Zocor Helped Save Lives by Lowering Risk of Heart Attack and Stroke in Patients with or at High Risk of Heart Disease The Lancet Study Shows.

Business Editors/Health & Pharmaceutical Writers

Large Outcomes Study of Cholesterol-Lowering Medicine Shows Need to

Consider Patient's Risk of Major Vascular Event,

Regardless of Cholesterol Level

According to the largest-ever study using a cholesterol-modifying medicine, published today in The Lancet, ZOCOR(R) (simvastatin) 40 mg helped save lives by reducing the risk of heart attack and stroke by one-fourth in a broad range of patients with heart disease or at high risk for heart disease.

These results were consistent even in patients whose cholesterol levels were not high enough to require drug treatment under current guidelines. The study also demonstrated heart disease risk reductions with Zocor 40 mg in all patient populations studied, including women, the elderly and high-risk groups, such as those with a history of heart attacks, diabetes, hypertension or vascular disease.

The Heart Protection Study, conducted by the clinical trials unit of world-renowned Oxford University, U.K., followed 20,536 patients considered to be at high risk for a heart attack for more than five years.

"The Heart Protection Study showed significant risk reduction even in patients who would not require treatment with cholesterol lowering medications under recently revised National Cholesterol Education Program Guidelines," said Antonio M. Gotto, Jr., M.D., D.Phil., the Stephen and Suzanne Weiss Dean, Weill Medical College of Cornell University and Provost for Medical Affairs, Cornell University. "The findings indicate that cholesterol-lowering therapy can produce benefits for a much wider range of people than we previously thought."

ZOCOR, a cholesterol-modifying medicine from Merck & Co., Inc., is used in addition to diet to modify cholesterol levels after diet and other non-drug measures have failed to achieve target levels. The Heart Protection Study was an investigational use of Zocor, because it included many high-risk patients who are not included in the current labeling.

ZOCOR(R)helped save lives by reducing heart attacks and stroke

The primary objective of the study was to determine whether ZOCOR 40 mg reduced the risk of death in a broad patient population at high risk for cardiovascular events. Participants also received antioxidant vitamins or placebo. Treatment with ZOCOR 40 mg as compared to placebo reduced the risk of death from any cause by 13 percent(i) (P<0.001). The risk of death from heart attack, stroke and related blood vessel diseases was reduced by 18 percent(ii) (P<0.001) in the group treated with ZOCOR 40 mg as compared to placebo. In contrast, antioxidant vitamins had no effect on the risk of death from heart attacks, other coronary causes or all causes.

ZOCOR(R) reduced risk of stroke, CHD and combined cardiovascular disease events

Secondary objectives of the study included an evaluation of ZOCOR 40 mg on:

-- ZOCOR is indicated to reduce elevated total-C, LDL-C, Apo B, and TG, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb(c)).

-- ZOCOR is indicated for the treatment of patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

-- ZOCOR is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).

-- ZOCOR is also indicated to 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.

Antioxidant vitamins did not affect the risk of any of these secondary objectives.

ZOCOR(R) reduced risk of heart attack, stroke in diabetes patients without heart disease

The Heart Protection Study was the first study designed to investigate the benefits of cholesterol-modifying therapy in patients with diabetes with or without a prior history of heart disease or high cholesterol. The study included 5,963 patients - about one-third of all patients in the study - with Type 1 or Type 2 diabetes. Of these patients, 3,982 had no prior history of heart disease.

"This study shows that approximately two thirds of people with diabetes will ultimately die of cardiovascular disease, including heart disease, stroke and other diseases of the blood vessels," Dr. Gotto said. "Of these, heart disease is the most common fatal cardiovascular disease and those with Type 2 diabetes have a two-fold to four-fold greater risk of heart disease. The addition of diabetes as a risk equivalent to heart disease was a significant change to the NCEP guidelines when they were revised last year."

Compared to placebo, ZOCOR 40 mg reduced the risk of suffering one or more major vascular events by 28 percent(viii) (P less than 0.0001) in patients with diabetes without prior heart disease.

Largest outcomes study of a statin compared ZOCOR 40 mg to antioxidants and placebo

The multi-center, double-blind Heart Protection Study was designed to determine the effect on survival of ZOCOR 40 mg and an antioxidant vitamin mixture (vitamins C 250 mg, E 600 mg and beta-carotene 20 mg), both alone and in combination. The trial included 20,536 patients considered to be at high risk for cardiovascular events due to one or more of the following factors: previous heart attack, other heart disease, diabetes, prior stroke, other blood vessel diseases, and high blood pressure. Patients were 40 to 80 years old, with 28 percent (n=5,806) of the study population age 70 and older. Twenty-five percent (n= 5,082) of the patients were women.

