ZOCOR- simvastatin tablet, film coated

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Active ingredient:
SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV)
Available from:
Merck Sharp & Dohme Corp.
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, ZOCOR® 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, ZOCOR is 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. ZOCOR is indicated to: - Reduce elevated total cholesterol (total-C), low-density lipoprotein cholestero
Product summary:
No. 8146 — Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other. They are supplied as follows: NDC 0006-0735-31 unit of use bottles of 30 NDC 0006-0735-54 unit of use bottles of 90. No. 8147 — Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other. They are supplied as follows: NDC 0006-0740-31 unit of use bottles of 30 NDC 0006-0740-54 unit of use bottles of 90. No. 8148 — Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other. They are supplied as follows: NDC 0006-0749-31 unit of use bottles of 30 NDC 0006-0749-54 unit of use bottles of 90. No. 6577 — Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other. They are supplied as follows: NDC 0006-0543-31 unit of use bottles of 30 NDC 0006-0543-54 unit of use bottles of 90. Storage Store between 5-30°C (41-86°F).
Authorization status:
New Drug Application
Authorization number:
0006-0543-31, 0006-0543-54, 0006-0726-31, 0006-0735-31, 0006-0735-54, 0006-0740-31, 0006-0740-54, 0006-0749-31, 0006-0749-54

ZOCOR- simvastatin tablet, film coated

Merck Sharp & Dohme Corp.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZOCOR safely and effectively. See full

prescribing information for ZOCOR.

ZOCOR (simvastatin) tablets, for oral use

Initial U.S. Approval: 1991

RECENT MAJOR CHANGES

Warnings and Precautions

Myopathy/Rhabdomyolysis (5.1)

10/2019

INDICATIONS AND USAGE

ZOCOR is 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

ZOCOR has 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 ZOCOR 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 ZOCOR 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 ZOCOR, patients

unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR 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 (10-17 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.

ZOCOR therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction

table. (5.1)

Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before

initiating therapy and as clinically indicated thereafter. (5.2)

ADVERSE REACTIONS

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

constipation, and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck &

Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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

Interacting Agents

Prescribing Recommendations

Strong CYP3A4 inhibitors (e.g., itraconazole,

ketoconazole, posaconazole, voriconazole,

erythromycin, clarithromycin, telithromycin, HIV

protease inhibitors, boceprevir, telaprevir, nefazodone,

cobicistat-containing products), gemfibrozil,

cyclosporine, danazol

Contraindicated with simvastatin

Niacin (≥1 g/day)

For Chinese patients, not recommended with simvastatin

Verapamil, diltiazem, dronedarone

Do not exceed 10 mg simvastatin daily

Amiodarone, amlodipine, ranolazine

Do not exceed 20 mg simvastatin daily

Lomitapide

For patients with HoFH, do not exceed 20 mg simvastatin daily

Daptomycin

Temporarily suspend simvastatin

Grapefruit juice

Avoid grapefruit juice

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

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

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

Monitor INR frequently until stable upon initiation or alteration of ZOCOR 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: 4/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events

1.2 Hyperlipidemia

1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)

1.4 Limitations of Use

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

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.

2.2 Restricted Dosing for 80 mg

2.3 Coadministration with Other Drugs

2.4 Patients with Homozygous Familial Hypercholesterolemia

2.5 Adolescents (10-17 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

7.8 Daptomycin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Chinese Patients

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Clinical Studies in Adults

14.2 Clinical Studies in Adolescents

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Muscle Pain

17.2 Liver Enzymes

17.3 Pregnancy

17.4 Breastfeeding

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

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, ZOCOR 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, ZOCOR is 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

ZOCOR is indicated to:

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

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

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

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

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

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

lll 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)

ZOCOR is 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, 10-17 years of age, with HeFH, if after an adequate

trial of diet therapy the following findings are present:

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

2. LDL cholesterol remains ≥160 mg/dL and

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

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

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130

mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic

adulthood CAD has not been determined.

1.4 Limitations of Use

ZOCOR 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, ZOCOR 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 ZOCOR 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 ZOCOR 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

ZOCOR, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of ZOCOR 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 ZOCOR 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 ZOCOR 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)]. ZOCOR 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 ZOCOR should be reduced by 50% if initiating lomitapide. ZOCOR dosage should not exceed 20

mg/day (or 40 mg/day for patients who have previously taken ZOCOR 80 mg/day chronically, e.g., for

12 months or more, without evidence of muscle toxicity) while taking lomitapide.

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

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

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

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

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

2.6 Patients with Renal Impairment

Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be

1

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.

necessary in patients with mild to moderate renal impairment. However, caution should be exercised

when ZOCOR 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 ZOCOR 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and ZOCOR 5

on the other.

Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain

on the other.

Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on

the other.

Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and

plain on the other.

Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side

and 80 on the other.

4 CONTRAINDICATIONS

ZOCOR is 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, ZOCOR

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 ZOCOR 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. ZOCOR 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, ZOCOR 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 ZOCOR should not

breastfeed their infants [see Use in Specific Populations (8.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

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

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

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

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

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

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

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

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

which 41,413 patients were treated with ZOCOR, 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

ZOCOR (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 ZOCOR 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 ZOCOR 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.

All patients starting therapy with ZOCOR, or whose dose of ZOCOR 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 ZOCOR. ZOCOR 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 ZOCOR 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. ZOCOR therapy should be discontinued if

markedly elevated CPK levels occur or myopathy is diagnosed or suspected. ZOCOR 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 [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 [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 [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 (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 myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered

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

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

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

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/Rhabdomyolys is

Interacting Agents

Prescribing Recommendations

Strong CYP3A4 Inhibitors,

e.g.:

Contraindicated with simvastatin

Itraconazole

Ketoconazole

Posaconazole

Voriconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Boceprevir

Telaprevir

Nefazodone

Cobicistat-containing

products

Gemfibrozil

Cyclosporine

Danazol

Niacin (≥1 g/day)

For Chinese patients, not

recommended with simvastatin

Verapamil

Diltiazem

Dronedarone

Do not exceed 10 mg simvastatin

daily

Amiodarone

Amlodipine

Ranolazine

Do not exceed 20 mg simvastatin

daily

Lomitapide

For patients with HoFH, do not

exceed 20 mg simvastatin daily

Daptomycin

Temporarily suspend simvastatin

Grapefruit juice

Avoid grapefruit juice

5.2 Liver Dysfunction

Persistent increases (to more than 3× 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 >3× 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 >3×

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 ZOCOR, promptly

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

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

(5.1)].

For patients with HoFH who have been taking 80 mg simvastatin

chronically (e.g., for 12 months or more) without evidence of muscle

toxicity, do not exceed 4 0 mg simvastatin when taking lomitapide.

(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 3× 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 ZOCOR.

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 35-71 years, 19% women, 100% Caucasians) treated with 20-40

mg/day of ZOCOR (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 ZOCOR and Greater than

Placebo in 4S

ZOCOR

(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

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