New Study Showed VYTORIN(R) (ezetimibe/simvastatin) Significantly More Effective than Crestor(R) (rosuvastatin) at Lowering LDL ''Bad'' Cholesterol At All Doses Compared

Results from a new clinical study which included 2,855 patientswith high cholesterol showed that VYTORIN(R) (ezetimibe/simvastatin)was significantly more effective than Crestor(R) (rosuvastatin) inreducing LDL "bad" cholesterol across all study dose comparisons,52-61 percent for VYTORIN 10/20 mg to 10/80 mg and 46-57 percent forCrestor 10 mg to 40 mg. In addition, both VYTORIN and Crestor raisedHDL "good" cholesterol by 8 percent, averaged across all dosesstudied. The primary endpoint of the study was LDL cholesterolreduction from baseline averaged across all doses. Key secondaryendpoints included LDL cholesterol reductions from baseline at eachdose comparison. With the results of this study, VYTORIN now has beenshown in clinical studies to provide greater LDL cholesterol loweringefficacy versus Zocor (simvastatin), Lipitor (atorvastatin) andCrestor (rosuvastatin) at all study dose comparisons.

In a post-hoc subgroup analysis of 715 high risk patients includedin the study, the results revealed that VYTORIN, as a result ofgreater LDL cholesterol reduction, helped significantly more high-riskpatients achieve an LDL cholesterol of less than 70 mg/dL and lessthan 100 mg/dL compared to patients taking Crestor (50 percent vs. 29percent; p <0.001 and 90 percent vs. 82 percent, p<0.05 respectively)averaged across the doses studied.

"In this study, VYTORIN was significantly more effective thanCrestor in reducing LDL cholesterol and averaged across the doses inattaining an LDL cholesterol goal of less than 100 mg/dL and LDLcholesterol of less than 70 mg/dL in high-risk patients," said MichaelDavidson, M.D., professor of medicine, director of PreventiveCardiology, Rush University Medical Center, Chicago. "These dataprovide further evidence that VYTORIN is an excellent option to helplower the LDL, or bad, cholesterol levels of patients with highcholesterol."

The results were presented today at the International Symposium onAtherosclerosis (ISA 2006) meeting in Rome.

VYTORIN, which contains ezetimibe and simvastatin, is the firstand only product approved to treat the two sources of cholesterol byinhibiting the production of cholesterol in the liver and blocking theabsorption of cholesterol in the intestine, including cholesterol fromfood. VYTORIN is marketed as INEGY outside the U.S.

"Recent data shows that many patients do not reach recommended LDLcholesterol treatment goals," added Dr. Davidson, who was theprincipal investigator of the study. "Now with the new recommendationsfrom the American Heart Association and the American College ofCardiology calling for more aggressive treatment of high cholesterolin certain high risk patients, physicians should consider providingmore patients with greater LDL cholesterol lowering right from thestart to help more patients reach recommended LDL cholesteroltreatment goals."

About the study

This double-blind, six-week, parallel-group study included 2,855patients. Patients were randomized equally to one of six treatmentgroups.

VYTORIN provided significantly greater LDL cholesterol reduction,compared to Crestor, when averaged across all dose comparisons (56percent vs. 52 percent; p<0.001), and at all individual dosecomparisons. The LDL cholesterol reductions for VYTORIN compared toCrestor were 52 percent, VYTORIN 10/20 mg vs. 46 percent, Crestor 10mg, 55 percent, VYTORIN 10/40 mg vs. 52 percent, Crestor 20 mg and 61percent, VYTORIN 10/80 mg vs. 57 percent for Crestor 40 mg. Inaddition, VYTORIN provided greater reductions compared to Crestor intotal cholesterol, apolipoprotein B, and non-HDL cholesterol whenaveraged across all doses studied and at each dose comparison. VYTORINalso lowered triglycerides by similar levels compared to Crestor whenaveraged across all doses studied. Effects on HDL cholesterol weresimilar between VYTORIN and Crestor, each raising HDL cholesterol by 8percent averaged across the doses studied. High triglycerides and lowHDL cholesterol are both risk factors for cardiovascular disease(CVD). The relationship between treatment-induced changes intriglycerides, HDL, and apolipoprotein B and reduction of CVD risk hasnot been established. Also, the clinical significance of the abovecomparisons has not been established.

Both medicines were generally well tolerated in this study.

As previously noted, the primary endpoint of the overall study wasLDL cholesterol reduction from baseline averaged across all doses. Keysecondary endpoints included changes from baseline in LDL cholesterolat each dose comparison and changes in total cholesterol,apolipoprotein B, non-HDL cholesterol, triglycerides and HDLcholesterol.

Important information about VYTORIN

VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicatedas adjunctive therapy to diet for the reduction of elevated totalcholesterol, LDL cholesterol, Apo B(1), triglycerides and non-HDLcholesterol and to increase HDL cholesterol in patients with primary(heterozygous familial and non-familial) hypercholesterolemia or mixedhyperlipidemia.

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

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

Selected cautionary information for VYTORIN

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

In three placebo-controlled, 12-week trials, the incidence ofconsecutive elevations (greater than or equal to 3 X ULN) in serumtransaminases were 1.7 percent overall for patients treated withVYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. Incontrolled long-term (48-week) extensions, which included bothnewly-treated and previously-treated patients, the incidence ofconsecutive elevations (greater than or equal to 3 X ULN) in serumtransaminases was 1.8 percent overall and 3.6 percent for patientstreated with VYTORIN 10/80 mg. These elevations in transaminases weregenerally asymptomatic, not associated with cholestasis and returnedto baseline after discontinuation of therapy or with continuedtreatment. Doctors should perform blood tests before, and periodicallyduring treatment with VYTORIN when clinically indicated to check forliver problems. People taking VYTORIN 10/80 mg should receive anadditional liver function test prior to and three months aftertitration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (aningredient in VYTORIN) in patients with moderate or severe hepaticinsufficiency, VYTORIN is not recommended in these patients. Thesafety and effectiveness of VYTORIN with fibrates have not beenestablished; therefore, co-administration with fibrates is notrecommended. Caution should be exercised when initiating VYTORIN inpatients treated with cyclosporine and in patients with severe renalinsufficiency.

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

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). VYTORIN is marketed as INEGY 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 toVYTORIN and the potential market for VYTORIN. Forward-lookingstatements relate to expectations or forecasts of future events.Schering-Plough does not assume the obligation to update anyforward-looking statement. Many factors could cause actual results todiffer materially from Schering-Plough's forward-looking statements,including market forces, economic factors, product availability,patent and other intellectual property protection, current and futurebranded, generic or over-the-counter competition, the regulatoryprocess, and any developments following regulatory approval, amongother uncertainties. For further details about these and other factorsthat may impact the forward-looking statements, see Schering-Plough'sSecurities and Exchange Commission filings, including Item 1A. RiskFactors in the Company's 2005 10-K.