Patients in the study were followed for an average of five years and were randomized to treatment with:

-- ZOCOR is indicated to reduce elevated total-C, LDL-C, Apo B, and TG, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb(c)).

-- ZOCOR is indicated for the treatment of patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

-- ZOCOR is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).

-- ZOCOR is also indicated to 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.

All treatment groups received standard community care during the trial, including aspirin, anticoagulants, nitrates, beta-blockers, calcium antagonists, and ACE inhibitors. The patient's personal physician could prescribe non-study statins at any time, at his or her discretion. Non-study statin use in the placebo group ranged from 4 percent in year one to 32 percent in year 5.

Patients had a range of LDL - or "bad" - cholesterol levels at entry into the study. Thirty-three percent (n=6,793) had levels at baseline below 116 mg/dL; 25 percent (n=5,063) were between 116 mg/dL and 135 mg/dL, and the remaining 42 percent (n=8,680) had levels greater than 135 mg/dL. Some of these patients would not have required drug treatment under the recently revised National Cholesterol Education Program guidelines, which recommend drug treatment for patients with LDL cholesterol levels above 130 mg/dL and having heart disease or an equivalent risk. These guidelines consider drug therapy optional for patients whose LDL cholesterol levels are between 100 mg/dL and 130 mg/dL.

ZOCOR(R) 40 mg was well tolerated in HPS

The 40 mg dose of ZOCOR was well tolerated in the study. The incidence of significant muscle enzyme elevation, indicating possible muscle damage, was low: 0.1 percent(ix) in the group treated with ZOCOR 40 mg versus 0.04 percent in the placebo group. The incidence of elevated liver enzyme levels (over four times the upper limit of normal) was low: 0.4 percent(x) in the group treated with ZOCOR 40 mg versus 0.3 percent in the placebo group. Patients received placebo for 4 weeks followed by simvastatin for four to six weeks prior to randomization, and those who attributed symptoms to the pre-randomization treatment did not continue in the study.

Selected cautionary information for ZOCOR(R)

ZOCOR should not be used by anyone allergic to any of its components, with liver disease, or by women who are pregnant, breast-feeding or likely to become pregnant. Muscle pain or weakness in patients taking ZOCOR should be reported to a doctor, because these could be signs of a serious side effect. Doctors may perform blood tests before and periodically during treatment with ZOCOR to check for liver problems. Patients taking the 80 mg strength of ZOCOR should receive an additional liver function test at three months. Patients should tell their doctors about other medications and foods they are taking in order to avoid possible drug interactions. In clinical trials, adverse reactions usually have been mild and transient. Most common side effects included headache (3.5 percent), abdominal pain (3.2 percent) and constipation (2.3 percent).

About Merck

Merck & Co., Inc. is a leading research-driven pharmaceutical products and services company. Merck discovers, develops, manufactures and markets a broad range of innovative products to improve human and animal health, directly and through its joint ventures.

Full prescribing information for ZOCOR(R) is attached. Additional information about ZOCOR(R) may be found by visiting www.zocor.com.

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Data from Heart Protection Study

Primary Endpoints:

(i) All Cause Mortality - 13% reduction with ZOCOR 40 mg vs.

placebo, (ZOCOR 1328/10269 = 12.9%, placebo 1507/10267 =

14.7%, P less than 0.001)

(ii) Deaths from heart disease and related blood vessel disease -

18% reduction with ZOCOR 40 mg vs. placebo (ZOCOR 781/10269 =

7.6%, placebo 937/10267 = 9.1%, P less than 0.001)

Secondary Endpoints:

(iii) Effect on stroke - 25% reduction with ZOCOR 40 mg vs.

placebo (444/10269 = 4.3%, placebo 585/10267 = 5.7%, P less

than 0.00001)

(iv) Major cardiovascular events - 24% reduction with ZOCOR 40 mg

vs. placebo (ZOCOR 2033/10269 = 19.8%; placebo 2585/10267 =

25.2%, P less than 0.00001)

(v) Effects on coronary events - 18% reduction in deaths

attributed to coronary causes with ZOCOR vs. placebo (ZOCOR

587/10,269 = 5.7%, placebo 707/10,267 = 6.9%, P=0.0005)

(vi) 38% reduction in non-fatal MI with ZOCOR vs. placebo (ZOCOR

357/10,269 = 3.5%, placebo 574/10,267 = 5.6%, P less than

0.0001)

(vii) Deaths not related to heart disease - No significant

difference between ZOCOR 40 mg and placebo (ZOCOR 547/10269 =

5.3%, placebo 570/10267 = 5.6%, P=not significant)

(viii) Heart attack and stroke in diabetic patients without prior

disease - 28% reduction with ZOCOR 40 mg vs. placebo (ZOCOR

276/2006 = 13.8%; placebo 367/1976 = 18.6%, P less than

0.0001)

Tolerability Data:

(ix) Muscle effects - CK greater than 10x upper limit of normal.

