Simvastatin

INDICATIONS & USAGE

• ●     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-C, LDL-C, Apo B, and TG, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb).

• ●     Treat patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

• ●     Treat patients with primary dysbetalipoproteinemia (Fredrickson type lll 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.

• ●     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.

CHD*orCHD risk equivalents (10-year risk > 20%)< 100100130 (100 to 129: drug optional)S2+ Risk factors (10-year risk20%)< 13013010-year risk 10 to 20%:130 10-year risk <10%:1600 to 1 Risk factor< 160160190 (160 to 189: LDL-lowering drug optional)After the LDL-C goal has been achieved, if the TG is still200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.
At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge.
The NCEP classification of cholesterol levels in pediatric patients with a familial history of either hypercholesterolemia or premature cardiovascular disease is summarized in Table 7.
TABLE 7: NCEP Classification of Cholesterol Levels in Pediatric Patients with a Familial History of Either HeFH or Premature CVD
CategoryTotal-C (mg/dL)LDL-C (mg/dL)Acceptable<170< 110Borderline170 to 199110 to 129High200130Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy.
Simvastatin is indicated to reduce elevated LDL-C and TG levels in patients with Type IIb hyperlipidemia (where hypercholesterolemia is the major abnormality). However, it has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V)3.

SIMVASTATIN CONTRAINDICATIONS

WARNINGS
PRECAUTIONS, Pregnancy

WARNINGS

Myopathy/Rhabdomyolysis











CLINICAL PHARMACOLOGY, PharmacokineticsPRECAUTIONS, Drug InteractionsDOSAGE AND ADMINISTRATION).
TABLE 8: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting AgentsPrescribing RecommendationsItraconazoleAvoid simvastatinKetoconazoleErythromycinClarithromycinTelithromycinHIV protease inhibitorsNefazodoneGemfibrozilDo not exceed 10 mg simvastatin dailyCyclosporineDanazolAmiodaroneDo not exceed 20 mg simvastatin dailyVerapamilGrapefruit juiceAvoid large quantities of grapefruit juice (> 1 quart daily)
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 4S (seeCLINICAL PHARMACOLOGY, Clinical Studies
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. Patients titrated to the 80 mg dose should receive an additional test prior to titration, 3 months after titration to the 80 mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3X ULN or greater persist, withdrawal of therapy with simvastatin is recommended.
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.

PRECAUTIONS

General
WARNINGSADVERSE REACTIONS

INFORMATION FOR PATIENTS

WARNINGS, Myopathy/Rhabdomyolysis

DRUG INTERACTIONS

CYP3A4 Interactions

WARNINGS, Myopathy/RhabdomyolysisCLINICAL PHARMACOLOGY, Pharmacokinetics









Interactions with lipid-lowering drugs that can cause myopathy when given alone
WARNINGS, Myopathy/Rhabdomyolysis
DOSAGE AND ADMINISTRATION

Other drug interactions
CLINICAL PHARMACOLOGY,PharmacokineticsWARNINGS, Myopathy/Rhabdomyolysis).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin (seeWARNINGS, Myopathy/Rhabdomyolysis).
Propranolol: In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.
Digoxin: Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.
Warfarin: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20, 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 reductase inhibitors, 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.

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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

PREGNANCY

CONTRAINDICATIONS


3CONTRAINDICATIONS

3

NURSING MOTHERS

CONTRAINDICATIONS

PEDIATRIC USE

CLINICAL PHARMACOLOGY, Clinical Studies in AdolescentsADVERSE REACTIONS, Adolescent PatientsDOSAGE AND ADMINISTRATION, Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia. Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy (seeCONTRAINDICATIONSandPRECAUTIONS, Pregnancy). Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.

GERIATRIC USE

CLINICAL PHARMACOLOGY

SIMVASTATIN ADVERSE REACTIONS

Clinical Adverse Experiences

In Adults



Scandinavian Simvastatin Survival Study

Clinical Adverse Experiences
CLINICAL PHARMACOLOGY, Clinical Studies



Heart Protection Study

Clinical Adverse Experiences
CLINICAL PHARMACOLOGY, Clinical Studies










Laboratory Tests
WARNINGS, Myopathy/Rhabdomyolysis

Concomitant Lipid-Lowering Therapy
WARNINGS, Myopathy/Rhabdomyolysis

Adolescent Patients (ages 10 to 17 years)
CLINICAL PHARMACOLOGY, Clinical Studies in AdolescentsPRECAUTIONS, Pediatric Use

OVERDOSAGE

DOSAGE & ADMINISTRATION

NCEP Treatment GuidelinesCLINICAL PHARMACOLOGY, Clinical Studies in Adults


Patients with Homozygous Familial Hypercholesterolemia


Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia
4CLINICAL PHARMACOLOGY

4


Concomitant LipidLowering Therapy
WARNINGS, Myopathy/RhabdomyolysisPRECAUTIONS, Drug Interactions

Patients taking Cyclosporine or Danazol
WARNINGS, Myopathy/Rhabdomyolysis

Patients taking Amiodarone or Verapamil
WARNINGS, Myopathy/RhabdomyolysisPRECAUTIONS, Drug Interactions, Other drug interactions

Patients with Renal Insufficiency
CLINICAL PHARMACOLOGY, PharmacokineticsWARNINGS, Myopathy/Rhabdomyolysis

HOW SUPPLIED

STORAGE AND HANDLING

INFORMATION FOR PATIENTS

Warnings and Precautions (5.1)

Muscle Pain


Liver Enzymes


Pregnancy


Breastfeeding

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

Simvastatin Simvastatin TABLET Product Information Product Type Human prescription drug label Item Code (Source) NDC:49349-651(NDC:16729-006) Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SIMVASTATIN SIMVASTATIN 40 mg Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline hydroxypropyl cellulose HYPROMELLOSES CROSCARMELLOSE SODIUM ferric oxide red lactose monohydrate MAGNESIUM STEARATE talc STARCH, CORN BUTYLATED HYDROXYANISOLE titanium dioxide ASCORBIC ACID CITRIC ACID MONOHYDRATE TRIETHYL CITRATE Product Characteristics Color Size Imprint Code Shape red 14 mm S6 OVAL Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49349-651-02 30 in 1 BLISTER PACK Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA078155 2011-09-09