Zocor^®

In the Scandinavian Simvastatin Survival Study (4S), the effect of
improving lipoprotein levels with ZOCOR on total mortality was assessed in 4444 patients
with coronary heart disease (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 cholesterol
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
cholesterol. Apolipoprotein B (Apo B) also falls substantially during treatment with
ZOCOR. Since each LDL particle contains one molecule of apolipoprotein B, and since
little apolipoprotein 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 cholesterol
and plasma triglycerides (TG) and increases HDL cholesterol. The effects of ZOCOR on
Lp(a), fibrinogen, and certain other independent biochemical risk markers for coronary
heart disease 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 b-hydroxyacid, a
potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an
assay in pharmacokinetic studies of the b-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.

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).

Clinical Studies

ZOCOR has been shown to be highly effective in
reducing total and LDL cholesterol 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
per 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 plasma
cholesterol (TOTAL-C), LDL cholesterol (LDL-C), total cholesterol/HDL cholesterol
(TOTAL-C/HDL-C) ratio, and LDL cholesterol/HDL cholesterol (LDL-C/HDL-C) ratio. ZOCOR also
decreased triglycerides (TG) and increased HDL cholesterol (HDL-C).

The results of a dose response study in patients with primary
hypercholesterolemia are presented in Table I.

In the Scandinavian Simvastatin Survival Study
(4S), the effect of therapy with ZOCOR on total mortality was assessed in 4444 patients
with coronary heart disease (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 daily (n=2221) or placebo (n=2223) for a median duration of 5.4 years. Over
the course of the study, treatment with ZOCOR led to mean reductions in total cholesterol,
LDL cholesterol and triglycerides of 25%, 35%, and 10%, respectively, and a mean increase
in HDL cholesterol of 8%. 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). 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 patients 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 patients 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 patients 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. The risk of mortality was significantly
decreased in patients >/= 60 years of age by 27% and in
patients <60 years of age by 37%. 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 women 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.

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 trial, patients with a mean baseline total
cholesterol value of 245 mg/dL (6.4 mmol/L) and a mean baseline LDL 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 trial 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).

In a study designed to evaluate the possible
effects of simvastatin on reproductive hormones and sperm characteristics in men with
familial hypercholesterolemia, there was a small decrease in the mean percentage of vital
sperm and a small increase in the mean percentage of abnormal forms, with these changes
achieving statistical significance at week 14. However, there was no effect on numbers or
concentration of motile sperm. Simvastatin had no effect on basal reproductive hormone
levels (prolactin, luteinizing hormone, follicle-stimulating hormone, and plasma
testosterone). Provocative testing (HCG stimulation) was not done. Treatment with another
HMG-CoA reductase inhibitor resulted in a statistically significant decrease in plasma
testosterone response to HCG.

In a study to evaluate the effect of simvastatin on adrenocortical
function in patients with Type II hypercholesterolemia, simvastatin had no effect on
basal adrenocortical function as assessed by determination of morning plasma cortisol
levels, urine free cortisol, and urinary excretion of 17-hydroxy steroids. Simvastatin
also had no effect on adrenocortical reserve as evaluated by the plasma cortisol response
to ACTH stimulation and insulin-induced hypoglycemia.

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

Hyperlipidemia

ZOCOR is indicated as an adjunct to diet to reduce elevated TOTAL-C,
LDL-C, Apo B, and TG levels in patients with primary hypercholesterolemia (heterozygous
familial and nonfamilial) and mixed dyslipidemia (Frederickson Types IIa and IIb**).

** Classification of Hyperlipoproteinemias

	Lipoproteins	Lipid Elevations
Type	elevated	major	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.

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 triglycerides. For patients with TG less than 400 mg/dL
(<4.5 mmol/L), LDL-C can be estimated using the following equation:

The National Cholesterol Education Program (NCEP) Treatment Guidelines
are summarized below:

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 cholesterol and triglyceride levels in
patients with Type IIb hyperlipoproteinemia (where hypercholesterolemia is the major
abnormality). However, it has not been studied in conditions where the major abnormality
is elevation of chylomicrons, VLDL or IDL (i.e., hyperlipoproteinemia types I, III,
IV, or V).**

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

Concomitant therapy with the tetralol-class calcium channel blocker
mibefradil (see WARNINGS, Skeletal Muscle and PRECAUTIONS, Drug Interactions).

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).

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

In the Scandinavian Simvastatin Survival Study
(see CLINICAL PHARMACOLOGY, Clinical Studies), the number of patients with more
than one transaminase elevation to > 3 times the upper limit of normal, over the course
of the study, was not significantly different between the simvastatin and placebo groups
(14 [0.7%] vs. 12 [0.6%]). 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 1986 simvastatin treated patients in 4S with normal liver function tests
(LFTs) at baseline, only 8 (0.4%) developed consecutive LFT elevations to > 3 times the
upper limit of normal 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.

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 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 three times the upper limit of normal 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 three times
the upper limit of normal) 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.