Prescribing information and patient product information forVYTORIN(R) is attached.

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

VYTORIN (R) is a trademark of MSP Marketing Services (C) LLC. Allother brands are trademarks of their respective owners and are nottrademarks of MSP Marketing Services (C) LLC.

9619607

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

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

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

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

DESCRIPTION

VYTORIN contains ezetimibe, a selective inhibitor of intestinal
cholesterol and related phytosterol absorption, and simvastatin, a
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
The chemical name of ezetimibe is
1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)-3(S)-hydroxypropyl)-4(S)-(
4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3
and its molecular weight is 409.4.
Ezetimibe is a white, crystalline powder that is freely to very
soluble in ethanol, methanol, and acetone and practically insoluble in
water. Its structural formula is:

(OBJECT OMITTED)

Simvastatin, an inactive lactone, is hydrolyzed to the
corresponding (beta)-hydroxyacid form, which is an inhibitor of
HMG-CoA reductase. Simvastatin is butanoic acid,
2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-
hydroxy-6-oxo-2H-pyran-2-yl)-ethyl)-1-naphthalenylester, (1S-(1(alpha)
,3(alpha),7(beta),8(beta)(2S*,4S*),-8a(beta))). The empirical formula
of simvastatin is C25H38O5 and its molecular weight is 418.57.
Simvastatin is a white to off-white, nonhygroscopic, crystalline
powder that is practically insoluble in water, and freely soluble in
chloroform, methanol and ethanol. Its structural formula is:

(OBJECT OMITTED)

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

CLINICAL PHARMACOLOGY

Background

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

Mode of Action

VYTORIN

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

Ezetimibe

Ezetimibe reduces blood cholesterol by inhibiting the absorption
of cholesterol by the small intestine. In a 2-week clinical study in
18 hypercholesterolemic patients, ezetimibe inhibited intestinal
cholesterol absorption by 54%, compared with placebo. Ezetimibe had no
clinically meaningful effect on the plasma concentrations of the
fat-soluble vitamins A, D, and E and did not impair adrenocortical
steroid hormone production.
Ezetimibe localizes 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).

Simvastatin

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

Pharmacokinetics

Absorption

VYTORIN

VYTORIN is bioequivalent to coadministered ezetimibe and
simvastatin.

Ezetimibe

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

Effect of Food on Oral Absorption

Ezetimibe

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

Simvastatin

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

Distribution

Ezetimibe

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

Simvastatin

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

Metabolism and Excretion

Ezetimibe

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

Simvastatin

Simvastatin is a lactone that is readily hydrolyzed in vivo to the
corresponding (beta)-hydroxyacid, a potent inhibitor of HMG-CoA
reductase. Inhibition of HMG-CoA reductase is a basis for an assay in
pharmacokinetic studies of the (beta)-hydroxyacid metabolites (active
inhibitors) and, following base hydrolysis, active plus latent
inhibitors (total inhibitors) in plasma following administration of
simvastatin. The major active metabolites of simvastatin present in
human plasma are the (beta)-hydroxyacid of simvastatin and its
6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.
Plasma concentrations of total radioactivity (simvastatin plus
14C-metabolites) peaked at 4 hours and declined rapidly to about 10%
of peak by 12 hours postdose. Since simvastatin undergoes extensive
first-pass extraction in the liver, the availability of the drug to
the general circulation is low (<5%).
Following an oral dose of 14C-labeled simvastatin in man, 13% of
the dose was excreted in urine and 60% in feces.

Special Populations

Geriatric Patients

Ezetimibe

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

Simvastatin

In a study including 16 elderly patients between 70 and 78 years
of age who received simvastatin 40 mg/day, the mean plasma level of
HMG-CoA reductase inhibitory activity was increased approximately 45%
compared with 18 patients between 18-30 years of age.

Pediatric Patients

Ezetimibe

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

Gender

Ezetimibe

In a multiple-dose study with ezetimibe given 10 mg once daily for
10 days, plasma concentrations for total ezetimibe were slightly
higher (<20%) in women than in men.

Race

Ezetimibe

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

Ezetimibe

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

Renal Insufficiency

Ezetimibe

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

Simvastatin

Pharmacokinetic studies with another statin having a similar
principal route of elimination to that of simvastatin have suggested
that for a given dose level higher systemic exposure may be achieved
in patients with severe renal insufficiency (as measured by creatinine
clearance).

Drug Interactions (See also PRECAUTIONS, Drug Interactions)

