These highlights do not include all the information needed to use simvastatin tablets safely and effectively. See full prescribing information for simvastatin tablets.,Simvastatin Tablets USP , Initial U.S. Approval: 1991
Simvastatin Information
Company Name American Health Packaging
Simvastatin (Simvastatin) . 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 (Simvastatin) tablets can be started simultaneously with diet.
Simvastatin (Simvastatin) tablet 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 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:
The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C
Simvastatin (Simvastatin) . Dosage And Administration
Concomitant Lipid-Lowering Therapy
Patients taking Cyclosporine or Danazol
Patients taking Amiodarone or Verapamil
Patients taking Diltiazem
Simvastatin (Simvastatin) . Contraindications
Simvastatin (Simvastatin) tablet is contraindicated in the following conditions:
Simvastatin (Simvastatin) . Warnings And Precautions
Simvastatin (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.
All patients starting therapy with Simvastatin (Simvastatin) , or whose dose of Simvastatin (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 (Simvastatin) therapy should be discontinued immediately if myopathy is diagnosed or suspected.
Many of the patients who have developed rhabdomyolysis on therapy with Simvastatin (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 (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 (Simvastatin) is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of Simvastatin (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 (Simvastatin) tablets concomitantly with these CYP3A4 inhibitors should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Simvastatin (Simvastatin) tablets should be suspended during the course of treatment.
The benefits of the combined use of Simvastatin (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 (Simvastatin) , as these agents can cause myopathy when given alone.
Cases of myopathy/rhabdomyolysis have been observed with Simvastatin (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 (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 (Simvastatin) 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of Simvastatin (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
Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received Simvastatin (Simvastatin) in clinical studies
In the Scandinavian Simvastatin (Simvastatin) Survival Study (4S) , 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 (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 (Simvastatin) group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 Simvastatin (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 (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.
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 (Simvastatin) .
As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with Simvastatin (Simvastatin) . These changes appeared soon after initiation of therapy with Simvastatin (Simvastatin) , were often transient, were not accompanied by any symptoms and did not require interruption of treatment.
Simvastatin (Simvastatin) . Adverse Reactions
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 (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 (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 (Simvastatin) tablets (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.
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 (Simvastatin) tablets 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with Simvastatin (Simvastatin) tablets compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was
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 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.
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 (Simvastatin) tablets (10 to 40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea .
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 (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, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, hepatic failure and depression.
An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Simvastatin (Simvastatin) . Drug Interactions
Simvastatin (Simvastatin) , like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin (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 (Simvastatin) . Hence when Simvastatin (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 (Simvastatin) .
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 (Simvastatin) tablets should be suspended during the course of treatment.
Simvastatin (Simvastatin) . Use In Specific Populations
Pregnancy Category X
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Simvastatin (Simvastatin) tablet 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 (Simvastatin) tablets during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins . Animal reproduction studies of Simvastatin (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 (Simvastatin) tablets may cause fetal harm when administered to a pregnant woman. If Simvastatin (Simvastatin) tablet is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to Simvastatin (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 (Simvastatin) was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.
Women of childbearing potential, who require treatment with Simvastatin (Simvastatin) tablets for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of Simvastatin (Simvastatin) tablets should be considered. If pregnancy occurs, Simvastatin (Simvastatin) tablets should be immediately discontinued.
Of the 2,423 patients who received Simvastatin (Simvastatin) tablets in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received Simvastatin (Simvastatin) tablets, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, Simvastatin (Simvastatin) tablets should be prescribed with caution in the elderly.
A pharmacokinetic study with Simvastatin (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 (Simvastatin) tablets significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients 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 (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.
Simvastatin (Simvastatin) . Overdosage
Significant lethality was observed in mice after a single oral dose of 9 g/m. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.
A few cases of overdosage with Simvastatin (Simvastatin) tablets have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of Simvastatin (Simvastatin) and its metabolites in man is not known at present.
Simvastatin (Simvastatin) . Description
Simvastatin (Simvastatin) is a lipid-lowering agent that is derived synthetically from a fermentation product of . After oral ingestion, Simvastatin (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 (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-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1-[1α,3α,7β,8β(2,4),-8aβ]]. The empirical formula of Simvastatin (Simvastatin) is CHO and its molecular weight is 418.57. Its structural formula is:
Simvastatin (Simvastatin) is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.
Simvastatin (Simvastatin) tablets for oral administration contain either 10 mg, 20 mg, 40 mg or 80 mg of Simvastatin (Simvastatin) and the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, hypromellose E5, croscarmellose sodium, ferric oxide red, lactose monohydrate, magnesium stearate, starch, talc, titanium dioxide, butylated hydroxyanisole , ascorbic acid, citric acid monohydrate, and triethyl citrate.
Simvastatin (Simvastatin) . Clinical Pharmacology
Simvastatin (Simvastatin) is a lactone that is readily hydrolyzed 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 (Simvastatin) .