(ZOCOR 10/10,269 = 0.1%; placebo 6/10,267 = 0.04%)

(x) Liver enzyme elevation - ALT greater than 4x upper limit of

normal (ZOCOR 43/10,269 = 0.42%; placebo 32/10,267 = 0.31%)

ZOCOR(R) is the Merck registered trademark for simvastatin.

VERSION: 7825442-(May 2002)

TABLETS

ZOCOR(R)

(SIMVASTATIN)

DESCRIPTION

ZOCOR(a) (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 (beta)-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-2H-pyran-2-yl)-ethyl)-1-naphthalenyl ester, (1S-(1(alpha),3(alpha),7(beta),8(beta)(2S*,4S*),-8a(beta))). The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57. Its structural formula is:

(GRAPHIC OMITTED)

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 ZOCOR for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxides, lactose, magnesium stearate, starch, talc, titanium dioxide and other ingredients. Butylated hydroxyanisole is added as a preservative.

CLINICAL PHARMACOLOGY

The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have established that elevated plasma levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (Apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of high-density lipoprotein cholesterol (HDL-C) and its transport complex, Apo A-I, are associated with decreased cardiovascular risk. High plasma triglycerides (TG) and cholesterol-enriched TG-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C and small LDL particles, as well as in association with non-lipid metabolic risk factors for CHD. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

In the Scandinavian Simvastatin Survival Study (4S), the effect of improving lipoprotein levels with ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol (total-C) 212-309 mg/dL (5.5-8.0 mmol/L). The patients were followed for a median of 5.4 years. In this multicenter, randomized, double-blind, placebo-controlled study, ZOCOR significantly reduced the risk of mortality by 30% (11.5% vs 8.2%, placebo vs ZOCOR); of CHD mortality by 42% (8.5% vs 5.0%); and of having a hospital-verified non-fatal myocardial infarction by 37% (19.6% vs 12.9%). Furthermore, ZOCOR significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (17.2% vs 11.4%) (see CLINICAL PHARMACOLOGY, Clinical Studies).

ZOCOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of ZOCOR may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apo B also falls substantially during treatment with ZOCOR. As each LDL particle contains one molecule of Apo B, and since in patients with predominant elevations in LDL-C (without accompanying elevation in VLDL) little Apo B is found in other lipoproteins, this strongly suggests that ZOCOR does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, ZOCOR reduces VLDL and TG and increases HDL-C. The effects of ZOCOR on Lp(a), fibrinogen, and certain other independent biochemical risk markers for CHD are unknown.

ZOCOR is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.

Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding (beta)-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the (beta)-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 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of simvastatin (estimated to be > 60% in man), the availability of drug to the general circulation is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reaches the general circulation as active inhibitors. Following administration of simvastatin tablets, the coefficient of variation, based on between-subject variability, was approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the general circulation.

Both simvastatin and its (beta)-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Animal studies have not been performed to determine whether simvastatin crosses the blood-brain and placental barriers. However, when radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier.

The major active metabolites of simvastatin present in human plasma are the (beta)-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 ZOCOR 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 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 PRECAUTIONS, Geriatric Use).

Kinetic studies with another reductase inhibitor, 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).

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.

The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).

Simvastatin is a substrate for CYP3A4 (see PRECAUTIONS, Drug Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study(b), 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity (measured using a radioenzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis) of 2.4-fold and 3.6-fold, respectively, and of simvastatin and its (beta)-hydroxyacid metabolite (measured using a chemical assay -- liquid chromatography/tandem mass spectrometry) of 16-fold and 7-fold, respectively. In a second study, 16 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity (using a validated enzyme inhibition assay different from that used in the first(b) study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis) of 1.13-fold and 1.18-fold, respectively, and of simvastatin and its (beta)-hydroxyacid metabolite (measured using a chemical assay -- liquid chromatography/tandem mass spectrometry) of 1.88-fold and 1.31-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.

Clinical Studies

Coronary Heart Disease

In 4S, the effect of therapy with ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either ZOCOR 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. After six weeks of treatment with ZOCOR the median (25th and 75th percentile) changes in LDL-C, TG, and HDL-C were -39% (-46, -31%), -19% (-31, 0%), and 6% (-3, 17%). Over the course of the study, treatment with ZOCOR 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%. ZOCOR significantly reduced the risk of mortality (Figure 1) by 30%, (p=0.0003, 182 deaths in the ZOCOR 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. ZOCOR also significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction (MI)) (Figure 2) 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%. ZOCOR 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). Furthermore, ZOCOR 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). ZOCOR 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 ZOCOR on mortality in women could not be adequately assessed. However, ZOCOR 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 ZOCOR 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, in this study, 1,021 of the patients were 65 and older. Cholesterol reduction with simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in these elderly patients, compared with younger patients.