No clinically significant pharmacokinetic interaction was seen
when ezetimibe was coadministered with simvastatin. Specific
pharmacokinetic drug interaction studies with VYTORIN have not been
performed.
Cytochrome P450: Ezetimibe had no significant effect on a series
of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV
midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9
and 3A4) in a "cocktail" study of twelve healthy adult males. This
indicates that ezetimibe is neither an inhibitor nor an inducer of
these cytochrome P450 isozymes, and it is unlikely that ezetimibe will
affect the metabolism of drugs that are metabolized by these enzymes.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose
had no effect on the metabolism of the probe cytochrome P450 isoform
3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates
that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not
expected to affect the plasma levels of other drugs metabolized by
CYP3A4.
Although the mechanism is not fully understood, cyclosporine has
been shown to increase the AUC of HMG-CoA reductase inhibitors. The
increase in AUC for simvastatin acid is presumably due, in part, to
inhibition of CYP3A4.
Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4
can raise the plasma levels of HMG-CoA reductase inhibitory activity
and increase the risk of myopathy. (See WARNINGS,
Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions.)
Antacids: In a study of twelve healthy adults, a single dose of
antacid (Supralox(TM) 20 mL) administration had no significant effect
on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide,
or ezetimibe based on AUC values. The Cmax value of total ezetimibe
was decreased by 30%.
Cholestyramine: In a study of forty healthy hypercholesterolemic
(LDL-C (>=)130 mg/dL) adult subjects, concomitant cholestyramine (4 g
twice daily) administration decreased the mean AUC of total ezetimibe
and ezetimibe approximately 55% and 80%, respectively.
Cyclosporine: In a study of eight post-renal transplant patients
with mildly impaired or normal renal function (creatinine clearance of
>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).
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).
Coadministration of fenofibrate (160 mg daily) with simvastatin
(80 mg daily) for 7 days had no effect on plasma AUC (and Cmax) of
either total HMG-CoA reductase inhibitory activity or fenofibric acid;
there was a modest reduction (approximately 35%) of simvastatin acid
which was not considered clinically significant (see WARNINGS,
Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions).
Gemfibrozil: In a study of twelve healthy adult males, concomitant
administration of gemfibrozil (600 mg twice daily) significantly
increased the oral bioavailability of total ezetimibe by a factor of
1.7. Ezetimibe (10 mg once daily) did not significantly affect the
bioavailability of gemfibrozil.
Coadministration of gemfibrozil (600 mg twice daily for 3 days)
with simvastatin (40 mg daily) resulted in clinically significant
increases in simvastatin acid AUC (185%) and Cmax (112%), possibly due
to inhibition of simvastatin acid glucuronidation by gemfibrozil (see
WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions,
DOSAGE AND ADMINISTRATION).
Grapefruit Juice: Grapefruit juice contains one or more components
that inhibit CYP3A4 and can increase the plasma concentrations of
drugs metabolized by CYP3A4. In one study(1), 10 subjects consumed 200
mL of double-strength grapefruit juice (one can of frozen concentrate
diluted with one rather than 3 cans of water) three times daily for 2
days and an additional 200 mL double-strength grapefruit juice
together with, and 30 and 90 minutes following, a single dose of 60 mg
simvastatin on the third day. This regimen of grapefruit juice
resulted in mean increases in the concentration (as measured by the
area under the concentration-time curve) of active and total HMG-CoA
reductase inhibitory activity (measured using a radioenzyme inhibition
assay both before (for active inhibitors) and after (for total
inhibitors) base hydrolysis) of 2.4-fold and 3.6-fold, respectively,
and of simvastatin and its (beta)-hydroxyacid metabolite (measured
using a chemical assay -- liquid chromatography/tandem mass
spectrometry) of 16-fold and 7-fold, respectively. In a second study,
16 subjects consumed one 8 oz glass of single-strength grapefruit
juice (one can of frozen concentrate diluted with 3 cans of water)
with breakfast for 3 consecutive days and a single dose of 20 mg
simvastatin in the evening of the third day. This regimen of
grapefruit juice resulted in a mean increase in the plasma
concentration (as measured by the area under the concentration-time
curve) of active and total HMG-CoA reductase inhibitory activity
(using a validated enzyme inhibition assay different from that used in
the first(1) study, both before (for active inhibitors) and after (for
total inhibitors) base hydrolysis) of 1.13-fold and 1.18-fold,
respectively, and of simvastatin and its (beta)-hydroxyacid metabolite
(measured using a chemical assay -- liquid chromatography/tandem mass
spectrometry) of 1.88-fold and 1.31-fold, respectively. The effect of
amounts of grapefruit juice between those used in these two studies on
simvastatin pharmacokinetics has not been studied.

ANIMAL PHARMACOLOGY

Ezetimibe

The hypocholesterolemic effect of ezetimibe was evaluated in
cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human
cholesterol metabolism. Ezetimibe was found to have an ED50 value of
0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol levels
in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and
700 (mu)g/kg/day, respectively. These results are consistent with
ezetimibe being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe
(ezetimibe-glucuronide) was administered intraduodenally, the
metabolite was as potent as ezetimibe in inhibiting the absorption of
cholesterol, suggesting that the glucuronide metabolite had activity
similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300
mg/kg/day), the concentration of cholesterol in gallbladder bile
increased ~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 ezetimibe for inhibiting cholesterol absorption.
Ezetimibe inhibited the absorption of 14C-cholesterol with no effect
on the absorption of triglycerides, fatty acids, bile acids,
progesterone, ethyl estradiol, or the fat-soluble vitamins A and D.
In 4- to 12-week toxicity studies in mice, ezetimibe did not
induce cytochrome P450 drug metabolizing enzymes. In toxicity studies,
a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase
inhibitors (parents or their active hydroxy acid metabolites) was seen
in rats, dogs, and rabbits.

CLINICAL STUDIES

Primary Hypercholesterolemia

VYTORIN

VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and
increases HDL-C in patients with hypercholesterolemia. Maximal to near
maximal response is generally achieved within 2 weeks and maintained
during chronic therapy.
VYTORIN is effective in men and women with hypercholesterolemia.
Experience in non-Caucasians is limited and does not permit a precise
estimate of the magnitude of the effects of VYTORIN.
In a multicenter, double-blind, placebo-controlled, 12-week trial,
1528 hypercholesterolemic patients were randomized to one of ten
treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20
mg, 40 mg, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80).
When patients receiving VYTORIN were compared to those receiving
all doses of simvastatin, VYTORIN significantly lowered total-C,
LDL-C, Apo B, TG, and non-HDL-C. The effects of VYTORIN on HDL-C were
similar to the effects seen with simvastatin. Further analysis showed
VYTORIN significantly increased HDL-C compared with placebo. (See
Table 1.) The lipid response to VYTORIN was similar in patients with
TG levels greater than or less than 200 mg/dL.

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

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

(a) For triglycerides, median % change from baseline

(b) Baseline - on no lipid-lowering drug

(c )VYTORIN doses pooled (10/10-10/80) significantly reduced
total-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin, and
significantly increased HDL-C compared to placebo.
In a multicenter, double-blind, controlled, 23-week study, 710
patients with known CHD or CHD risk equivalents, as defined by the
NCEP ATP III guidelines, and an LDL-C (>=)130 mg/dL were randomized to
one of four treatment groups: coadministered ezetimibe and simvastatin
equivalent to VYTORIN (10/10, 10/20, and 10/40), or simvastatin 20 mg.
Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose
titrated at 6-week intervals to a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or
10/40 were significantly larger than with simvastatin 20 mg (see Table
2).



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

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

In a multicenter, double-blind, 24-week, forced titration study,
788 patients with primary hypercholesterolemia, who had not met their
NCEP ATP III target LDL-C goal, were randomized to receive
coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10
and 10/20) or atorvastatin 10 mg. For all three treatment groups, the
dose of the statin was titrated at 6-week intervals to 80 mg. At each
pre-specified dose comparison, VYTORIN lowered LDL-C to a greater
degree than atorvastatin (see Table 3).


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

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

(a) For triglycerides, median % change from baseline

(b) Baseline - on no lipid-lowering drug

(c) Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and
80 mg through Weeks 6, 12, 18, and 24
(d) VYTORIN: 10/10 start dose titrated to 10/20, 10/40, and 10/80
through Weeks 6, 12, 18, and 24
(e) VYTORIN: 10/20 start dose titrated to 10/40, 10/40, and 10/80
through Weeks 6, 12, 18, and 24
(f) p(<=)0.05 for difference with atorvastatin in the specified
week
(g )Data pooled for common doses of VYTORIN at Weeks 18 and 24.

