simvastatin tablets 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

N

TOTAL-C

LDL-C

HDL-C

TG

Lower Dose Comparative Study

(Mean % Change at Week 6)

Simvastatin Tablets 5 mg q.p.m.

Simvastatin Tablets 10 mg q.p.m.

Scandinavian Simvastatin Survival Study

(Mean % Change at Week 6)

Placebo

2223

Simvastatin Tablets 20 mg q.p.m.

2221

Upper Dose Comparative Study

(Mean % Change Averaged at Weeks 18 and 24)

Simvastatin Tablets 40 mg q.p.m.

Simvastatin Tablets 80 mg q.p.m.

Multi-Center Combined Hyperlipidemia Study

(Mean % Change at Week 6)

Placebo

Simvastatin Tablets 40 mg q.p.m.

Simvastatin Tablets 80 mg q.p.m.

Hypertriglyceridemia (Frederickson type IV)

The results of a subgroup analysis in 74 patients with type lV 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 lV Hyperlipidemia Median

Percent Change (25

and 75

percentile) from Baseline

TREATMENT

N

Total-C

LDL-C

HDL-C

TG

VLDL-C

Non-

HDL-C

Placebo

*

median percent change

mean baseline LDL-C 24 4 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.

th

th

*

(-7, +7)

(-8, +14)

(-3, +10)

(-25, +13)

(-25, +11)

(-9, +8)

Simvastatin

Tablets 40

mg/day

(-34, -19)

(-40, -17)

(+5, +23)

(-43, -16)

(-54, -23)

(-42, -23)

Simvastatin

Tablets 80

mg/day

(-38, -24)

(-46, -26)

(+5, +23)

(-45, -18)

(-57, -28)

(-49, -32)

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysis in 7 patients with type lll 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 lll Hyperlipidemia Median

Percent Change (min, max) from Baseline

TREATMENT

N

Total-C

LDL-C +

IDL

HDL-C

TG

VLDL-

C+IDL

Non-

HDL-C

Placebo

(-24, +34)

(-27, +23)

(-21, +16)

(-22, +90)

(-28, +78)

(-26, -39)

Simvastatin

Tablets 40

mg/day

(-66, -39)

(-60, -31)

(-8, +23)

(-74, -16)

(-90, -37)

(-72, -44)

Simvastatin

Tablets 80

mg/day

(-55, -41)

(-57, -28)

(-5, +29)

(-58, +2)

(-72, -39)

(-61, -46)

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

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

C = 36, TG = 4 04 , VLDL-C = 83, and non-HDL-C = 215

*

The median baseline values (mg/dL) were: total-C = 324 , LDL-C = 121, HDL-C = 31, TG = 4 11, VLD-

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

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 tablets 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)

Dos age

Duration

N

Total-C

LDL-C HDL-C

TG

Apo B

Placebo

24 Weeks

% Change from

Baseline

(95% CI)

(-2.2, 5.3)

(-3.4, 5.5)

(-0.7,

8.0)

-3.2

(-11.8,

5.4)

-0.5

(-4.7, 3.6)

Mean baseline,

mg/dL

(SD)

278.6

(51.8)

211.9

(49.0)

46.9

(11.9)

90.0

(50.7)

186.3

(38.1)

Simvastatin

Tablets

24 Weeks

% Change from

Baseline

(95% CI)

-26.5

(-29.6, -

23.3)

-36.8

(-40.5, -

33.0)

(4.6,

11.9)

-7.9

(-15.8,

0.0)

-32.4

(-35.9, -

29.0)

Mean baseline,

mg/dL

(SD)

270.2

(44.0)

203.8

(41.5)

47.7

(9.0)

78.3

(46.0)

179.9

(33.8)

After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0 to

289.0 mg/dL) in the simvastatin tablets 40 mg group compared to 207.8 mg/dL (range: 128.0 to

334.0 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 20 mg are brick red coloured oval shaped, biconvex, film-coated tablets, debossed

"S 5" on one side and plain on other side.

