FDA Approves ZOCOR 40 mg as Starting Dose for People at High Risk of Coronary Events because of Coronary Heart Disease or Diabetes.

Business Editors/Health/Medical Writers

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--April 17, 2003

Merck & Co., Inc. (NYSE:MRK) announced today that the Food and Drug Administration (FDA) has approved changes to the prescribing information for ZOCOR(R) (simvastatin) to include results from the landmark Heart Protection Study with ZOCOR 40 mg, the largest cholesterol treatment study ever conducted.

As a result of the FDA's decision, ZOCOR 40 mg is now recommended, along with diet, as the starting dose for ZOCOR for people with coronary heart disease (CHD) or diabetes. ZOCOR 40 mg is the first and only cholesterol-lowering medication proven to reduce the risk of heart attack and stroke in people with heart disease or diabetes regardless of cholesterol level. Treatment with ZOCOR 40 mg as compared to placebo reduced the risk of death from any cause by 13 percent (ZOCOR 1328/10269 vs. placebo 1507/10267, p=0.0003).

"The new use has the potential to change the treatment approach of people with CHD and those with diabetes. It demonstrates that the millions of people who suffer from CHD or diabetes could benefit from treatment with simvastatin 40 mg known as ZOCOR," said

Alan J. Garber, M.D., Ph.D., chief of Endocrinology, Diabetes and Metabolism, The Methodist Hospital in Houston. "This news is particularly relevant in light of the latest NCEP Guidelines, which call for aggressive treatment of patients at high-risk for heart attacks such as people with diabetes or CHD."

ZOCOR 40 mg reduced the risk of non-fatal heart attack by 38 percent

The Heart Protection Study, conducted by the Clinical Trial Service Unit of world-renowned Oxford University, U.K., followed 20,536 people considered to be at high risk for a heart attack for five years. The study results demonstrated that ZOCOR 40 mg reduced the risk of non-fatal heart attack by 38 percent compared to placebo in people with heart disease or at high risk for heart disease, such as people with diabetes (ZOCOR 40 mg 357/10,269 vs. 574/10,267 for placebo, p<0.0001). The study also demonstrated that ZOCOR 40 mg reduced the risk of stroke by 25 percent (ZOCOR 40 mg 444/10,269 vs. 585/10267 for placebo, p<0.0001). In addition, the study demonstrated risk reductions in major coronary events* with ZOCOR 40mg in all high risk patient groups studied such as those with a history of heart attacks, diabetes or vascular disease including women and the elderly. Importantly, in patients at high risk of CHD, these results were consistent even in those patients whose cholesterol levels were not high enough to require drug treatment under current guidelines.

The recommended usual starting dose for ZOCOR is 20 to 40 mg once a day in the evening. For patients at high risk for a CHD event due to existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter. The prescribing information has additional information on dosing recommendations in special populations and with certain concomitant medications.

Patients in this study were 40 to 80 years old. Twenty-five percent (n=5,082) of the patients were women. Patients were at high risk of a major coronary event because of existing coronary heart disease, diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease or hypertension (males over 65 years). Patients had a range of LDL - the so-called "bad" - cholesterol levels. Seventeen percent (n=3421) had levels at baseline below 100 mg/dL (of whom 953 had LDL-C levels below 80 mg/dL); 34 percent (n=7,068) were between 100 mg/dL and 130 mg/dL, and the remaining 49 percent (n=10,047) had levels greater than 130 mg/dL.

ZOCOR 40 mg is the only statin proven to reduce the risk of heart attack and stroke in people with diabetes

The Heart Protection Study with ZOCOR 40 mg was the first study designed to investigate the benefits of ZOCOR 40 mg in people with diabetes with or without a prior history of heart disease or high cholesterol. The study included 5,963 people -- about 29 percent of all people in the study -- with diabetes (of all patients studied 26 percent had Type II diabetes and 3 percent had Type I diabetes). Compared to placebo, ZOCOR 40 mg reduced the risk of suffering one or more major coronary events by 27 percent (ZOCOR 40 mg 279/2978 vs. 377/2985 for placebo, p<0.0001) in people with diabetes with or without prior heart disease with the greatest effect seen in diabetic patients without CHD.