(GRAPHIC OMITTED)

Angiographic Studies

In the Multicenter Anti-Atheroma Study, the effect of therapy with simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic men and women with coronary heart disease. In this randomized, double-blind, controlled study, patients with a mean baseline total-C value of 245 mg/dL (6.4 mmol/L) and a mean baseline LDL-C value of 170 mg/dL (4.4 mmol/L) were treated with conventional measures and with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. A total of 347 patients had a baseline angiogram and at least one follow-up angiogram. The co-primary endpoints of the study 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 final angiogram by both these parameters (mean changes in minimum lumen diameter: -0.04 mm with simvastatin vs -0.12 mm with placebo; mean changes in mean lumen diameter: -0.03 mm with simvastatin vs -0.08 mm with placebo), as well as by change from baseline in percent diameter stenosis (0.9% simvastatin vs 3.6% placebo). After four years, the groups also differed significantly in the proportions of patients categorized with disease progression (23% simvastatin vs 33% placebo) and disease regression (18% simvastatin vs 12% placebo). In addition, simvastatin significantly decreased the proportion of patients with new lesions (13% simvastatin vs 24% placebo) and with new total occlusions (5% vs 11%). The mean change per-patient in mean and minimum lumen diameters, calculated by comparing angiograms, in the subset of 274 patients who had matched angiographic projections at baseline, two and four years is presented below (Figures 3 and 4).

(GRAPHIC OMITTED)

Primary Hypercholesterolemia (Fredrickson type lla and llb)

ZOCOR has been shown to be highly effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during chronic therapy. Furthermore, improving lipoprotein levels with ZOCOR improved survival in patients with CHD and hypercholesterolemia treated with 20-40 mg/day for a median of 5.4 years.

In a multicenter, double-blind, placebo-controlled, dose-response study in patients with familial or non-familial hypercholesterolemia, ZOCOR given as a single dose in the evening (the recommended dosing) was similarly effective as when given on a twice-daily basis. ZOCOR consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio. ZOCOR also decreased TG and increased HDL-C.

The results of studies depicting the mean response to simvastatin in patients with primary hypercholesterolemia and combined (mixed) hyperlipidemia are presented in Table 1.

                                TABLE 1

     Mean Response in Patients with Primary Hypercholesterolemia
                 and Combined (mixed) Hyperlipidemia
        (Mean Percent Change from Baseline After 6 to 24 Weeks)
------------------------------------  --------------------------------
TREATMENT                               N  TOTAL-C  LDL-C  HDL-C TG(a)
------------------------------------  --------------------------------

Lower Dose Comparative Study
(Mean % Change at Week 6)

ZOCOR 5 mg q.p.m.                      109   -19     -26      10   -12

ZOCOR 10 mg q.p.m.                     110   -23     -30      12   -15


Scandinavian Simvastatin
Survival Study
(Mean % Change at Week 6)
Placebo                               2223   -1      -1       0     -2

ZOCOR 20 mg q.p.m.                    2221   -28     -38      8    -19

Upper Dose Comparative Study
(Mean % Change Averaged at
Weeks 18 and 24)

ZOCOR 40 mg q.p.m.                     433   -31     -41      9    -18

ZOCOR 80 mg q.p.m.                     664   -36     -47      8    -24


Multi-Center Combined
Hyperlipidemia Study
(Mean % Change at Week 6)
                                       125    1       2       3     -4
Placebo
                                       123   -25     -29      13   -28
ZOCOR 40 mg q.p.m.

ZOCOR 80 mg q.p.m.                     124   -31     -36      16   -33
------------------------------------  --------------------------------
(a)median percent change

In the Upper Dose Comparative Study, the mean reduction in LDL-C was 47% at the 80-mg dose. Of the 664 patients randomized to 80 mg, 475 patients with plasma TG <= 200 mg/dL had a median reduction in TG of 21%, while in 189 patients with TG > 200 mg/dL, the median reduction in TG was 36%. In these studies, patients with TG > 350 mg/dL were excluded.

In the Multi-Center Combined Hyperlipidemia Study, a randomized, 3-period crossover study, 130 patients with combined hyperlipidemia (LDL-C>130 mg/dL and TG: 300-700 mg/dL) were treated with placebo, ZOCOR 40, and 80 mg/day for 6 weeks. In a dose-dependent manner ZOCOR 40 and 80 mg/day, respectively, decreased mean LDL-C by 29 and 36% (placebo: +2%) and median TG levels by 28 and 33% (placebo: 4%), and increased mean HDL-C by 13 and 16% (placebo: 3%) and apolipoprotein A-I by 8 and 11% (placebo: 4%).

Hypertriglyceridemia (Fredrickson type lV)

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 2. 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.