In a multicenter, double-blind, 24-week trial, 214 patients with
type 2 diabetes mellitus treated with thiazolidinediones
(rosiglitazone or pioglitazone) for a minimum of 3 months and
simvastatin 20 mg for a minimum of 6 weeks, were randomized to receive
either simvastatin 40 mg or the coadministered active ingredients
equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at
baseline were 89 mg/dL and 7.1%, respectively.
VYTORIN 10/20 was significantly more effective than doubling the
dose of simvastatin to 40 mg. The median percent changes from baseline
for VYTORIN vs simvastatin were: LDL-C -25% and -5%; total-C -16% and
-5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C
and TG between the two treatment groups were not significantly
different.

Ezetimibe

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

Simvastatin

In two large, placebo-controlled clinical trials, the Scandinavian
Simvastatin Survival Study (N=4,444 patients) and the Heart Protection
Study (N=20,536 patients), the effects of treatment with simvastatin
were assessed in patients at high risk of coronary events because of
existing coronary heart disease, diabetes, peripheral vessel disease,
history of stroke or other cerebrovascular disease. Simvastatin was
proven to reduce: the risk of total mortality by reducing CHD deaths;
the risk of non-fatal myocardial infarction and stroke; and the need
for coronary and non-coronary revascularization procedures.
No incremental benefit of VYTORIN on cardiovascular morbidity and
mortality over and above that demonstrated for simvastatin has been
established.

Homozygous Familial Hypercholesterolemia (HoFH)

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

INDICATIONS AND USAGE

Primary Hypercholesterolemia

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

Homozygous Familial Hypercholesterolemia (HoFH)

VYTORIN is indicated for the reduction of elevated total-C and
LDL-C in patients with homozygous familial hypercholesterolemia, as an
adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if
such treatments are unavailable.
Therapy with lipid-altering agents should be a component of
multiple risk-factor intervention in individuals at increased risk for
atherosclerotic vascular disease due to hypercholesterolemia.
Lipid-altering agents should be used in addition to an appropriate
diet (including restriction of saturated fat and cholesterol) and when
the response to diet and other non-pharmacological measures has been
inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines,
summarized in Table 4.)



Table 4
Summary of NCEP ATP III Guidelines

LDL Level at
Which to LDL Level at
LDL Goal Initiate Which to
Risk Category (mg/dL) TherapeuticConsider Drug
Lifestyle Therapy
Changes(a) (mg/dL)
(mg/dL)
----------------------------------------------------------------------
(greater
CHD or CHD risk equivalents(b) less (greater than=)130
(10-year risk greater than20%)(c) than100 than=)100 (100-129:
drug
optional)(d)
----------------------------------------------------------------------
10-year risk
10-20%:
(greater
2+ Risk factors(e) less (greater than=)130(c)
(10-year risk (less than=)20%)(c) than130 than=)130 10-year risk
less
than10%:
(greater
than=)160(c)
----------------------------------------------------------------------
(greater
than=)190
0-1 Risk factor(f) less (greater (160-189:
than160 than=)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 VYTORIN, secondary causes for
dyslipidemia (i.e., diabetes, hypothyroidism, obstructive liver
disease, chronic renal failure, and drugs that increase LDL-C and
decrease HDL-C (progestins, anabolic steroids, and corticosteroids)),
should be excluded or, if appropriate, treated. A lipid profile should
be performed to measure total-C, LDL-C, HDL-C and TG. For TG levels
>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.

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

Pregnancy and lactation. Atherosclerosis is a chronic process and
the discontinuation of lipid-lowering drugs during pregnancy should
have little impact on the outcome of long-term therapy of primary
hypercholesterolemia. Moreover, cholesterol and other products of the
cholesterol biosynthesis pathway are essential components for fetal
development, including synthesis of steroids and cell membranes.
Because of the ability of inhibitors of HMG-CoA reductase such as
simvastatin to decrease the synthesis of cholesterol and possibly
other products of the cholesterol biosynthesis pathway, VYTORIN is
contraindicated during pregnancy and in nursing mothers. VYTORIN
should be administered to women of childbearing age only when such
patients are highly unlikely to conceive. If the patient becomes
pregnant while taking this drug, VYTORIN should be discontinued
immediately and the patient should be apprised of the potential hazard
to the fetus (see PRECAUTIONS, Pregnancy).

WARNINGS

Myopathy/Rhabdomyolysis

In clinical trials, there was no excess of myopathy or
rhabdomyolysis associated with ezetimibe compared with the relevant
control arm (placebo or HMG-CoA reductase inhibitor alone). However,
myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA
reductase inhibitors and other lipid-lowering drugs. In clinical
trials, the incidence of CK >10 X the upper limit of normal (ULN) was
0.2% for VYTORIN. (See PRECAUTIONS, Skeletal Muscle.)
Simvastatin, like other inhibitors of HMG-CoA reductase,
occasionally causes myopathy manifested as muscle pain, tenderness or
weakness with creatine kinase above 10 X ULN. Myopathy sometimes takes
the form of rhabdomyolysis with or without acute renal failure
secondary to myoglobinuria, and rare fatalities have occurred. The
risk of myopathy is increased by high levels of HMG-CoA reductase
inhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk of
myopathy/rhabdomyolysis is dose related. In a clinical trial database
in which 41,050 patients were treated with simvastatin with 24,747
(approximately 60%) treated for at least 4 years, the incidence of
myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80
mg/day, respectively. In these trials, patients were carefully
monitored and some interacting medicinal products were excluded.
All patients starting therapy with VYTORIN or whose dose of
VYTORIN is being increased, should be advised of the risk of myopathy
and told to report promptly any unexplained muscle pain, tenderness or
weakness. VYTORIN therapy should be discontinued immediately if
myopathy is diagnosed or suspected. In most cases, muscle symptoms and
CK increases resolved when simvastatin treatment was promptly
discontinued. Periodic CK determinations may be considered in patients
starting therapy with simvastatin or whose dose is being increased,
but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy
with simvastatin have had complicated medical histories, including
renal insufficiency usually as a consequence of long-standing diabetes
mellitus. Such patients taking VYTORIN merit closer monitoring.
Therapy with VYTORIN should be temporarily stopped a few days prior to
elective major surgery and when any major medical or surgical
condition supervenes.
Because VYTORIN contains simvastatin, the risk of
myopathy/rhabdomyolysis is increased by concomitant use of VYTORIN
with the following:
Potent inhibitors of CYP3A4: Simvastatin, like several other
inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4
(CYP3A4). When simvastatin is used with a potent inhibitor of CYP3A4,
elevated plasma levels of HMG-CoA reductase inhibitory activity can
increase the risk of myopathy and rhabdomyolysis, particularly with
higher doses of simvastatin.
The use of VYTORIN concomitantly with the potent CYP3A4 inhibitors
itraconazole, ketoconazole, erythromycin, clarithromycin,
telithromycin, HIV protease inhibitors, nefazodone, or large
quantities of grapefruit juice (>1 quart daily) should be avoided.
Concomitant use of other medicines labeled as having a potent
inhibitory effect on CYP3A4 should be avoided unless the benefits of
combined therapy outweigh the increased risk. If treatment with
itraconazole, ketoconazole, erythromycin, clarithromycin or
telithromycin is unavoidable, therapy with VYTORIN should be suspended
during the course of treatment.

