SIMVASTATIN tablet, film coated

Simvastatin by

Drug Labeling and Warnings

Simvastatin by is a Prescription medication manufactured, distributed, or labeled by MedVantx, Inc., Aurobindo Pharma Limited, Blenheim Pharmacal, Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE


    Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin tablets can be started simultaneously with diet.

    1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events


    In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin tablets are indicated to: 


     

    • Reduce the risk of total mortality by reducing CHD deaths.
    • Reduce the risk of non-fatal myocardial infarction and stroke.
    • Reduce the need for coronary and non-coronary revascularization procedures.

    1.2 Hyperlipidemia


    Simvastatin tablets are indicated to:


     

    • Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
    • Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia).
    • Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).
    • Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

    1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)


    Simvastatin tablets are indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:


     


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


      2.  LDL cholesterol remains ≥160 mg/dL and 

    • There is a positive family history of premature cardiovascular disease (CVD) or
    • Two or more other CVD risk factors are present in the adolescent patient.

    The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

    1.4 Limitations of Use


    Simvastatin tablets have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing


    The dosage range is 5 to 80 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 20 to 40 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 Patients with Homozygous Familial Hypercholesterolemia


    The recommended dosage is 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. 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.

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


    The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines

    1

    and

    Clinical Studies (14.2)

    ]. Adjustments should be made at intervals of 4 weeks or more.


     


    2

  • 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):495-501. 1992.

  • 2

    National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.

    • 2.4 Patients with Renal Impairment


    Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored

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

    .

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


    Because of an increased risk for myopathy, caution should be used when treating Chinese patients with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) 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).]

    2.6 Coadministration with Other Drugs


    Concomitant Lipid-Lowering Therapy

        


    Patients taking Cyclosporine or Danazol

     


    Patients taking Amiodarone or Verapamil

     

    Patients taking Diltiazem  

  • 3 DOSAGE FORMS AND STRENGTHS

    • Tablets simvastatin 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side.
    • Tablets simvastatin 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side.
    • Tablets simvastatin 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side.
    • Tablets simvastatin 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side.
    • Tablets simvastatin 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side.
  • 4 CONTRAINDICATIONS


    Simvastatin tablets are contraindicated in the following conditions:


     

    • Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].
    • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].
    • Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, simvastatin tablets should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
    • Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with simvastatin tablets should not breastfeed their infants [see Use in Specific Populations (8.3)].
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Myopathy/Rhabdomyolysis


    Simvastatin, like other statins, 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), uncontrolled hypothyroidism, and renal impairment.



    As with other statins, the risk of myopathy/rhabdomyolysis is dose related.


     

     


    In a clinical trial database in which 41,050 patients were treated with simvastatin with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.



    All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. 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. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.



    Drug Interactions


     


    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, and other antifungal azoles, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). The use of simvastatin concomitantly with these CYP3A4 inhibitors should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment.

    [See Drug Interactions (7).]


     


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

    the

    potential risks of combinations: gemfibrozil, other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), cyclosporine, danazol, amiodarone, verapamil, or diltiazem.


     


    Caution should be used when prescribing

    other

    fibrates with simvastatin, as these agents can cause myopathy when given alone.


     


    Cases of myopathy/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. 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.


     


    Prescribing recommendations for interacting agents are summarized in Table 1

    [see also Dosage and Administration (2.6), Drug Interactions (7), Clinical Pharmacology (12.3)]

    .



    TABLE 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
    * The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination.
    † The benefits of the use of simvastatin in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations.
    ‡ The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
    § The combined use of simvastatin in patients receiving diltiazem should not exceed 40 mg daily unless the clinical benefit is likely to outweigh the increased risk of myopathy.
    Interacting Agents
    		Prescribing Recommendations
       Itraconazole
       Ketoconazole
       Erythromycin
       Clarithromycin
       Telithromycin
       HIV protease inhibitors
       Nefazodone
    		   Avoid simvastatin
       Gemfibrozil*
       Cyclosporine†
       Danazol†
    		   Do not exceed 10 mg simvastatin daily
       Amiodarone‡
       Verapamil‡
    		   Do not exceed 20 mg simvastatin daily
       Diltiazem§   Do not exceed 40 mg simvastatin daily
       Grapefruit juice
    		   Avoid large quantities of grapefruit juice (>1 quart daily)

    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. 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.