Skeletal Muscle

Rare cases of rhabdomyolysis with acute renal
failure secondary to myoglobinuria have been associated with simvastatin therapy.
Rhabdomyolysis has also been associated with other HMG-CoA reductase inhibitors when they
were administered alone or concomitantly with 1) immunosuppressive therapy, including
cyclosporine in transplant patients; 2) gemfibrozil or lipid-lowering doses (>/=1 g/day) of nicotinic acid in non-transplant patients;
3) the macrolide antibiotics erythromycin and clarithromycin, or 4) the
antidepressant nefazodone. Rhabdomyolysis has occurred with simvastatin in combination
with the tetralol-class calcium channel blocker mibefradil which is a potent inhibitor of
cytochrome P450 3A4 (see CONTRAINDICATIONS). Some of the patients who had
rhabdomyolysis in association with the reductase inhibitors had pre-existing renal
insufficiency, usually as a consequence of long-standing diabetes. In most subjects who
have had an unsatisfactory lipid response to either simvastatin or gemfibrozil alone, the
possible benefits of combined therapy with these drugs are not considered to outweigh the
risk of severe myopathy, rhabdomyolysis, and acute renal failure. While it is not known
whether this interaction occurs with fibrates other than gemfibrozil, myopathy and
rhabdomyolysis have occasionally been associated with the use of other fibrates alone,
including clofibrate. Therefore, the combined use of simvastatin with other fibrates
should generally be avoided.

Myopathy or rhabdomyolysis has occurred in
transplant and non-transplant patients receiving ZOCOR or another HMG-CoA reductase
inhibitor following the initiation of treatment with the antifungal agents itraconazole
and ketoconazole. In a study in normal volunteers, plasma levels of another HMG-CoA
reductase inhibitor were increased about 20-fold when administered concomitantly with
itraconazole. This is probably related to metabolism of both drugs by the same P-450
isoform. Based on this data, therapy with ZOCOR should be temporarily interrupted if
systemic azole derivative antifungal therapy is required.

Myopathy should be considered in any patient with diffuse myalgias,
muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised
to report promptly unexplained muscle pain, tenderness or weakness, particularly if
accompanied by malaise or fever. Simvastatin therapy should be discontinued if markedly
elevated CPK levels occur or myopathy is diagnosed or suspected.

Homozygous Familial Hypercholesterolemia

ZOCOR is less effective in patients with the rare homozygous familial
hypercholesterolemia, possibly because these patients have few functional LDL receptors.

Information for Patients

Patients should be advised to report promptly unexplained muscle pain,
tenderness, or weakness, particularly if accompanied by malaise or fever (see WARNINGS, Skeletal
Muscle).

Mibefradil (see CONTRAINDICATIONS), Immunosuppressive Drugs,
Itraconazole, Ketoconazole, Gemfibrozil, Niacin (Nicotinic Acid), Erythromycin,
Clarithromycin, Nefazodone: See WARNINGS, Skeletal Muscle.

Antipyrine: Simvastatin had no effect on the pharmacokinetics of
antipyrine. However, since simvastatin is metabolized by the cytochrome P-450 isoform 3A4,
this does not preclude an interaction with other drugs metabolized by the same isoform.

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.

Endocrine Function

HMG-CoA reductase inhibitors interfere with
cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid
production. However, clinical studies have shown that simvastatin does not reduce basal
plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma
testosterone concentration (see CLINICAL PHARMACOLOGY, Clinical Studies). Another
HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to
HCG; the effect of simvastatin on HCG-stimulated testosterone secretion has not been
studied.

Results of clinical trials with drugs in this class have been inconsistent
with regard to drug effects on basal and reserve steroid levels. The effects of HMG-CoA
reductase inhibitors on male fertility have not been studied in adequate numbers of male
patients. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are
unknown. Patients treated with simvastatin who develop clinical evidence of endocrine
dysfunction should be evaluated appropriately. Caution should also be exercised if an
HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is
administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone,
cimetidine) that may decrease the levels or activity of endogenous steroid hormones.

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 44 times higher than the mean drug level in humans taking
40 mg/day.

There were cataracts in female rats after two years of treatment with 50
and 100 mg/kg/day (110 and 120 times the human AUC at 40 mg/day) and in dogs in three
month studies at 90 and 360 mg/kg/day and at two years at 50 mg/kg/day. These treatment
levels represented plasma drug levels (AUC) of approximately 42, 40, and 26 times the mean
human plasma drug exposure after a 40 milligram daily dose.

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 3, 15, and 33 times higher than the mean
human plasma drug concentration (as total inhibitory activity) after a 40 mg oral
dose. Liver carcinomas were significantly increased in high-dose females and mid- and
high-dose males with a maximum incidence of 90 percent 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. Although mice were given up to 500 times the
human dose (HD) on a mg/kg/body weight basis, blood levels of HMG-CoA reductase inhibitory
activity were only 3-33 times higher in mice than in humans given 40 mg of ZOCOR.

There was decreased fertility in male rats treated with simvastatin for 34
weeks at 25 mg/kg body weight (15 times the maximum human exposure level, based on
AUC, in patients receiving 40 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 44 times higher than those in humans
taking 40 mg/day), 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 7 times the human exposure level, based on AUC, at
40 mg/day). The clinical significance of these findings is unclear.

Pregnancy

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 6 times (rat) or 4
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*** 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.

^*** 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.

Nursing Mothers

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.

Clinical Adverse Experiences