According to the National Institutes of Health's (NIH) new NCEP Guidelines, people with diabetes without heart disease have the same risk of having a heart attack as someone who has heart disease without diabetes. "The real problem is that the link between diabetes and heart disease is often misunderstood, underestimated or ignored. One survey found that more than two thirds of people with diabetes are unaware they face an increased risk of heart attack and stroke," said Dr. Garber. According to data from the United Kingdom Prospective Diabetes Study, the greatest predictor for coronary risk in people with Type II diabetes is high LDL cholesterol, followed by low HDL cholesterol, high blood sugar and high blood pressure. Dr. Garber commented, "So for people with diabetes, managing their risk factors for heart attack and stroke is as important as managing glucose." For physicians treating people with diabetes, the Heart Protection Study results support starting patients on ZOCOR 40 mg along with diet immediately upon diagnosis, regardless of their cholesterol or blood sugar levels.

ZOCOR 40 mg helped save lives by reducing fatal heart attacks in high-risk patients

The overall primary objective of the Heart Protection Study was to determine whether ZOCOR 40 mg reduced the risk of death in a broad patient population at high risk for cardiovascular events. Treatment with ZOCOR 40 mg as compared to placebo reduced the risk of death from any cause by 13 percent (ZOCOR 1328/10269 vs. placebo 1507/10267, p=0.0003). The risk of death from heart attack, and related coronary events was reduced by 18 percent in the group treated with ZOCOR 40 mg as compared to placebo (ZOCOR 587/10269 vs. placebo 707/10267, p=0.0005).

The safety profile of ZOCOR 40 mg was comparable to placebo in the Heart Protection Study

During the five-year Heart Protection Study, the safety profiles were comparable between patients treated with ZOCOR 40 mg and patients treated with placebo. The number of patients who discontinued the study due to adverse reactions was also comparable (4.8 percent for people on ZOCOR and 5.1 percent for people on placebo). In this trial, only serious adverse effects and discontinuations due to any adverse effects were recorded. The incidence of myopathy/rhabdomyolysis was <0.1 percent in people on ZOCOR 40 mg.

Additional information about ZOCOR

ZOCOR, a cholesterol-lowering prescription medicine from Merck & Co., Inc., is used along with diet to improve cholesterol levels in people with high-cholesterol, when diet alone is not enough. The medication has been proven to significantly improve LDL and HDL cholesterol levels, as well as triglyceride levels. ZOCOR is one of the most studied statins on the market today and the efficacy of ZOCOR has been well documented in numerous clinical trials. In the past 10 years, more than 140 million prescriptions have been written for ZOCOR.

Selected cautionary information for ZOCOR

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 people 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. People taking 80 mg of ZOCOR should receive an additional liver function test at three months. To help avoid serious side effects, discuss with your doctor medicine or food you should avoid while taking ZOCOR. 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 global 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.

FORWARD LOOKING STATEMENT:

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements include statements regarding product development and product potential. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect the company's businesses, particularly those mentioned in the cautionary statements in Item 1 of our Form 10-K for the year ended Dec. 31, 2002, and in our periodic reports on Form 10-Q and Form 8-K (if any) which we incorporate by reference.

* Coronary death and non-fatal heart attack.

