Merck and Schering-Plough to Develop Another New Cholesterol Lowering Medicine.

New Medicine Will Be Fixed Dose Combination of Ezetimibe and Atorvastatin 

WHITEHOUSE STATION, N.J. -- Merck & Co., Inc. (NYSE: MRK) announced today an agreement to commence development of an ezetimibe and atorvastatin combination product in collaboration with Schering-Plough Corporation.

Merck and Schering-Plough are the two parent companies of Merck/Schering-Plough Pharmaceuticals, a joint venture that was formed in 2000 to develop and market in the United States new prescription medicines in cholesterol management and respiratory disease. The cholesterol collaboration was expanded in 2001 and includes worldwide markets (excluding Japan). The joint venture/partnership also markets ZETIA([R]) (ezetimibe) and VYTORIN([R]) (ezetimibe/simvastatin) in the U.S. and these medicines are marketed as EZETROL and INEGY, respectively, in many countries outside the U.S.

"Everyone at Merck is delighted that we have entered into this agreement with Schering-Plough," said Richard T. Clark, president and chief executive officer of Merck & Co., Inc. "This agreement exemplifies Merck's Plan to Win by expanding our lead in cutting-edge science through investments in our own internal research as well as through external collaborations and is a logical next step for our very strong and successful partnership with Schering-Plough."

The development program is timed such that this combination product could be available at the time that patent exclusivity for atorvastatin expires in the U.S. and internationally.

The cholesterol-management market is one of the largest worldwide, with total worldwide sales of $32 billion (IMS Full Year 2006 Constant USD) and sales in the U.S. of $22 billion in 2006 (IMS Health).

"Based on the outstanding performance of VYTORIN and INEGY in markets around the world, the excellent LDL cholesterol efficacy and wide acceptance of the dual inhibition approach to the treatment of elevated cholesterol has clearly been established. The development of ezetimibe and atorvastatin is an extension of this approach," said Peter Loescher, president, Global Human Health, Merck & Co., Inc.

ZETIA, which works in the digestive tract to inhibit the absorption of cholesterol, is complementary to the class of cholesterol-lowering agents known as statins, which work in the liver to reduce the production of cholesterol. In a multi-center, double blind, placebo controlled 12-week clinical trial in 628 patients with high cholesterol, the co-administration of atorvastatin (10 mg, 20 mg, 40 mg, 80 mg) with ZETIA 10mg lowered LDL "bad" cholesterol by an average of 53 to 61 percent from baseline across the dosing range compared to average LDL cholesterol reductions of 37 to 54 percent with atorvastatin alone. ZETIA, either alone or in addition to a statin, has not been shown to prevent heart disease or heart attacks.

ZETIA is indicated, along with a healthy diet, for use either by itself or together with statins in patients with high cholesterol to reduce LDL cholesterol and total cholesterol when the response to diet has been inadequate. It is also available in a once-daily tablet with Zocor (simvastatin), a Merck statin and marketed under the brand names VYTORIN in the United States and INEGY internationally.

Important information about ZETIA

ZETIA is a prescription medication and should not be taken by people who are allergic to any of its ingredients. When ZETIA is prescribed with a statin, it should not be taken by women who are nursing or pregnant or who may become pregnant, or by anyone with active liver disease. Statins should not be taken by anyone with these conditions. If you have ever had liver problems or are pregnant or nursing, your doctor will decide if ZETIA is right for you. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment.

Due to the unknown effects of increased exposure to ZETIA in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients. In clinical trials, there was no increased incidence of myopathy (muscle pain) or rhabdomyolysis (muscle breakdown) associated with ZETIA; however myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs.

There are no adequate and well-controlled studies of ZETIA in pregnant women. ZETIA should not be used in pregnant or nursing women unless the benefit outweighs the potential risks.

When ZETIA was co-administered with a statin, consecutive elevations in liver enzymes, more than three times the upper limit of normal, were slightly higher than those with the statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA was co-administered with fenofibrate, consecutive elevations in liver enzymes more than three times the upper limit of normal, were 2.7 percent, and 4.5 percent in patients treated with fenofibrate alone. Caution should be exercised when initiating ZETIA in patients treated with cyclosporine, particularly in patients with severe renal insufficiency, due to increased blood levels of ZETIA.

In clinical trials, most frequent side effects for ZETIA alone versus placebo included: back pain (4.1 percent vs. 3.9 percent), arthralgia (3.8 percent vs. 3.4 percent), and fatigue (2.2 percent vs. 1.8 percent); for ZETIA plus statin versus statin or placebo alone: back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent), abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent), and fatigue (2.8 percent vs. 1.4 percent vs. 1.9 percent).

Important information about VYTORIN

VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet when diet alone is not enough, for the reduction of elevated total cholesterol, LDL cholesterol, Apo B1, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia. No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

VYTORIN is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN.

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (eN3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (4 -week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (eN3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.

VYTORIN has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicine to address unmet medical needs. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

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 are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. 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 Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

1 Apo B is the protein component of lipoproteins, LDL and VLDL, which carry cholesterol in the blood.

ZETIA([R]) and VYTORIN([R]) are registered trademarks of MSP Singapore Company LLC.

Full prescribing information and patient prescribing information for ZETIA([R]) and VYTORIN([R]) is attached. Additional information about ZETIA and VYTORIN may be found by visiting www.zetia.com or www.vytorin.com.

                                                               9619608

    VYTORIN (R) 10/10
    (EZETIMIBE 10 MG/SIMVASTATIN 10 MG TABLETS)

    VYTORIN (R) 10/20
    (EZETIMIBE 10 MG/SIMVASTATIN 20 MG TABLETS)

    VYTORIN (R) 10/40
    (EZETIMIBE 10 MG/SIMVASTATIN 40 MG TABLETS)

    VYTORIN (R) 10/80
    (EZETIMIBE 10 MG/SIMVASTATIN 80 MG TABLETS)

    DESCRIPTION

    VYTORIN contains ezetimibe, a selective inhibitor of intestinal
cholesterol and related phytosterol absorption, and simvastatin, a
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.

    The chemical name of ezetimibe is
1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)-3(S)-hydroxypropyl)-4(S)-(
4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3
and its molecular weight is 409.4.

    Ezetimibe is a white, crystalline powder that is freely to very
soluble in ethanol, methanol, and acetone and practically insoluble in
water. Its structural formula is:

    (OBJECT OMITTED)

    Simvastatin, an inactive lactone, is hydrolyzed to the
corresponding (beta)-hydroxyacid form, which is an inhibitor of
HMG-CoA reductase. 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.

    Simvastatin is a white to off-white, nonhygroscopic, crystalline
powder that is practically insoluble in water, and freely soluble in
chloroform, methanol and ethanol. Its structural formula is:

    VYTORIN is available for oral use as tablets containing 10 mg of
ezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of
simvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or
80 mg of simvastatin (VYTORIN 10/80). Each tablet contains the
following inactive ingredients: butylated hydroxyanisole NF, citric
acid monohydrate USP, croscarmellose sodium NF, hydroxypropyl
methylcellulose USP, lactose monohydrate NF, magnesium stearate NF,
microcrystalline cellulose NF, and propyl gallate NF.

    CLINICAL PHARMACOLOGY

    Background

    Clinical studies have demonstrated that elevated levels of total
cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and
apolipoprotein B (Apo B), the major protein constituent of LDL,
promote human atherosclerosis. In addition, decreased levels of
high-density lipoprotein cholesterol (HDL-C) are associated with the
development of atherosclerosis. Epidemiologic studies have established
that cardiovascular morbidity and mortality vary directly with the
level of total-C and LDL-C and inversely with the level of HDL-C. Like
LDL, cholesterol-enriched triglyceride-rich lipoproteins, including
very-low-density lipoproteins (VLDL), intermediate-density
lipoproteins (IDL), and remnants, can also promote atherosclerosis.
The independent effect of raising HDL-C or lowering triglycerides (TG)
on the risk of coronary and cardiovascular morbidity and mortality has
not been determined.

    Mode of Action

    VYTORIN

    Plasma cholesterol is derived from intestinal absorption and
endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two
lipid-lowering compounds with complementary mechanisms of action.
VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and
increases HDL-C through dual inhibition of cholesterol absorption and
synthesis.

    Ezetimibe

    Ezetimibe reduces blood cholesterol by inhibiting the absorption
of cholesterol by the small intestine. The molecular target of
ezetimibe has been shown to be the sterol transporter, Niemann-Pick
C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of
cholesterol and phytosterols. In a 2-week clinical study in
18 hypercholesterolemic patients, ezetimibe inhibited intestinal
cholesterol absorption by 54%, compared with placebo. Ezetimibe had no
clinically meaningful effect on the plasma concentrations of the
fat-soluble vitamins A, D, and E and did not impair adrenocortical
steroid hormone production.

    Ezetimibe localizes at the brush border of the small intestine and
inhibits the absorption of cholesterol, leading to a decrease in the
delivery of intestinal cholesterol to the liver. This causes a
reduction of hepatic cholesterol stores and an increase in clearance
of cholesterol from the blood; this distinct mechanism is
complementary to that of HMG-CoA reductase inhibitors (see CLINICAL
STUDIES).

    Simvastatin

    Simvastatin reduces cholesterol by inhibiting the conversion of
HMG-CoA to mevalonate, an early step in the biosynthetic pathway for
cholesterol. In addition, simvastatin reduces VLDL and TG and
increases HDL-C.

    Pharmacokinetics

    Absorption

    VYTORIN

    VYTORIN is bioequivalent to coadministered ezetimibe and
simvastatin.

    Ezetimibe

    After oral administration, ezetimibe is absorbed and extensively
conjugated to a pharmacologically active phenolic glucuronide
(ezetimibe-glucuronide).

    Effect of Food on Oral Absorption

    Ezetimibe

    Concomitant food administration (high-fat or non-fat meals) had no
effect on the extent of absorption of ezetimibe when administered as
10-mg tablets. The Cmax value of ezetimibe was increased by 38% with
consumption of high-fat meals.

    Simvastatin

    Relative to the fasting state, the plasma profiles of both active
and total inhibitors of HMG-CoA reductase were not affected when
simvastatin was administered immediately before an American Heart
Association recommended low-fat meal.

    Distribution

    Ezetimibe

    Ezetimibe and ezetimibe-glucuronide are highly bound (greater than
90%) to human plasma proteins.

    Simvastatin

    Both simvastatin and its (beta)-hydroxyacid metabolite are highly
bound (approximately 95%) to human plasma proteins. When radiolabeled
simvastatin was administered to rats, simvastatin-derived
radioactivity crossed the blood-brain barrier.

    Metabolism and Excretion

    Ezetimibe

    Ezetimibe is primarily metabolized in the small intestine and
liver via glucuronide conjugation with subsequent biliary and renal
excretion. Minimal oxidative metabolism has been observed in all
species evaluated.

    In humans, ezetimibe is rapidly metabolized to
ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the
major drug-derived compounds detected in plasma, constituting
approximately 10 to 20% and 80 to 90% of the total drug in plasma,
respectively. Both ezetimibe and ezetimibe-glucuronide are slowly
eliminated from plasma with a half-life of approximately 22 hours for
both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time
profiles exhibit multiple peaks, suggesting enterohepatic recycling.

    Following oral administration of 14C-ezetimibe (20 mg) to human
subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide)
accounted for approximately 93% of the total radioactivity in plasma.
After 48 hours, there were no detectable levels of radioactivity in
the plasma.

    Approximately 78% and 11% of the administered radioactivity were
recovered in the feces and urine, respectively, over a 10-day
collection period. Ezetimibe was the major component in feces and
accounted for 69% of the administered dose, while
ezetimibe-glucuronide was the major component in urine and accounted
for 9% of the administered dose.

    Simvastatin

    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 a 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. 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.

    Following an oral dose of 14C-labeled simvastatin in man, 13% of
the dose was excreted in urine and 60% in feces. 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. Since simvastatin undergoes extensive first-pass extraction
in the liver, the availability of the drug to the general circulation
is low (less than5%).

    Special Populations

    Geriatric Patients

    Ezetimibe

    In a multiple-dose study with ezetimibe given 10 mg once daily for
10 days, plasma concentrations for total ezetimibe were about 2-fold
higher in older ((greater than=)65 years) healthy subjects compared to
younger subjects.

    Simvastatin

    In a study including 16 elderly patients between 70 and 78 years
of age who received simvastatin 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.

    Pediatric Patients

    Ezetimibe

    In a multiple-dose study with ezetimibe given 10 mg once daily for
7 days, the absorption and metabolism of ezetimibe were similar in
adolescents (10 to 18 years) and adults. Based on total ezetimibe,
there are no pharmacokinetic differences between adolescents and
adults. Pharmacokinetic data in the pediatric population less than 10
years of age are not available.

    Gender

    Ezetimibe

    In a multiple-dose study with ezetimibe given 10 mg once daily for
10 days, plasma concentrations for total ezetimibe were slightly
higher (less than20%) in women than in men.

    Race

    Ezetimibe

    Based on a meta-analysis of multiple-dose pharmacokinetic studies,
there were no pharmacokinetic differences between Black and Caucasian
subjects. Studies in Asian subjects indicated that the
pharmacokinetics of ezetimibe were similar to those seen in Caucasian
subjects.

    Hepatic Insufficiency

    Ezetimibe

    After a single 10-mg dose of ezetimibe, the mean exposure (based
on area under the curve (AUC)) to total ezetimibe was increased
approximately 1.7-fold in patients with mild hepatic insufficiency
(Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC
values for total ezetimibe and ezetimibe increased approximately 3- to
4-fold and 5- to 6-fold, respectively, in patients with moderate
(Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh
score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in
patients with moderate hepatic insufficiency, the mean AUC for total
ezetimibe and ezetimibe increased approximately 4-fold compared to
healthy subjects.

    Renal Insufficiency

    Ezetimibe

    After a single 10-mg dose of ezetimibe in patients with severe
renal disease (n=8; mean CrCl (less than=)30 mL/min/1.73 m2), the mean
AUC for total ezetimibe and ezetimibe increased approximately
1.5-fold, compared to healthy subjects (n=9).

    Simvastatin

    Pharmacokinetic studies with another statin having a similar
principal route of elimination to that of simvastatin 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).

    Drug Interactions (See also PRECAUTIONS, Drug Interactions)

    No clinically significant pharmacokinetic interaction was seen
when ezetimibe was coadministered with simvastatin. Specific
pharmacokinetic drug interaction studies with VYTORIN have not been
performed.

    Cytochrome P450: Ezetimibe had no significant effect on a series
of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV
midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9
and 3A4) in a "cocktail" study of twelve healthy adult males. This
indicates that ezetimibe is neither an inhibitor nor an inducer of
these cytochrome P450 isozymes, and it is unlikely that ezetimibe will
affect the metabolism of drugs that are metabolized by these enzymes.

    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.

    Although the mechanism is not fully understood, cyclosporine has
been shown to increase the AUC of HMG-CoA reductase inhibitors. The
increase in AUC for simvastatin acid is presumably due, in part, to
inhibition of CYP3A4.

    Simvastatin is a substrate for CYP3A4. 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.)

    Antacids: In a study of twelve healthy adults, a single dose of
antacid (Supralox(TM) 20 mL) administration had no significant effect
on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide,
or ezetimibe based on AUC values. The Cmax value of total ezetimibe
was decreased by 30%.

    Cholestyramine: In a study of forty healthy hypercholesterolemic
(LDL-C (greater than=)130 mg/dL) adult subjects, concomitant
cholestyramine (4 g twice daily) administration decreased the mean AUC
of total ezetimibe and ezetimibe approximately 55% and 80%,
respectively.

    Cyclosporine: In a study of eight post-renal transplant patients
with mildly impaired or normal renal function (creatinine clearance of
greater than50 mL/min), stable doses of cyclosporine (75 to 150 mg
twice daily) increased the mean AUC and Cmax values of total ezetimibe
3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to
4.4-fold), respectively, compared to a historical healthy control
population (n=17). In a different study, a renal transplant patient
with severe renal insufficiency (creatinine clearance of 13.2
mL/min/1.73 m2) who was receiving multiple medications, including
cyclosporine, demonstrated a 12-fold greater exposure to total
ezetimibe compared to healthy subjects. In a two-period crossover
study in twelve healthy subjects, daily administration of 20 mg
ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day
7 resulted in a mean 15% increase in cyclosporine AUC (range 10%
decrease to 51% increase) compared to a single 100-mg dose of
cyclosporine alone (see PRECAUTIONS, Drug Interactions).

