Merck and Schering-Plough Announce First Global Marketing Approval of Ezetimibe/Simvastatin Tablet in...

Merck and Schering-Plough Announce First Global Marketing Approval of Ezetimibe/Simvastatin Tablet in Mexico for Treatment of Elevated Cholesterol Levels



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Whitehouse Station, N.J.
& Kenilworth, N.J.–(HISPANIC PR WIRE – BUSINESS WIRE)–March 19, 2004–Merck
& Co., Inc. (NYSE:MRK) and Schering-Plough Corporation (NYSE:SGP) today
announced that ezetimibe/simvastatin tablets have received marketing approval
in Mexico for the treatment of elevated cholesterol levels (hypercholesterolemia).
The approval in Mexico represents the first approval of a product that achieves
dual inhibition of two sources of cholesterol by inhibiting both cholesterol
production in the liver and cholesterol absorption in the intestine.

Ezetimibe/simvastatin contains
the active ingredients of the cholesterol-lowering drugs ezetimibe, which inhibits
cholesterol absorption in the intestine, and simvastatin, which reduces cholesterol
production in the liver. ZETIA(TM) is the U.S. trade name for ezetimibe, which
is marketed and sold in the United States by Merck/Schering-Plough Pharmaceuticals,
a joint venture between Merck and Schering-Plough. Simvastatin is marketed by
Merck under the trade name ZOCOR(R).

“By targeting the two
sources of cholesterol, ezetimibe and simvastatin have been proven to significantly
reduce LDL cholesterol and the availability of a single tablet in Mexico provides
physicians with an important therapeutic advance that could be another option
for the treatment of patients with high cholesterol,” said Raymond V. Gilmartin,
chairman, president and chief executive officer, Merck.

“The first global approval
of an ezetimibe/simvastatin single tablet represents a significant achievement
as we work to maximize the opportunity to become a formidable competitor in
the cholesterol management market – the largest market in the world,” said
Fred Hassan, chairman and chief executive officer, Schering-Plough.

In the United States, a
New Drug Application for VYTORIN(TM) (ezetimibe/simvastatin) was submitted on
September 24, 2003. The filing was accepted by the U.S. Food and Drug Administration
on November 23, 2003 and is currently under standard review.

In Mexico, ezetimibe/simvastatin
will be available in several dosing strengths combining ezetimibe with simvastatin
10/10mg, 10/20mg, 10/40mg or 10/80mg and will be launched in April 2004.

Important information about
ezetimibe/simvastatin

In clinical trials of ezetimibe
co-administered with simvastatin, there was no increased incidence of myopathy
or rhabdomyolysis associated with ezetimibe/simvastatin. However, myopathy and
rhabdomyolysis are known adverse reactions to statins and other lipid-lowering
drugs. All patients starting therapy with ezetimibe/simvastatin or whose dose
of ezetimibe/simvastatin is being increased should be advised of the risk of
myopathy and told to report promptly any unexplained muscle pain, tenderness
or weakness because they could be signs of serious side effects. It is recommended
that liver function tests be performed before treatment with ezetimibe/simvastatin
begins and thereafter as clinically indicated. Patients titrated to the 10/80
mg dose should receive an additional liver function 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. Due to the unknown effects of
the increased exposure to ezetimibe/simvastatin in patients with moderate or
severe hepatic insufficiency, ezetimibe/simvastatin is not recommended in these
patients. The safety and effectiveness of ezetimibe/simvastatin with fibrates
have not been established; therefore, co-administration with fibrates is not
recommended.

Ezetimibe/simvastatin should
not be used in pregnant or nursing women. In clinical trials, ezetimibe/simvastatin
was generally well tolerated. The most common side effects included headache,
dizziness, arthralgia, myalgia and asthenia.

Important information about
ezetimibe

When ezetimibe is used with
a statin, liver function tests should be performed at the start of therapy and
after that in accordance with the label for that statin. Due to the unknown
effects of the increased exposure to ezetimibe in patients with moderate or
severe hepatic insufficiency, ezetimibe is not recommended in these patients.
In clinical trials, there was no increased incidence of myopathy or rhabdomyolysis
associated with ezetimibe. However, myopathy and rhabdomyolysis are known adverse
reactions to statins and other lipid-lowering drugs. There are no adequate and
well-controlled studies of ezetimibe in pregnant women. Ezetimibe should not
be used in pregnant or nursing women unless the benefit outweighs the potential
risks. The safety and effectiveness of ezetimibe with fibrates have not been
established; therefore, co-administration with fibrates is not recommended.