Full prescribing information for ZOCOR(R) is attached and is also available at www.zocor.com

TABLETS
ZOCOR(R)
(SIMVASTATIN)

DESCRIPTION

    ZOCOR(1) (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 study2, 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 first2 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 in Adults
Reductions in Risk of CHD Mortality and Cardiovascular Events

    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 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)) 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.
    The Heart Protection Study (HPS) was a large, multi-center,
placebo-controlled, double-blind study with a mean duration of 5 years
conducted in 20,536 patients (10,269 on ZOCOR 40 mg and 10,267 on
placebo). Patients were allocated to treatment using a covariate
adaptive method3 which took into account the distribution of 10
important baseline characteristics of patients already enrolled and
minimized the imbalance of those characteristics across the groups.
Patients had a mean age of 64 years (range 40-80 years), were 97%
Caucasian and were at high risk of developing a major coronary event
because of existing coronary heart disease (65%), diabetes (Type 2,
26%; Type 1, 3%), history of stroke or other cerebrovascular disease
(16%), peripheral vessel disease (33%), or hypertension in males 65
years of age and older (6%). At baseline, 3,421 patients (17%) had
LDL-C levels below 100 mg/dL, of whom 953 (9%) had LDL-C levels below
80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL;
and 10,047 patients (49%) had levels greater than 130 mg/dL.
    The HPS results showed that ZOCOR 40 mg/day significantly reduced:
total and CHD mortality; non-fatal myocardial infarctions, stroke, and
revascularization procedures (coronary and non-coronary) (see Table
1).

                                 TABLE 1
                 Summary of Heart Protection Study Results
----------------------------------------------------------------------
Endpoint           ZOCOR        Placebo   Risk Reduction(%)  p-Value
                (N=10,269)    (N=10,267)      (95% CI)
                   n (%)+       n (%)+
----------------------------------------------------------------------
Primary

  Mortality     1,328 (12.9) 1,507 (14.7)      13          p=0.0003
                                              (6-19)

  CHD mortality    587 (5.7)    707 (6.9)      18          p=0.0005
                                              (8-26)
----------------------------------------------------------------------
Secondary

  Non-fatal MI     357 (3.5)    574 (5.6)       38         p<0.0001
                                             (30-46)

  Stroke           444 (4.3)    585 (5.7)       25         p<0.0001
                                             (15-34)
----------------------------------------------------------------------
Tertiary

  Coronary
   revascularization 513 (5)    725 (7.1)       30         p<0.0001
                                              (22-38)

  Peripheral and
   other
   non-coronary
   revascularization 450 (4.4)   532 (5.2)      16         p=0.006
                                               (5-26)
----------------------------------------------------------------------
+ n = number of patients with indicated event

    Two composite endpoints were defined in order to have sufficient
events to assess relative risk reductions across a range of baseline
characteristics (see Figure 1). A composite of major coronary events
(MCE) was comprised of CHD mortality and non-fatal MI (analyzed by
time-to-first event; 898 patients treated with ZOCOR had events and
1,212 patients on placebo had events). A composite of major vascular
events (MVE) was comprised of MCE, stroke and revascularization
procedures including coronary, peripheral and other non-coronary
procedures (analyzed by time-to-first event; 2,033 patients treated
with ZOCOR had events and 2,585 patients on placebo had events).
Significant relative risk reductions were observed for both composite
endpoints (27% for MCE and 24% for MVE, p<0.0001). Furthermore,
treatment with ZOCOR produced significant relative risk reductions for
all components of the composite endpoints. The risk reductions
produced by ZOCOR in both MCE and MVE were evident and consistent
regardless of cardiovascular disease related medical history at study
entry (i.e., CHD alone; or peripheral vascular disease,
cerebrovascular disease, diabetes or treated hypertension, with or
without CHD), gender, age, creatinine levels up to the entry limit of
2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1,
baseline concomitant cardiovascular medications (i.e., aspirin, beta
blockers, or calcium channel blockers), smoking status, alcohol
intake, or obesity. Diabetics showed risk reductions for MCE and MVE
due to ZOCOR treatment regardless of baseline HbA1c levels or obesity
with the greatest effects seen for diabetics without CHD.

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

                            (TABLE OMITTED)

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

Angiographic Studies

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

Modifications of Lipid Profiles
Primary 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 2.