  • 6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience


    Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.


     


    In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).



    Scandinavian Simvastatin Survival Study


     


    In 4S involving 4,444 (age range 35 to 71 years, 19% women, 100% Caucasians) treated with 20 to 40 mg/day of simvastatin (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.



    TABLE 2 Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin and Greater than Placebo in 4S
    Simvastatin
    (N = 2,221)
    %
    		Placebo
    (N = 2,223)
    %
       Body as a Whole 
          Edema/swelling 
          Abdominal pain

    2.7
    5.9
    2.3
    5.8
       Cardiovascular System Disorders 
          Atrial fibrillation

    5.7
    5.1
       Digestive System Disorders 
             Constipation 
          Gastritis

    2.2
    4.9
    1.6
    3.9
       Endocrine Disorders 
          Diabetes mellitus

    4.2
    3.6
       Musculoskeletal Disorders 
          Myalgia

    3.7
    3.2
       Nervous System / Psychiatric Disorders 
          Headache 
          Insomnia 
          Vertigo

    2.5
    4
    4.5
    2.1
    3.8
    4.2
       Respiratory System Disorders 
          Bronchitis 
          Sinusitis

    6.6
    2.3
    6.3
    1.8
       Skin / Skin Appendage Disorders 
          Eczema

    4.5
    3
       Urogenital System Disorders 
          Infection, urinary tract

    3.2
    3.1

    Heart Protection Study


     


    In the Heart Protection Study (HPS), involving 20,536 patients (age range 40 to 80 years, 25% women, 97% Caucasians, 3% other races) treated with simvastatin 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with simvastatin compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin.



    Other Clinical Studies


     


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



    Laboratory Tests


     


    Marked persistent increases of hepatic transaminases have been noted

    [see Warnings and Precautions (5.2)]

    . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK.

    [See Warnings and Precautions (5.1).]



    Adolescent Patients (ages 10 to 17 years)


     


    In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10 to 17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or simvastatin (10 to 40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea

    [see Use in Specific Populations (8.4) and Clinical Studies (14.2)]

    .

    6.2 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, memory impairment, paresthesia, peripheral neuropathy, vomiting and anemia, rhabdomyolysis, hepatitis/jaundice, hepatic failure, 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.

  • 7 DRUG INTERACTIONS

    7.1 CYP3A4 Interactions


    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.


     


    The risk of myopathy is increased by reducing the elimination of simvastatin. Hence when simvastatin is used with an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin.

    [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]



    Itraconazole, ketoconazole, and other antifungal azoles


    Macrolide antibiotics erythromycin, clarithromycin, and the ketolide antibiotic telithromycin


    HIV protease inhibitors


    Antidepressant nefazodone


    Grapefruit juice in large quantities (>1 quart daily)


     


    Concomitant use of these drugs and any medication labeled as having a strong inhibitory effect on CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment.

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


    The risk of myopathy is increased by gemfibrozil

    [see Dosage and Administration (2.6)]

    and to a lesser extent by other fibrates

    [see

    Warnings and Precautions (5.1)]

    .

    7.3 Cyclosporine or Danazol


    The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin

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

    .

    7.4 Amiodarone, Verapamil, or Diltiazem


    The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone, verapamil, or diltiazem with higher doses of simvastatin

    [see Warnings and Precautions (5.1)]

    .

    7.5 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 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).]

    7.6 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)]

    .

    7.7 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.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy


    Pregnancy Category X [See Contraindications (4).]


     


    Simvastatin is contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with simvastatin during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins

    in utero

    . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin may cause fetal harm when administered to a pregnant woman. If simvastatin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.


     


    There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review

    3

     

     

    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

    2

    surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.


     


    Women of childbearing potential, who require treatment with simvastatin for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin should be considered. If pregnancy occurs, simvastatin should be immediately discontinued.