                                TABLE 2
                  Six-week, Lipid-lowering Effects of
                Simvastatin in Type lV Hyperlipidemia
    Median Percent Change (25th and 75th percentile) from Baseline

----------------------------------------------------------------------
TREATMENT N  Total-C  LDL-C    HDL-C       TG        VLDL-C  Non-HDL-C
--------- - ----------------------------------------------------------

Placebo  74    +2        +1       +3         -9         -7        +1
            (-7,+7)  (-8,+14) (-3, +10)(-25, +13)  (-25,+11) (-9, +8)


ZOCOR 40
mg/day   74    -25      -28       +11        -29        -37       -32
            (-34,-19)(-40,-17)(+5, +23)(-43, -16)  (-54,-23)(-42, -23)


ZOCOR 80
mg/day   74    -32      -37       +15        -34        -41       -38
            (-38,-24)(-46,-26)(+5, +23)(-45, -18)  (-57,-28)(-49, -32)
----------------------------------------------------------------------

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 3. In this study 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.

                                TABLE 3
            Six-week, Lipid-lowering Effects of Simvastatin
                      in Type lll Hyperlipidemia
             Median Percent Change (min,max) from Baseline

----------------------------------------------------------------------
TREATMENT N Total-C  LDL-C+IDL   HDL-C    TG     VLDL-C+IDL  Non-HDL-C
--------- - ----------------------------------------------------------
Placebo   7    -8       -8        -2      +4        -4         -8
           (-24,+34) (-27,+23)(-21,+16)(-22,+90)(-28,+78)  (-26,-39)

ZOCOR 40
mg/day    7   -50      -50        +7     -41       -58        -57
           (-66,-39) (-60,-31) (-8,+23)(-74,-16)(-90,-37)  (-72,-44)

ZOCOR 80
mg/day    7   -52      -51        +7     -38       -60        -59
           (-55,-41) (-57,-28) (-5,+29)(-58,+2) (-72,-39)  (-61,-46)
----------------------------------------------------------------------

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 12 patients 15-39 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. Eleven of the 12 patients had reductions in LDL-C. In those patients with reductions, 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 inhibitors of HMG-CoA reductase 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 (hCG). In another 24-week study, simvastatin 20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20-40 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.

INDICATIONS AND USAGE

Therapy with lipid-altering agents should be considered in those individuals at increased risk for atherosclerosis-related clinical events as a function of cholesterol level, the presence of CHD, or other risk factors. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when the response to diet and other nonpharmacological measures alone has been inadequate (see National Cholesterol Education Program (NCEP) Treatment Guidelines, below).

Coronary Heart Disease

In patients with coronary heart disease and hypercholesterolemia, ZOCOR is indicated to:

-- ZOCOR is indicated to reduce elevated total-C, LDL-C, Apo B, and TG, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb(c)).

-- ZOCOR is indicated for the treatment of patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

-- ZOCOR is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).

-- ZOCOR is also indicated to 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.

(For a discussion of efficacy results in the elderly and other pre-defined subgroups, see CLINICAL PHARMACOLOGY, Clinical Studies.)

Hyperlipidemia

-- ZOCOR is indicated to reduce elevated total-C, LDL-C, Apo B, and TG, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb(c)).

-- ZOCOR is indicated for the treatment of patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).

-- ZOCOR is indicated for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).

-- ZOCOR is also indicated to 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.

General Recommendations

Prior to initiating therapy with simvastatin, secondary causes for hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism) should be excluded, and a lipid profile performed to measure total-C, HDL-C, and TG. For patients with TG less than 400 mg/dL (< 4.5 mmol/L), LDL-C can be estimated using the following equation:

LDL-C = total-C - ((0.20 x TG) + HDL-C) ---------------------

                                                Lipid
                     Lipoproteins            Elevations
Type              elevatedmajor                 minor
----              -------------                 -----
I (rare)          chylomicrons             TG         ->C
IIa               LDL                       C         --
IIb               LDL, VLDL                 C         TG
III (rare)        IDL                     C/TG        --
IV                VLDL                     TG         ->C
V (rare)          chylomicrons, VLDL       TG         ->C

    C = cholesterol, TG = triglycerides,
    LDL = low-density lipoprotein,
    VLDL = very-low-density lipoprotein,
    IDL = intermediate-density lipoprotein.

For TG levels > 400 mg/dL (> 4.5 mmol/L), this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In many hypertriglyceridemic patients, LDL-C may be low or normal despite elevated total-C. In such cases, ZOCOR is not indicated.

Lipid determinations should be performed at intervals of no less than four weeks and dosage adjusted according to the patient's response to therapy.