                                TABLE 2
                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+

----------------------------------------------------------------------

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)
Placebo                     125          1         2        3    -4

ZOCOR 40 mg q.p.m.          123        -25       -29       13   -28

ZOCOR 80 mg q.p.m.          124        -31       -36       16   -33

----------------------------------------------------------------------
+ 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 3. 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 3
                  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 4. 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 4
                 Six-week, Lipid-lowering Effects of
                Simvastatin in Type lll Hyperlipidemia
             Median Percent Change (min,max) from Baseline

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

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.

Clinical Studies in Adolescents

    In a double-blind, placebo-controlled study, 175 patients (99
adolescent boys and 76 post-menarchal girls) 10-17 years of age (mean
age 14.1 years) with heterozygous familial hypercholesterolemia (heFH)
were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks
(base study). Inclusion in the study required a baseline LDL-C level
between 160 and 400 mg/dL and at least one parent with an LDL-C level
>189 mg/dL. The dosage of simvastatin (once daily in the evening) was
10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg
thereafter. In a 24-week extension, 144 patients elected to continue
therapy and received simvastatin 40 mg or placebo.
    ZOCOR significantly decreased plasma levels of total-C, LDL-C, and
Apo B (see Table 5). Results from the extension at 48 weeks were
comparable to those observed in the base study.

                                TABLE 5

     Lipid-lowering Effects of Simvastatin in Adolescent Patients
           with Heterozygous Familial Hypercholesterolemia
----------------------------------------------------------------------
                  (Mean Percent Change from Baseline)
----------------------------------------------------------------------

Dosage   Duration  N           Total-C   LDL-C   HDL-C   TG+  Apo B

----------------------------------------------------------------------
                     % Change
                       from
                      Baseline
Placebo 24 Weeks  67  (95% CI)  1.6       1.1    3.6   -3.2    -0.5
                              (-2.2,    (-3.4, (-0.7, (-11.8, (-4.7,
                               5.3)      5.5)    8.0)  5.4)    3.6)

                       Mean
                      baseline,
                       mg/dL  278.6     211.9   46.9   90.0   186.3
                       (SD)   (51.8)    (49.0) (11.9) (50.7)  (38.1)
----------------------------------------------------------------------
                      % Change
                        from
                      Baseline
ZOCOR   24 Weeks  106 (95% CI) -26.5     -36.8    8.3   -7.9    -32.4
                              (-29.6,   (-40.5,  (4.6, (-15.8, (-35.9,
                               -23.3)    -33.0)  11.9)   0.0)   -29.0)

                        Mean
                      baseline,
                       mg/dL   270.2     203.8   47.7   78.3    179.9
                        (SD)   (44.0)    (41.5)  (9.0) (46.0)   (33.8)
----------------------------------------------------------------------
  +median percent change

    After 24 weeks of treatment, the mean achieved LDL-C value was
124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Zocor 40 mg group
compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo
group.
    The safety and efficacy of doses above 40 mg daily have not been
studied in children with heterozygous familial hypercholesterolemia.
The long-term efficacy of simvastatin therapy in childhood to reduce
morbidity and mortality in adulthood has not been established.

INDICATIONS AND USAGE

    Lipid-altering agents should be used in addition to a diet
restricted in saturated fat and cholesterol (see National Cholesterol
Education Program (NCEP) Treatment Guidelines, below).
    In patients with CHD or at high risk of CHD, ZOCOR can be started
simultaneously with diet.

Reductions in Risk of CHD Mortality and Cardiovascular Events

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

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

Patients with Hypercholesterolemia Requiring Modifications of
Lipid Profiles

    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 IIb4).
    --  Treat patients with hypertriglyceridemia (Fredrickson type lV
        hyperlipidemia).
    --  Treat patients with primary dysbetalipoproteinemia
        (Fredrickson type lll hyperlipidemia).
    --  Reduce total-C and LDL-C in patients with homozygous familial
        hypercholesterolemia as an adjunct to other lipid-lowering
        treatments (e.g., LDL apheresis) or if such treatments are
        unavailable.