    Fenofibrate: In a study of thirty-two healthy hypercholesterolemic
(LDL-C (greater than=)130 mg/dL) adult subjects, concomitant
fenofibrate (200 mg once daily) administration increased the mean Cmax
and AUC values of total ezetimibe approximately 64% and 48%,
respectively. Pharmacokinetics of fenofibrate were not significantly
affected by ezetimibe (10 mg once daily).

    Coadministration of fenofibrate (160 mg daily) with simvastatin
(80 mg daily) for 7 days had no effect on plasma AUC (and Cmax) of
either total HMG-CoA reductase inhibitory activity or fenofibric acid;
there was a modest reduction (approximately 35%) of simvastatin acid
which was not considered clinically significant (see WARNINGS,
Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions).

    Gemfibrozil: In a study of twelve healthy adult males, concomitant
administration of gemfibrozil (600 mg twice daily) significantly
increased the oral bioavailability of total ezetimibe by a factor of
1.7. Ezetimibe (10 mg once daily) did not significantly affect the
bioavailability of gemfibrozil.

    Coadministration of gemfibrozil (600 mg twice daily for 3 days)
with simvastatin (40 mg daily) resulted in clinically significant
increases in simvastatin acid AUC (185%) and Cmax (112%), possibly due
to inhibition of simvastatin acid glucuronidation by gemfibrozil (see
WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions,
DOSAGE AND ADMINISTRATION).

    Grapefruit Juice: Grapefruit juice contains one or more components
that inhibit CYP3A4 and can increase the plasma concentrations of
drugs metabolized by CYP3A4. In one study(1), 10 subjects consumed
200 mL of double-strength grapefruit juice (one can of frozen
concentrate diluted with one rather than 3 cans of water) three times
daily for 2 days and an additional 200 mL double-strength grapefruit
juice together with, and 30 and 90 minutes following, a single dose of
60 mg simvastatin on the third day. This regimen of grapefruit juice
resulted in mean increases in the concentration (as measured by the
area under the concentration-time curve) of active and total HMG-CoA
reductase inhibitory activity (measured using a radioenzyme inhibition
assay both before (for active inhibitors) and after (for total
inhibitors) base hydrolysis) of 2.4-fold and 3.6-fold, respectively,
and of simvastatin and its (beta)-hydroxyacid metabolite (measured
using a chemical assay -- liquid chromatography/tandem mass
spectrometry) of 16-fold and 7-fold, respectively. In a second study,
16 subjects consumed one 8 oz glass of single-strength grapefruit
juice (one can of frozen concentrate diluted with 3 cans of water)
with breakfast for 3 consecutive days and a single dose of 20 mg
simvastatin in the evening of the third day. This regimen of
grapefruit juice resulted in a mean increase in the plasma
concentration (as measured by the area under the concentration-time
curve) of active and total HMG-CoA reductase inhibitory activity
(using a validated enzyme inhibition assay different from that used in
the first(1) 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.

    ANIMAL PHARMACOLOGY

    Ezetimibe

    The hypocholesterolemic effect of ezetimibe was evaluated in
cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human
cholesterol metabolism. Ezetimibe was found to have an ED50 value of
0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol levels
in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and
700 (mu)g/kg/day, respectively. These results are consistent with
ezetimibe being a potent cholesterol absorption inhibitor.

    In a rat model, where the glucuronide metabolite of ezetimibe
(ezetimibe-glucuronide) was administered intraduodenally, the
metabolite was as potent as ezetimibe in inhibiting the absorption of
cholesterol, suggesting that the glucuronide metabolite had activity
similar to the parent drug.

    In 1-month studies in dogs given ezetimibe (0.03 to
300 mg/kg/day), the concentration of cholesterol in gallbladder bile
increased tilde2- to 4-fold. However, a dose of 300 mg/kg/day
administered to dogs for one year did not result in gallstone
formation or any other adverse hepatobiliary effects. In a 14-day
study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat
or cholesterol-rich diet, the concentration of cholesterol in
gallbladder bile was either unaffected or reduced to normal levels,
respectively.

    A series of acute preclinical studies was performed to determine
the selectivity of ezetimibe for inhibiting cholesterol absorption.
Ezetimibe inhibited the absorption of 14C-cholesterol with no effect
on the absorption of triglycerides, fatty acids, bile acids,
progesterone, ethyl estradiol, or the fat-soluble vitamins A and D.

    In 4- to 12-week toxicity studies in mice, ezetimibe did not
induce cytochrome P450 drug metabolizing enzymes. In toxicity studies,
a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase
inhibitors (parents or their active hydroxy acid metabolites) was seen
in rats, dogs, and rabbits.

    CLINICAL STUDIES

    Primary Hypercholesterolemia

    VYTORIN

    VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and
increases HDL-C in patients with hypercholesterolemia. Maximal to near
maximal response is generally achieved within 2 weeks and maintained
during chronic therapy.

    VYTORIN is effective in men and women with hypercholesterolemia.
Experience in non-Caucasians is limited and does not permit a precise
estimate of the magnitude of the effects of VYTORIN.

    Five multicenter, double-blind studies conducted with either
VYTORIN or coadministered ezetimibe and simvastatin equivalent to
VYTORIN in patients with primary hypercholesterolemia are reported:
two were comparisons with simvastatin, two were comparisons with
atorvastatin, and one was a comparison with rosuvastatin.

    In a multicenter, double-blind, placebo-controlled, 12-week trial,
1528 hypercholesterolemic patients were randomized to one of ten
treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg,
20 mg, 40 mg, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80).

    When patients receiving VYTORIN were compared to those receiving
all doses of simvastatin, VYTORIN significantly lowered total-C,
LDL-C, Apo B, TG, and non-HDL-C. The effects of VYTORIN on HDL-C were
similar to the effects seen with simvastatin. Further analysis showed
VYTORIN significantly increased HDL-C compared with placebo. (See
Table 1.) The lipid response to VYTORIN was similar in patients with
TG levels greater than or less than 200 mg/dL.

                                Table 1
   Response to VYTORIN in Patients with Primary Hypercholesterolemia
             (Mean(a) % Change from Untreated Baseline(b))

          Treatment
                                                                Non-
                                    Total- LDL- Apo  HDL-        HDL-
         (Daily Dose)           N      C     C    B    C  TG(a)   C
---------------------------------------------------------------------
Pooled data (All VYTORIN
 doses)(c)                     609    -38  -53  -42   +7   -24   -49
---------------------------------------------------------------------
Pooled data (All simvastatin
 doses)(c)                     622    -28  -39  -32   +7   -21   -36
---------------------------------------------------------------------
Ezetimibe 10 mg                149    -13  -19  -15   +5   -11   -18
---------------------------------------------------------------------
Placebo                        148     -1   -2    0    0    -2    -2
---------------------------------------------------------------------
VYTORIN by dose
---------------------------------------------------------------------
                        10/10  152    -31  -45  -35   +8   -23   -41
---------------------------------------------------------------------
                        10/20  156    -36  -52  -41  +10   -24   -47
---------------------------------------------------------------------
                        10/40  147    -39  -55  -44   +6   -23   -51
---------------------------------------------------------------------
                        10/80  154    -43  -60  -49   +6   -31   -56
---------------------------------------------------------------------
Simvastatin by dose
---------------------------------------------------------------------
10 mg                          158    -23  -33  -26   +5   -17   -30
---------------------------------------------------------------------
20 mg                          150    -24  -34  -28   +7   -18   -32
---------------------------------------------------------------------
40 mg                          156    -29  -41  -33   +8   -21   -38
---------------------------------------------------------------------
80 mg                          158    -35  -49  -39   +7   -27   -45
---------------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c )VYTORIN doses pooled (10/10-10/80) significantly reduced
total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin, and
significantly increased HDL-C compared to placebo.

    In a multicenter, double-blind, controlled, 23-week study,
710 patients with known CHD or CHD risk equivalents, as defined by the
NCEP ATP III guidelines, and an LDL-C (greater than=)130 mg/dL were
randomized to one of four treatment groups: coadministered ezetimibe
and simvastatin equivalent to VYTORIN (10/10, 10/20, and 10/40), or
simvastatin 20 mg. Patients not reaching an LDL-C less than100 mg/dL
had their simvastatin dose titrated at 6-week intervals to a maximal
dose of 80 mg.

    At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or
10/40 were significantly larger than with simvastatin 20 mg (see
Table 2).

                                Table 2
  Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk
                Equivalents and an LDL-C (greater than=)130 mg/dL

             Simvastatin   VYTORIN       VYTORIN       VYTORIN
                20 mg       10/10         10/20         10/40
------------------------------------------------------------------
N                   253           251           109            97
------------------------------------------------------------------
Mean baseline
 LDL-C              174           165           167           171
------------------------------------------------------------------
Percent
 change LDL-C       -38           -47           -53           -59
------------------------------------------------------------------


    In a multicenter, double-blind, 6-week study, 1902 patients with
primary hypercholesterolemia, who had not met their NCEP ATP III
target LDL-C goal, were randomized to one of eight treatment groups:
VYTORIN (10/10, 10/20, 10/40, or 10/80) or atorvastatin (10 mg, 20 mg,
40 mg, or 80 mg).

    Across the dosage range, when patients receiving VYTORIN were
compared to those receiving milligram-equivalent statin doses of
atorvastatin, VYTORIN lowered total-C, LDL-C, Apo B, and non-HDL-C
significantly more than atorvastatin. Only the 10/40 mg and 10/80 mg
VYTORIN doses increased HDL-C significantly more than the
corresponding milligram-equivalent statin dose of atorvastatin. The
effects of VYTORIN on TG were similar to the effects seen with
atorvastatin. (See Table 3.)

                                Table 3
     Response to VYTORIN and Atorvastatin in Patients with Primary
  Hypercholesterolemia (Mean(a) % Change from Untreated Baseline(b))

       Treatment
                                                                Non-
                              Total-  LDL-   Apo                HDL-
      (Daily Dose)        N    C(c)   C(c)   B(c)  HDL-C TG(a)  C(c)
---------------------------------------------------------------------
VYTORIN by dose
---------------------------------------------------------------------
                  10/10  230  -34(d) -47(d) -37(d)   +8   -26  -43(d)
---------------------------------------------------------------------
                  10/20  233  -37(d) -51(d) -40(d)   +7   -25  -46(d)
---------------------------------------------------------------------
                  10/40  236  -41(d) -57(d) -46(d) +9(d)  -27  -52(d)
---------------------------------------------------------------------
                  10/80  224  -43(d) -59(d) -48(d) +8(d)  -31  -54(d)
---------------------------------------------------------------------
Atorvastatin by dose
---------------------------------------------------------------------
10 mg                    235    -27    -36    -31    +7   -21    -34
---------------------------------------------------------------------
20 mg                    230    -32    -44    -37    +5   -25    -41
---------------------------------------------------------------------
40 mg                    232    -36    -48    -40    +4   -24    -45
---------------------------------------------------------------------
80 mg                    230    -40    -53    -44    +1   -32    -50
---------------------------------------------------------------------

    (a )For triglycerides, median % change from baseline

    (b )Baseline - on no lipid-lowering drug

    (c) VYTORIN doses pooled (10/10-10/80) provided significantly
greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to
atorvastatin doses pooled (10-80).

    (d) pless than0.05 for difference with atorvastatin at equal mg
doses of the simvastatin component

    In a multicenter, double-blind, 24-week, forced titration study,
788 patients with primary hypercholesterolemia, who had not met their
NCEP ATP III target LDL-C goal, were randomized to receive
coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10
and 10/20) or atorvastatin 10 mg. For all three treatment groups, the
dose of the statin was titrated at 6-week intervals to 80 mg. At each
pre-specified dose comparison, VYTORIN lowered LDL-C to a greater
degree than atorvastatin (see Table 4).

                                Table 4
     Response to VYTORIN and Atorvastatin in Patients with Primary
  Hypercholesterolemia (Mean(a) % Change from Untreated Baseline(b))

                             Total-                             Non-
       Treatment         N      C   LDL-C  Apo B  HDL-C  TG(a)  HDL-C
---------------------------------------------------------------------
Week 6
---------------------------------------------------------------------
Atorvastatin 10 mg(c)   262    -28    -37    -32     +5   -23    -35
---------------------------------------------------------------------
VYTORIN 10/10(d)        263  -34(f) -46(f) -38(f) +8(f)   -26  -43(f)
---------------------------------------------------------------------
VYTORIN 10/20(e)        263  -36(f) -50(f) -41(f) +10(f)  -25  -46(f)
---------------------------------------------------------------------
Week 12
---------------------------------------------------------------------
Atorvastatin 20 mg      246    -33    -44    -38     +7   -28    -42
---------------------------------------------------------------------
VYTORIN 10/20           250  -37(f) -50(f) -41(f)    +9   -28  -46(f)
---------------------------------------------------------------------
VYTORIN 10/40           252  -39(f) -54(f) -45(f) +12(f)  -31  -50(f)
---------------------------------------------------------------------
Week 18
---------------------------------------------------------------------
Atorvastatin 40 mg      237    -37    -49    -42     +8   -31    -47
---------------------------------------------------------------------
VYTORIN 10/40(g)        482  -40(f) -56(f) -45(f) +11(f)  -32  -52(f)
---------------------------------------------------------------------
Week 24
---------------------------------------------------------------------
Atorvastatin 80 mg      228    -40    -53    -45     +6   -35    -50
---------------------------------------------------------------------
VYTORIN 10/80(g)        459  -43(f) -59(f) -49(f) +12(f)  -35  -55(f)
---------------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and
80 mg through Weeks 6, 12, 18, and 24

    (d) VYTORIN: 10/10 start dose titrated to 10/20, 10/40, and 10/80
through Weeks 6, 12, 18, and 24

    (e) VYTORIN: 10/20 start dose titrated to 10/40, 10/40, and 10/80
through Weeks 6, 12, 18, and 24

    (f) p(less than=)0.05 for difference with atorvastatin in the
specified week

    (g )Data pooled for common doses of VYTORIN at Weeks 18 and 24.

    In a multicenter, double-blind, 6-week study, 2959 patients with
primary hypercholesterolemia, who had not met their NCEP ATP III
target LDL-C goal, were randomized to one of six treatment groups:
VYTORIN (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40
mg).

    The effects of VYTORIN and rosuvastatin on total-C, LDL-C, Apo B,
TG, non-HDL-C and HDL-C are shown in Table 5.

                                Table 5

     Response to VYTORIN and Rosuvastatin in Patients with Primary
  Hypercholesterolemia (Mean(a) % Change from Untreated Baseline(b))

       Treatment
                                                                Non-
                              Total-  LDL-   Apo   HDL-         HDL-
      (Daily Dose)        N    C(c)   C(c)   B(c)    C  TG(a)   C(c)
---------------------------------------------------------------------
VYTORIN by dose
---------------------------------------------------------------------
                  10/20  476  -37(d) -52(d) -42(d)  +7  -23(d) -47(d)
---------------------------------------------------------------------
                  10/40  477  -39(e) -55(e) -44(e)  +8    -27  -50(e)
---------------------------------------------------------------------
                  10/80  474  -44(f) -61(f) -50(f)  +8  -30(f) -56(f)
---------------------------------------------------------------------
Rosuvastatin by dose
---------------------------------------------------------------------
10 mg                    475    -32    -46    -37   +7    -20    -42
---------------------------------------------------------------------
20 mg                    478    -37    -52    -43   +8    -26    -48
---------------------------------------------------------------------
40 mg                    475    -41    -57    -47   +8    -28    -52
---------------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) VYTORIN doses pooled (10/20-10/80) provided significantly
greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to
rosuvastatin doses pooled (10-40 mg).

    (d) pless than0.05 vs. rosuvastatin 10 mg

    (e) pless than0.05 vs. rosuvastatin 20 mg

    (f) pless than0.05 vs. rosuvastatin 40 mg

    In a multicenter, double-blind, 24-week trial, 214 patients with
type 2 diabetes mellitus treated with thiazolidinediones
(rosiglitazone or pioglitazone) for a minimum of 3 months and
simvastatin 20 mg for a minimum of 6 weeks, were randomized to receive
either simvastatin 40 mg or the coadministered active ingredients
equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at
baseline were 89 mg/dL and 7.1%, respectively.

    VYTORIN 10/20 was significantly more effective than doubling the
dose of simvastatin to 40 mg. The median percent changes from baseline
for VYTORIN vs simvastatin were: LDL-C -25% and -5%; total-C -16% and
-5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C
and TG between the two treatment groups were not significantly
different.

    Ezetimibe

    In two multicenter, double-blind, placebo-controlled, 12-week
studies in 1719 patients with primary hypercholesterolemia, ezetimibe
significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), and
TG (-8%), and increased HDL-C (+3%) compared to placebo. Reduction in
LDL-C was consistent across age, sex, and baseline LDL-C.