Other drugs:

Gemfibrozil, particularly with higher doses of VYTORIN, and other
fibrates: The safety and effectiveness of ezetimibe administered with
fibrates have not been established. Therefore, the concomitant use of
VYTORIN and fibrates should be avoided.
There is an increased risk of myopathy when simvastatin is used
concomitantly with fibrates (especially gemfibrozil). The combined use
of simvastatin with gemfibrozil should be avoided, unless the benefits
are likely to outweigh the increased risks of this drug combination.
The dose of simvastatin should not exceed 10 mg daily in patients
receiving concomitant medication with gemfibrozil. Therefore, although
not recommended, if VYTORIN is used in combination with gemfibrozil,
the dose should not exceed 10/10 mg daily. (See PRECAUTIONS, Drug
Interactions, Other drug interactions, Fibrates, and DOSAGE AND
ADMINISTRATION.)
Niacin ((>=)1 g/day): Caution should be used when prescribing
lipid-lowering doses ((>=)1 g/day) of niacin with VYTORIN, as niacin
can cause myopathy when given alone. The benefit of further
alterations in lipid levels by the combined use of VYTORIN with niacin
should be carefully weighed against the potential risks of this drug
combination (see PRECAUTIONS, Drug Interactions, Interactions with
lipid-lowering drugs that can cause myopathy when given alone).
Cyclosporine or danazol with higher doses of VYTORIN: The dose of
VYTORIN should not exceed 10/10 mg daily in patients receiving
concomitant medication with cyclosporine or danazol. The benefits of
the use of VYTORIN in patients receiving cyclosporine or danazol
should be carefully weighed against the risks of these combinations.
(See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug
Interactions, Other drug interactions).
Amiodarone or verapamil with higher doses of VYTORIN: The dose of
VYTORIN should not exceed 10/20 mg daily in patients receiving
concomitant medication with amiodarone or verapamil. The combined use
of VYTORIN at doses higher than 10/20 mg daily with amiodarone or
verapamil should be avoided unless the clinical benefit is likely to
outweigh the increased risk of myopathy. (See PRECAUTIONS, Drug
Interactions, Other drug interactions). In an ongoing clinical trial,
myopathy has been reported in 6% of patients receiving simvastatin 80
mg and amiodarone. In an analysis of clinical trials involving 25,248
patients treated with simvastatin 20 to 80 mg, the incidence of
myopathy was higher in patients receiving verapamil and simvastatin
(4/635; 0.63%) than in patients taking simvastatin without a calcium
channel blocker (13/21,224; 0.061%).
Prescribing recommendations for interacting agents are summarized
in Table 5 (see also CLINICAL PHARMACOLOGY, Pharmacokinetics;
PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION).


TABLE 5
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis
------------------------------------------------------
Interacting Agents Prescribing Recommendations
------------------------------------------------------
Itraconazole Avoid VYTORIN
Ketoconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Fibrates*
------------------------------------------------------
Cyclosporine Do not exceed 10/10 mg
Danazol VYTORIN daily
------------------------------------------------------
Amiodarone Do not exceed 10/20 mg
Verapamil VYTORIN daily
------------------------------------------------------
Grapefruit juice Avoid large quantities of
grapefruit juice (greater
than1 quart daily)
------------------------------------------------------

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



Liver Enzymes

In three placebo-controlled, 12-week trials, the incidence of
consecutive elevations ((>=)3 X ULN) in serum transaminases was 1.7%
overall for patients treated with VYTORIN and appeared to be
dose-related with an incidence of 2.6% for patients treated with
VYTORIN 10/80. In controlled long-term (48-week) extensions, which
included both newly-treated and previously-treated patients, the
incidence of consecutive elevations ((>=)3 X ULN) in serum
transaminases was 1.8% overall and 3.6% for patients treated with
VYTORIN 10/80. These elevations in transaminases were generally
asymptomatic, not associated with cholestasis, and returned to
baseline after discontinuation of therapy or with continued treatment.
It is recommended that liver function tests be performed before
the initiation of treatment with VYTORIN, and thereafter when
clinically indicated. Patients titrated to the 10/80-mg dose should
receive an additional test prior to titration, 3 months after
titration to the 10/80-mg dose, and periodically thereafter (e.g.,
semiannually) for the first year of treatment. Patients who develop
increased transaminase levels should be monitored with a second liver
function evaluation to confirm the finding and be followed thereafter
with frequent liver function tests until the abnormality(ies) return
to normal. Should an increase in AST or ALT of 3 X ULN or greater
persist, withdrawal of therapy with VYTORIN is recommended.
VYTORIN should be used with caution in patients who consume
substantial quantities of alcohol and/or have a past history of liver
disease. Active liver diseases or unexplained persistent transaminase
elevations are contraindications to the use of VYTORIN.

PRECAUTIONS

Information for Patients

Patients should be advised about substances they should not take
concomitantly with VYTORIN and be advised to report promptly
unexplained muscle pain, tenderness, or weakness (see list below and
WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to
inform other physicians prescribing a new medication that they are
taking VYTORIN.

Skeletal Muscle

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

Hepatic Insufficiency

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

VYTORIN

CYP3A4 Interactions

Potent inhibitors of CYP3A4 (below) increase the risk of myopathy
by reducing the elimination of the simvastatin component of VYTORIN.
See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY,
Pharmacokinetics, Drug Interactions.

Itraconazole

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Nefazodone

Large quantities of grapefruit juice (>1 quart daily)

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

See WARNINGS, Myopathy/Rhabdomyolysis.