The NCEP Treatment Guidelines are summarized in Table 4:

                                TABLE 4
                      NCEP Treatment Guidelines:
      LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
             and Drug Therapy in Different Risk Categories

----------------------------------------------------------------------
                                 LDL Level at Which      LDL Level at
Risk Category        LDL Goal  to Initiate Therapeutic  Which to
                     (mg/dL)     Lifestyle Changes      Consider Drug
                                      (mg/dL)         Therapy (mg/dL)
----------------------------- ------------------------------- --------
CHD+ or CHD risk
equivalents           <100            =>100                =>130
(10-year risk >20%)                                   (100-129: drug
                                                      optional)++

2+ Risk factors       <130            =>130
(10 year risk <=20%)                       10-year risk 10-20%: =>130
                                           10-year risk <10%:  => 160

0-1 Risk factor+++    <160            =>160                =>190
                                              (160-189: LDL-lowering
                                                      drug optional)
----------------------------------------------------------------------

+ CHD, coronary heart disease

++ Some authorities recommend use of LDL-lowering drugs in this

category if an LDL-C level of <100 mg/dL cannot be achieved by

therapeutic lifestyle changes. Others prefer use of drugs that

primarily modify triglycerides and HDL-C, e.g., nicotinic acid

or fibrate. Clinical judgment also may call for deferring drug

therapy in this subcategory.

+++ Almost all people with 0-1 risk factor have a 10-year risk

<10%; thus, 10-year risk assessment in people with 0-1 risk

factor is not necessary.

After the LDL-C goal has been achieved, if the TG is still =>200 mg/dL, non-HDL-C (total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.

At the time of hospitalization for an acute coronary event, consideration can be given to initiating drug therapy at discharge if the LDL-C is => 130 mg/dL (see NCEP Treatment Guidelines, above).

Since the goal of treatment is to lower LDL-C, the NCEP recommends that LDL-C levels be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the total-C be used to monitor therapy.

ZOCOR is indicated to reduce elevated LDL-C and TG levels in patients with Type IIb hyperlipidemia (where hypercholesterolemia is the major abnormality). However, it has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).(c)

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

Active liver disease or unexplained persistent elevations of serum transaminases (see WARNINGS).

Pregnancy and lactation. 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. 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 ZOCOR to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, ZOCOR is contraindicated during pregnancy and in nursing mothers. ZOCOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ZOCOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

WARNINGS

Myopathy/Rhabdomyolysis

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X 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 HMG-CoA reductase inhibitory activity in plasma.

-- The risk of myopathy/rhabdomyolysis is increased by

concomitant use of simvastatin with the following:

Potent inhibitors of CYP3A4: Cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily), particularly with higher doses of simvastatin (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, CYP3A4 Interactions).

Lipid-lowering drugs that can cause myopathy when given alone: Gemfibrozil, other fibrates, or lipid-lowering doses (=>1 g/day) of niacin, particularly with higher doses of simvastatin (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone).

Other drugs: Amiodarone or verapamil with higher doses of simvastatin (see PRECAUTIONS, Drug Interactions, Other drug interactions). In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone. In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635; 0.63%) than in patients taking simvastatin without a calcium channel blocker (13/21,224; 0.061%).

-- The risk of myopathy/rhabdomyolysis is dose related. The

incidence in clinical trials, in which patients were carefully

monitored and some interacting drugs were excluded, has been

approximately 0.02% at 20 mg, 0.07% at 40 mg and 0.3% at 80

mg.

Consequently:

1. Use of simvastatin concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, or clarithromycin is unavoidable, therapy with simvastatin should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.

2. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, gemfibrozil, other fibrates or lipid-lowering doses (=>1 g/day) of niacin. The combined use of simvastatin with fibrates or niacin should be avoided unless the benefit of further alteration in lipid levels is likely to outweigh the increased risk of this drug combination. Addition of these drugs to simvastatin typically provides little additional reduction in LDL-C, but further reductions of TG and further increases in HDL-C may be obtained.

3. The dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. 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.

4. 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. The presence of these symptoms, and/or a CK level >10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from treatment, muscle symptoms and CK increases resolved. 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.

5. 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.

Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

In 4S (see CLINICAL PHARMACOLOGY, Clinical Studies), 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, only 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 periodically thereafter (e.g., semiannually) for the first year of treatment or until one year after the last elevation in dose. Patients titrated to the 80-mg dose should receive an additional test at 3 months. 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 ZOCOR is recommended.

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.

As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.

PRECAUTIONS

General

Simvastatin may cause elevation of CK and transaminase levels (see WARNINGS and ADVERSE REACTIONS). This should be considered in the differential diagnosis of chest pain in a patient on therapy with simvastatin.

Information for Patients

Patients should be advised about substances they should not take concomitantly with simvastatin and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking ZOCOR.

Drug Interactions

CYP3A4 Interactions

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. Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of simvastatin.

See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics.

