Zocor (Simvastatin)

ZOCOR®

Frosst

Simvastatin

Lipid Metabolism Regulator

Action And Clinical Pharmacology: Simvastatin is a cholesterol-lowering agent derived synthetically from a fermentation product of A. terreus.

After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding b-hydroxyacid form. This principal metabolite is a specific 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 reduces cholesterol production by the liver and induces some changes in cholesterol transport and disposition in the blood and tissues. The mechanism(s) of this effect is believed to involve both reduction of the synthesis of Low Density Lipoprotein (LDL), and an increase in LDL catabolism as a result of induction of the hepatic LDL receptors.

Simvastatin has complex pharmacokinetic characteristics.

Indications And Clinical Uses: Hypercholesterolemia: As an adjunct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated total and Low Density Lipoprotein-cholesterol (LDL-C) levels in patients with primary hypercholesterolemia (Types IIa and IIb) when the response to diet and other nonpharmacological measures alone has been inadequate.

A disorder of lipid metabolism characterized by elevated serum cholesterol levels in association with normal triglyceride levels (Type IIa) or with increased triglyceride levels (Type IIb).

After establishing that the elevation in plasma lipids represents a primary disorder not due to underlying conditions such as poorly controlled diabetes mellitus, hypothyroidism, the nephrotic syndrome, liver disease or dysproteinemias, it should ideally be determined that patients for whom treatment with simvastatin is being considered have an elevated LDL-C level as the cause for an elevated total serum cholesterol. This may be particularly relevant for patients with total triglycerides over 4.52 mmol/L (400 mg/dL) or with markedly elevated HDL-C values, where non-LDL lipoprotein fractions may contribute significantly to total cholesterol levels without apparent increase in cardiovascular risk. In most patients LDL-C may be estimated according to the following equation:

LDL-C(mmol/L) = Total cholesterol-[(0.37 x triglycerides)+HDL-C]

LDL-C(mg/dL) = Total cholesterol-[(0.16 x triglycerides)+HDL-C]

When total triglycerides are greater than 4.52 mmol/L (400 mg/dL) this equation is less accurate. In such patients, LDL-cholesterol may be obtained by ultra centrifugation.

Simvastatin is also indicated for the reduction of elevated cholesterol levels in patients with combined hypercholesterolemia and hypertriglyceridemia, when the hypercholesterolemia is the abnormality of most concern.

Coronary Heart Disease: In patients with coronary heart disease and primary hypercholesterolemia, simvastatin is indicated to: reduce the risk of total mortality by reducing coronary death; reduce the risk of nonfatal myocardial infarction; reduce the risk for undergoing myocardial revascularization procedures.

In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with simvastatin on total mortality was assessed in 4 444 patients with coronary heart disease (CHD) and baseline total cholesterol (5.5 to 8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet and standard care and either simvastatin 20 to 40 mg daily (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 cholesterol, LDL-cholesterol, and triglycerides of 25%, 35%, and 10%, respectively, and a mean increase in HDL-cholesterol of 8%. Simvastatin reduced the risk of death by 30% (182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD death was reduced by 42% (111 vs 189). Simvastatin also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34% (431 patients vs 622 patients with one or more events). The risk of having a hospital-verified nonfatal MI was reduced by 37%. Furthermore, simvastatin reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (252 vs 383 patients).

The 4S study excluded patients with familial hypercholesterolemia (FH) or with congestive heart failure. It is not established to what extent the findings of the 4S study can be extrapolated to these subpopulations of hypercholesterolemic patients. a) In patients with heterozygous FH optimal reduction in total and LDL-cholesterol necessitates a combination drug therapy in the majority of patients. (For homozygous FH see Precautions, Use in Homozygous Familial Hypercholesterolemia). b) Among patients who developed symptoms of heart failure during the 4S study, trends in reduced mortality (19% lower with simvastatin treatment compared to placebo), with reductions of similar magnitude in numbers of patients with major coronary events and numbers of major coronary events were consistent between this group and the total study cohort.

Because there were only 57 deaths among the patients with angina alone at baseline and 53 deaths among female patients, the effect of simvastatin on mortality in these subgroups could not be adequately assessed. However, trends in reduced coronary mortality and in major coronary events were consistent between these subgroups and the total study cohort.

Simvastatin was also found to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL-cholesterol to target levels. In one study in 404 hypercholesterolemic men and women with coronary heart disease [(Multicenter Anti-Atheroma Study (MAAS)], simvastatin monotherapy was shown to significantly slow the progression of coronary atherosclerosis as assessed by quantitative angiography and significantly reduce the development of both new lesions and new total occlusion.

