FDA Approves New Indication for ZETIA(R) (ezetimibe) - Merck/Schering-Plough's Cholesterol Lowering Drug - For Administration in Combination with Fenofibrate, along With Diet

Merck/Schering-Plough Pharmaceuticals announced today that theU.S. Food and Drug Administration (FDA) has approved ZETIA(R)(ezetimibe) for use, along with diet, in combination with fenofibratefor the reduction of elevated total cholesterol and LDL "bad"cholesterol in patients with mixed hyperlipidemia, when diet alone isnot enough. ZETIA is the first in a class of cholesterol-loweringagents that inhibits the intestinal absorption of cholesterol througha unique mechanism of action.

With this new indication, ZETIA offers patients with mixedhyperlipidemia another treatment option when it is prescribed incombination with fenofibrate. Fenofibrate is commonly used along withdiet to treat hyperlipidemia and has proven efficacy in loweringtriglyceride levels and increasing HDL "good" cholesterol. The use ofZETIA with fibrates other than fenofibrate is not recommended untiluse in patients is studied.

Mixed hyperlipidemia is a metabolic disorder characterized byelevated LDL cholesterol, elevated triglycerides (a form of fat in thebloodstream), and reduced levels of HDL cholesterol.

"This is an exciting new development in the treatment of mixedhyperlipidemia. ZETIA and fenofibrate taken together offercomplementary lowering of LDL and total cholesterol in patients withmixed hyperlipidemia," said Harold E. Bays, M.D., medical director,president of L-MARC Research Center, Louisville, KY.

Approval was based on the results from a clinical trial whichshowed that combination therapy of 10 mg of ZETIA co-administered with160 mg of fenofibrate significantly reduced LDL cholesterol levelswhen compared to either treatment alone (p Less than 0.001). Patientsin a 12-week study who were co-administrated ZETIA 10 mg andfenofibrate 160 mg (n=183) showed a 20 percent reduction in LDLcholesterol levels compared to a 6 percent reduction in LDLcholesterol levels with 160 mg fenofibrate as monotherapy (n=188) anda 13 percent reduction in LDL cholesterol levels with 10 mg ZETIA asmonotherapy (n=185).

The study consisted of patients with mixed hyperlipidemia; 625patients were treated for up to 12 weeks with 576 of these patientscontinuing treatment for up to an additional 48 weeks. The changes inlipid endpoints after an additional 48 weeks of treatment with ZETIAco-administered with fenofibrate or with fenofibrate alone wereconsistent with the 12-week data.

In this study, ZETIA co-administered with fenofibrate appeared tobe well tolerated. For patients taking ZETIA and fenofibrate in whomgallstones (cholelithiasis) are suspected, physicians should performgallbladder studies and consider alternative lipid-lowering therapy.While this study was not designed to compare how often infrequentevents occurred, the rates for gallbladder removal (cholecystectomy)were 0.6 percent for fenofibrate alone and 1.7 percent for ZETIA andfenofibrate together.

ZETIA, along with diet, is indicated for use either by itself ortogether with statins or fenofibrate in patients with high cholesterolto reduce LDL cholesterol and total cholesterol when the response todiet and exercise has been inadequate. ZETIA, which works in thedigestive tract, is complementary to the class of cholesterol-loweringagents known as statins, which work in the liver to reduce theproduction of cholesterol. ZETIA, alone or in combination withstatins, has been proven to significantly improve LDL cholesterollevels. ZETIA, either alone or in addition to a statin or fenofibrate,has not been shown to prevent heart disease or heart attacks.

Important information about ZETIA

ZETIA is a prescription medication and should not be taken bypeople who are allergic to any of its ingredients. When ZETIA isprescribed with a statin, it should not be taken by women who arenursing or pregnant or who may become pregnant, or by anyone withactive liver disease. Statins should not be taken by anyone with theseconditions. If you have ever had liver problems or are pregnant ornursing, your doctor will decide if ZETIA is right for you. Yourdoctor may do blood tests to check your liver before you start takingZETIA with a statin and during treatment.