    Simvastatin

    In two large, placebo-controlled clinical trials, the Scandinavian
Simvastatin Survival Study (N=4,444 patients) and the Heart Protection
Study (N=20,536 patients), the effects of treatment with simvastatin
were assessed 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. Simvastatin was
proven to reduce: the risk of total mortality by reducing CHD deaths;
the risk of non-fatal myocardial infarction and stroke; and the need
for coronary and non-coronary revascularization procedures.

    No incremental benefit of VYTORIN on cardiovascular morbidity and
mortality over and above that demonstrated for simvastatin has been
established.

    Homozygous Familial Hypercholesterolemia (HoFH)

    A double-blind, randomized, 12-week study was performed in
patients with a clinical and/or genotypic diagnosis of HoFH. Data were
analyzed from a subgroup of patients (n=14) receiving simvastatin
40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg
(n=5) produced a reduction of LDL-C of 13% from baseline on
simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent
to VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction of
LDL-C of 23% from baseline on simvastatin 40 mg. In those patients
coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/80,
n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg
was produced.

    INDICATIONS AND USAGE

    Primary Hypercholesterolemia

    VYTORIN is indicated as adjunctive therapy to diet for the
reduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to
increase HDL-C in patients with primary (heterozygous familial and
non-familial) hypercholesterolemia or mixed hyperlipidemia.

    Homozygous Familial Hypercholesterolemia (HoFH)

    VYTORIN is indicated for the reduction of elevated 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.

    Therapy with lipid-altering agents should be a component of
multiple risk-factor intervention in individuals at increased risk for
atherosclerotic vascular disease due to hypercholesterolemia.
Lipid-altering agents should be used in addition to an appropriate
diet (including restriction of saturated fat and cholesterol) and when
the response to diet and other non-pharmacological measures has been
inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines,
summarized in Table 6.)

                                Table 6
                  Summary of NCEP ATP III Guidelines

                                        LDL Level at
                                         Which to       LDL Level at
                            LDL          Initiate         Which to
Risk Category               Goal        Therapeutic    Consider Drug
                           (mg/dL)      Lifestyle         Therapy
                                        Changes(a)        (mg/dL)
                                         (mg/dL)
---------------------------------------------------------------------
                                                    (greater than=)130
CHD or CHD risk                                              (100-129:
 equivalents(b)      less than 100  (greater than=)100           drug
(10-year risk                                             optional)(d)
greater than 20%)(c)

---------------------------------------------------------------------
                                                          10-year risk
                                                               10-20%:
2+ Risk factors(e)   less than 130  (greater than=)130
(10-year risk                                    (greater than=)130(c)
(less than=)20%)(c)                                       10-year risk
                                                         less than10%:
                                                 (greater than=)160(c)
---------------------------------------------------------------------
                                                    (greater than=)190
                                                             (160-189:
0-1 Risk factor(f)   less than 160  (greater than=)160    LDL-lowering
                                                               drug
                                                             optional)
---------------------------------------------------------------------

    (a) Therapeutic lifestyle changes include: 1) dietary changes:
reduced intake of saturated fats (less than7% of total calories) and
cholesterol (less than200 mg per day), and enhancing LDL lowering with
plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber
(10-25 g/d), 2) weight reduction, and 3) increased physical activity.

    (b) CHD risk equivalents comprise: diabetes, multiple risk factors
that confer a 10-year risk for CHD greater than20%, and other clinical
forms of atherosclerotic disease (peripheral arterial disease,
abdominal aortic aneurysm and symptomatic carotid artery disease).

    (c) Risk assessment for determining the 10-year risk for
developing CHD is carried out using the Framingham risk scoring. Refer
to JAMA, May 16, 2001; 285 (19): 2486-2497, or the NCEP website
(http://www.nhlbi.nih.gov) for more details.

    (d) Some authorities recommend use of LDL-lowering drugs in this
category if an LDL cholesterol less than100 mg/dL cannot be achieved
by therapeutic lifestyle changes. Others prefer use of drugs that
primarily modify triglycerides and HDL, e.g., nicotinic acid or
fibrate. Clinical judgment also may call for deferring drug therapy in
this subcategory.

    (e) Major risk factors (exclusive of LDL cholesterol) that modify
LDL goals include cigarette smoking, hypertension (BP
(greater than=)140/90 mm Hg or on anti-hypertensive medication), low
HDL cholesterol (less than40 mg/dL), family history of premature CHD
(CHD in male first-degree relative less than55 years; CHD in female
first-degree relative less than65 years), age (men (greater than=)45
years; women (greater than=)55 years). HDL cholesterol
(greater than=)60 mg/dL counts as a "negative" risk factor; its
presence removes one risk factor from the total count.

    (f) Almost all people with 0-1 risk factor have a 10-year risk
less than10%; thus, 10-year risk assessment in people with 0-1 risk
factor is not necessary.

    Prior to initiating therapy with VYTORIN, secondary causes for
dyslipidemia (i.e., diabetes, hypothyroidism, obstructive liver
disease, chronic renal failure, and drugs that increase LDL-C and
decrease HDL-C (progestins, anabolic steroids, and corticosteroids)),
should be excluded or, if appropriate, treated. A lipid profile should
be performed to measure total-C, LDL-C, HDL-C and TG. For TG levels
greater than400 mg/dL (greater than4.5 mmol/L), LDL-C concentrations
should be determined by ultracentrifugation.

    At the time of hospitalization for an acute coronary event, lipid
measures should be taken on admission or within 24 hours. These values
can guide the physician on initiation of LDL-lowering therapy before
or at discharge.

    CONTRAINDICATIONS

    Hypersensitivity to any component of this medication.

    Active liver disease or unexplained persistent elevations in serum
transaminases (see WARNINGS, Liver Enzymes).

    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
simvastatin to decrease the synthesis of cholesterol and possibly
other products of the cholesterol biosynthesis pathway, VYTORIN is
contraindicated during pregnancy and in nursing mothers. VYTORIN
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, VYTORIN should be discontinued
immediately and the patient should be apprised of the potential hazard
to the fetus (see PRECAUTIONS, Pregnancy).

    WARNINGS

    Myopathy/Rhabdomyolysis

    In clinical trials, there was no excess of myopathy or
rhabdomyolysis associated with ezetimibe compared with the relevant
control arm (placebo or HMG-CoA reductase inhibitor alone). However,
myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA
reductase inhibitors and other lipid-lowering drugs. In clinical
trials, the incidence of CK greater than10 X the upper limit of normal
(ULN) was 0.2% for VYTORIN. (See PRECAUTIONS, Skeletal Muscle.)

    Simvastatin, like other inhibitors of HMG-CoA reductase,
occasionally causes myopathy manifested as muscle pain, tenderness or
weakness with creatine kinase above 10 X 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.

    As with other HMG-CoA reductase inhibitors, the risk of
myopathy/rhabdomyolysis is dose related. In a clinical trial database
in which 41,050 patients were treated with simvastatin with 24,747
(approximately 60%) treated for at least 4 years, the incidence of
myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and
80 mg/day, respectively. In these trials, patients were carefully
monitored and some interacting medicinal products were excluded.

    All patients starting therapy with VYTORIN or whose dose of
VYTORIN is being increased, should be advised of the risk of myopathy
and told to report promptly any unexplained muscle pain, tenderness or
weakness. VYTORIN therapy should be discontinued immediately if
myopathy is diagnosed or suspected. In most cases, muscle symptoms and
CK increases resolved when simvastatin treatment was promptly
discontinued. 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.

    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 taking VYTORIN merit closer monitoring.
Therapy with VYTORIN should be temporarily stopped a few days prior to
elective major surgery and when any major medical or surgical
condition supervenes.

    Because VYTORIN contains simvastatin, the risk of
myopathy/rhabdomyolysis is increased by concomitant use of VYTORIN
with the following:

    Potent inhibitors of CYP3A4: Simvastatin, like several other
inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4
(CYP3A4). When simvastatin is used with a potent inhibitor of CYP3A4,
elevated plasma levels of HMG-CoA reductase inhibitory activity can
increase the risk of myopathy and rhabdomyolysis, particularly with
higher doses of simvastatin.

    The use of VYTORIN concomitantly with the potent CYP3A4 inhibitors
itraconazole, ketoconazole, erythromycin, clarithromycin,
telithromycin, HIV protease inhibitors, nefazodone, or large
quantities of grapefruit juice (greater than1 quart daily) should be
avoided. Concomitant use of other medicines labeled as having a potent
inhibitory effect on CYP3A4 should be avoided unless the benefits of
combined therapy outweigh the increased risk. If treatment with
itraconazole, ketoconazole, erythromycin, clarithromycin or
telithromycin is unavoidable, therapy with VYTORIN should be suspended
during the course of treatment.

    Other drugs:

    Gemfibrozil, particularly with higher doses of VYTORIN: There is
an increased risk of myopathy when simvastatin is used concomitantly
with fibrates (especially gemfibrozil). The combined use of
simvastatin with gemfibrozil should be avoided, unless the benefits
are likely to outweigh the increased risks of this drug combination.
The dose of simvastatin should not exceed 10 mg daily in patients
receiving concomitant medication with gemfibrozil. Therefore, although
not recommended, if VYTORIN is used in combination with gemfibrozil,
the dose should not exceed 10/10 mg daily. (See CLINICAL PHARMACOLOGY,
Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with
lipid-lowering drugs that can cause myopathy when given alone, Other
drug interactions, and DOSAGE AND ADMINISTRATION.)

    Other lipid-lowering drugs (other fibrates or
(greater than=)1 g/day of niacin): Caution should be used when
prescribing other fibrates or lipid-lowering doses
((greater than=)1 g/day) of niacin with VYTORIN, as these agents can
cause myopathy when given alone. The safety and effectiveness of
VYTORIN administered with other fibrates or ((greater than=)1 g/day)
of niacin have not been established. Therefore, the benefit of further
alterations in lipid levels by the combined use of VYTORIN with other
fibrates or niacin should be carefully weighed against the potential
risks of these drug combinations. (See CLINICAL PHARMACOLOGY,
Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with
lipid-lowering drugs that can cause myopathy when given alone, Other
drug interactions, and DOSAGE AND ADMINISTRATION.)

    Cyclosporine or danazol with higher doses of VYTORIN: The dose of
VYTORIN should not exceed 10/10 mg daily in patients receiving
concomitant medication with cyclosporine or danazol. The benefits of
the use of VYTORIN in patients receiving cyclosporine or danazol
should be carefully weighed against the risks of these combinations.
(See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug
Interactions, Other drug interactions.)

    Amiodarone or verapamil with higher doses of VYTORIN: The dose of
VYTORIN should not exceed 10/20 mg daily in patients receiving
concomitant medication with amiodarone or verapamil. The combined use
of VYTORIN at doses higher than 10/20 mg daily with amiodarone or
verapamil should be avoided unless the clinical benefit is likely to
outweigh the increased risk of myopathy. (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%).

    Prescribing recommendations for interacting agents are summarized
in Table 7 (see also CLINICAL PHARMACOLOGY, Pharmacokinetics;
PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).

                               TABLE 7
             Drug Interactions Associated with Increased
                   Risk of Myopathy/Rhabdomyolysis
----------------------------------------------------------------------
Interacting Agents         Prescribing Recommendations
----------------------------------------------------------------------
Itraconazole               Avoid VYTORIN
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Fibrates*
----------------------------------------------------------------------
Cyclosporine               Do not exceed 10/10 mg VYTORIN daily
Danazol
----------------------------------------------------------------------
Amiodarone                 Do not exceed 10/20 mg VYTORIN daily
Verapamil
----------------------------------------------------------------------
Grapefruit juice           Avoid large quantities of grapefruit juice
                            (greater than1 quart daily)
----------------------------------------------------------------------

    *For additional information regarding gemfibrozil, see DOSAGE AND
ADMINISTRATION.

    Liver Enzymes

    In three placebo-controlled, 12-week trials, the incidence of
consecutive elevations ((greater than=)3 X ULN) in serum transaminases
was 1.7% overall for patients treated with VYTORIN and appeared to be
dose-related with an incidence of 2.6% for patients treated with
VYTORIN 10/80. In controlled long-term (48-week) extensions, which
included both newly-treated and previously-treated patients, the
incidence of consecutive elevations ((greater than=)3 X ULN) in serum
transaminases was 1.8% overall and 3.6% for patients treated with
VYTORIN 10/80. These elevations in transaminases were generally
asymptomatic, not associated with cholestasis, and returned to
baseline after discontinuation of therapy or with continued treatment.

    It is recommended that liver function tests be performed before
the initiation of treatment with VYTORIN, and thereafter when
clinically indicated. Patients titrated to the 10/80-mg dose should
receive an additional test prior to titration, 3 months after
titration to the 10/80-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 3 X ULN or greater
persist, withdrawal of therapy with VYTORIN is recommended.

    VYTORIN 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 persistent transaminase
elevations are contraindications to the use of VYTORIN.

    PRECAUTIONS

    Information for Patients

    Patients should be advised about substances they should not take
concomitantly with VYTORIN 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 VYTORIN.

    Skeletal Muscle

    In post-marketing experience with ezetimibe, cases of myopathy and
rhabdomyolysis have been reported regardless of causality. Most
patients who developed rhabdomyolysis were taking a statin prior to
initiating ezetimibe. However, rhabdomyolysis has been reported very
rarely with ezetimibe monotherapy and very rarely with the addition of
ezetimibe to agents known to be associated with increased risk of
rhabdomyolysis, such as fibrates.

    Hepatic Insufficiency

    Due to the unknown effects of the increased exposure to ezetimibe
in patients with moderate or severe hepatic insufficiency, VYTORIN is
not recommended in these patients. (See CLINICAL PHARMACOLOGY,
Pharmacokinetics, Special Populations.)

    Drug Interactions (See also CLINICAL PHARMACOLOGY, Drug
Interactions)

    VYTORIN

    CYP3A4 Interactions

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

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

    Itraconazole

    Ketoconazole

    Erythromycin

    Clarithromycin

    Telithromycin

    HIV protease inhibitors

    Nefazodone

    Large quantities of grapefruit juice (greater than1 quart daily)

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

    See WARNINGS, Myopathy/Rhabdomyolysis.

    The risk of myopathy is increased by gemfibrozil and to a lesser
extent by other fibrates and niacin (nicotinic acid)
((greater than=)1 g/day).

    Other drug interactions

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

    Cholestyramine: Concomitant cholestyramine administration
decreased the mean AUC of total ezetimibe approximately 55%. The
incremental LDL-C reduction due to adding VYTORIN to cholestyramine
may be reduced by this interaction.

    Cyclosporine or Danazol: The risk of myopathy/rhabdomyolysis is
increased by concomitant administration of cyclosporine or danazol
particularly with higher doses of VYTORIN (see CLINICAL PHARMACOLOGY,
Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis).

    Caution should be exercised when using VYTORIN and cyclosporine
concomitantly due to increased exposure to both ezetimibe and
cyclosporine (see DOSAGE AND ADMINISTRATION, Patients taking
Cyclosporine or Danazol). Cyclosporine concentrations should be
monitored in patients receiving VYTORIN and cyclosporine (see CLINICAL
PHARMACOLOGY, Drug Interactions).

    The degree of increase in ezetimibe exposure may be greater in
patients with severe renal insufficiency. In patients treated with
cyclosporine, the potential effects of the increased exposure to
ezetimibe from concomitant use should be carefully weighed against the
benefits of alterations in lipid levels provided by ezetimibe. In a
pharmacokinetic study in post-renal transplant patients with mildly
impaired or normal renal function (creatinine clearance of
greater than50 mL/min), concomitant cyclosporine administration
increased the mean AUC and Cmax of total ezetimibe 3.4-fold
(range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold),
respectively. In a separate study, the total ezetimibe exposure
increased 12-fold in one renal transplant patient with severe renal
insufficiency receiving multiple medications, including cyclosporine.
(See CLINICAL PHARMACOLOGY, Drug Interactions and WARNINGS,
Myopathy/Rhabdomyolysis.)

    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 plasma digoxin concentrations
compared to concomitant administration of placebo and digoxin.
Patients taking digoxin should be monitored appropriately when VYTORIN
is initiated.

    Fibrates: The safety and effectiveness of VYTORIN administered
with fibrates have not been established.

    Fibrates may increase cholesterol excretion into the bile, leading
to cholelithiasis. In a preclinical study in dogs, ezetimibe increased
cholesterol in the gallbladder bile (see ANIMAL PHARMACOLOGY).
Coadministration of VYTORIN with fibrates is not recommended until use
in patients is studied. (See WARNINGS, Myopathy/Rhabdomyolysis.)