Contra-Indications: Hypersensitivity to any component of this preparation. Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy and lactation (see Precautions).

Manufacturers’ Warnings In Clinical States: Hepatic Effects: In clinical trials, marked persistent increases (to more than 3 times the upper limit of normal) in serum transaminases have occurred in 1% of adult patients who received simvastatin (see Adverse Effects, Laboratory Tests). When the drug 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. Some of these patients had abnormal liver function tests prior to therapy with simvastatin and/or consumed substantial quantities of alcohol.

In the Scandinavian Simvastatin Survival Study, the number of patients with more than one transaminase elevation to >3 times the upper limit of normal, over the course of the study, was not significantly different between the simvastatin and placebo groups (14[0.7%] vs 12[0.6%]). The frequency of single elevations of ALT to 3 times the upper limit of normal was significantly higher in the simvastatin group in the first year of the study (20 vs 8, p=0.023), but not thereafter. Elevated transaminases resulted in the discontinuation of 8 patients from the therapy in the simvastatin group (n=2 221) and 5 in the placebo group (n=2 223). All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

It is recommended that liver function tests be performed at baseline and periodically thereafter (e.g., semiannually) for the first year of treatment or until 1 year after the last elevation in dose in all patients. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.

If the transaminase levels show evidence of progression, particularly if they rise to 3 times the upper limit of normal and are persistent, the drug should be discontinued.

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 disease or unexplained persistent transaminase elevations are contraindications to the use of simvastatin; if such a condition should develop during therapy, the drug should be discontinued.

Moderate (less than 3 times the upper limit of normal) elevations of serum transaminases have been reported following therapy with simvastatin (see Adverse Effects). These changes were not specific to simvastatin and were also observed with comparative lipid-lowering agents. They generally appeared within the first 3 months after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptom and did not require interruption of treatment.

Muscle Effects: CPK: Transient mild elevations of creatine phosphokinase (CPK) levels (from skeletal muscles) have been seen commonly in patients receiving simvastatin, but these have been usually of no clinical significance.

Myalgia: Myalgia and muscle cramps have also been associated with therapy with simvastatin.

Myopathy: Myopathy has been reported with simvastatin (incidence
In the case of lovastatin, a closely related HMG-CoA reductase inhibitor, the risk of myopathy is known to be increased by concomitant immunosuppressive therapy including cyclosporins, and by concomitant therapy with gemfibrozil or with lipid-lowering doses of niacin (nicotinic acid) (see Precautions, Drug Interactions). Also, there have been rare reports of severe rhabdomyolysis that precipitated acute renal failure. Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin.

Myopathy or rhabdomyolysis has occurred in transplant and nontransplant patients receiving simvastatin or another HMG-CoA reductase inhibitor following the initiation of treatment with the antifungal agent itraconazole. In a study in normal volunteers, plasma levels of another HMG-CoA reductase inhibitor were increased about 20-fold when administered concomitantly with itraconazole. This is probably related to metabolism of both drugs by the same P450 isoform. Based on this data, therapy with simvastatin should be temporarily interrupted if systemic azole derivative antifungal therapy is required. A case of myositis and rhabdomyolysis has also been reported following the addition of the antidepressant nefazodone to the regimen of a patient previously taking simvastatin.

Therefore, the benefits and risks of using simvastatin concomitantly with immunosuppressive drugs, fibrates, erythromycin, systemic azole derivative antifungal agents, nefazodone or lipid-lowering doses of niacin should be carefully considered (see Precautions, Cytochrome P450 Inhibitors).

Interruption of therapy with simvastatin should be considered in any patient with an acute, serious condition, suggestive of a myopathy or having a risk factor predisposing to the development of renal failure or rhabdomyolysis, such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders and uncontrolled seizures.

Precautions: General: Before instituting therapy with simvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet and exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see Indications). The patient should be advised to inform subsequent physicians of the prior use of simvastatin or any other lipid-lowering agent.

In primary prevention intervention, the effects of simvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortality have not been established.

Homozygous Familial Hypercholesterolemia: Simvastatin is not effective or is less effective in patients with rare homozygous familial hypercholesterolemia.

Effect on the Lens: Current long-term data from clinical trials do not indicate an adverse effect of simvastatin on the human lens.

Effect on CoQ10 Levels (Ubiquinone): Significant decreases in circulating CoQ10 levels in patients treated with simvastatin and other statins have been observed. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not been established.

Effect on Lipoprotein(a): In some patients, the beneficial effect of lowered total cholesterol and LDL-C levels may be partly blunted by a concomitant increase in the Lipoprotein(a) [Lp(a)] level. Further research is currently ongoing to elucidate the significance of Lp(a) plasma level variations. Therefore, until further experience is obtained, it is suggested, when feasible, that Lp(a) measurements be carried out in patients placed on therapy with simvastatin.