Important information about
simvastatin

Simvastatin should not be
used by anyone allergic to any of its components, with liver disease, or by
women who are pregnant, breast-feeding or likely to become pregnant. Muscle
pain or weakness in people taking simvastatin should be reported to a doctor
because these could be signs of a serious side effect. Doctors may perform blood
tests before and periodically during treatment with simvastatin to check for
liver problems. People taking 80 mg of simvastatin should receive an additional
liver function test at three months. To help avoid serious side effects, discuss
with your doctor medicine or food you should avoid while taking simvastatin.
In clinical trials, adverse reactions usually have been mild and transient.
Most common side effects included headache (3.5 percent), abdominal pain (3.2
percent) and constipation (2.3 percent).

About Merck

Merck & Co., Inc. which
operates in many countries as Merck Sharp & Dohme, is a global research-driven
pharmaceutical products company. Merck discovers, develops, manufactures and
markets a broad range of innovative products to improve human and animal health,
directly and through its joint ventures.

About Schering-Plough

Schering-Plough Corporation
is a research-based company engaged in the discovery, development, manufacturing
and marketing of pharmaceutical products worldwide.

MERCK FORWARD-LOOKING STATEMENT:
This press release contains “forward-looking statements” as that term
is defined in the Private Securities Litigation Reform Act of 1995. These statements
involve risks and uncertainties, which may cause results to differ materially
from those set forth in the statements. The forward-looking statements include
statements regarding product development. 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 our Form 10-K for the year ended Dec.
31, 2003, and in its periodic reports on Form 10-Q and Form 8-K (if any) which
are incorporated by reference.

SCHERING-PLOUGH DISCLOSURE
NOTICE: The information in this press release includes certain “forward-looking”
information including the market potential for VYTORIN (ezetimibe/simvastatin)
and ZETIA (ezetimibe). Forward-looking statements relate to expectations or
forecasts of future events. Please carefully consider any forward-looking statement
and understand that many factors cause actual results to differ from Schering-Plough’s
forward-looking statements. The reader of this release should understand that
the extent that VYTORIN and ZETIA will be prescribed will be determined by market
forces and the market viability of any particular product is subject to substantial
risks and uncertainties. In addition, the forward-looking statements may also
be affected by general market and economic factors, product availability, current
and future branded, generic or over-the-counter competition, federal and state
regulations and legislation, the regulatory process for new products and indications,
manufacturing issues, trade buying patterns, patent positions and the outcome
of litigation and investigations. Schering-Plough does not assume the obligation
to update any forward-looking statement. For further details and a discussion
of other risks and uncertainties that may affect forward-looking statements,
see the company’s Securities and Exchange Commission filings, including the
company’s 10-K filed Feb. 26, 2004.

Schering-Plough is a research-based
company engaged in the discovery, development, manufacturing and marketing of
pharmaceutical products worldwide.

Full prescribing information
and patient product information for ZETIA(TM) is attached.

ZETIA(TM) and VYTORIN(TM)
are trademarks of MSP Marketing Services (C) LLC. All other brands are trademarks
of their respective owners and are not trademarks of MSP Marketing Services
(C) LLC.

25751710T

ZETIA(TM) (ezetimibe) Tablets

Patient Information about
ZETIA (zt’-e-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.

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, and rash.

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 March 2003

Manufactured for:

Merck/Schering-Plough Pharmaceuticals

North Wales, PA 19454, USA

By:

Schering Corporation

Kenilworth, NJ 07033, USA

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

All rights reserved.

Printed in USA.

VERSION 25751817

ZETIA(TM)

(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 C(24)H(21)F(2)NO(3). 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. The effects
of ezetimibe given either alone or in addition to an HMG-CoA reductase inhibitor
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 (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 than90%) 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 (14)C-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,equal to)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 than10 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 Blacks and Caucasians. There were too few patients in other racial or
ethnic groups to permit further pharmacokinetic comparisons.

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 3-4 fold and 5-6 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,equal
to30 mL/min/1.73 m(2)), 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.

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,equal to)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, or fluvastatin. 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),
or fluvastatin (20 mg once daily).

Fenofibrate: In a study
of thirty-two healthy hypercholesterolemic (LDL-C (greater than,equal to)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,equal to)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.

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 ED(50) value of 0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol
levels in monkeys. The ED(50) 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 (0.03-300 mg/kg/day), the concentration of cholesterol in gallbladder
bile increased 2- 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 (0.3-5 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 (14)C 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.

Experience in non-Caucasians
is limited and does not permit a precise estimate of the magnitude of the effects
of ZETIA.

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-C LDL-C  Apo B  TG(a) HDL-C

            
group

———————————————————–

           
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

———————————————————–

Pooled Data  Placebo 
431     0    +1     -2    
0      -2

(c) (Studies———————————————–

1 & 2)    
Ezetimibe 1288   -13   -18    -16   
-8      +1

———————————————————–

*T

(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

(Mean(a) % Change from Untreated
Baseline(b))

     Treatment     
N    Total  LDL-C  Apo B  TG(a) HDL-C

    (Daily
Dose)          -C 

———————————————————

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)       

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