     


    4

  • 3

    Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996

  • 4

    Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996

    • 8.3 Nursing Mothers


    It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother

    [see Contraindications (4)]

    .

    8.4 Pediatric Use


    Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo.

    Doses greater than 40 mg have not been studied in this population.

    In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

    [See Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Studies (14.2).]

    Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy

    [see Contraindications (4) and Use in Specific Populations (8.1)].

    Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.

    8.5 Geriatric Use


    Of the 2,423 patients who received simvastatin in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin should be prescribed with caution in the elderly.

    [See Clinical Pharmacology (12.3).]


     


    A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients

    [see Clinical Studies (14.1)]

    . In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.

    8.6 Renal Impairment


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

    [See Dosage and Administration (2.4).]

    8.7 Hepatic Impairment


    Simvastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels

    [see Contraindications (4) and Warnings and Precautions (5.2)]

    .

  • 10 OVERDOSAGE


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

    2

    . No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m

    2

    , respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.


     


    A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

  • 11 DESCRIPTION


    Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of

    Aspergillus terreus

    . After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.


     


    Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2

    H

    -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1

    S

    -[1α,3α,7β,8β(2

    S

    *,4

    S

    *),-8aβ]]. The molecular formula of simvastatin is C

    25

    H

    38

    O

    5

    and its molecular weight is 418.57. Its structural formula is:


    Chemical Structure

    Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.


     


    Tablets simvastatin for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: ascorbic acid, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, hydroxypropyl cellulose, hypromellose, titanium dioxide, talc, citric acid monohydrate, isopropyl alcohol, magnesium stearate and butylated hydroxyanisole. Simvastatin 5 mg also contains ferric oxide yellow, simvastatin 10 mg and simvastatin 20 mg also contains ferric oxide red and ferric oxide yellow, simvastatin 40 mg and simvastatin 80 mg also contains ferric oxide red.

  • 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

    14

    C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus

    14

    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 80 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.


     


    In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients

    [see Use in Specific Populations (8.5)]

    .


     


    Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).


     


    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 Exposure
    Coadministered Drug
    or Grapefruit Juice    		Dosing of Coadministered Drug or
    Grapefruit Juice    		Dosing of SimvastatinGeometric Mean Ratio
    (Ratio* with / without
    coadministered drug)
    No Effect = 1
    AUC Cmax
    * Results based on a chemical assay except results with propranolol as indicated.
    † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
    ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.
    § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
    Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
    # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
    Þ Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk 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 Drug Interactions (7.5)].
       Avoid taking with simvastatin [see Warnings and Precautions (5.1)]
          Telithromycin†
    		200 mg QD for 4 days
    		80 mg
    		simvastatin acid‡
    simvastatin
    		12
    8.9
    		15
    5.3
          Nelfinavir†
    		1250 mg BID for 14 days
    		20 mg QD for 28 days
    		simvastatin acid‡
    simvastatin
    6
    6.2
          Itraconazole†
    		200 mg QD for 4 days
    		80 mg
    		simvastatin acid‡
    simvastatin
    		 
    		13.1
    13.1
       Avoid >1 quart of grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
          Grapefruit Juice§
          (high dose)
    		200 mL of double-strength
    TID
    		60 mg single dose
    		simvastatin acid
    simvastatin
    		7
    16
    		 
          Grapefruit Juice§
          (low dose)
    		8 oz (about 237 mL) of
    single-strength#
    		20 mg single dose
    		simvastatin acid
    simvastatin
    		1.3
    1.9
    		 