Following an oral dose of C-labeled Simvastatin (Simvastatin) in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (Simvastatin (Simvastatin) plus C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since Simvastatin (Simvastatin) undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (
Both Simvastatin (Simvastatin) and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled Simvastatin (Simvastatin) was administered, Simvastatin (Simvastatin) -derived radioactivity crossed the blood-brain barrier.
The major active metabolites of Simvastatin (Simvastatin) present in human plasma are the β-hydroxyacid of Simvastatin (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 (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 (Simvastatin) tablets 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients
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 (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.
In a study of 12 healthy volunteers, Simvastatin (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 (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 (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.
Simvastatin (Simvastatin) . Nonclinical Toxicology
In a 72-week carcinogenicity study, mice were administered daily doses of Simvastatin (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 (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 (Simvastatin) than in humans given 80 mg Simvastatin (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 alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an chromosome aberration study in CHO cells, or an chromosomal aberration assay in mouse bone marrow.
There was decreased fertility in male rats treated with Simvastatin (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 (Simvastatin) was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.
CNS Toxicity
Optic nerve degeneration was seen in clinically normal dogs treated with Simvastatin (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 (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).
Simvastatin (Simvastatin) . Clinical Studies
Reductions in Risk of CHD Mortality and Cardiovascular Events
In 4S, the effect of therapy with Simvastatin (Simvastatin) tablets on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either Simvastatin (Simvastatin) tablets 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with Simvastatin (Simvastatin) tablets led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin (Simvastatin) tablets significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the Simvastatin (Simvastatin) tablets group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin (Simvastatin) tablets significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p
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 (Simvastatin) tablets 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.
The HPS results showed that Simvastatin (Simvastatin) tablets 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4).
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 (Simvastatin) tablets had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with Simvastatin (Simvastatin) tablets had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p
Angiographic Studies
In the Multicenter Anti-Atheroma Study, the effect of Simvastatin (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 (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 (Simvastatin) tablets significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, Simvastatin (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 (Simvastatin) tablet has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4 to 6 weeks and maintained during chronic therapy. Simvastatin (Simvastatin) tablets consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; Simvastatin (Simvastatin) tablets also decreased TG and increased HDL-C (see Table 5).
Hypertriglyceridemia (Frederickson type IV)
The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6.
Dysbetalipoproteinemia (Fredrickson type lll)
The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7.
Homozygous Familial Hypercholesterolemia
In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia received Simvastatin (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 (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 (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 (Simvastatin) 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, Simvastatin (Simvastatin) 20 to 40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to Simvastatin (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.
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 (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 (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 (Simvastatin) 40 mg or placebo.
Simvastatin (Simvastatin) tablets significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study.
After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0 to 289.0 mg/dL) in the Simvastatin (Simvastatin) tablets 40 mg group compared to 207.8 mg/dL (range: 128.0 to 334.0 mg/dL) in the placebo group.
The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The long-term efficacy of Simvastatin (Simvastatin) therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Simvastatin (Simvastatin) . How Supplied/storage And Handling
Simvastatin (Simvastatin) Tablets 10 mg are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed "S4" on one side and plain on other side.
Bottles of 30 Tablets (NDC 16729-004-10)
Bottles of 60 Tablets (NDC 16729-004-12)
Bottles of 90 Tablets (NDC 16729-004-15)
Bottles of 1000 Tablets (NDC 16729-004-17)
Simvastatin (Simvastatin) Tablets 20 mg are brick red coloured oval shaped, biconvex, film-coated tablets, debossed "S5" on one side and plain on other side.
Bottles of 30 Tablets (NDC 16729-005-10)
Bottles of 60 Tablets (NDC 16729-005-12)
Bottles of 90 Tablets (NDC 16729-005-15)
Bottles of 1000 Tablets (NDC 16729-005-17)
Simvastatin (Simvastatin) Tablets 40 mg are brick red coloured, oval shaped, biconvex, film-coated tablets, debossed "S6" on one side and plain on other side.
Bottles of 30 Tablets (NDC 16729-006-10)
Bottles of 60 Tablets (NDC 16729-006-12)
Bottles of 90 Tablets (NDC 16729-006-15)
Bottles of 1000 Tablets (NDC 16729-006-17)
Simvastatin (Simvastatin) Tablets 80 mg are brick red coloured,capsule-shaped, biconvex, film-coated tablets, debossed with "SMV" on one side and "80" on the other side.
Bottles of 30 Tablets (NDC 16729-007-10)
Bottles of 60 Tablets (NDC 16729-007-12)
Bottles of 90 Tablets (NDC 16729-007-15)
Bottles of 1000 Tablets (NDC 16729-007-17)
Store between 5 to 30° C (41 to 86° F).
"Dispense in tight containers as defined in the USP"
Simvastatin (Simvastatin) . 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.
Simvastatin (Simvastatin)