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

Other drug interactions

Danazol: The risk of myopathy/rhabdomyolysis is increased by
concomitant administration of danazol particularly with higher doses
of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS,
Myopathy/Rhabdomyolysis).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is
increased by concomitant administration of amiodarone or verapamil
with higher doses of VYTORIN (see WARNINGS, Myopathy/Rhabdomyolysis).
Cholestyramine: Concomitant cholestyramine administration
decreased the mean AUC of total ezetimibe approximately 55%. The
incremental LDL-C reduction due to adding VYTORIN to cholestyramine
may be reduced by this interaction.
Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by
concomitant administration of cyclosporine particularly with higher
doses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics and
WARNINGS, Myopathy/Rhabdomyolysis).
Caution should be exercised when using VYTORIN and cyclosporine
concomitantly due to increased exposure to both ezetimibe and
cyclosporine (see DOSAGE AND ADMINISTRATION, Patients taking
Cyclosporine or Danazol). Cyclosporine concentrations should be
monitored in patients receiving VYTORIN and cyclosporine (see CLINICAL
PHARMACOLOGY, Drug Interactions).
The degree of increase in ezetimibe exposure may be greater in
patients with severe renal insufficiency. In patients treated with
cyclosporine, the potential effects of the increased exposure to
ezetimibe from concomitant use should be carefully weighed against the
benefits of alterations in lipid levels provided by ezetimibe. In a
pharmacokinetic study in post-renal transplant patients with mildly
impaired or normal renal function (creatinine clearance of >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 and WARNINGS, Myopathy/Rhabdomyolysis.)
Digoxin: Concomitant administration of a single dose of digoxin in
healthy male volunteers receiving simvastatin resulted in a slight
elevation (less than 0.3 ng/mL) in plasma digoxin concentrations
compared to concomitant administration of placebo and digoxin.
Patients taking digoxin should be monitored appropriately when VYTORIN
is initiated.
Fibrates: The safety and effectiveness of VYTORIN administered
with fibrates have not been established.
Fibrates may increase cholesterol excretion into the bile, leading
to cholelithiasis. In a preclinical study in dogs, ezetimibe increased
cholesterol in the gallbladder bile (see ANIMAL PHARMACOLOGY).
Coadministration of VYTORIN with fibrates is not recommended until use
in patients is studied. (See WARNINGS, Myopathy/Rhabdomyolysis.)
Warfarin: Simvastatin 20-40 mg/day modestly potentiated the effect
of coumarin anticoagulants: the prothrombin time, reported as
International Normalized Ratio (INR), increased from a baseline of 1.7
to 1.8 and from 2.6 to 3.4 in a normal volunteer study and in a
hypercholesterolemic patient study, respectively. With other statins,
clinically evident bleeding and/or increased prothrombin time has been
reported in a few patients taking coumarin anticoagulants
concomitantly. In such patients, prothrombin time should be determined
before starting VYTORIN and frequently enough during early therapy to
ensure that no significant alteration of prothrombin time occurs. Once
a stable prothrombin time has been documented, prothrombin times can
be monitored at the intervals usually recommended for patients on
coumarin anticoagulants. If the dose of VYTORIN is changed or
discontinued, the same procedure should be repeated. Simvastatin
therapy has not been associated with bleeding or with changes in
prothrombin time in patients not taking anticoagulants.
Concomitant administration of ezetimibe (10 mg once daily) had no
significant effect on bioavailability of warfarin and prothrombin time
in a study of twelve healthy adult males. There have been
post-marketing reports of increased International Normalized Ratio
(INR) in patients who had ezetimibe added to warfarin. Most of these
patients were also on other medications.
The effect of VYTORIN on the prothrombin time has not been
studied.

Ezetimibe

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

Simvastatin

Propranolol: In healthy male volunteers there was a significant
decrease in mean Cmax, but no change in AUC, for simvastatin total and
active inhibitors with concomitant administration of single doses of
simvastatin and propranolol. The clinical relevance of this finding is
unclear. The pharmacokinetics of the enantiomers of propranolol were
not affected.

CNS Toxicity

Optic nerve degeneration was seen in clinically normal dogs
treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that
produced mean plasma drug levels about 12 times higher than the mean
plasma drug level in humans taking 80 mg/day.
A chemically similar drug in this class also produced optic nerve
degeneration (Wallerian degeneration of retinogeniculate fibers) in
clinically normal dogs in a dose-dependent fashion starting at 60
mg/kg/day, a dose that produced mean plasma drug levels about 30 times
higher than the mean plasma drug level in humans taking the highest
recommended dose (as measured by total enzyme inhibitory activity).
This same drug also produced vestibulocochlear Wallerian-like
degeneration and retinal ganglion cell chromatolysis in dogs treated
for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma
drug level similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and
edema, mononuclear cell infiltration of perivascular spaces,
perivascular fibrin deposits and necrosis of small vessels were seen
in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose
that produced mean plasma drug levels that were about 14 times higher
than the mean plasma drug levels in humans taking 80 mg/day. Similar
CNS vascular lesions have been observed with several other drugs of
this class.
There were cataracts in female rats after two years of treatment
with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day,
respectively) and in dogs after three months at 90 mg/kg/day (19
times) and at two years at 50 mg/kg/day (5 times).

Carcinogenesis, Mutagenesis, Impairment of Fertility

VYTORIN

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

Ezetimibe

A 104-week dietary carcinogenicity study with ezetimibe was
conducted in rats at doses up to 1500 mg/kg/day (males) and 500
mg/kg/day (females) (~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).

Simvastatin

In a 72-week carcinogenicity study, mice were administered daily
doses of simvastatin of 25, 100, and 400 mg/kg body weight, which
resulted in mean plasma drug levels approximately 1, 4, and 8 times
higher than the mean human plasma drug level, respectively (as total
inhibitory activity based on AUC) after an 80-mg oral dose. Liver
carcinomas were significantly increased in high-dose females and mid-
and high-dose males with a maximum incidence of 90% in males. The
incidence of adenomas of the liver was significantly increased in mid-
and high-dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high-dose males and females.
Adenomas of the Harderian gland (a gland of the eye of rodents) were
significantly higher in high-dose mice than in controls. No evidence
of a tumorigenic effect was observed at 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to
25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean
plasma drug levels were 1 times higher than humans given 80 mg
simvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was a
statistically significant increase in the incidence of thyroid
follicular adenomas in female rats exposed to approximately 11 times
higher levels of simvastatin than in humans given 80 mg simvastatin
(as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and
100 mg/kg/day produced hepatocellular adenomas and carcinomas (in
female rats at both doses and in males at 100 mg/kg/day). Thyroid
follicular cell adenomas were increased in males and females at both
doses; thyroid follicular cell carcinomas were increased in females at
100 mg/kg/day. The increased incidence of thyroid neoplasms appears to
be consistent with findings from other HMG-CoA reductase inhibitors.
These treatment levels represented plasma drug levels (AUC) of
approximately 7 and 15 times (males) and 22 and 25 times (females) the
mean human plasma drug exposure after an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbial
mutagenicity (Ames) test with or without rat or mouse liver metabolic
activation. In addition, no evidence of damage to genetic material was
noted in an in vitro alkaline elution assay using rat hepatocytes, a
V-79 mammalian cell forward mutation study, an in vitro chromosome
aberration study in CHO cells, or an in vivo chromosomal aberration
assay in mouse bone marrow.
There was decreased fertility in male rats treated with
simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum
human exposure level, based on AUC, in patients receiving 80 mg/day);
however, this effect was not observed during a subsequent fertility
study in which simvastatin was administered at this same dose level to
male rats for 11 weeks (the entire cycle of spermatogenesis including
epididymal maturation). No microscopic changes were observed in the
testes of rats from either study. At 180 mg/kg/day, (which produces
exposure levels 22 times higher than those in humans taking 80 mg/day
based on surface area, mg/m2), seminiferous tubule degeneration
(necrosis and loss of spermatogenic epithelium) was observed. In dogs,
there was drug-related testicular atrophy, decreased spermatogenesis,
spermatocytic degeneration and giant cell formation at 10 mg/kg/day,
(approximately 2 times the human exposure, based on AUC, at 80
mg/day). The clinical significance of these findings is unclear.