       Avoid taking with >10 mg simvastatin, based on clinical and/or post-marketing experience [see Warnings and Precautions (5.1)]
          Gemfibrozil
    		600 mg BID for 3 days
    		40 mg
    		simvastatin acid
    simvastatin
    		2.85
    1.35
    		2.18
    0.91
       Avoid taking with >20 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
    		2.3
    2.5
    		2.4
    2.1
       Avoid taking with >40 mg simvastatin, based on clinical and/or post-marketing experience [see Warnings and Precautions (5.1)]
          Diltiazem
    		120 mg BID for 10 days
    		80 mg on Day 10
    		simvastatin acid
    simvastatin
    		2.69
    3.1
    		2.69
    2.88
          Diltiazem120 mg BID for 14 days
    		20 mg on  Day 14
    		simvastatin
    		4.6
    		3.6
       No dosing adjustments required for the following:
          Fenofibrate
    		160 mg QD x 14 days
    		80 mg QD on Days
    8 to 14
    		simvastatin acid
    simvastatin
    		0.64
    0.89
    		0.89
    0.83
          Niacin extended-releaseÞ
    		2 g single dose
    		20 mg single dose
    		simvastatin acid
    simvastatin
    		1.6
    1.4
    		1.84
    1.08
          Amlodipine
    		10 mg QD x 10 days
    		80 mg on Day 10
    		simvastatin acid
    simvastatin
    		1.58
    1.77
    		1.56
    1.47
          Propranolol
    		80 mg single dose
    		80 mg single dose
    		total inhibitor



    active inhibitor
    		0.79



    0.79
    		↓ from
    33.6 to 21.1
    ng·eq/mL

    ↓ from 7 to 4.7
    ng·eq/mL

    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

    2

    ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

    13.2 Animal Toxicology and/or Pharmacology


    CNS Toxicity


     


    Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day.


     


    A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.


     


    CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.


     


    There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

  • 14 CLINICAL STUDIES

    14.1 Clinical Studies in Adults


    Reductions in Risk of CHD Mortality and Cardiovascular Events


     


    In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non­-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years), compared with younger patients.


     


    The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method

    5

     which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-­C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.


     


    The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; non-­fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).



    TABLE 4 Summary of Heart Protection Study Results
    † n = number of patients with indicated event
    Endpoint
    		Simvastatin
    (N=10,269)
    n (%)†
    		Placebo
    (N=10,267)
    n (%)†
    		Risk Reduction
    (%)
    (95% CI)
    		p-Value
       Primary 
          Mortality 
          CHD mortality
    1,328 (12.9)
    587 (5.7)
    1,507 (14.7)
    707 (6.9)
    13 (6-19)
    18 (8-26)
    p=0.0003
    p=0.0005
       Secondary 
          Non-fatal MI 
          Stroke
    357 (3.5)
    444 (4.3)
    574 (5.6)
    585 (5.7)
    38 (30-46)
    25 (15-34)
    p<0.0001
    p<0.0001
       Tertiary
          Coronary revascularization
          Peripheral and other non-coronary 
          revascularization

    513 (5)
    450 (4.4)
    725 (7.1)
    532 (5.2)
    30 (22-38)
    16 (5-26)
    p<0.0001
    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 had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with simvastatin had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Treatment with simvastatin produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD.


     


    Figure 1 The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS



    Figure 1 The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS

    N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.



    Angiographic Studies


     


    In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Simvastatin significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions.



    Modifications of Lipid Profiles


     


    Primary Hyperlipidemia (Fredrickson type lla and llb)


     


    Simvastatin has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4 to 6 weeks and maintained during chronic therapy. Simvastatin consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin also decreased TG and increased HDL-C (see Table 5).



    TABLE 5 Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)
    † median percent change
    ‡ mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL
    § mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL
    || mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL
    21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded
    †† mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
    TREATMENT
    		N
    		TOTAL-C
    		LDL-C
    		HDL-C
    		TG†
       Lower Dose Comparative Study‡
       (Mean % Change at Week 6)
       Simvastatin 5 mg q.p.m.
       Simvastatin 10 mg q.p.m.


    109
    110

    -19
    -23

    -26
    -30

    10
    12

    -12
    -15
       Scandinavian Simvastatin Survival Study§
       (Mean % Change at Week 6)
       Placebo
       Simvastatin 20 mg q.p.m.


    2223
    2221

    -1
    -28

    -1
    -38

    0
    8

    -2
    -19
       Upper Dose Comparative Study||
       (Mean % Change Averaged at Weeks 18 and 24)
       Simvastatin 40 mg q.p.m.
       Simvastatin 80 mg q.p.m.