    Warfarin: 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 a normal volunteer study and in a
hypercholesterolemic patient study, respectively. With other statins,
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 VYTORIN and frequently enough during early therapy to
ensure 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 VYTORIN 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.

    Concomitant administration of ezetimibe (10 mg once daily) had no
significant effect on bioavailability of warfarin and prothrombin time
in a study of twelve healthy adult males. There have been
post-marketing reports of increased International Normalized Ratio
(INR) in patients who had ezetimibe added to warfarin. Most of these
patients were also on other medications.

    The effect of VYTORIN on the prothrombin time has not been
studied.

    Ezetimibe

    Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate
administration increased total ezetimibe concentrations approximately
1.5-fold.

    Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil
administration increased total ezetimibe concentrations approximately
1.7-fold.

    Simvastatin

    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
simvastatin and propranolol. The clinical relevance of this finding is
unclear. The pharmacokinetics of the enantiomers of propranolol were
not affected.

    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

    VYTORIN

    No animal carcinogenicity or fertility studies have been conducted
with the combination of ezetimibe and simvastatin. The combination of
ezetimibe with simvastatin did not show evidence of mutagenicity in
vitro in a microbial mutagenicity (Ames) test with Salmonella
typhimurium and Escherichia coli with or without metabolic activation.
No evidence of clastogenicity was observed in vitro in a chromosomal
aberration assay in human peripheral blood lymphocytes with ezetimibe
and simvastatin with or without metabolic activation. There was no
evidence of genotoxicity at doses up to 600 mg/kg with the combination
of ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleus
test.

    Ezetimibe

    A 104-week dietary carcinogenicity study with ezetimibe was
conducted in rats at doses up to 1500 mg/kg/day (males) and
500 mg/kg/day (females) (tilde20 times the human exposure at 10 mg
daily based on AUC0-24hr for total ezetimibe). A 104-week dietary
carcinogenicity study with ezetimibe was also conducted in mice at
doses up to 500 mg/kg/day (greater than150 times the human exposure at
10 mg daily based on AUC0-24hr for total ezetimibe). There were no
statistically significant increases in tumor incidences in
drug-treated rats or mice.

    No evidence of mutagenicity was observed in vitro in a microbial
mutagenicity (Ames) test with Salmonella typhimurium and Escherichia
coli with or without metabolic activation. No evidence of
clastogenicity was observed in vitro in a chromosomal aberration assay
in human peripheral blood lymphocytes with or without metabolic
activation. In addition, there was no evidence of genotoxicity in the
in vivo mouse micronucleus test.

    In oral (gavage) fertility studies of ezetimibe conducted in rats,
there was no evidence of reproductive toxicity at doses up to
1000 mg/kg/day in male or female rats (tilde7 times the human exposure
at 10 mg daily based on AUC0-24hr for total ezetimibe).

    Simvastatin

    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.

    VYTORIN

    As safety in pregnant women has not been established, treatment
should be immediately discontinued as soon as pregnancy is recognized.
VYTORIN 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.

    Ezetimibe

    In oral (gavage) embryo-fetal development studies of ezetimibe
conducted in rats and rabbits during organogenesis, there was no
evidence of embryolethal effects at the doses tested (250, 500,
1000 mg/kg/day). In rats, increased incidences of common fetal
skeletal findings (extra pair of thoracic ribs, unossified cervical
vertebral centra, shortened ribs) were observed at 1000 mg/kg/day
(tilde10 times the human exposure at 10 mg daily based on AUC0-24hr
for total ezetimibe). In rabbits treated with ezetimibe, an increased
incidence of extra thoracic ribs was observed at 1000 mg/kg/day
(150 times the human exposure at 10 mg daily based on AUC0-24hr for
total ezetimibe). Ezetimibe crossed the placenta when pregnant rats
and rabbits were given multiple oral doses.

    Multiple-dose studies of ezetimibe coadministered with HMG-CoA
reductase inhibitors (statins) in rats and rabbits during
organogenesis result in higher ezetimibe and statin exposures.
Reproductive findings occur at lower doses in coadministration therapy
compared to monotherapy.

    Simvastatin

    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 review2 of
approximately 100 prospectively followed pregnancies in women exposed
to simvastatin or another structurally related HMG-CoA reductase
inhibitor, the incidences of congenital anomalies, spontaneous
abortions and fetal 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.

    Labor and Delivery

    The effects of VYTORIN on labor and delivery in pregnant women are
unknown.

    Nursing Mothers

    In rat studies, exposure to ezetimibe in nursing pups was up to
half of that observed in maternal plasma. It is not known whether
ezetimibe or simvastatin are excreted into human breast milk. Because
a small amount of another drug in the same class as simvastatin is
excreted in human milk and because of the potential for serious
adverse reactions in nursing infants, women who are nursing should not
take VYTORIN (see CONTRAINDICATIONS).

    Pediatric Use

    VYTORIN

    There are insufficient data for the safe and effective use of
VYTORIN in pediatric patients. (See Ezetimibe and Simvastatin below.)

    Ezetimibe

    The pharmacokinetics of ezetimibe in adolescents (10 to 18 years)
have been shown to be similar to that in adults. Treatment experience
with ezetimibe in the pediatric population is limited to 4 patients (9
to 17 years) with homozygous sitosterolemia and 5 patients (11 to
17 years) with HoFH. Treatment with ezetimibe in children (less than
10 years) is not recommended.

    Simvastatin

    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. Adolescent females should be counseled on appropriate
contraceptive methods while on therapy with simvastatin (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

    Of the patients who received VYTORIN in clinical studies, 792 were
65 and older (this included 176 who were 75 and older). The safety of
VYTORIN was similar between these patients and younger patients.
Greater sensitivity of some older individuals cannot be ruled out.
(See CLINICAL PHARMACOLOGY, Special Populations and ADVERSE
REACTIONS.)

    ADVERSE REACTIONS

    VYTORIN has been evaluated for safety in more than 3800 patients
in clinical trials. VYTORIN was generally well tolerated.

    Table 8 summarizes the frequency of clinical adverse experiences
reported in (greater than=)2% of patients treated with VYTORIN
(n=1236) and at an incidence greater than placebo regardless of
causality assessment from three similarly designed,
placebo-controlled trials.

                              Table 8*
                Clinical Adverse Events Occurring in
(greater than=)2% of Patients Treated with VYTORIN and at an Incidence
                        Greater than Placebo,
                       Regardless of Causality
---------------------------------------------------------------------

                                    Ezetimibe
  Body System/Organ Class   Placebo   10 mg   Simvastatin** VYTORIN**
       Adverse Event          (%)      (%)         (%)         (%)
                             n=311    n=302      n=1234      n=1236
--------------------------- ------- --------- ------------- ---------
  Body as a whole - general
   disorders
        Headache               6.4       6.0           5.9       6.8
  Infection and
   infestations
    Influenza                  1.0       1.0           1.9       2.6
    Upper respiratory tract
     infection                 2.6       5.0           5.0       3.9
  Musculoskeletal and
   connective tissue
   disorders
    Myalgia                    2.9       2.3           2.6       3.5
    Pain in extremity          1.3       3.0           2.0       2.3
--------------------------- ------- --------- ------------- ---------

    *Includes two placebo-controlled combination studies in which the
active ingredients equivalent to VYTORIN were coadministered and one
placebo-controlled study in which VYTORIN was administered.

    **All doses.

    Post-marketing Experience

    The adverse reactions reported for VYTORIN are consistent with
those previously reported with ezetimibe and/or simvastatin.

    Ezetimibe

    Other adverse experiences reported with ezetimibe in
placebo-controlled studies, regardless of causality assessment: Body
as a whole - general disorders: fatigue; Gastrointestinal system
disorders: abdominal pain, diarrhea; Infection and infestations:
infection viral, pharyngitis, sinusitis; Musculoskeletal system
disorders: arthralgia, back pain; Respiratory system disorders:
coughing.

    Post-marketing Experience

    The following adverse reactions have been reported in
post-marketing experience, regardless of causality assessment:

    Hypersensitivity reactions, including anaphylaxis, angioedema,
rash, and urticaria; arthralgia; myalgia; elevations in liver
transaminases; hepatitis; thrombocytopenia; pancreatitis; nausea;
cholelithiasis; cholecystitis; elevated creatine phosphokinase; and,
very rarely, myopathy/rhabdomyolysis (see WARNINGS,
Myopathy/Rhabdomyolysis).

    Simvastatin

    Other adverse experiences reported with simvastatin in
placebo-controlled clinical studies, regardless of causality
assessment: Body as a whole - general disorders: asthenia; Eye
disorders: cataract; Gastrointestinal system disorders: abdominal
pain, constipation, diarrhea, dyspepsia, flatulence, nausea; Skin and
subcutaneous tissue disorders: eczema, pruritus, rash.

    The following effects have been reported with other HMG-CoA
reductase inhibitors. Not all the effects listed below have
necessarily been associated with simvastatin therapy.

    Musculoskeletal system disorders: muscle cramps, myalgia,
myopathy, rhabdomyolysis, arthralgias.

    Nervous system disorders: dysfunction of certain cranial nerves
(including alteration of taste, impairment of extra-ocular movement,
facial paresis), tremor, dizziness, memory loss, paresthesia,
peripheral neuropathy, peripheral nerve palsy, psychic disturbances.

    Ear and labyrinth disorders: vertigo.

    Psychiatric disorders: anxiety, insomnia, depression, loss of
libido.

    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 system disorders: pancreatitis, vomiting.

    Hepatobiliary disorders: hepatitis, including chronic active
hepatitis, cholestatic jaundice, fatty change in liver, and, rarely,
cirrhosis, fulminant hepatic necrosis, and hepatoma.

    Metabolism and nutrition disorders: anorexia.

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

    Reproductive system and breast disorders: gynecomastia, erectile
dysfunction.

    Eye disorders: 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 Enzymes). About 5% of patients taking simvastatin
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.

    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 simvastatin (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, Special Populations and
PRECAUTIONS, Pediatric Use).

    OVERDOSAGE

    VYTORIN

    No specific treatment of overdosage with VYTORIN can be
recommended. In the event of an overdose, symptomatic and supportive
measures should be employed.

    Ezetimibe

    In clinical studies, administration of ezetimibe, 50 mg/day to
15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients
with primary hypercholesterolemia for up to 56 days, was generally
well tolerated.

    A few cases of overdosage have been reported; most have not been
associated with adverse experiences. Reported adverse experiences have
not been serious.

    Simvastatin

    A few cases of overdosage with simvastatin have been reported; the
maximum dose taken was 3.6 g. All patients recovered without sequelae.

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

    DOSAGE AND ADMINISTRATION

    The patient should be placed on a standard cholesterol-lowering
diet before receiving VYTORIN and should continue on this diet during
treatment with VYTORIN. The dosage should be individualized according
to the baseline LDL-C level, the recommended goal of therapy, and the
patient's response. (See NCEP Adult Treatment Panel (ATP) III
Guidelines, summarized in Table 6.) VYTORIN should be taken as a
single daily dose in the evening, with or without food.

    The dosage range is 10/10 mg/day through 10/80 mg/day. The
recommended usual starting dose is 10/20 mg/day. Initiation of therapy
with 10/10 mg/day may be considered for patients requiring less
aggressive LDL-C reductions. Patients who require a larger reduction
in LDL-C (greater than 55%) may be started at 10/40 mg/day. After
initiation or titration of VYTORIN, lipid levels may be analyzed after
2 or more weeks and dosage adjusted, if needed. See below for dosage
recommendations for patients receiving certain concomitant therapies
and for those with renal insufficiency.

    Patients with Homozygous Familial Hypercholesterolemia

    The recommended dosage for patients with homozygous familial
hypercholesterolemia is VYTORIN 10/40 mg/day or 10/80 mg/day in the
evening. VYTORIN should be used as an adjunct to other lipid-lowering
treatments (e.g., LDL apheresis) in these patients or if such
treatments are unavailable.

    Patients with Hepatic Insufficiency

    No dosage adjustment is necessary in patients with mild hepatic
insufficiency (see PRECAUTIONS, Hepatic Insufficiency).

    Patients with Renal Insufficiency

    No dosage adjustment is necessary in patients with mild or
moderate renal insufficiency. However, for patients with severe renal
insufficiency, VYTORIN should not be started unless the patient has
already tolerated treatment with simvastatin at a dose of 5 mg or
higher. Caution should be exercised when VYTORIN is administered to
these patients and they should be closely monitored (see CLINICAL
PHARMACOLOGY, Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis).

    Geriatric Patients

    No dosage adjustment is necessary in geriatric patients (see
CLINICAL PHARMACOLOGY, Special Populations).

    Coadministration with Bile Acid Sequestrants

    Dosing of VYTORIN should occur either (greater than=)2 hours
before or (greater than=)4 hours after administration of a bile acid
sequestrant (see PRECAUTIONS, Drug Interactions).

    Patients taking Cyclosporine or Danazol

    Caution should be exercised when initiating VYTORIN in the setting
of cyclosporine. In patients taking cyclosporine or danazol, VYTORIN
should not be started unless the patient has already tolerated
treatment with simvastatin at a dose of 5 mg or higher. The dose of
VYTORIN should not exceed 10/10 mg/day.

    Patients taking Amiodarone or Verapamil

    In patients taking amiodarone or verapamil concomitantly with
VYTORIN, the dose should not exceed 10/20 mg/day (see WARNINGS,
Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other drug
interactions).

    Patients taking other Concomitant Lipid-Lowering Therapy

    The safety and effectiveness of VYTORIN administered with fibrates
have not been established. Therefore, the combination of VYTORIN and
fibrates should be avoided (see WARNINGS, Myopathy/Rhabdomyolysis, and
PRECAUTIONS, Drug Interactions, Other drug interactions).

    There is an increased risk of myopathy when simvastatin is used
concomitantly with fibrates (especially gemfibrozil). Therefore,
although not recommended, if VYTORIN is used in combination with
gemfibrozil, the dose should not exceed 10/10 mg daily (see WARNINGS,
Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions, Other
drug interactions).

    HOW SUPPLIED

    No. 3873 -- Tablets VYTORIN 10/10 are white to off-white
capsule-shaped tablets with code "311" on one side.

    They are supplied as follows:

    NDC 66582-311-31 bottles of 30

    NDC 66582-311-54 bottles of 90

    NDC 66582-311-82 bottles of 1000 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

    NDC 66582-311-87 bottles of 10,000 (If repackaged in blisters,
then opaque or light-resistant blisters should be used.)

    NDC 66582-311-28 unit dose packages of 100.

    No. 3874 -- Tablets VYTORIN 10/20 are white to off-white
capsule-shaped tablets with code "312" on one side.

    They are supplied as follows:

    NDC 66582-312-31 bottles of 30

    NDC 66582-312-54 bottles of 90

    NDC 66582-312-82 bottles of 1000 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

    NDC 66582-312-87 bottles of 10,000 (If repackaged in blisters,
then opaque or light-resistant blisters should be used.)

    NDC 66582-312-28 unit dose packages of 100.

    No. 3875 -- Tablets VYTORIN 10/40 are white to off-white
capsule-shaped tablets with code "313" on one side.

    They are supplied as follows:

    NDC 66582-313-31 bottles of 30

    NDC 66582-313-54 bottles of 90

    NDC 66582-313-74 bottles of 500 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

    NDC 66582-313-86 bottles of 5000 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

    NDC 66582-313-52 unit dose packages of 50.

    No. 3876 -- Tablets VYTORIN 10/80 are white to off-white
capsule-shaped tablets with code "315" on one side.

    They are supplied as follows:

    NDC 66582-315-31 bottles of 30

    NDC 66582-315-54 bottles of 90

    NDC 66582-315-74 bottles of 500 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

    NDC 66582-315-66 bottles of 2500 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

    NDC 66582-315-52 unit dose packages of 50.

    Storage

    Store at 20-25(degrees)C (68-77(degrees)F). (See USP Controlled
Room Temperature.) Keep container tightly closed.

    Storage of 10,000, 5000, and 2500 count bottles

    Store bottle of 10,000 VYTORIN 10/10 and 10/20, 5000 VYTORIN
10/40, and 2500 VYTORIN 10/80 capsule-shaped tablets at
20-25(degrees)C (68-77(degrees)F). (See USP Controlled Room
Temperature.) Store in original container until time of use. When
product container is subdivided, repackage into a tightly-closed,
light-resistant container. Entire contents must be repackaged
immediately upon opening.

    Issued November 2006

    Printed in USA

    Manufactured for:
    MERCK/Schering-Plough Pharmaceuticals
    North Wales, PA 19454, USA

    By:
    MSD Technology Singapore Pte. Ltd.
    Singapore 637766
    Or
    Merck Sharp & Dohme (Italia) S.p.A.
    Via Emilia, 21
    27100 - Pavia
    Italy
    Or
    Merck Sharp & Dohme Ltd.
    Cramlington,
    Northumberland, UK NE23 3JU

    (1) Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther
1998;64(5):477-83.