Adolescent Patients with Heterozygous Familial
Hypercholesterolemia (HeFH)

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

    1.  LDL cholesterol remains =>190 mg/dL; or
    2.  LDL cholesterol remains =>160 mg/dL and
    --  There is a positive family history of premature cardiovascular
        disease (CVD) or
    --  Two or more other CVD risk factors are present in the
        adolescent patient

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

General Recommendations

    Prior to initiating therapy with simvastatin, secondary causes for
hypercholesterolemia (e.g., 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)

    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 6:

                             TABLE 6 NCEP
                         Treatment Guidelines:
      LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes
             and Drug Therapy in Different Risk Categories
----------------------------------------------------------------------
                             LDL Level at Which to     LDL Level at
 Risk Category    LDL Goal   Initiate Therapeutic   Which to Consider
                                 Lifestyle        Drug Therapy Changes
                   (mg/dL)         (mg/dL)                (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
(10 year risk <=20%)                                  10-20%: =>130

                                                      10-year risk
                                                       <10%: =>160

0-1 Risk factor ss.  <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.
ss.  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).
    The NCEP classification of cholesterol levels in pediatric
patients with a familial history of either hypercholesterolemia or
premature cardiovascular disease is summarized in Table 7.

                                TABLE 7
              NCEPClassification of Cholesterol Levels in
              Pediatric Patients with a Familial History
                    of Either HeFH or Premature CVD
----------------------------------------------------------------------
      Category            Total-C (mg/dL)           LDL-C (mg/dL)
----------------------------------------------------------------------
     Acceptable                <170                     <110
     Borderline              170-199                  110-129
        High                  =>200                    =>130
----------------------------------------------------------------------

    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).4

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;
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 thereafter when clinically indicated.
Patients titrated to the 80-mg dose should receive an additional test
prior to titration, 3 months after titration to the 80-mg dose, and
periodically thereafter (e.g., semiannually) for the first year of
treatment. Patients who develop increased transaminase levels should
be monitored with a second liver function evaluation to confirm the
finding and be followed thereafter with frequent liver function tests
until the abnormality(ies) return to normal. Should an increase in AST
or ALT of 3X ULN or greater persist, withdrawal of therapy with 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 CYP3A4 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 review5 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 of simvastatin in patients 10-17 years of
age with heterozygous familial hypercholesterolemia have been
evaluated in a controlled clinical trial in adolescent boys and in
girls who were at least 1 year post-menarche. Patients treated with
simvastatin had an adverse experience profile generally similar to
that of patients treated with placebo. Doses greater than 40 mg have
not been studied in this population. In this limited controlled study,
there was no detectable effect on growth or sexual maturation in the
adolescent boys or girls, or any effect on menstrual cycle length in
girls. See CLINICAL PHARMACOLOGY, Clinical Studies in Adolescents;
ADVERSE REACTIONS, Adolescent Patients; and DOSAGE AND ADMINISTRATION,
Adolescents (10-17 years of age) with Heterozygous Familial
Hypercholesterolemia. Adolescent females should be counseled on
appropriate contraceptive methods while on simvastatin therapy (see
CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Simvastatin has not
been studied in patients younger than 10 years of age, nor in
pre-menarchal girls.

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, 1,021 (23%) of 4,444
patients were 65 or older. In 4S, lipid-lowering efficacy was at least
as great in elderly patients compared with younger patients. In this
study, ZOCOR significantly reduced total mortality and CHD mortality
in elderly patients with a history of CHD. There were no overall
differences in safety between older and younger patients in 4S. In
HPS, 52% of patients were elderly (4,891 patients 65-69 years and
5,806 patients 70 years or older). The relative risk reductions of CHD
death, non-fatal MI, coronary and non-coronary revascularization
procedures, and stroke were similar in older and younger patients (see
CLINICAL PHARMACOLOGY). In HPS, among 32,145 patients entering the
active run-in period, there were 2 cases of myopathy/rhabdomyolysis;
these patients were aged 67 and 73. Of the 7 cases of
myopathy/rhabdomyolysis among 10,269 patients allocated to
simvastatin, 4 were aged 65 or more (at baseline), of whom one was
over 75.