    433
    664

    -31
    -36

    -41
    -47

    9
    8

    -18
    -24
       Multi-Center Combined Hyperlipidemia Study††
       (Mean % Change at Week 6)
       Placebo
       Simvastatin 40 mg q.p.m
       Simvastatin 80 mg q.p.m


    125
    123
    124

    1
    -25
    -31

    2
    -29
    -36

    3
    13
    16

    -4
    -28
    -33

    Hypertriglyceridemia (Fredrickson type IV)


     


    The results of a subgroup analysis in 74 patients with type IV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.



    TABLE 6 Six-week, Lipid-lowering Effects of Simvastatin in Type IV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline†
    † The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.
    TREATMENT
    		   N   
    		Total-C
    		LDL-C
    		HDL-C
    		TG
    		VLDL-C
    		Non-HDL-C
       Placebo
    		   74   
    		+2
    (-7, +7)
    		+1
    (-8, +14)
    		+3
    (-3, +10)
    		-9
    (-25, +13)
    		-7
    (-25, +11)
    		+1
    (-9, +8)
       Simvastatin 40 mg/day
    		   74   
    		-25
    (-34, -19)
    		-28
    (-40, -17)
    		+11
    (+5, +23)
    		-29
    (-43, -16)
    		-37
    (-54, -23)
    		-32
    (-42, -23)
       Simvastatin 80 mg/day
    		   74   
    		-32
    (-38, -24)
    		-37
    (-46, -26)
    		+15
    (+5, +23)
    		-34
    (-45, -18)
    		-41
    (-57, -28)
    		-38
    (-49, -32)

    Dysbetalipoproteinemia (Fredrickson type III)


     


    The results of a subgroup analysis in 7 patients with type III hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7.



    TABLE 7 Six-week, Lipid-lowering Effects of Simvastatin in Type III Hyperlipidemia Median Percent Change (min, max) from Baseline†
    † The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
    TREATMENT
    		      N      
    		Total-C
    		LDL-C + IDL
    		HDL-C
    		TG
    		VLDL-C+IDL
    		Non-HDL-C
       Placebo
    		      7      
    		-8
    (-24, +34)
    		-8
    (-27, +23)
    		-2
    (-21, +16)
    		+4
    (-22, +90)
    		-4
    (-28, +78)
    		-8
    (-26, -39)
       Simvastatin 40 mg/day
    		      7      
    		-50
    (-66, -39)
    		-50
    (-60, -31)
    		+7
    (-8, +23)
    		-41
    (-74, -16)
    		-58
    (-90, -37)
    		-57
    (-72, -44)
       Simvastatin 80 mg/day
    		      7      
    		-52
    (-55, -41)
    		-51
    (-57, -28)
    		+7
    (-5, +29)
    		-38
    (-58, +2)
    		-60
    (-72, -39)
    		-59
    (-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 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.


     


    6

  • 5

    D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453

  • 6

    D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453

    • 14.2 Clinical Studies in Adolescents


    In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-­C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo.


     


    Simvastatin significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study.



    TABLE 8 Lipid-lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)
    † median percent change
    Dosage
    		Duration
    		N
    		Total-C
    		LDL-C
    		HDL-C
    		TG†
    		Apo B
       Placebo
    		24 Weeks
    		67
    		% Change from Baseline
    (95% CI)
    		1.6
    (-2.2, 5.3)
    		1.1
    (-3.4, 5.5)
    		3.6
    (-0.7, 8)
    		-3.2
    (-11.8, 5.4)
    		-0.5
    (-4.7, 3.6)
    Mean baseline, mg/dL
    (SD)
    		278.6
    (51.8)
    		211.9
    (49)
    		46.9
    (11.9)
    		90
    (50.7)
    		186.3
    (38.1)
       Simvastatin
    		24 Weeks
    		106
    		% Change from Baseline
    (95% CI)
    		-26.5
    (-29.6, -23.3)
    		-36.8
    (-40.5, -33)
    		8.3
    (4.6, 11.9)
    		-7.9
    (-15.8, 0)
    		-32.4
    (-35.9, -29)
    Mean baseline, mg/dL
    (SD)
    		270.2
    (44)
    		203.8
    (41.5)
    		47.7
    (9)
    		78.3
    (46)
    		179.9
    (33.8)

    After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64 to 289 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128 to 334 mg/dL) in the placebo group.