    (2) 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.
 9621004

    VYTORIN(R) (ezetimibe/simvastatin) Tablets
    Patient Information about VYTORIN (VI-tor-in)
    Generic name: ezetimibe/simvastatin tablets

    Read this information carefully before you start taking VYTORIN.
Review this information each time you refill your prescription for
VYTORIN as there may be new information. This information does not
take the place of talking with your doctor about your medical
condition or your treatment. If you have any questions about VYTORIN,
ask your doctor. Only your doctor can determine if VYTORIN is right
for you.

    What is VYTORIN?

    VYTORIN contains two cholesterol-lowering medications, ezetimibe
and simvastatin, available as a tablet in four strengths:

    --  VYTORIN 10/10 (ezetimibe 10 mg/simvastatin 10 mg)

    --  VYTORIN 10/20 (ezetimibe 10 mg/simvastatin 20 mg)

    --  VYTORIN 10/40 (ezetimibe 10 mg/simvastatin 40 mg)

    --  VYTORIN 10/80 (ezetimibe 10 mg/simvastatin 80 mg)

    VYTORIN is a medicine used to lower levels of total cholesterol,
LDL (bad) cholesterol, and fatty substances called triglycerides in
the blood. In addition, VYTORIN raises levels of HDL (good)
cholesterol. It is used for patients who cannot control their
cholesterol levels by diet alone. You should stay on a
cholesterol-lowering diet while taking this medicine.

    VYTORIN works to reduce your cholesterol in two ways. It reduces
the cholesterol absorbed in your digestive tract, as well as the
cholesterol your body makes by itself. VYTORIN does not help you lose
weight.

    For more information about cholesterol, see the section called
"What should I know about high cholesterol?"

    Who should not take VYTORIN?

    Do not take VYTORIN:

    --  If you are allergic to ezetimibe or simvastatin, the active
        ingredients in VYTORIN, or to the inactive ingredients. For a
        list of inactive ingredients, see the "Inactive ingredients"
        section at the end of this information sheet.

    --  If you have active liver disease or repeated blood tests
        indicating possible liver problems.

    --  If you are pregnant, or think you may be pregnant, or planning
        to become pregnant or breast-feeding.

    VYTORIN is not recommended for use in children under 10 years of
age.

    What should I tell my doctor before and while taking VYTORIN?

    Tell your doctor right away if you experience unexplained muscle
pain, tenderness, or weakness. This is because on rare occasions,
muscle problems can be serious, including muscle breakdown resulting
in kidney damage.

    The risk of muscle breakdown is greater at higher doses of
VYTORIN.

    The risk of muscle breakdown is greater in patients with kidney
problems.

    Taking VYTORIN with certain substances can increase the risk of
muscle problems. It is particularly important to tell your doctor if
you are taking any of the following:

    --  cyclosporine

    --  danazol

    --  antifungal agents (such as itraconazole or ketoconazole)

    --  fibric acid derivatives (such as gemfibrozil, bezafibrate, or
        fenofibrate)

    --  the antibiotics erythromycin, clarithromycin, and
        telithromycin

    --  HIV protease inhibitors (such as indinavir, nelfinavir,
        ritonavir, and saquinavir)

    --  the antidepressant nefazodone

    --  amiodarone (a drug used to treat an irregular heartbeat)

    --  verapamil (a drug used to treat high blood pressure, chest
        pain associated with heart disease, or other heart conditions)

    --  large doses ((greater than=)1 g/day) of niacin or nicotinic
        acid

    --  large quantities of grapefruit juice (greater than1 quart
        daily)

    It is also important to tell your doctor if you are taking
coumarin anticoagulants (drugs that prevent blood clots, such as
warfarin).

    Tell your doctor about any prescription and nonprescription
medicines you are taking or plan to take, including natural or herbal
remedies.

    Tell your doctor about all your medical conditions including
allergies.

    Tell your doctor if you:

    --  drink substantial quantities of alcohol or ever had liver
        problems. VYTORIN may not be right for you.

    --  are pregnant or plan to become pregnant. Do not use VYTORIN if
        you are pregnant, trying to become pregnant or suspect that
        you are pregnant. If you become pregnant while taking VYTORIN,
        stop taking it and contact your doctor immediately.

    --  are breast-feeding. Do not use VYTORIN if you are
        breast-feeding.

    Tell other doctors prescribing a new medication that you are
taking VYTORIN.

    How should I take VYTORIN?

    Your doctor has prescribed your dose of VYTORIN. The available
doses of VYTORIN are 10/10, 10/20, 10/40, and 10/80. The usual daily
starting dose is VYTORIN 10/20.

    --  Take VYTORIN once a day, in the evening, with or without food.

    --  Try to take VYTORIN as prescribed. If you miss a dose, do not
        take an extra dose. Just resume your usual schedule.

    --  Continue to follow a cholesterol-lowering diet while taking
        VYTORIN. Ask your doctor if you need diet information.

    --  Keep taking VYTORIN unless your doctor tells you to stop. If
        you stop taking VYTORIN, your cholesterol may rise again.

    What should I do in case of an overdose?

    Contact your doctor immediately.

    What are the possible side effects of VYTORIN?

    See your doctor regularly to check your cholesterol level and to
check for side effects. Your doctor may do blood tests to check your
liver before you start taking VYTORIN and during treatment.

    In clinical studies patients reported the following common side
effects while taking VYTORIN: headache and muscle pain (see What
should I tell my doctor before and while taking VYTORIN?).

    The following side effects have been reported in general use with
either ezetimibe or simvastatin tablets (tablets that contain the
active ingredients of VYTORIN):

    --  allergic reactions including swelling of the face, lips,
        tongue, and/or throat that may cause difficulty in breathing
        or swallowing (which may require treatment right away), rash,
        hives; joint pain; muscle pain; alterations in some laboratory
        blood tests; liver problems; inflammation of the pancreas;
        nausea; gallstones; inflammation of the gallbladder.

    Tell your doctor if you are having these or any other medical
problems while on VYTORIN. This is not a complete list of side
effects. For a complete list, ask your doctor or pharmacist.

    What should I know about high cholesterol?

    Cholesterol is a type of fat found in your blood. Cholesterol
comes from two sources. It is produced by your body and it comes from
the food you eat. Your total cholesterol is made up of both LDL and
HDL cholesterol.

    LDL cholesterol is called "bad" cholesterol because it can build
up in the wall of your arteries and form plaque. Over time, plaque
build-up can cause a narrowing of the arteries. This narrowing can
slow or block blood flow to your heart, brain, and other organs. High
LDL cholesterol is a major cause of heart disease and stroke.

    HDL cholesterol is called "good" cholesterol because it keeps the
bad cholesterol from building up in the arteries.

    Triglycerides also are fats found in your body.

    General Information about VYTORIN

    Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use VYTORIN for a
condition for which it was not prescribed. Do not give VYTORIN to
other people, even if they have the same condition you have. It may
harm them.

    This summarizes the most important information about VYTORIN. If
you would like more information, talk with your doctor. You can ask
your pharmacist or doctor for information about VYTORIN that is
written for health professionals. For additional information, visit
the following web site: vytorin.com.

    Inactive ingredients:

    Butylated hydroxyanisole NF, citric acid monohydrate USP,
croscarmellose sodium NF, hydroxypropyl methylcellulose USP, lactose
monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF,
and propyl gallate NF.

    Issued November 2006

    Manufactured for:
    Merck/Schering-Plough Pharmaceuticals
    North Wales, PA 19454, USA

    By:
    MSD Technology Singapore Pte. Ltd.
    Singapore 637766
    Or
    Merck Sharp & Dohme (Italia) S.p.A.
    Via Emilia, 21
    27100 - Pavia
    Italy
    Or
    Merck Sharp & Dohme Ltd.
    Cramlington,
    Northumberland, UK NE23 3JU
                                                        29480923T
                                                        REV 11

ZETIA(R)
(EZETIMIBE)
TABLETS

DESCRIPTION

   ZETIA (ezetimibe) is in a class of lipid-lowering compounds that
selectively inhibits the intestinal absorption of cholesterol and
related phytosterols. The chemical name of ezetimibe is
1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)-3(S)-hydroxypropyl)-4(S)-
(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3.
Its molecular weight is 409.4 and its structural formula is:

    (OBJECT OMITTED)

    Ezetimibe is a white, crystalline powder that is freely to very
soluble in ethanol, methanol, and acetone and practically insoluble in
water. Ezetimibe has a melting point of about 163(degree)C and is
stable at ambient temperature. ZETIA is available as a tablet for oral
administration containing 10 mg of ezetimibe and the following
inactive ingredients: croscarmellose sodium NF, lactose monohydrate
NF, magnesium stearate NF, microcrystalline cellulose NF, povidone
USP, and sodium lauryl sulfate NF.

    CLINICAL PHARMACOLOGY

    Background

    Clinical studies have demonstrated that elevated levels of total
cholesterol (total-C), low density lipoprotein cholesterol (LDL-C) and
apolipoprotein B (Apo B), the major protein constituent of LDL,
promote human atherosclerosis. In addition, decreased levels of high
density lipoprotein cholesterol (HDL-C) are associated with the
development of atherosclerosis. Epidemiologic studies have established
that cardiovascular morbidity and mortality vary directly with the
level of total-C and LDL-C and inversely with the level of HDL-C. Like
LDL, cholesterol-enriched triglyceride-rich lipoproteins, including
very-low-density lipoproteins (VLDL), intermediate-density
lipoproteins (IDL), and remnants, can also promote atherosclerosis.
The independent effect of raising HDL-C or lowering triglycerides (TG)
on the risk of coronary and cardiovascular morbidity and mortality has
not been determined.
    ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C
in patients with hypercholesterolemia. Administration of ZETIA with an
HMG-CoA reductase inhibitor is effective in improving serum total-C,
LDL-C, Apo B, TG, and HDL-C beyond either treatment alone.
Administration of ZETIA with fenofibrate is effective in improving
serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed
hyperlipidemia as compared to either treatment alone. The effects of
ezetimibe given either alone or in addition to an HMG-CoA reductase
inhibitor or fenofibrate on cardiovascular morbidity and mortality
have not been established.

    Mode of Action

    Ezetimibe reduces blood cholesterol by inhibiting the absorption
of cholesterol by the small intestine. In a 2-week clinical study in
18 hypercholesterolemic patients, ZETIA inhibited intestinal
cholesterol absorption by 54%, compared with placebo. ZETIA had no
clinically meaningful effect on the plasma concentrations of the
fat-soluble vitamins A, D, and E (in a study of 113 patients), and did
not impair adrenocortical steroid hormone production (in a study of
118 patients).
    The cholesterol content of the liver is derived predominantly from
three sources. The liver can synthesize cholesterol, take up
cholesterol from the blood from circulating lipoproteins, or take up
cholesterol absorbed by the small intestine. Intestinal cholesterol is
derived primarily from cholesterol secreted in the bile and from
dietary cholesterol.
    Ezetimibe has a mechanism of action that differs from those of
other classes of cholesterol-reducing compounds (HMG-CoA reductase
inhibitors, bile acid sequestrants (resins), fibric acid derivatives,
and plant stanols).
    Ezetimibe does not inhibit cholesterol synthesis in the liver, or
increase bile acid excretion. Instead, ezetimibe localizes and appears
to act at the brush border of the small intestine and inhibits the
absorption of cholesterol, leading to a decrease in the delivery of
intestinal cholesterol to the liver. This causes a reduction of
hepatic cholesterol stores and an increase in clearance of cholesterol
from the blood; this distinct mechanism is complementary to that of
HMG-CoA reductase inhibitors and of fenofibrate (see CLINICAL
STUDIES).

    Pharmacokinetics

    Absorption

    After oral administration, ezetimibe is absorbed and extensively
conjugated to a pharmacologically active phenolic glucuronide
(ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted
adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5
ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide
mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours
(Tmax). There was no substantial deviation from dose proportionality
between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot
be determined, as the compound is virtually insoluble in aqueous media
suitable for injection. Ezetimibe has variable bioavailability; the
coefficient of variation, based on inter-subject variability, was 35
to 60% for AUC values.

    Effect of Food on Oral Absorption

    Concomitant food administration (high fat or non-fat meals) had no
effect on the extent of absorption of ezetimibe when administered as
ZETIA 10-mg tablets. The Cmax value of ezetimibe was increased by 38%
with consumption of high fat meals. ZETIA can be administered with or
without food.

    Distribution

    Ezetimibe and ezetimibe-glucuronide are highly bound (greater
than 90%) to human plasma proteins.

    Metabolism and Excretion

    Ezetimibe is primarily metabolized in the small intestine and
liver via glucuronide conjugation (a phase II reaction) with
subsequent biliary and renal excretion. Minimal oxidative metabolism
(a phase I reaction) has been observed in all species evaluated.
    In humans, ezetimibe is rapidly metabolized to
ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the
major drug-derived compounds detected in plasma, constituting
approximately 10 to 20% and 80 to 90% of the total drug in plasma,
respectively. Both ezetimibe and ezetimibe-glucuronide are slowly
eliminated from plasma with a half-life of approximately 22 hours for
both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time
profiles exhibit multiple peaks, suggesting enterohepatic recycling.
    Following oral administration of 14C-ezetimibe (20 mg) to human
subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide)
accounted for approximately 93% of the total radioactivity in plasma.
After 48 hours, there were no detectable levels of radioactivity in
the plasma.
    Approximately 78% and 11% of the administered radioactivity were
recovered in the feces and urine, respectively, over a 10-day
collection period. Ezetimibe was the major component in feces and
accounted for 69% of the administered dose, while
ezetimibe-glucuronide was the major component in urine and accounted
for 9% of the administered dose.

    Special Populations

    Geriatric Patients

    In a multiple-dose study with ezetimibe given 10 mg once daily for
10 days, plasma concentrations for total ezetimibe were about 2-fold
higher in older ((greater than=)65 years) healthy subjects compared to
younger subjects.

    Pediatric Patients

    In a multiple-dose study with ezetimibe given 10 mg once daily for
7 days, the absorption and metabolism of ezetimibe were similar in
adolescents (10 to 18 years) and adults. Based on total ezetimibe,
there are no pharmacokinetic differences between adolescents and
adults. Pharmacokinetic data in the pediatric population less than 10
years of age are not available.

    Gender

    In a multiple-dose study with ezetimibe given 10 mg once daily for
10 days, plasma concentrations for total ezetimibe were slightly
higher (less than20%) in women than in men.

    Race

    Based on a meta-analysis of multiple-dose pharmacokinetic studies,
there were no pharmacokinetic differences between Black and Caucasian
subjects. Studies in Asian subjects indicated that the
pharmacokinetics of ezetimibe were similar to those seen in Caucasian
subjects.

    Hepatic Insufficiency

    After a single 10-mg dose of ezetimibe, the mean area under the
curve (AUC) for total ezetimibe was increased approximately 1.7-fold
in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6),
compared to healthy subjects. The mean AUC values for total ezetimibe
and ezetimibe were increased approximately 3- to 4-fold and 5- to
6-fold, respectively, in patients with moderate (Child-Pugh score 7 to
9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a
14-day, multiple-dose study (10 mg daily) in patients with moderate
hepatic insufficiency, the mean AUC values for total ezetimibe and
ezetimibe were increased approximately 4-fold on Day 1 and Day 14
compared to healthy subjects. Due to the unknown effects of the
increased exposure to ezetimibe in patients with moderate or severe
hepatic insufficiency, ZETIA is not recommended in these patients (see
CONTRAINDICATIONS and PRECAUTIONS, Hepatic Insufficiency).

    Renal Insufficiency

    After a single 10-mg dose of ezetimibe in patients with severe
renal disease (n=8; mean CrCl less than=30 mL/min/1.73 m2), the mean
AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe
were increased approximately 1.5-fold, compared to healthy subjects
(n=9).