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
In Adults

    Adverse experiences occurring in adults at an incidence of 1% or
greater in patients treated with ZOCOR, regardless of causality, in
controlled clinical studies are shown in Table 8.

                                TABLE 8
                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 9.

                                TABLE 9
            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
----------------------------------------------------------------------


Heart Protection Study
Clinical Adverse Experiences

    In HPS (see CLINICAL PHARMACOLOGY, Clinical Studies), involving
20,536 patients treated with ZOCOR 40 mg/day (n=10,269) or placebo
(n=10,267), the safety profiles were comparable between patients
treated with ZOCOR and patients treated with placebo over the mean 5
years of the study. In this large trial, only serious adverse events
and discontinuations due to any adverse events were recorded.
Discontinuation rates due to adverse experiences were comparable (4.8%
in patients treated with ZOCOR compared with 5.1% in patients treated
with placebo). The incidence of myopathy/rhabdomyolysis was <0.1% in
patients treated with ZOCOR.
    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).

Adolescent Patients (ages 10-17 years)

    In a 48-week controlled study in adolescent boys and girls who
were at least 1 year post-menarche, 10-17 years of age with
heterozygous familial hypercholesterolemia (n=175), the safety and
tolerability profile of the group treated with ZOCOR (10-40 mg daily)
was generally similar to that of the group treated with placebo, with
the most common adverse experiences observed in both groups being
upper respiratory infection, headache, abdominal pain, and nausea.
(see CLINICAL PHARMACOLOGY, Clinical Studies in Adolescents, and
PRECAUTIONS, Pediatric Use).

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. In patients with CHD or at high risk of CHD, ZOCOR can be
started simultaneously with diet. The dosage should be individualized
according to the goals of therapy and the patient's response (For the
treatment of adult dyslipidemia, see NCEP Treatment Guidelines. For
the reduction in risks of major coronary events, see CLINICAL
PHARMACOLOGY, Clinical Studies in Adults). The dosage range is 5-80
mg/day (see below).
    The recommended usual starting dose is 20 to 40 mg once a day in
the evening. For patients at high risk for a CHD event due to existing
coronary heart disease, diabetes, peripheral vessel disease, history
of stroke or other cerebrovascular disease, the recommended starting
dose is 40 mg/day. Lipid determinations should be performed after 4
weeks of therapy and periodically thereafter. See below for dosage
recommendations in special populations (i.e., homozygous familial
hypercholesterolemia, adolescents and renal insufficiency) or for
patients receiving concomitant therapy (i.e., cyclosporine,
amiodarone, verapamil, fibrates or niacin).

Patients with Homozygous Familial Hypercholesterolemia

    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.

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

    The recommended usual starting dose is 10 mg once a day in the
evening. The recommended dosing range is 10-40 mg/day; the maximum
recommended dose is 40 mg/day. Doses should be individualized
according to the recommended goal of therapy (see NCEP Pediatric Panel
Guidelines6 and CLINICAL PHARMACOLOGY). Adjustments should be made at
intervals of 4 weeks or more.

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 (=>1 g/day) of niacin, the dose of
ZOCOR should not exceed 10 mg/day (see WARNINGS,
Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions).

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.

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).

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:
(GRAPHIC OMITTED)

Tablets ZOCOR (simvastatin) 80 mg are manufactured for:
(GRAPHIC OMITTED)

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

Issued
Printed in USA

--------
1   Registered trademark of MERCK & CO., Inc. COPYRIGHT(c)MERCK & CO.,
    Inc., 1991, 1995, 1998, 2002 All rights reserved
2   Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther
    1998;64(5):477-83.
3   D.R. Taves, Minimization: a new method of assigning patients to
    treatment and control groups. Clin. Pharmacol. Ther. 15 (1974),
    pp. 443-453
4  Classification of Hyperlipoproteinemias
                                                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.

5   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.

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