Pregnancy

Pregnancy Category: X

See CONTRAINDICATIONS.

VYTORIN

As safety in pregnant women has not been established, treatment
should be immediately discontinued as soon as pregnancy is recognized.
VYTORIN should be administered to women of child-bearing potential
only when such patients are highly unlikely to conceive and have been
informed of the potential hazards.

Ezetimibe

In oral (gavage) embryo-fetal development studies of ezetimibe
conducted in rats and rabbits during organogenesis, there was no
evidence of embryolethal effects at the doses tested (250, 500, 1000
mg/kg/day). In rats, increased incidences of common fetal skeletal
findings (extra pair of thoracic ribs, unossified cervical vertebral
centra, shortened ribs) were observed at 1000 mg/kg/day (~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 coadministered with HMG-CoA
reductase inhibitors (statins) in rats and rabbits during
organogenesis result in higher ezetimibe and statin exposures.
Reproductive findings occur at lower doses in coadministration therapy
compared to monotherapy.

Simvastatin

Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day
or in rabbits at doses up to 10 mg/kg daily. These doses resulted in 3
times (rat) or 3 times (rabbit) the human exposure based on mg/m2
surface area. However, in studies with another structurally-related
HMG-CoA reductase inhibitor, skeletal malformations were observed in
rats and mice.
Rare reports of congenital anomalies have been received following
intrauterine exposure to HMG-CoA reductase inhibitors. In a review2
of approximately 100 prospectively followed pregnancies in women
exposed to simvastatin or another structurally related HMG-CoA
reductase inhibitor, the incidences of congenital anomalies,
spontaneous abortions and fetal deaths/stillbirths did not exceed what
would be expected in the general population. The number of cases is
adequate only to exclude a 3- to 4-fold increase in congenital
anomalies over the background incidence. In 89% of the prospectively
followed pregnancies, drug treatment was initiated prior to pregnancy
and was discontinued at some point in the first trimester when
pregnancy was identified.

Labor and Delivery

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

Nursing Mothers

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

Pediatric Use

VYTORIN

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

Ezetimibe

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

Simvastatin

Safety and effectiveness of simvastatin in patients 10-17 years of
age with heterozygous familial hypercholesterolemia have been
evaluated in a controlled clinical trial in adolescent boys and in
girls who were at least 1 year post-menarche. Patients treated with
simvastatin had an adverse experience profile generally similar to
that of patients treated with placebo. Doses greater than 40 mg have
not been studied in this population. In this limited controlled study,
there was no detectable effect on growth or sexual maturation in the
adolescent boys or girls, or any effect on menstrual cycle length in
girls. Adolescent females should be counseled on appropriate
contraceptive methods while on therapy with simvastatin (see
CONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Simvastatin has not
been studied in patients younger than 10 years of age, nor in
pre-menarchal girls.

Geriatric Use

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

ADVERSE REACTIONS

VYTORIN has been evaluated for safety in more than 3800 patients
in clinical trials. VYTORIN was generally well tolerated.
Table 6 summarizes the frequency of clinical adverse experiences
reported in (>=)2% of patients treated with VYTORIN (n=1236) and at an
incidence greater than placebo regardless of causality assessment from
three similarly designed, placebo-controlled trials.

Table 6*
Clinical Adverse Events Occurring in (greater than=)2% of Patients
Treated with VYTORIN and at an Incidence Greater than Placebo,
Regardless of Causality
----------------------------------------------------------------------

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

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

**All doses.



Post-marketing Experience

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

Ezetimibe

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

Post-marketing Experience

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

Simvastatin

Other adverse experiences reported with simvastatin in
placebo-controlled clinical studies, regardless of causality
assessment: Body as a whole - general disorders: asthenia; Eye
disorders: cataract; Gastrointestinal system disorders: abdominal
pain, constipation, diarrhea, dyspepsia, flatulence, nausea; Skin and
subcutaneous tissue disorders: eczema, pruritus, rash.
The following effects have been reported with other HMG-CoA
reductase inhibitors. Not all the effects listed below have
necessarily been associated with simvastatin therapy.
Musculoskeletal system disorders: muscle cramps, myalgia,
myopathy, rhabdomyolysis, arthralgias.
Nervous system disorders: dysfunction of certain cranial nerves
(including alteration of taste, impairment of extra-ocular movement,
facial paresis), tremor, dizziness, memory loss, paresthesia,
peripheral neuropathy, peripheral nerve palsy, psychic disturbances.

Ear and labyrinth disorders: vertigo.

Psychiatric disorders: anxiety, insomnia, depression, loss of
libido.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome
has been reported rarely which has included one or more of the
following features: anaphylaxis, angioedema, lupus erythematous-like
syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis,
purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA,
ESR increase, eosinophilia, arthritis, arthralgia, urticaria,
asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea,
toxic epidermal necrolysis, erythema multiforme, including
Stevens-Johnson syndrome.

Gastrointestinal system disorders: pancreatitis, vomiting.

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

Metabolism and nutrition disorders: anorexia.

Skin and subcutaneous tissue disorders: alopecia, pruritus. A
variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive system and breast disorders: gynecomastia, erectile
dysfunction.
Eye disorders: progression of cataracts (lens opacities),
ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline
phosphatase, (gamma)-glutamyl transpeptidase, and bilirubin; thyroid
function abnormalities.

Laboratory Tests

Marked persistent increases of serum transaminases have been noted
(see WARNINGS, Liver Enzymes). About 5% of patients taking simvastatin
had elevations of CK levels of 3 or more times the normal value on one
or more occasions. This was attributable to the noncardiac fraction of
CK. Muscle pain or dysfunction usually was not reported (see WARNINGS,
Myopathy/Rhabdomyolysis).

Concomitant Lipid-Lowering Therapy

In controlled clinical studies in which simvastatin was
administered concomitantly with cholestyramine, no adverse reactions
peculiar to this concomitant treatment were observed. The adverse
reactions that occurred were limited to those reported previously with
simvastatin or cholestyramine.