Hypersensitivity: In few instances eosinophilia and skin eruptions appear to be associated with simvastatin treatment. If hypersensitivity is suspected, simvastatin should be discontinued.

Pregnancy: Simvastatin is contraindicated during pregnancy.

Atherosclerosis is a chronic process and the discontinuation of lipid metabolism regulators during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as simvastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, simvastatin is contraindicated during pregnancy. Simvastatin 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 should be discontinued immediately and the patient apprised of the potential hazard to the fetus.

A few reports have been received of congenital anomalies in infants whose mothers were treated during a critical period of pregnancy with HMG-CoA reductase inhibitors (see Contraindications). In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal death/stillbirths did not exceed what would be expected in the general population. As safety in pregnant women has not been established and there is no apparent benefit to therapy with simvastatin during pregnancy, treatment should be immediately discontinued as soon as pregnancy is recognized.

Lactation: It is not known whether simvastatin or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, women taking simvastatin should not nurse (see Contraindications).

Children: Limited experience is available in children. However, safety and effectiveness in children have not been established.

Geriatrics: For patients over the age of 65 years who received simvastatin in controlled clinical studies, efficacy, as assessed by reduction in total and LDL cholesterol levels, appeared similar to that seen in the population as a whole, and there was no apparent increase in the frequency and severity of clinical or laboratory adverse findings.

Patients with Impaired Renal Function: Simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance
Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with simvastatin and other HMG-CoA reductase inhibitors have suggested that these agents do not reduce plasma cortisol concentration or impair adrenal reserve and do not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.

Patients treated with simvastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones (see Drug Interactions, Cytochrome P450 Inhibitors).

Drug Interactions: Concomitant Therapy with other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is limited.

Bile Acid Sequestrants: Preliminary evidence suggests that the cholesterol-lowering effects of simvastatin and the bile acid sequestrant, cholestyramine, are additive.

When simvastatin is used concurrently with cholestyramine or any other resin, an interval of at least 2 hours should be maintained between the 2 drugs, since the absorption of simvastatin may be impaired by the resin.

Gemfibrozil, Fenofibrate and Niacin: Myopathy, including rhabdomyolysis, has occurred in patients who were receiving co-administration of simvastatin and other HMG-CoA reductase inhibitors with fibric acid derivatives and niacin, particularly in subjects with pre-existing renal insufficiency (see Warnings, Muscle Effects).

Erythromycin: see Warnings, Muscle Effects.

Coumarin Anticoagulants: In 2 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 Ratios (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. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to insure 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, 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.

Digoxin: Concomitant administration of simvastatin and digoxin in normal volunteers resulted in a slight elevation.
Antipyrine: Antipyrine was used as a model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P450 system). Simvastatin had little or no detectable effect on the pharmacokinetics of antipyrine in hypercholesterolemic patients.

Cytochrome P450 Inhibitors: Simvastatin is metabolized by the microsomal hepatic enzyme system (cytochrome P450 system) as are most other HMG-CoA reductase inhibitors. While simvastatin did not interact with antipyrine, it may interact with erythromycin, a known inhibitor of cytochrome P450 isoform 3A4. Drugs or common agents such as grapefruit juice that inhibit this enzyme may represent a potential for drug interactions when combined with simvastatin. Caution should thus be exercised with concomitant use of drugs such as immunosuppressants, antifungal agents (e.g., itraconazole, ketoconazole), macrolide antibiotics including erythromycin, antidepressent (e.g., nefazodone) or grapefruit juice (see Warnings, Myopathy and Precautions, Endocrine Function and Patients with Impaired Renal Function).

Other Concomitant Therapy: In clinical studies, simvastatin was used concomitantly with angiotensin converting enzyme (ACE) inhibitors, beta-blockers, calcium-channel blockers, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) without evidence of clinically significant adverse interactions.

Drug/Laboratory Test Interactions : Simvastatin may elevate serum transaminase and creatine phosphokinase levels (from skeletal muscles) (see Adverse Effects, Laboratory Tests). In the differential diagnosis of chest pain in a patient on therapy with simvastatin cardiac and noncardiac fractions of these enzymes should be determined.

Adverse Reactions: Based on experience in a total of over 2 300 patients, of whom more than 1 200 were treated for 1 year and over 230 for 2 years or more, simvastatin is generally well tolerated and adverse reactions are usually mild and transient.

In premarketing controlled clinical trials, 1% of patients were withdrawn due to adverse experiences attributable to simvastatin.