    Drug Interactions (See also PRECAUTIONS, Drug Interactions)

    ZETIA had no significant effect on a series of probe drugs
(caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to
be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a
"cocktail" study of twelve healthy adult males. This indicates that
ezetimibe is neither an inhibitor nor an inducer of these cytochrome
P450 isozymes, and it is unlikely that ezetimibe will affect the
metabolism of drugs that are metabolized by these enzymes.
    Warfarin: Concomitant administration of ezetimibe (10 mg once
daily) had no significant effect on bioavailability of warfarin and
prothrombin time in a study of twelve healthy adult males. There have
been post-marketing reports of increased International Normalized
Ratio (INR) in patients who had ezetimibe added to warfarin. Most of
these patients were also on other medications (See PRECAUTIONS, Drug
Interactions).
    Digoxin: Concomitant administration of ezetimibe (10 mg once
daily) had no significant effect on the bioavailability of digoxin and
the ECG parameters (HR, PR, QT, and QTc intervals) in a study of
twelve healthy adult males.
    Gemfibrozil: In a study of twelve healthy adult males, concomitant
administration of gemfibrozil (600 mg twice daily) significantly
increased the oral bioavailability of total ezetimibe by a factor of
1.7. Ezetimibe (10 mg once daily) did not significantly affect the
bioavailability of gemfibrozil.
    Oral Contraceptives: Co-administration of ezetimibe (10 mg once
daily) with oral contraceptives had no significant effect on the
bioavailability of ethinyl estradiol or levonorgestrel in a study of
eighteen healthy adult females.
    Cimetidine: Multiple doses of cimetidine (400 mg twice daily) had
no significant effect on the oral bioavailability of ezetimibe and
total ezetimibe in a study of twelve healthy adults.
    Antacids: In a study of twelve healthy adults, a single dose of
antacid (Supralox(TM) 20 mL) administration had no significant effect
on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide,
or ezetimibe based on AUC values. The Cmax value of total ezetimibe
was decreased by 30%.
    Glipizide: In a study of twelve healthy adult males, steady-state
levels of ezetimibe (10 mg once daily) had no significant effect on
the pharmacokinetics and pharmacodynamics of glipizide. A single dose
of glipizide (10 mg) had no significant effect on the exposure to
total ezetimibe or ezetimibe.
    HMG-CoA Reductase Inhibitors: In studies of healthy
hypercholesterolemic (LDL-C (greater than=)130 mg/dL) adult subjects,
concomitant administration of ezetimibe (10 mg once daily) had no
significant effect on the bioavailability of either lovastatin,
simvastatin, pravastatin, atorvastatin, fluvastatin, or rosuvastatin.
No significant effect on the bioavailability of total ezetimibe and
ezetimibe was demonstrated by either lovastatin (20 mg once daily),
pravastatin (20 mg once daily), atorvastatin (10 mg once daily),
fluvastatin (20 mg once daily), or rosuvastatin (10 mg once daily).
(See PRECAUTIONS, Skeletal Muscle.)
    Fenofibrate: In a study of thirty-two healthy hypercholesterolemic
(LDL-C (greater than=)130 mg/dL) adult subjects, concomitant
fenofibrate (200 mg once daily) administration increased the mean Cmax
and AUC values of total ezetimibe approximately 64% and 48%,
respectively. Pharmacokinetics of fenofibrate were not significantly
affected by ezetimibe (10 mg once daily).
    Cholestyramine: In a study of forty healthy hypercholesterolemic
(LDL-C (greater than=)130 mg/dL) adult subjects, concomitant
cholestyramine (4 g twice daily) administration decreased the mean AUC
values of total ezetimibe and ezetimibe approximately 55% and 80%,
respectively.
    Cyclosporine: In a study of eight post-renal transplant patients
with mildly impaired or normal renal function (creatinine clearance of
greater than50 mL/min), stable doses of cyclosporine (75 to 150 mg
twice daily) increased the mean AUC and Cmax values of total ezetimibe
3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to
4.4-fold), respectively, compared to a historical healthy control
population (n=17). In a different study, a renal transplant patient
with severe renal insufficiency (creatinine clearance of
13.2 mL/min/1.73 m2) who was receiving multiple medications, including
cyclosporine, demonstrated a 12-fold greater exposure to total
ezetimibe compared to healthy subjects. In a two-period crossover
study in twelve healthy subjects, daily administration of 20 mg
ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day
7 resulted in a mean 15% increase in cyclosporine AUC (range 10%
decrease to 51% increase) compared to a single 100-mg dose of
cyclosporine alone (see PRECAUTIONS, Drug Interactions).

    ANIMAL PHARMACOLOGY

    The hypocholesterolemic effect of ezetimibe was evaluated in
cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human
cholesterol metabolism. Ezetimibe was found to have an ED50 value of
0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol levels
in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and
700 (mu)g/kg/day, respectively. These results are consistent with
ZETIA being a potent cholesterol absorption inhibitor.
    In a rat model, where the glucuronide metabolite of ezetimibe (SCH
60663) was administered intraduodenally, the metabolite was as potent
as the parent compound (SCH 58235) in inhibiting the absorption of
cholesterol, suggesting that the glucuronide metabolite had activity
similar to the parent drug.
    In 1-month studies in dogs given ezetimibe (0.03 to 300
mg/kg/day), the concentration of cholesterol in gallbladder bile
increased tilde2- to 4-fold. However, a dose of 300 mg/kg/day
administered to dogs for one year did not result in gallstone
formation or any other adverse hepatobiliary effects. In a 14-day
study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat
or cholesterol-rich diet, the concentration of cholesterol in
gallbladder bile was either unaffected or reduced to normal levels,
respectively.
    A series of acute preclinical studies was performed to determine
the selectivity of ZETIA for inhibiting cholesterol absorption.
Ezetimibe inhibited the absorption of 14C-cholesterol with no effect
on the absorption of triglycerides, fatty acids, bile acids,
progesterone, ethyl estradiol, or the fat-soluble vitamins A and D.
    In 4- to 12-week toxicity studies in mice, ezetimibe did not
induce cytochrome P450 drug metabolizing enzymes. In toxicity studies,
a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase
inhibitors (parents or their active hydroxy acid metabolites) was seen
in rats, dogs, and rabbits.

    CLINICAL STUDIES

    Primary Hypercholesterolemia

    ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C
in patients with hypercholesterolemia. Maximal to near maximal
response is generally achieved within 2 weeks and maintained during
chronic therapy.
    ZETIA is effective in patients with hypercholesterolemia, in men
and women, in younger and older patients, alone or administered with
an HMG-CoA reductase inhibitor. Experience in pediatric and adolescent
patients (ages 9 to 17) has been limited to patients with homozygous
familial hypercholesterolemia (HoFH) or sitosterolemia.

    Monotherapy

    In two, multicenter, double-blind, placebo-controlled, 12-week
studies in 1719 patients with primary hypercholesterolemia, ZETIA
significantly lowered total-C, LDL-C, Apo B, and TG, and increased
HDL-C compared to placebo (see Table 1). Reduction in LDL-C was
consistent across age, sex, and baseline LDL-C.


                                Table 1
    Response to ZETIA in Patients with Primary Hypercholesterolemia
             (Mean(a) % Change from Untreated Baseline(b))

                                 Treatment  N   Total LDL Apo TG  HDL-
                                   group        - C   - C  B  (a)  C
------------------------------------------ --- ------ --- --- --- ----
                                  Placebo  205    +1  +1  -1   -1  -1
           Study 1(c)            ------------- ------ --- --- --- ----
                                 Ezetimibe 622   -12 -18 -15   -7  +1
---------------------------------------------- ------ --- --- --- ----
                                  Placebo  226    +1  +1  -1   +2  -2
           Study 2(c)            ------------- ------ --- --- --- ----
                                 Ezetimibe 666   -12 -18 -16   -9  +1
---------------------------------------------- ------ --- --- --- ----
                                  Placebo  431     0  +1  -2    0  -2
 Pooled Data(c) (Studies 1 & 2)  ------------- ------ --- --- --- ----
                                 Ezetimibe1288   -13 -18 -16   -8  +1
----------------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) ZETIA significantly reduced total-C, LDL-C, Apo B, and TG, and
increased HDL-C compared to placebo.

    Combination with HMG-CoA Reductase Inhibitors

    ZETIA Added to On-going HMG-CoA Reductase Inhibitor Therapy

    In a multicenter, double-blind, placebo-controlled, 8-week study,
769 patients with primary hypercholesterolemia, known coronary heart
disease or multiple cardiovascular risk factors who were already
receiving HMG-CoA reductase inhibitor monotherapy, but who had not met
their NCEP ATP II target LDL-C goal were randomized to receive either
ZETIA or placebo in addition to their on-going HMG-CoA reductase
inhibitor therapy.
    ZETIA, added to on-going HMG-CoA reductase inhibitor therapy,
significantly lowered total-C, LDL-C, Apo B, and TG, and increased
HDL-C compared with an HMG-CoA reductase inhibitor administered alone
(see Table 2). LDL-C reductions induced by ZETIA were generally
consistent across all HMG-CoA reductase inhibitors.


                                Table 2

      Response to Addition of ZETIA to On-going HMG-CoA Reductase
      Inhibitor Therapy(a )in Patients with Hypercholesterolemia
              (Mean(b) % Change from Treated Baseline(c))

   Treatment      N    Total-C       LDL-C     Apo B  TG(b)   HDL-C
  (Daily Dose)
----------------------------------------------------------------------
On-going HMG-CoA
 reductase
 inhibitor
 +Placebo(d)     390      -2            -4     -3      -3      +1
----------------------------------------------------------------------
On-going HMG-CoA
 reductase
 inhibitor
 +ZETIA(d)       379     -17           -25    -19     -14      +3
----------------------------------------------------------------------

    (a) Patients receiving each HMG-CoA reductase inhibitor: 40%
atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin,
cerivastatin, lovastatin)

    (b) For triglycerides, median % change from baseline

    (c) Baseline - on an HMG-CoA reductase inhibitor alone.

    (d) ZETIA + HMG-CoA reductase inhibitor significantly reduced
total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to HMG-CoA
reductase inhibitor alone.

    ZETIA Initiated Concurrently with an HMG-CoA Reductase Inhibitor

    In four, multicenter, double-blind, placebo-controlled, 12-week
trials, in 2382 hypercholesterolemic patients, ZETIA or placebo was
administered alone or with various doses of atorvastatin, simvastatin,
pravastatin, or lovastatin.
    When all patients receiving ZETIA with an HMG-CoA reductase
inhibitor were compared to all those receiving the corresponding
HMG-CoA reductase inhibitor alone, ZETIA significantly lowered
total-C, LDL-C, Apo B, and TG, and, with the exception of pravastatin,
increased HDL-C compared to the HMG-CoA reductase inhibitor
administered alone. LDL-C reductions induced by ZETIA were generally
consistent across all HMG-CoA reductase inhibitors. (See footnote c,
Tables 3 to 6.)


                                Table 3
       Response to ZETIA and Atorvastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
               (Meana % Change from Untreated Baselineb)

     Treatment        N   Total-C   LDL-C   Apo B    TGa    HDL-C
    (Daily Dose)
-----------------------------------------------------------------
Placebo               60      +4      +4      +3      -6      +4
-----------------------------------------------------------------
ZETIA                 65     -14     -20     -15      -5      +4
-----------------------------------------------------------------
Atorvastatin 10 mg    60     -26     -37     -28     -21      +6
-----------------------------------------------------------------
ZETIA +
Atorvastatin 10 mg    65     -38     -53     -43     -31      +9
-----------------------------------------------------------------
Atorvastatin 20 mg    60     -30     -42     -34     -23      +4
-----------------------------------------------------------------
ZETIA +
Atorvastatin 20 mg    62     -39     -54     -44     -30      +9
-----------------------------------------------------------------
Atorvastatin 40 mg    66     -32     -45     -37     -24      +4
-----------------------------------------------------------------
ZETIA +
Atorvastatin 40 mg    65     -42     -56     -45     -34      +5
-----------------------------------------------------------------
Atorvastatin 80 mg    62     -40     -54     -46     -31      +3
-----------------------------------------------------------------
ZETIA +
Atorvastatin 80 mg    63     -46     -61     -50     -40      +7
-----------------------------------------------------------------
Pooled data (All
 Atorvastatin
 Doses)c             248     -32     -44     -36     -24      +4
-----------------------------------------------------------------
Pooled data (All
 ZETIA +
Atorvastatin Doses)c 255     -41     -56     -45     -33      +7
-----------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) ZETIA + all doses of atorvastatin pooled (10-80 mg)
significantly reduced total-C, LDL-C, Apo B, and TG, and increased
HDL-C compared to all doses of atorvastatin pooled (10-80 mg).


                                Table 4
       Response to ZETIA and Simvastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
             (Mean(a) % Change from Untreated Baseline(b))

     Treatment        N   Total-C  LDL-C    Apo B   TG(a)   HDL-C
    (Daily Dose)
-----------------------------------------------------------------
Placebo               70      -1      -1       0      +2      +1
-----------------------------------------------------------------
ZETIA                 61     -13     -19     -14     -11      +5
-----------------------------------------------------------------
Simvastatin 10 mg     70     -18     -27     -21     -14      +8
-----------------------------------------------------------------
ZETIA +
Simvastatin 10 mg     67     -32     -46     -35     -26      +9
-----------------------------------------------------------------
Simvastatin 20 mg     61     -26     -36     -29     -18      +6
-----------------------------------------------------------------
ZETIA +
Simvastatin 20 mg     69     -33     -46     -36     -25      +9
-----------------------------------------------------------------
Simvastatin 40 mg     65     -27     -38     -32     -24      +6
-----------------------------------------------------------------
ZETIA +
Simvastatin 40 mg     73     -40     -56     -45     -32     +11
-----------------------------------------------------------------
Simvastatin 80 mg     67     -32     -45     -37     -23      +8
-----------------------------------------------------------------
ZETIA +
Simvastatin 80 mg     65     -41     -58     -47     -31      +8
-----------------------------------------------------------------
Pooled data (All
 Simvastatin
 Doses)(c)           263     -26     -36     -30     -20      +7
-----------------------------------------------------------------
Pooled data (All
 ZETIA +
Simvastatin
 Doses)(c)           274     -37     -51     -41     -29      +9
-----------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) ZETIA + all doses of simvastatin pooled (10-80 mg)
significantly reduced total-C, LDL-C, Apo B, and TG, and increased
HDL-C compared to all doses of simvastatin pooled (10-80 mg).


                                Table 5
       Response to ZETIA and Pravastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
             (Mean(a) % Change from Untreated Baseline(b))

     Treatment         N  Total-C  LDL-C   Apo B   TG(a)   HDL-C
    (Daily Dose)
-----------------------------------------------------------------
Placebo               65       0      -1      -2      -1      +2
-----------------------------------------------------------------
ZETIA                 64     -13     -20     -15      -5      +4
-----------------------------------------------------------------
Pravastatin 10 mg     66     -15     -21     -16     -14      +6
-----------------------------------------------------------------
ZETIA +
Pravastatin 10 mg     71     -24     -34     -27     -23      +8
-----------------------------------------------------------------
Pravastatin 20 mg     69     -15     -23     -18      -8      +8
-----------------------------------------------------------------
ZETIA +
Pravastatin 20 mg     66     -27     -40     -31     -21      +8
-----------------------------------------------------------------
Pravastatin 40 mg     70     -22     -31     -26     -19      +6
-----------------------------------------------------------------
ZETIA +
Pravastatin 40 mg     67     -30     -42     -32     -21      +8
-----------------------------------------------------------------
Pooled data (All
 Pravastatin
 Doses)(c)           205     -17     -25     -20     -14      +7
-----------------------------------------------------------------
Pooled data (All
 ZETIA +
Pravastatin
 Doses)(c)           204     -27     -39     -30     -21      +8
-----------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) ZETIA + all doses of pravastatin pooled (10-40 mg)
significantly reduced total-C, LDL-C, Apo B, and TG compared to all
doses of pravastatin pooled (10-40 mg).


                                Table 6
        Response to ZETIA and Lovastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
             (Mean(a) % Change from Untreated Baseline(b))

     Treatment         N  Total-C  LDL-C   Apo B   TG(a)   HDL-C
    (Daily Dose)
-----------------------------------------------------------------
Placebo               64      +1       0      +1      +6       0
-----------------------------------------------------------------
ZETIA                 72     -13     -19     -14      -5      +3
-----------------------------------------------------------------
Lovastatin 10 mg      73     -15     -20     -17     -11      +5
-----------------------------------------------------------------
ZETIA +
Lovastatin 10 mg      65     -24     -34     -27     -19      +8
-----------------------------------------------------------------
Lovastatin 20 mg      74     -19     -26     -21     -12      +3
-----------------------------------------------------------------
ZETIA +
Lovastatin 20 mg      62     -29     -41     -34     -27      +9
-----------------------------------------------------------------
Lovastatin 40 mg      73     -21     -30     -25     -15      +5
-----------------------------------------------------------------
ZETIA +
Lovastatin 40 mg      65     -33     -46     -38     -27      +9
-----------------------------------------------------------------
Pooled data (All
 Lovastatin
 Doses)(c)           220     -18     -25     -21     -12      +4
-----------------------------------------------------------------
Pooled data (All
 ZETIA +
Lovastatin Doses)(c) 192     -29     -40     -33     -25      +9
-----------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    (c) ZETIA + all doses of lovastatin pooled (10-40 mg)
significantly reduced total-C, LDL-C, Apo B, and TG, and increased
HDL-C compared to all doses of lovastatin pooled (10-40 mg).