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

HIV protease inhibitors

Nefazodone

Cyclosporine

Large quantities of grapefruit juice (>1 quart daily)

Interactions with lipid-lowering drugs that can cause myopathy when given alone

The risk of myopathy is also increased by the following lipid-lowering drugs that are not potent CYP3A inhibitors, but which can cause myopathy when given alone.

See WARNINGS, Myopathy/Rhabdomyolysis.

Gemfibrozil

Other fibrates

Niacin (nicotinic acid) (>1 g/day)

Other drug interactions

Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil (see WARNINGS, Myopathy/Rhabdomyolysis).

Propranolol: In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of ZOCOR and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.

Digoxin: Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.

Warfarin: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to 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 or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

CNS Toxicity

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

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

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 HMG-CoA reductase inhibitors. 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/m2), 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.

Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS.

Safety in pregnant women has not been established.

Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg daily. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.

Rare reports of congenital anomalies have been received following intrauterine exposure to HMG-CoA reductase inhibitors. In a review(d) of approximately 100 prospectively followed pregnancies in women exposed to ZOCOR or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with ZOCOR during pregnancy (see CONTRAINDICATIONS), treatment should be immediately discontinued as soon as pregnancy is recognized. ZOCOR should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.

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 (see CONTRAINDICATIONS).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with simvastatin is not recommended at this time.

Geriatric Use

A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S and other large clinical studies conducted with simvastatin, 22% of patients were elderly (1,522 of 6,985 patients were =>65 years). Simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD (see CLINICAL PHARMACOLOGY). Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg/day dosage range.

ADVERSE REACTIONS

In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse experiences attributable to ZOCOR. Adverse reactions have usually been mild and transient. ZOCOR has been evaluated for serious adverse reactions in more than 21,000 patients and is generally well tolerated.

Clinical Adverse Experiences

Adverse experiences occurring at an incidence of 1% or greater in patients treated with ZOCOR, regardless of causality, in controlled clinical studies are shown in Table 5.

                                TABLE 5
                Adverse Experiences in Clinical Studies
        Incidence 1 Percent or Greater, Regardless of Causality
---------------------------------------------------------------------
                           ZOCOR          Placebo     Cholestyramine
                        (N = 1,583)      (N = 157)       (N = 179)
                             %               %               %
---------------------------------------------------------------------
Body as a Whole
    Abdominal pain          3.2             3.2              8.9
    Asthenia                1.6             2.5              1.1
Gastrointestinal
    Constipation            2.3             1.3             29.1
    Diarrhea                1.9             2.5              7.8
    Dyspepsia               1.1             --               4.5
    Flatulence              1.9             1.3             14.5
    Nausea                  1.3             1.9             10.1
Nervous System/
    Psychiatric
    Headache                3.5             5.1              4.5
Respiratory
    Upper respiratory
         infection          2.1             1.9              3.4
---------------------------------------------------------------------

Scandinavian Simvastatin Survival Study

Clinical Adverse Experiences

In 4S (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 4,444 patients treated with 20-40 mg/day of ZOCOR (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. The clinical adverse experiences reported as possibly, probably, or definitely drug-related in => 0.5% in either treatment group are shown in Table 6.

                                TABLE 6
            Drug-Related Clinical Adverse Experiences in 4S
                   Incidence 0.5 Percent or Greater
----------------------------------------------------------------------
                                 ZOCOR                 Placebo
                              (N = 2,221)            (N = 2,223)
                                   %                      %
----------------------------------------------------------------------
Body as a Whole
    Abdominal pain                0.9                    0.9
Gastrointestinal
    Diarrhea                      0.5                    0.3
    Dyspepsia                     0.6                    0.5
    Flatulence                    0.9                    0.7
    Nausea                        0.4                    0.6
Musculoskeletal
    Myalgia                       1.2                    1.3
Skin
    Eczema                        0.8                    0.8
    Pruritus                      0.5                    0.4
    Rash                          0.6                    0.6
Special Senses
    Cataract                      0.5                    0.8
----------------------------------------------------------------------

The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with simvastatin therapy.

Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.

Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more 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.

Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.

Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.

Reproductive: gynecomastia, loss of libido, erectile dysfunction.

Eye: progression of cataracts (lens opacities), ophthalmoplegia.

Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, (gamma)-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.

Laboratory Tests

Marked persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). 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. Muscle pain or dysfunction usually was not reported (see WARNINGS, Myopathy/Rhabdomyolysis).

Concomitant Lipid-Lowering Therapy

In controlled clinical studies in which simvastatin was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with simvastatin or cholestyramine. The combined use of simvastatin at doses exceeding 10 mg/day with gemfibrozil, other fibrates or lipid-lowering doses (=>1 g/day) of niacin should be avoided (see WARNINGS, Myopathy/Rhabdomyolysis).

OVERDOSAGE

Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, 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 ZOCOR have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 450 mg. Until further experience is obtained, no specific treatment of overdosage with ZOCOR can be recommended.