Adolescent Patients (ages 10-17 years)

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

OVERDOSAGE

VYTORIN

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

Ezetimibe

In clinical studies, administration of ezetimibe, 50 mg/day to 15
healthy subjects for up to 14 days, or 40 mg/day to 18 patients with
primary hypercholesterolemia for up to 56 days, was generally well
tolerated.
A few cases of overdosage have been reported; most have not been
associated with adverse experiences. Reported adverse experiences have
not been serious.

Simvastatin

A few cases of overdosage with simvastatin have been reported; the
maximum dose taken was 3.6 g. All patients recovered without sequelae.
The dialyzability of simvastatin and its metabolites in man is not
known at present.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering
diet before receiving VYTORIN and should continue on this diet during
treatment with VYTORIN. The dosage should be individualized according
to the baseline LDL-C level, the recommended goal of therapy, and the
patient's response. (See NCEP Adult Treatment Panel (ATP) III
Guidelines, summarized in Table 4.) VYTORIN should be taken as a
single daily dose in the evening, with or without food.
The dosage range is 10/10 mg/day through 10/80 mg/day. The
recommended usual starting dose is 10/20 mg/day. Initiation of therapy
with 10/10 mg/day may be considered for patients requiring less
aggressive LDL-C reductions. Patients who require a larger reduction
in LDL-C (greater than 55%) may be started at 10/40 mg/day. After
initiation or titration of VYTORIN, lipid levels may be analyzed after
2 or more weeks and dosage adjusted, if needed. See below for dosage
recommendations for patients receiving certain concomitant therapies
and for those with renal insufficiency.

Patients with Homozygous Familial Hypercholesterolemia

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

Patients with Hepatic Insufficiency

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

Patients with Renal Insufficiency

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

Geriatric Patients

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

Coadministration with Bile Acid Sequestrants

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

Patients taking Cyclosporine or Danazol

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

Patients taking Amiodarone or Verapamil

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

Patients taking other Concomitant Lipid-Lowering Therapy

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

HOW SUPPLIED

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

They are supplied as follows:

NDC 66582-311-31 bottles of 30

NDC 66582-311-54 bottles of 90

NDC 66582-311-82 bottles of 1000 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)
NDC 66582-311-87 bottles of 10,000 (If repackaged in blisters,
then opaque or light-resistant blisters should be used.)

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

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

They are supplied as follows:

NDC 66582-312-31 bottles of 30

NDC 66582-312-54 bottles of 90

NDC 66582-312-82 bottles of 1000 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)
NDC 66582-312-87 bottles of 10,000 (If repackaged in blisters,
then opaque or light-resistant blisters should be used.)

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

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

They are supplied as follows:

NDC 66582-313-31 bottles of 30

NDC 66582-313-54 bottles of 90

NDC 66582-313-74 bottles of 500 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)
NDC 66582-313-86 bottles of 5000 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

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

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

They are supplied as follows:

NDC 66582-315-31 bottles of 30

NDC 66582-315-54 bottles of 90

NDC 66582-315-74 bottles of 500 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)
NDC 66582-315-66 bottles of 2500 (If repackaged in blisters, then
opaque or light-resistant blisters should be used.)

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

Storage

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

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

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

Issued November 2005

Printed in USA

Manufactured for:

MERCK/Schering-Plough Pharmaceuticals

North Wales, PA 19454, USA

By:

MSD Technology Singapore Pte. Ltd.

Singapore 637766

Or

Merck Sharp & Dohme (Italia) S.p.A.

Via Emilia, 21

27100 - Pavia

Italy

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

(2) Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson,
W.P., Postmarketing Surveillance of Lovastatin and Simvastatin
Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446,
1996.

9621003

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

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

What is VYTORIN?

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

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

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

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

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

VYTORIN is a medicine used to lower levels of total cholesterol,
LDL (bad) cholesterol, and fatty substances called triglycerides in
the blood. In addition, VYTORIN raises levels of HDL (good)
cholesterol. It is used for patients who cannot control their
cholesterol levels by diet alone. You should stay on a
cholesterol-lowering diet while taking this medicine.
VYTORIN works to reduce your cholesterol in two ways. It reduces
the cholesterol absorbed in your digestive tract, as well as the
cholesterol your body makes by itself. VYTORIN does not help you lose
weight.
For more information about cholesterol, see the section called
"What should I know about high cholesterol?"

Who should not take VYTORIN?

Do not take VYTORIN:

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

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

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

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

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

Tell your doctor right away if you experience unexplained muscle
pain, tenderness, or weakness. This is because on rare occasions,
muscle problems can be serious, including muscle breakdown resulting
in kidney damage.
The risk of muscle breakdown is greater at higher doses of
VYTORIN.
The risk of muscle breakdown is greater in patients with kidney
problems.
Taking VYTORIN with certain substances can increase the risk of
muscle problems. It is particularly important to tell your doctor if
you are taking any of the following:

-- cyclosporine
-- danazol
-- antifungal agents (such as itraconazole or ketoconazole)
-- fibric acid derivatives (such as gemfibrozil, bezafibrate, or
fenofibrate)
-- the antibiotics erythromycin, clarithromycin, and
telithromycin
-- HIV protease inhibitors (such as indinavir, nelfinavir,
ritonavir, and saquinavir)
-- the antidepressant nefazodone
-- amiodarone (a drug used to treat an irregular heartbeat)
-- verapamil (a drug used to treat high blood pressure, chest
pain associated with heart disease, or other heart conditions)
-- large doses ((>=)1 g/day) of niacin or nicotinic acid
-- large quantities of grapefruit juice (>1 quart daily)

It is also important to tell your doctor if you are taking
coumarin anticoagulants (drugs that prevent blood clots, such as
warfarin).
Tell your doctor about any prescription and nonprescription
medicines you are taking or plan to take, including natural or herbal
remedies.
Tell your doctor about all your medical conditions including
allergies.

Tell your doctor if you:

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

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

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

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

How should I take VYTORIN?

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

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

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

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

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

What should I do in case of an overdose?

Contact your doctor immediately.

What are the possible side effects of VYTORIN?

See your doctor regularly to check your cholesterol level and to
check for side effects. Your doctor may do blood tests to check your
liver before you start taking VYTORIN and during treatment.
In clinical studies patients reported the following common side
effects while taking VYTORIN: headache and muscle pain (see What
should I tell my doctor before and while taking VYTORIN?).
The following side effects have been reported in general use with
either ezetimibe or simvastatin tablets (tablets that contain the
active ingredients of VYTORIN):

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

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

What should I know about high cholesterol?

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

Triglycerides also are fats found in your body.

General Information about VYTORIN

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

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

Issued June 2005
Manufactured for:
Merck/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA

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