    Combination with Fenofibrate

    In a multicenter, double-blind, placebo-controlled, clinical study
in patients with mixed hyperlipidemia, 625 patients were treated for
up to 12 weeks and 576 for up to an additional 48 weeks. Patients were
randomized to receive placebo, ZETIA alone, 160 mg fenofibrate alone,
or ZETIA and 160 mg fenofibrate in the 12-week study. After completing
the 12-week study, eligible patients were assigned to ZETIA
co-administered with fenofibrate or fenofibrate monotherapy for an
additional 48 weeks.
    ZETIA co-administered with fenofibrate significantly lowered
total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate
administered alone. The percent decrease in TG and percent increase in
HDL-C for ZETIA co-administered with fenofibrate were comparable to
those for fenofibrate administered alone (see Table 7).


                                Table 7
       Response to ZETIA and Fenofibrate Initiated Concurrently
                 in Patients with Mixed Hyperlipidemia
       (Mean(a) % Change from Untreated Baseline(b) at 12 weeks)

     Treatment      N  Total-C  LDL-C   Apo B   TG(a)  HDL-C  Non-HDL-
    (Daily Dose)                                                   C
----------------------------------------------------------------------
Placebo            63       0       0      -1      -9      +3       0
----------------------------------------------------------------------
ZETIA             185     -12     -13     -11     -11      +4     -15
----------------------------------------------------------------------
Fenofibrate
 160 mg   188     -11      -6     -15     -43     +19     -16
----------------------------------------------------------------------
ZETIA  +
 Fenofibrate
 160 mg           183     -22     -20     -26     -44     +19     -30
----------------------------------------------------------------------

    (a) For triglycerides, median % change from baseline

    (b) Baseline - on no lipid-lowering drug

    The changes in lipid endpoints after an additional 48 weeks of
treatment with ZETIA co-administered with fenofibrate or with
fenofibrate alone were consistent with the 12-week data displayed
above.

    Homozygous Familial Hypercholesterolemia (HoFH)

    A study was conducted to assess the efficacy of ZETIA in the
treatment of HoFH. This double-blind, randomized, 12-week study
enrolled 50 patients with a clinical and/or genotypic diagnosis of
HoFH, with or without concomitant LDL apheresis, already receiving
atorvastatin or simvastatin (40 mg). Patients were randomized to one
of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA
administered with atorvastatin or simvastatin (40 mg), or ZETIA
administered with atorvastatin or simvastatin (80 mg). Due to
decreased bioavailability of ezetimibe in patients concomitantly
receiving cholestyramine (see PRECAUTIONS), ezetimibe was dosed at
least 4 hours before or after administration of resins. Mean baseline
LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg
or simvastatin 80 mg alone and 316 mg/dL in the group randomized to
ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. ZETIA,
administered with atorvastatin or simvastatin (40 and 80 mg statin
groups, pooled), significantly reduced LDL-C (21%) compared with
increasing the dose of simvastatin or atorvastatin monotherapy from 40
to 80 mg (7%). In those treated with ZETIA plus 80 mg atorvastatin or
with ZETIA plus 80 mg simvastatin, LDL-C was reduced by 27%.

    Homozygous Sitosterolemia (Phytosterolemia)

    A study was conducted to assess the efficacy of ZETIA in the
treatment of homozygous sitosterolemia. In this multicenter,
double-blind, placebo-controlled, 8-week trial, 37 patients with
homozygous sitosterolemia with elevated plasma sitosterol levels
(greater than 5 mg/dL) on their current therapeutic regimen (diet,
bile-acid-binding resins, HMG-CoA reductase inhibitors, ileal bypass
surgery and/or LDL apheresis), were randomized to receive ZETIA (n=30)
or placebo (n=7). Due to decreased bioavailability of ezetimibe in
patients concomitantly receiving cholestyramine (see PRECAUTIONS),
ezetimibe was dosed at least 2 hours before or 4 hours after resins
were administered. Excluding the one subject receiving LDL apheresis,
ZETIA significantly lowered plasma sitosterol and campesterol, by 21%
and 24% from baseline, respectively. In contrast, patients who
received placebo had increases in sitosterol and campesterol of 4% and
3% from baseline, respectively. For patients treated with ZETIA, mean
plasma levels of plant sterols were reduced progressively over the
course of the study. The effects of reducing plasma sitosterol and
campesterol on reducing the risks of cardiovascular morbidity and
mortality have not been established.
    Reductions in sitosterol and campesterol were consistent between
patients taking ZETIA concomitantly with bile acid sequestrants (n=8)
and patients not on concomitant bile acid sequestrant therapy (n=21).

    INDICATIONS AND USAGE

    Primary Hypercholesterolemia

    Monotherapy

    ZETIA, administered alone, is indicated as adjunctive therapy to
diet for the reduction of elevated total-C, LDL-C, and Apo B in
patients with primary (heterozygous familial and non-familial)
hypercholesterolemia.

    Combination Therapy with HMG-CoA Reductase Inhibitors

    ZETIA, administered in combination with an HMG-CoA reductase
inhibitor, is indicated as adjunctive therapy to diet for the
reduction of elevated total-C, LDL-C, and Apo B in patients with
primary (heterozygous familial and non-familial) hypercholesterolemia.

    Combination Therapy with Fenofibrate

    ZETIA, administered in combination with fenofibrate, is indicated
as adjunctive therapy to diet for the reduction of elevated total-C,
LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia.

    Homozygous Familial Hypercholesterolemia (HoFH)

    The combination of ZETIA and atorvastatin or simvastatin, is
indicated for the reduction of elevated total-C and LDL-C levels in
patients with HoFH, as an adjunct to other lipid-lowering treatments
(e.g., LDL apheresis) or if such treatments are unavailable.

    Homozygous Sitosterolemia

    ZETIA is indicated as adjunctive therapy to diet for the reduction
of elevated sitosterol and campesterol levels in patients with
homozygous familial sitosterolemia.
    Therapy with lipid-altering agents should be a component of
multiple risk-factor intervention in individuals at increased risk for
atherosclerotic vascular disease due to hypercholesterolemia.
Lipid-altering agents should be used in addition to an appropriate
diet (including restriction of saturated fat and cholesterol) and when
the response to diet and other non-pharmacological measures has been
inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines,
summarized in Table 8.)


                                Table 8
                  Summary of NCEP ATP III Guidelines

                                        LDL Level at
                                         Which to         LDL level at
                         LDL             Initiate            Which to
 Risk Category           Goal           Therapeutic      Consider Drug
                        (mg/dL)          Lifestyle           Therapy
                                         Changes(a)          (mg/dL)
                                          (mg/dL)
----------------------------------------------------------------------
                                                    (greater than=)130
CHD or CHD risk                                              (100-129:
equivalents(b)      less than 100  (greater than=)100            drug
(10-year risk                                             optional)(d)
greater than 20%)(c)

----------------------------------------------------------------------
                                                          10-year risk
                                                               10-20%:
2+ Risk factors(e)  less than 130  (greater than=)130
(10-year risk                                    (greater than=)130(c)
(less than=)20%)(c)                                       10-year risk
                                                        less than 10%:
                                                 (greater than=)160(c)
----------------------------------------------------------------------
                                                    (greater than=)190
                                                             (160-189:
0-1 Risk factor(f)  less than160   (greater than=)160     LDL-lowering
                                                              drug
                                                            optional)
----------------------------------------------------------------------

    (a) Therapeutic lifestyle changes include: 1) dietary changes:
reduced intake of saturated fats (less than7% of total calories) and
cholesterol (less than200 mg per day), and enhancing LDL lowering with
plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber
(10-25 g/d), 2) weight reduction, and 3) increased physical activity.
    (b) CHD risk equivalents comprise: diabetes, multiple risk factors
that confer a 10-year risk for CHD greater than20%, and other clinical
forms of atherosclerotic disease (peripheral arterial disease,
abdominal aortic aneurysm and symptomatic carotid artery disease).

    (c) Risk assessment for determining the 10-year risk for
developing CHD is carried out using the Framingham risk scoring. Refer
to JAMA, May 16, 2001; 285 (19): 2486-2497, or the NCEP website
(http://www.nhlbi.nih.gov) for more details.

    (d) Some authorities recommend use of LDL-lowering drugs in this
category if an LDL cholesterol less than100 mg/dL cannot be achieved
by therapeutic lifestyle changes. Others prefer use of drugs that
primarily modify triglycerides and HDL, e.g., nicotinic acid or
fibrate. Clinical judgment also may call for deferring drug therapy in
this subcategory.
    (e) Major risk factors (exclusive of LDL cholesterol) that modify
LDL goals include cigarette smoking, hypertension (BP
(greater than=)140/90 mm Hg or on anti-hypertensive medication), low
HDL cholesterol (less than40 mg/dL), family history of premature CHD
(CHD in male first-degree relative less than 55 years; CHD in female
first-degree relative less than65 years), age (men (greater than=)45
years; women (greater than=)55 years). HDL cholesterol
(greater than=)60 mg/dL counts as a "negative" risk factor; its
presence removes one risk factor from the total count.
    (f) Almost all people with 0-1 risk factor have a 10-year risk
less than10%; thus, 10-year risk assessment in people with 0-1 risk
factor is not necessary.

    Prior to initiating therapy with ZETIA, secondary causes for
dyslipidemia (i.e., diabetes, hypothyroidism, obstructive liver
disease, chronic renal failure, and drugs that increase LDL-C and
decrease HDL-C (progestins, anabolic steroids, and corticosteroids)),
should be excluded or, if appropriate, treated. A lipid profile should
be performed to measure total-C, LDL-C, HDL-C and TG. For TG levels
greater than400 mg/dL (greater than4.5 mmol/L), LDL-C concentrations
should be determined by ultracentrifugation.
    At the time of hospitalization for an acute coronary event, lipid
measures should be taken on admission or within 24 hours. These values
can guide the physician on initiation of LDL-lowering therapy before
or at discharge.

    CONTRAINDICATIONS

    Hypersensitivity to any component of this medication.

    The combination of ZETIA with an HMG-CoA reductase inhibitor is
contraindicated in patients with active liver disease or unexplained
persistent elevations in serum transaminases.
    All HMG-CoA reductase inhibitors are contraindicated in pregnant
and nursing women. When ZETIA is administered with an HMG-CoA
reductase inhibitor in a woman of childbearing potential, refer to the
pregnancy category and product labeling for the HMG-CoA reductase
inhibitor. (See PRECAUTIONS, Pregnancy.)

    PRECAUTIONS

    Concurrent administration of ZETIA with a specific HMG-CoA
reductase inhibitor or fenofibrate should be in accordance with the
product labeling for that medication.

    Liver Enzymes

    In controlled clinical monotherapy studies, the incidence of
consecutive elevations ((greater than=)3 X the upper limit of normal
(ULN)) in serum transaminases was similar between ZETIA (0.5%) and
placebo (0.3%).
    In controlled clinical combination studies of ZETIA initiated
concurrently with an HMG-CoA reductase inhibitor, the incidence of
consecutive elevations ((greater than=)3 X ULN) in serum transaminases
was 1.3% for patients treated with ZETIA administered with HMG-CoA
reductase inhibitors and 0.4% for patients treated with HMG-CoA
reductase inhibitors alone. These elevations in transaminases were
generally asymptomatic, not associated with cholestasis, and returned
to baseline after discontinuation of therapy or with continued
treatment. When ZETIA is co-administered with an HMG-CoA reductase
inhibitor, liver function tests should be performed at initiation of
therapy and according to the recommendations of the HMG-CoA reductase
inhibitor.

    Skeletal Muscle

    In clinical trials, there was no excess of myopathy or
rhabdomyolysis associated with ZETIA compared with the relevant
control arm (placebo or HMG-CoA reductase inhibitor alone). However,
myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA
reductase inhibitors and other lipid-lowering drugs. In clinical
trials, the incidence of CPK greater than10 X ULN was 0.2% for ZETIA
vs 0.1% for placebo, and 0.1% for ZETIA co-administered with an
HMG-CoA reductase inhibitor vs 0.4% for HMG-CoA reductase inhibitors
alone.
    In post-marketing experience with ZETIA, cases of myopathy and
rhabdomyolysis have been reported regardless of causality. Most
patients who developed rhabdomyolysis were taking an HMG-CoA reductase
inhibitor prior to initiating ZETIA. However, rhabdomyolysis has been
reported very rarely with ZETIA monotherapy and very rarely with the
addition of ZETIA to agents known to be associated with increased risk
of rhabdomyolysis, such as fibrates. All patients starting therapy
with ezetimibe should be advised of the risk of myopathy and told to
report promptly any unexplained muscle pain, tenderness or weakness.
ZETIA and any HMG-CoA reductase inhibitor or fibrate that the patient
is taking concomitantly should be immediately discontinued if myopathy
is diagnosed or suspected. The presence of these symptoms and a
creatine phosphokinase (CPK) level greater than10 times the ULN
indicates myopathy.

    Hepatic Insufficiency

    Due to the unknown effects of the increased exposure to ezetimibe
in patients with moderate or severe hepatic insufficiency, ZETIA is
not recommended in these patients. (See CLINICAL PHARMACOLOGY, Special
Populations.)
    Drug Interactions (See also CLINICAL PHARMACOLOGY, Drug
Interactions)
    Cholestyramine: Concomitant cholestyramine administration
decreased the mean AUC of total ezetimibe approximately 55%. The
incremental LDL-C reduction due to adding ezetimibe to cholestyramine
may be reduced by this interaction.
    Fibrates: The co-administration of ezetimibe with fibrates other
than fenofibrate has not been studied.
    Fibrates may increase cholesterol excretion into the bile, leading
to cholelithiasis. In a preclinical study in dogs, ezetimibe increased
cholesterol in the gallbladder bile (see ANIMAL PHARMACOLOGY).
Co-administration of ZETIA with fibrates other than fenofibrate is not
recommended until use in patients is studied.
    Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate
administration increased total ezetimibe concentrations approximately
1.5-fold. If cholelithiasis is suspected in a patient receiving ZETIA
and fenofibrate, gallbladder studies are indicated and alternative
lipid-lowering therapy should be considered (see ADVERSE REACTIONS and
the product labeling for fenofibrate).
    Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil
administration increased total ezetimibe concentrations approximately
1.7-fold. No clinical data are available.
    HMG-CoA Reductase Inhibitors: No clinically significant
pharmacokinetic interactions were seen when ezetimibe was
co-administered with atorvastatin, simvastatin, pravastatin,
lovastatin, fluvastatin, or rosuvastatin.
    Cyclosporine: Caution should be exercised when using ZETIA and
cyclosporine concomitantly due to increased exposure to both ezetimibe
and cyclosporine. Cyclosporine concentrations should be monitored in
patients receiving ZETIA and cyclosporine.
    The degree of increase in ezetimibe exposure may be greater in
patients with severe renal insufficiency. In patients treated with
cyclosporine, the potential effects of the increased exposure to
ezetimibe from concomitant use should be carefully weighed against the
benefits of alterations in lipid levels provided by ezetimibe. In a
pharmacokinetic study in post-renal transplant patients with mildly
impaired or normal renal function (creatinine clearance of greater
than 50 mL/min), concomitant cyclosporine administration increased the
mean AUC and Cmax of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold)
and 3.9-fold (range 3.0- to 4.4-fold), respectively. In a separate
study, the total ezetimibe exposure increased 12-fold in one renal
transplant patient with severe renal insufficiency receiving multiple
medications, including cyclosporine (see CLINICAL PHARMACOLOGY, Drug
Interactions).
    Warfarin: If ezetimibe is added to warfarin, the International
Normalized Ratio should be appropriately monitored.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    A 104-week dietary carcinogenicity study with ezetimibe was
conducted in rats at doses up to 1500 mg/kg/day (males) and 500
mg/kg/day (females) (tilde20 times the human exposure at 10 mg daily
based on AUC0-24hr for total ezetimibe). A 104-week dietary
carcinogenicity study with ezetimibe was also conducted in mice at
doses up to 500 mg/kg/day (greater than150 times the human exposure at
10 mg daily based on AUC0-24hr for total ezetimibe). There were no
statistically significant increases in tumor incidences in
drug-treated rats or mice.
    No evidence of mutagenicity was observed in vitro in a microbial
mutagenicity (Ames) test with Salmonella typhimurium and Escherichia
coli with or without metabolic activation. No evidence of
clastogenicity was observed in vitro in a chromosomal aberration assay
in human peripheral blood lymphocytes with or without metabolic
activation. In addition, there was no evidence of genotoxicity in the
in vivo mouse micronucleus test.
    In oral (gavage) fertility studies of ezetimibe conducted in rats,
there was no evidence of reproductive toxicity at doses up to 1000
mg/kg/day in male or female rats (tilde7 times the human exposure at
10 mg daily based on AUC0-24hr for total ezetimibe).