The dialyzability of simvastatin and its metabolites in man is not known at present.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering diet before receiving ZOCOR and should continue on this diet during treatment with ZOCOR. The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy (see NCEP Treatment Guidelines), and the patient's response. The dosage range is 5-80 mg/day (see below).

The recommended usual starting dose is 20 mg once a day in the evening. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg/day in the evening. Adjustments of dosage should be made at intervals of 4 weeks or more. See below for dosage recommendations for patients receiving concomitant therapy with cyclosporine, fibrates or niacin, and for those with severe renal insufficiency.

Dosage in Patients with Homozygous Familial Hypercholesterolemia

Based on the results of a controlled clinical study, the recommended dosage for patients with homozygous familial hypercholesterolemia is ZOCOR 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. ZOCOR should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Dosage in Patients taking Cyclosporine

In patients taking cyclosporine concomitantly with ZOCOR (see WARNINGS, Myopathy/Rhabdomyolysis), therapy should begin with 5 mg/day and should not exceed 10 mg/day.

Dosage in Patients taking Amiodarone or Verapamil

In patients taking amiodarone or verapamil concomitantly with ZOCOR, the dose should not exceed 20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug interactions).

Concomitant Lipid-Lowering Therapy

ZOCOR is effective alone or when used concomitantly with bile-acid sequestrants. If ZOCOR is used in combination with gemfibrozil, other fibrates or lipid-lowering doses (=> 1g/day) of niacin, the dose of ZOCOR should not exceed 10 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).

Dosage in Patients with Renal Insufficiency

Because ZOCOR does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal insufficiency. However, caution should be exercised when ZOCOR is administered to patients with severe renal insufficiency; such patients should be started at 5 mg/day and be closely monitored (see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis).

HOW SUPPLIED

No. 3588-- Tablets ZOCOR 5 mg are buff, shield-shaped, film-coated tablets, coded MSD 726 on one side and ZOCOR on the other. They are supplied as follows:

NDC 0006-0726-31 unit of use bottles of 30

NDC 0006-0726-61 unit of use bottles of 60

NDC 0006-0726-54 unit of use bottles of 90

NDC 0006-0726-28 unit dose packages of 100

NDC 0006-0726-82 bottles of 1000.

No. 3589-- Tablets ZOCOR 10 mg are peach, shield-shaped, film-coated tablets, coded MSD 735 on one side and ZOCOR on the other. They are supplied as follows:

NDC 0006-0735-31 unit of use bottles of 30

NDC 0006-0735-54 unit of use bottles of 90

NDC 0006-0735-28 unit dose packages of 100

NDC 0006-0735-82 bottles of 1000

NDC 0006-0735-87 bottles of 10,000.

No. 3590-- Tablets ZOCOR 20 mg are tan, shield-shaped, film-coated tablets, coded MSD 740 on one side and ZOCOR on the other. They are supplied as follows:

NDC 0006-0740-31 unit of use bottles of 30

NDC 0006-0740-61 unit of use bottles of 60

NDC 0006-0740-54 unit of use bottles of 90

NDC 0006-0740-28 unit dose packages of 100

NDC 0006-0740-82 bottles of 1000

NDC 0006-0740-87 bottles of 10,000.

No. 3591-- Tablets ZOCOR 40 mg are brick red, shield-shaped, film-coated tablets, coded MSD 749 on one side and ZOCOR on the other. They are supplied as follows:

NDC 0006-0749-31 unit of use bottles of 30

NDC 0006-0749-61 unit of use bottles of 60

NDC 0006-0749-54 unit of use bottles of 90

NDC 0006-0749-28 unit dose packages of 100

NDC 0006-0749-82 bottles of 1000.

No. 6577-- Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other. They are supplied as follows:

NDC 0006-0543-31 unit of use bottles of 30

NDC 0006-0543-61 unit of use bottles of 60

NDC 0006-0543-54 unit of use bottles of 90

NDC 0006-0543-28 unit dose packages of 100

NDC 0006-0543-82 bottles of 1000.

Storage

Store between 5-30(degree)C (41-86(degree)F). ---------------------------------------------------------------------- Tablets ZOCOR (simvastatin) 5 mg, 10 mg, 20 mg, and 40 mg are manufactured by: MERCK & CO., INC.

Tablets ZOCOR (simvastatin) 80 mg are manufactured for: MERCK & CO., INC.

By: MERCK SHARP & DOHME LTD, Cramlington, Northumberland, UK NE23 3JU

Issued May 2002 Printed in USA

(a) Registered trademark of MERCK & CO., Inc.

COPYRIGHT(c)MERCK & CO., Inc., 1991, 1995, 1998, 2002

All rights reserved

(b) Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther

1998;64(5):477-83.

(c) Classification of Hyperlipoproteinemias

(d) 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.