In the Scandinavian Simvastatin Survival Study (4S) involving 4 444 patients treated with 20 to 40 mg/day of simvastatin (n=2 221) or placebo (n=2 223), the safety and tolerability profiles were comparable between groups over the median 5.4 years of the study.

Ophthalmological Observations: See Precautions, Effect on the Lens.

Laboratory Tests: Marked persistent increases of serum transaminases have been noted (see Warnings).

About 5% of patients had elevations of creatine phosphokinase (CPK) levels 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CPK. Myopathy has been reported rarely (see Warnings, Muscle Effects and Precautions, Drug/Laboratory Test Interactions).

The following additional adverse reactions were reported either in uncontrolled clinical trials or in marketed use; however a causal relationship to therapy with simvastatin has not been established.

Dermatologic: erythema multiforme including Stevens-Johnson syndrome.

Gastrointestinal: vomiting.

Hematologic: anemia; leukopenia; purpura.

Hepatic: rarely hepatitis; jaundice.

Musculoskeletal: rarely rhabdomyolysis; muscle cramps; myalgia.

Nervous System/Psychiatric: dizziness; paresthesia; depression; peripheral neuropathy; rarely, peripheral neuropathy with muscle weakness or sensory disturbance has been reported.

Skin: rash; pruritus; alopecia.

Miscellaneous: pancreatitis.

Laboratory Tests: Elevated alkaline phosphatase and g-glutamyl transpeptidase have been reported.

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema; arthralgia; arthritis; dyspnea; eosinophilia; ESR increased; fever; flushing; lupus-like syndrome; malaise; photosensitivity; polymyalgia rheumatica; thrombocytopenia; urticaria; vasculitis.

Others: Although the following adverse reactions were not observed in clinical trials with simvastatin, they have been reported following treatment with other HMG-CoA reductase inhibitors: anorexia, psychic disturbances including anxiety, and hypospermia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: A few cases of overdosage have been reported; no patient had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 450 mg.

In the event of overdosage, treatment should be symptomatic and supportive, liver function should be monitored, and appropriate therapy instituted.

The dialyzability of simvastatin and its metabolites is not known.

Dosage And Administration: The patient should be placed on a diet, at least an equivalent to the American Heart Association (AHA) step 1, before receiving simvastatin and should continue on this diet during treatment with the drug. If appropriate, a program of weight control and physical exercise should be implemented.

Hypercholesterolemia: The usual starting dose is 10 mg/day given as a single dose in the evening. Patients with mild to moderate hypercholesterolemia can be treated with a starting dose of 5 mg of simvastatin. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 40 mg daily given as a single dose in the evening.

Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of simvastatin if cholesterol levels fall below the targeted range, such as that recommended by the Second Report of the U.S. National Cholesterol Education Program (NCEP).

Coronary Heart Disease: Patients with coronary heart disease and primary hypercholesterolemia can be treated with a starting dose of 20 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above.

Concomitant Therapy: See Drug Interactions, Concomitant Therapy with other Lipid Metabolism Regulators.

In patients taking immunosuppressive drugs concomitantly with simvastatin, the maximum recommended dosage is 10 mg/day (see Warnings, Muscle Effects).

Availability And Storage: 5 mg: Each buff-colored, shield-shaped, film-coated tablet, engraved 726 on one side and Z on the other, contains: simvastatin 5 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, pregelatinized starch, talc, titanium dioxide and yellow ferric oxide. Blister packages of 30.

10 mg: Each peach-colored, shield-shaped, film-coated tablet, engraved 735 on one side and Z on the other, contains: simvastatin 10 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc, titanium dioxide and yellow ferric oxide. Blister packages of 30. High density polyethylene bottles of 500.

20 mg: Each tan-colored, shield-shaped, film-coated tablet, engraved 740 on one side and Z on the other, contains: simvastatin 20 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc, titanium dioxide and yellow ferric oxide. Blister packages of 30. High density polyethylene bottles of 100.

40 mg: Each brick-red colored, shield-shaped, film-coated tablet, engraved 749 on one side and Z on the other, contains: simvastatin 40 mg. Nonmedicinal ingredients: ascorbic acid, butylated hydroxyanisole, citric acid, hydroxypropyl cellulose, lactose, magnesium stearate, methylcellulose, microcrystalline cellulose, pregelatinized starch, red ferric oxide, talc and titanium dioxide. Blister packages of 30.

Store at room temperature (15 to 30°C). (Shown in Product Recognition Section)

ZOCOR® Frosst Simvastatin Lipid Metabolism Regulator

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Hypercholesterolemia

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