    Pregnancy

    Pregnancy Category: C

    There are no adequate and well-controlled studies of ezetimibe in
pregnant women. Ezetimibe should be used during pregnancy only if the
potential benefit justifies the risk to the fetus.
    In oral (gavage) embryo-fetal development studies of ezetimibe
conducted in rats and rabbits during organogenesis, there was no
evidence of embryolethal effects at the doses tested (250, 500, 1000
mg/kg/day). In rats, increased incidences of common fetal skeletal
findings (extra pair of thoracic ribs, unossified cervical vertebral
centra, shortened ribs) were observed at 1000 mg/kg/day (tilde10 times
the human exposure at 10 mg daily based on AUC0-24hr for total
ezetimibe). In rabbits treated with ezetimibe, an increased incidence
of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the
human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).
Ezetimibe crossed the placenta when pregnant rats and rabbits were
given multiple oral doses.
    Multiple-dose studies of ezetimibe given in combination with
HMG-CoA reductase inhibitors (statins) in rats and rabbits during
organogenesis result in higher ezetimibe and statin exposures.
Reproductive findings occur at lower doses in combination therapy
compared to monotherapy.
    All HMG-CoA reductase inhibitors are contraindicated in pregnant
and nursing women. When ZETIA is administered with an HMG-CoA
reductase inhibitor in a woman of childbearing potential, refer to the
pregnancy category and product labeling for the HMG-CoA reductase
inhibitor. (See CONTRAINDICATIONS.)

    Labor and Delivery

    The effects of ZETIA on labor and delivery in pregnant women are
unknown.

    Nursing Mothers

    In rat studies, exposure to total ezetimibe in nursing pups was up
to half of that observed in maternal plasma. It is not known whether
ezetimibe is excreted into human breast milk; therefore, ZETIA should
not be used in nursing mothers unless the potential benefit justifies
the potential risk to the infant.

    Pediatric Use

    The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have
been shown to be similar to that in adults. Treatment experience with
ZETIA in the pediatric population is limited to 4 patients (9 to 17
years) in the sitosterolemia study and 5 patients (11 to 17 years) in
the HoFH study. Treatment with ZETIA in children (less than10 years)
is not recommended. (See CLINICAL PHARMACOLOGY, Special Populations.)

    Geriatric Use

    Of the patients who received ZETIA in clinical studies, 948 were
65 and older (this included 206 who were 75 and older). The
effectiveness and safety of ZETIA were similar between these patients
and younger subjects. Greater sensitivity of some older individuals
cannot be ruled out. (See CLINICAL PHARMACOLOGY, Special Populations,
and ADVERSE REACTIONS.)

    ADVERSE REACTIONS

    ZETIA has been evaluated for safety in more than 4700 patients in
clinical trials. Clinical studies of ZETIA (administered alone or with
an HMG-CoA reductase inhibitor) demonstrated that ZETIA was generally
well tolerated. The overall incidence of adverse events reported with
ZETIA was similar to that reported with placebo, and the
discontinuation rate due to adverse events was also similar for ZETIA
and placebo.

    Monotherapy

    Adverse experiences reported in (greater than=)2% of patients
treated with ZETIA and at an incidence greater than placebo in
placebo-controlled studies of ZETIA, regardless of causality
assessment, are shown in Table 9.

                               Table 9*
 Clinical Adverse Events Occurring in (greater than=)2% of Patients
                 Treated with ZETIA and at an Incidence
                         Greater than Placebo,
                        Regardless of Causality


Body System/Organ Class           Placebo      ZETIA 10 mg
 Adverse Event                      (%)            (%)
                                  n = 795        n = 1691
----------------------------------------------------------
Body as a whole - general
 disorders
   Fatigue                            1.8             2.2
Gastro-intestinal system
 disorders
   Abdominal pain                     2.8             3.0
   Diarrhea                           3.0             3.7
Infection and infestations
   Infection viral                    1.8             2.2
   Pharyngitis                        2.1             2.3
   Sinusitis                          2.8             3.6
Musculo-skeletal system
 disorders
   Arthralgia                         3.4             3.8
   Back pain                          3.9             4.1
Respiratory system disorders
   Coughing                           2.1             2.3
----------------------------------------------------------

    *Includes patients who received placebo or ZETIA alone reported in
Table 10.

    The frequency of less common adverse events was comparable between
ZETIA and placebo.

    Combination with an HMG-CoA Reductase Inhibitor

    ZETIA has been evaluated for safety in combination studies in more
than 2000 patients.
    In general, adverse experiences were similar between ZETIA
administered with HMG-CoA reductase inhibitors and HMG-CoA reductase
inhibitors alone. However, the frequency of increased transaminases
was slightly higher in patients receiving ZETIA administered with
HMG-CoA reductase inhibitors than in patients treated with HMG-CoA
reductase inhibitors alone. (See PRECAUTIONS, Liver Enzymes.)
    Clinical adverse experiences reported in (greater than=)2% of
patients and at an incidence greater than placebo in four
placebo-controlled trials where ZETIA was administered alone or
initiated concurrently with various HMG-CoA reductase inhibitors,
regardless of causality assessment, are shown in Table 10.


                               Table 10*
   Clinical Adverse Events occurring in (greater than=)2% of Patients
    and at an Incidence Greater than Placebo, Regardless of Causality,
                  in ZETIA/Statin Combination Studies
----------------------------------------------------------------------

Body System/Organ Class                                        ZETIA +
                                            ZETIA    All        All
                                 Placebo    10mg   Statins** Statins**
Adverse Event                       (%)     (%)      (%)        (%)
                                  n=259     n=262   n=936      n=925
----------------------------------------------------------------------
Body as a whole - general disorders
   Chest pain                      1.2       3.4     2.0       1.8
   Dizziness                       1.2       2.7     1.4       1.8
   Fatigue                         1.9       1.9     1.4       2.8
   Headache                        5.4       8.0     7.3       6.3
Gastro-intestinal system disorders
   Abdominal pain                  2.3       2.7     3.1       3.5
   Diarrhea                        1.5       3.4     2.9       2.8
Infection and infestations
   Pharyngitis                     1.9       3.1     2.5       2.3
   Sinusitis                       1.9       4.6     3.6       3.5
   Upper respiratory tract
    infection                     10.8      13.0    13.6      11.8
Musculo-skeletal system disorders
   Arthralgia                      2.3       3.8     4.3       3.4
   Back pain                       3.5       3.4     3.7       4.3
   Myalgia                         4.6       5.0     4.1       4.5
----------------------------------------------------------------------

    *Includes four placebo-controlled combination studies in which
ZETIA was initiated concurrently with an HMG-CoA reductase inhibitor.

    **All Statins = all doses of all HMG-CoA reductase inhibitors.

    Combination with Fenofibrate

    In a clinical study involving 625 patients treated for up to 12
weeks and 576 patients treated for up to an additional 48 weeks,
co-administration of ZETIA and fenofibrate was well tolerated. This
study was not designed to compare treatment groups for infrequent
events. Incidence rates (95% CI) for clinically important elevations
(greater than 3 X ULN, consecutive) in serum transaminases were 4.5%
(1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ZETIA
co-administered with fenofibrate, respectively, adjusted for treatment
exposure. Corresponding incidence rates for cholecystectomy were 0.6%
(0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and ZETIA
co-administered with fenofibrate, respectively (see PRECAUTIONS, Drug
Interactions). The numbers of patients exposed to co-administration
therapy as well as fenofibrate and ezetimibe monotherapy were
inadequate to assess gallbladder disease risk. There were no CPK
elevations greater than 10 X ULN in any of the treatment groups.

    Post-marketing Experience

    The following adverse reactions have been reported in
post-marketing experience, regardless of causality assessment:
    Hypersensitivity reactions, including anaphylaxis, angioedema,
rash, and urticaria; arthralgia; myalgia; elevated creatine
phosphokinase; myopathy/rhabdomyolysis (very rarely; see PRECAUTIONS,
Skeletal Muscle); elevations in liver transaminases; hepatitis;
thrombocytopenia; pancreatitis; nausea; cholelithiasis; cholecystitis.

    OVERDOSAGE

    In clinical studies, administration of ezetimibe, 50 mg/day to 15
healthy subjects for up to 14 days, or 40 mg/day to 18 patients with
primary hypercholesterolemia for up to 56 days, was generally well
tolerated.
    A few cases of overdosage with ZETIA have been reported; most have
not been associated with adverse experiences. Reported adverse
experiences have not been serious. In the event of an overdose,
symptomatic and supportive measures should be employed.

    DOSAGE AND ADMINISTRATION

    The patient should be placed on a standard cholesterol-lowering
diet before receiving ZETIA and should continue on this diet during
treatment with ZETIA.
    The recommended dose of ZETIA is 10 mg once daily. ZETIA can be
administered with or without food.
    ZETIA may be administered with an HMG-CoA reductase inhibitor (in
patients with primary hypercholesterolemia) or with fenofibrate (in
patients with mixed hyperlipidemia) for incremental effect. For
convenience, the daily dose of ZETIA may be taken at the same time as
the HMG-CoA reductase inhibitor or fenofibrate, according to the
dosing recommendations for the respective medications.

    Patients with Hepatic Insufficiency

    No dosage adjustment is necessary in patients with mild hepatic
insufficiency (see PRECAUTIONS, Hepatic Insufficiency).

    Patients with Renal Insufficiency

    No dosage adjustment is necessary in patients with renal
insufficiency (see CLINICAL PHARMACOLOGY, Special Populations).

    Geriatric Patients

    No dosage adjustment is necessary in geriatric patients (see
CLINICAL PHARMACOLOGY, Special Populations).

    Co-administration with Bile Acid Sequestrants

    Dosing of ZETIA should occur either (greater than=)2 hours before
or (greater than=)4 hours after administration of a bile acid
sequestrant (see PRECAUTIONS, Drug Interactions).

    HOW SUPPLIED

    No. 3861 - Tablets ZETIA, 10 mg, are white to off-white,
capsule-shaped tablets debossed with "414" on one side. They are
supplied as follows:

    NDC 66582-414-31 bottles of 30

    NDC 66582-414-54 bottles of 90

    NDC 66582-414-74 bottles of 500

    NDC 66582-414-28 unit dose packages of 100.

    Storage

    Store at 25(degree)C (77(degree)F); excursions permitted to
15-30(degree)C (59-86(degree)F). (See USP Controlled Room
Temperature.) Protect from moisture.

    Issued May 2006
    Printed in USA.

    Manufactured for:
    Merck/Schering-Plough Pharmaceuticals
    North Wales, PA 19454, USA
    By:
    Schering Corporation
    Kenilworth, NJ 07033, USA
    or
    Merck & Co., Inc.
    Whitehouse Station, NJ 08889, USA

    COPYRIGHT (C) 2001, 2002, 2005 Merck/Schering-Plough
Pharmaceuticals.

    All rights reserved.
                                                         29480800T
                                                            REV 08


                     ZETIA(R) (ezetimibe) Tablets

               Patient Information about ZETIA (zt'-c-a)
                  Generic name: ezetimibe (-zt'--mib)

    Read this information carefully before you start taking ZETIA and
each time you get more ZETIA. There may be new information. This
information does not take the place of talking with your doctor about
your medical condition or your treatment. If you have any questions
about ZETIA, ask your doctor. Only your doctor can determine if ZETIA
is right for you.

    What is ZETIA?

    ZETIA is a medicine used to lower levels of total cholesterol and
LDL (bad) cholesterol in the blood. It is used for patients who cannot
control their cholesterol levels by diet alone. It can be used by
itself or with other medicines to treat high cholesterol. You should
stay on a cholesterol-lowering diet while taking this medicine.
    ZETIA works to reduce the amount of cholesterol your body absorbs.
ZETIA does not help you lose weight.
    For more information about cholesterol, see the "What should I
know about high cholesterol?" section that follows.

    Who should not take ZETIA?

    --  Do not take ZETIA if you are allergic to ezetimibe, the active
        ingredient in ZETIA, or to the inactive ingredients. For a
        list of inactive ingredients, see the "Inactive ingredients"
        section that follows.

    --  If you have active liver disease, do not take ZETIA while
        taking cholesterol-lowering medicines called statins.

    --  If you are pregnant or breast-feeding, do not take ZETIA while
        taking a statin.

    What should I tell my doctor before and while taking ZETIA?

    Tell your doctor about any prescription and non-prescription
medicines you are taking or plan to take, including natural or herbal
remedies.
    Tell your doctor about all your medical conditions including
allergies.

    Tell your doctor if you:

    --  ever had liver problems. ZETIA may not be right for you.

    --  are pregnant or plan to become pregnant. Your doctor will
        decide if ZETIA is right for you.

    --  are breast-feeding. We do not know if ZETIA can pass to your
        baby through your milk. Your doctor will decide if ZETIA is
        right for you.

    --  experience unexplained muscle pain, tenderness, or weakness.

    How should I take ZETIA?

    --  Take ZETIA once a day, with or without food. It may be easier
        to remember to take your dose if you do it at the same time
        every day, such as with breakfast, dinner, or at bedtime. If
        you also take another medicine to reduce your cholesterol, ask
        your doctor if you can take them at the same time.

    --  If you forget to take ZETIA, take it as soon as you remember.
        However, do not take more than one dose of ZETIA a day.

    --  Continue to follow a cholesterol-lowering diet while taking
        ZETIA. Ask your doctor if you need diet information.

    --  Keep taking ZETIA unless your doctor tells you to stop. It is
        important that you keep taking ZETIA even if you do not feel
        sick.

    See your doctor regularly to check your cholesterol level and to
check for side effects. Your doctor may do blood tests to check your
liver before you start taking ZETIA with a statin and during
treatment.

    What are the possible side effects of ZETIA?

    In clinical studies patients reported few side effects while
taking ZETIA. These included stomach pain and feeling tired.
    Very rarely, patients have experienced severe muscle problems
while taking ZETIA, usually when ZETIA was added to a statin drug. If
you experience unexplained muscle pain, tenderness, or weakness while
taking ZETIA, contact your doctor immediately. You need to do this
promptly, because on rare occasions, these muscle problems can be
serious, with muscle breakdown resulting in kidney damage.
    Additionally, the following side effects have been reported in
general use: allergic reactions (which may require treatment right
away) including swelling of the face, lips, tongue, and/or throat that
may cause difficulty in breathing or swallowing, rash, and hives;
joint pain; muscle aches; alterations in some laboratory blood tests;
liver problems; inflammation of the pancreas; nausea; gallstones;
inflammation of the gallbladder.
    Tell your doctor if you are having these or any other medical
problems while on ZETIA. For a complete list of side effects, ask your
doctor or pharmacist.

    What should I know about high cholesterol?

    Cholesterol is a type of fat found in your blood. Your total
cholesterol is made up of LDL and HDL cholesterol.
    LDL cholesterol is called "bad" cholesterol because it can build
up in the wall of your arteries and form plaque. Over time, plaque
build-up can cause a narrowing of the arteries. This narrowing can
slow or block blood flow to your heart, brain, and other organs. High
LDL cholesterol is a major cause of heart disease and stroke.
    HDL cholesterol is called "good" cholesterol because it keeps the
bad cholesterol from building up in the arteries.

    Triglycerides also are fats found in your blood.

    General Information about ZETIA

    Medicines are sometimes prescribed for conditions that are not
mentioned in patient information leaflets. Do not use ZETIA for a
condition for which it was not prescribed. Do not give ZETIA to other
people, even if they have the same condition you have. It may harm
them.
    This summarizes the most important information about ZETIA. If you
would like more information, talk with your doctor. You can ask your
pharmacist or doctor for information about ZETIA that is written for
health professionals.

    Inactive ingredients:

    Croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, povidone, and sodium lauryl sulfate.

    Issued July 2005

    Printed in USA.

    Manufactured for:
    Merck/Schering-Plough Pharmaceuticals
    North Wales, PA 19454, USA
    By:
    Schering Corporation
    Kenilworth, NJ 07033, USA
    or
    Merck & Co., Inc.
    Whitehouse Station, NJ 08889, USA


    COPYRIGHT (C) Merck/Schering-Plough Pharmaceuticals, 2001, 2002.
    All rights reserved.
    Printed in USA.