Due to the unknown effects of increased exposure to ZETIA inpatients with moderate or severe hepatic insufficiency, ZETIA is notrecommended in these patients. In clinical trials, there was noincreased incidence of myopathy (muscle pain) or rhabdomyolysis(muscle breakdown) associated with ZETIA; however myopathy andrhabdomyolysis are known adverse reactions to statins and otherlipid-lowering drugs. There are no adequate and well-controlledstudies of ZETIA in pregnant women. ZETIA should not be used inpregnant or nursing women unless the benefit outweighs the potentialrisks.

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

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

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture betweenMerck & Co., Inc. and Schering-Plough Corporation formed to developand market in the United States new prescription medicines incholesterol management. The collaboration includes worldwide markets(excluding Japan). ZETIA is marketed as EZETROL in more than 50nations outside the U.S.

Merck forward-looking statement

This press release contains "forward-looking statements" as thatterm is defined in the Private Securities Litigation Reform Act of1995. These statements are based on management's current expectationsand involve risks and uncertainties, which may cause results to differmaterially from those set forth in the statements. The forward-lookingstatements may include statements regarding product development,product potential or financial performance. No forward-lookingstatement can be guaranteed, and actual results may differ materiallyfrom those projected. Merck undertakes no obligation to publiclyupdate any forward-looking statement, whether as a result of newinformation, future events, or otherwise. Forward-looking statementsin this press release should be evaluated together with the manyuncertainties that affect Merck's business, particularly thosementioned in the cautionary statements in Item 1 of Merck's Form 10-Kfor the year ended Dec. 31, 2005, and in its periodic reports on Form10-Q and Form 8-K, which the Company incorporates by reference.

Schering-Plough disclosure notice

The information in this press release includes certain"forward-looking statements" within the meaning of the SecuritiesLitigation Reform Act of 1995, including statements relating to ZETIAand EZETROL and the potential market for these medications.Forward-looking statements relate to expectations or forecasts offuture events. Schering-Plough does not assume the obligation toupdate any forward-looking statement. Many factors could cause actualresults to differ materially from Schering-Plough's forward-lookingstatements, including market forces, economic factors, productavailability, patent and other intellectual property protection,current and future branded, generic or over-the-counter competition,the regulatory process, and any developments following regulatoryapproval, among other uncertainties. For further details about theseand other factors that may impact the forward-looking statements, seeSchering-Plough's Securities and Exchange Commission filings,including Item 1A. Risk Factors in the Company's 2005 10-K.

Full prescribing information and patient product information forZETIA(R) is attached.

ZETIA(R) is a registered trademark of MSP Singapore Company, LLC.

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 (>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 ((>=)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 <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 (<20%) 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 <=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 (>=)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 (>=)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 (>=)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
>50 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 ~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 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 (>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)
----------------------------------------------------------------------
(>=)130
CHD or CHD risk equivalents(b) <100 (>=)100 (100-129:
(10-year risk >20%)(c) drug
optional)(d)
----------------------------------------------------------------------
10-year risk
10-20%:
2+ Risk factors(e) <130 (>=)130 (>=)130(c)
(10-year risk (<=)20%)(c) 10-year risk
<10%:
(>=)160(c)
----------------------------------------------------------------------
(>=)190
(160-189:
0-1 Risk factor(f) <160 (>=)160 LDL-lowering
drug
optional)
----------------------------------------------------------------------

(a) Therapeutic lifestyle changes include: 1) dietary changes:
reduced intake of saturated fats (<7% of total calories) and
cholesterol (<200 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 >20%, 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 <100 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 (>=)140/90 mm Hg
or on anti-hypertensive medication), low HDL cholesterol (<40 mg/dL),
family history of premature CHD (CHD in male first-degree relative <55
years; CHD in female first-degree relative <65 years), age (men (>=)45
years; women (>=)55 years). HDL cholesterol (>=)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
<10%; 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
>400 mg/dL (>4.5 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 ((>=)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 ((>=)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 >10 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 >10 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 >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) (~20 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 (>150 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 (~7 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 (~10 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 (<10 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 (>=)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 (>=)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 (>=)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 (>=)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
(> 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 > 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 (>=)2 hours before or (>=)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.