     


    The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING


    Simvastatin Tablets USP, 5 mg

    are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side. They are supplied as follows:



                Bottles of 30                 NDC: 16714-681-01 (Child Resistant Closure)


                Bottles of 90                 NDC: 16714-681-02 (Child Resistant Closure)



    Simvastatin Tablets USP, 10 mg

    are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side. They are supplied as follows:



                Bottles of 30                 NDC: 16714-682-01 (Child Resistant Closure)


                Bottles of 90                 NDC: 16714-682-02 (Child Resistant Closure)


                Bottles of 1000             NDC: 16714-682-03 (Non-Child Resistant Closure)



    Simvastatin Tablets USP, 20 mg

    are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side. They are supplied as follows:



                Bottles of 30                 NDC: 16714-683-01 (Child Resistant Closure)


                Bottles of 90                 NDC: 16714-683-02 (Child Resistant Closure)


                Bottles of 1000             NDC: 16714-683-03 (Non-Child Resistant Closure)



    Simvastatin Tablets USP, 40 mg

    are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side. They are supplied as follows:



                Bottles of 30                 NDC: 16714-684-01 (Child Resistant Closure)


                Bottles of 90                 NDC: 16714-684-02 (Child Resistant Closure)


                Bottles of 1000             NDC: 16714-684-03 (Non-Child Resistant Closure)



    Simvastatin Tablets USP, 80 mg

    are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side. They are supplied as follows:



                Bottles of 30                 NDC: 16714-685-01 (Child Resistant Closure)


                Bottles of 90                 NDC: 16714-685-02 (Child Resistant Closure)


                Bottles of 1000             NDC: 16714-685-03 (Non-Child Resistant Closure)



    Store at

    20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

  • 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 Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking simvastatin.

    17.1 Muscle Pain


    All patients starting therapy with simvastatin

     

    should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.

    17.2 Liver Enzymes


    It is recommended that liver function tests be performed before the initiation of simvastatin, and thereafter when clinically indicated. 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.

    17.3 Pregnancy


    Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using simvastatin. Discuss future pregnancy plans with your patients, and discuss when to stop taking simvastatin

     

    if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking simvastatin and call their healthcare professional.

    17.4 Breastfeeding


    Women who are breastfeeding should not use simvastatin. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.


     


    Manufactured for: Northstar Rx LLC


                                Memphis, TN 38141


                                Toll Free: 1-800-206-7821


     


    Manufactured by:  Aurobindo Pharma Limited


                                Unit-VII (SEZ), Mahaboob Nagar (Dt)


                                AP-509302, INDIA


     


    M.L.No.: 22/MN/AP/2009/F/G


     


    Issued: 07/2010

  • PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 40 mg (30 Tablet Bottle)



    simvastatin 40mg tablet

     

  • INGREDIENTS AND APPEARANCE
    SIMVASTATIN 
    simvastatin tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 66116-408(NDC:16714-684)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    SIMVASTATIN (UNII: AGG2FN16EV) (SIMVASTATIN - UNII:AGG2FN16EV) SIMVASTATIN40 mg
    Inactive Ingredients
    Ingredient NameStrength
    ASCORBIC ACID (UNII: PQ6CK8PD0R)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    HYDROXYPROPYL CELLULOSE (UNII: RFW2ET671P)  
    HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    TALC (UNII: 7SEV7J4R1U)  
    CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)  
    ISOPROPYL ALCOHOL (UNII: ND2M416302)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    Product Characteristics
    ColorPINKScoreno score
    ShapeROUND (Biconvex) Size10mm
    FlavorImprint Code A;03
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 66116-408-3030 in 1 BOTTLE
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07769112/20/2006
    Labeler - MedVantx, Inc. (806427725)
    Registrant - Aurobindo Pharma Limited (650082092)
    Establishment
    NameAddressID/FEIBusiness Operations
    Blenheim Pharmacal, Inc.171434587REPACK
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