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

Ther. 15 (1974 ), pp. 4 4 3-4 53

*

median percent change

Bottles of 30 NDC 63187-075-30

Simvastatin tablets USP 10 mg are brick red coloured, oval shaped, biconvex, film-coated tablets,

debossed "S 4" on one side and plain on other side.

Bottles of 90 Tablets NDC 63187-191-90

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

"S 6" on one side and plain on other side.

Bottles of 30 Tablets (NDC 63187-449-30)

Bottles of 60 Tablets (NDC 63187-449-90)

Storage

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature].

"Dispense in tight containers as defined in the USP"

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 tablets.

17.1 Muscle Pain

All patients starting therapy with simvastatin tablets 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 tablets are increased when taking certain types of medication or consuming

larger quantities of 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 tablets, 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 tablets. Discuss future pregnancy plans with your patients, and

discuss when to stop taking simvastatin tablets if they are trying to conceive. Patients should be advised

that if they become pregnant they should stop taking simvastatin tablets and call their healthcare

professional.

17.4 Breastfeeding

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

Bottles of 90 NDC 63187-075-90

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

Manufactured For:

Accord Healthcare, Inc.,

1009, Slater Road,

Suite 210-B,

Durham, NC 27703,

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No : 457, 458,

Village – Matoda,

Bavla Road, Ta.- Sanand,

Dist.- Ahmedabad – 382 210.

India.

10 1331 8 644882

Issued February 2013

Manufactured By:

Intas Pharmaceuticals Limited,

Plot No. 5, 6 & 7, Pharmez,

Sarkhej-Bavla, National Highway No. 8-A,

Near Village Matoda, Tal Sanand,

Ahmedabad - 382 213, Gujarat, India

51 1118 0 700311

Issued July 2011

Repackaged by:

Proficient Rx LP

Thousand Oaks, CA 91320

PRINCIPAL DISPLAY PANEL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

SIMVASTATIN

simvastatin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 318 7-0 75(NDC:16 729 -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

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

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

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

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

TALC (UNII: 7SEV7J4R1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

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

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

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

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

Product Characteristics

Color

RED (Brick Red)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

11mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 318 7-0 75-30

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

11/0 1/20 18

2

NDC:6 318 7-0 75-6 0

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

11/0 1/20 18

3

NDC:6 318 7-0 75-9 0

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

11/0 1/20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 155

0 2/26 /20 0 8

SIMVASTATIN

simvastatin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 318 7-19 1(NDC:16 729 -0 0 4)

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

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

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

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

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

TALC (UNII: 7SEV7J4R1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

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

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

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

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

Product Characteristics

Color

RED (Brick Red)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

8 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 318 7-19 1-30

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

11/0 1/20 18

2

NDC:6 318 7-19 1-6 0

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

11/0 1/20 18

3

NDC:6 318 7-19 1-9 0

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

11/0 1/20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 155

0 2/26 /20 0 8

SIMVASTATIN

simvastatin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 318 7-449 (NDC:16 729 -0 0 6 )

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

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

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

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

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

TALC (UNII: 7SEV7J4R1U)

Proficient Rx LP

STARCH, CO RN (UNII: O8 232NY3SJ)

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

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

ASCO RBIC ACID (UNII: PQ6 CK8 PD0 R)

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

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

Product Characteristics

Color

RED (Brick Red)

S core

no sco re

S hap e

OVAL (OVAL)

S iz e

14mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 318 7-449 -30

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

11/0 1/20 18

2

NDC:6 318 7-449 -6 0

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

11/0 1/20 18

3

NDC:6 318 7-449 -9 0

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

11/0 1/20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 155

0 2/26 /20 0 8

Labeler -

Proficient Rx LP (079196022)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Pro ficient Rx LP

0 79 19 6 0 22

REPACK(6 318 7-0 75, 6 318 7-19 1, 6 318 7-449 ) , RELABEL(6 318 7-0 75, 6 318 7-19 1, 6 318 7-449 )

Revised: 1/2020

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