Merck Expresses Confidence in the Efficacy and Safety Profiles of ZETIA® (ezetimibe) and VYTORIN® (ezetimibe/simvastatin) as Effective Medicines for Managing Elevated Cholesterol

Sun Nov 15, 2009 6:12pm EST
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http://www.businesswire.com/news/home/20091115005070/en

ORLANDO, Fla.--(Business Wire)--
At the American Heart Association meeting today, Merck & Co., Inc. said it is
confident in the safety and efficacy profiles of ZETIA® (ezetimibe) and VYTORIN®
(ezetimibe/simvastatin), and issued the following comment in response to
misinterpretation of results from a small 200-patient imaging study called
ARBITER 6. 

"The results of the small ARBITER 6 study do not, in any way, change our view of
ZETIA and VYTORIN as effective medicines for fighting high LDL cholesterol,"
said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "Nothing from
this study, which a New England Journal of Medicine editorial says has 'several
limitations,' changes the well established understanding that lowering LDL
cholesterol is the primary target of therapy according to the guidelines. ZETIA
and VYTORIN, when used as a supplement to a healthy diet, are effective in
reducing LDL cholesterol," said Dr. Kim. "We encourage patients to continue
taking their medication as prescribed by their physicians, and of course to
speak to their physician if they have concerns." 

The results of ARBITER 6 were widely predicted because the study design favored
niacin as the patient population selected had well-controlled LDL cholesterol
and relatively low HDL cholesterol. Also, it is important to remember that
ARBITER 6 is not an outcomes study, and does not have the rigor or size to
provide meaningful insight into the effect of either niacin or ezetimibe on
clinical outcomes. Merck has reviewed the data from 43 completed shorter-term
clinical trials involving approximately 2,400 patients who received ezetimibe
alone and 13,600 patients who received ezetimibe with statins, as well as two
longer-term studies, and is confident that the data support the safety profiles
of ZETIA and VYTORIN as described in their labels. 

"Any suggestion that the results of ARBITER 6 can definitively answer the
question of the impact of ezetimibe on cardiovascular outcomes or that its
results have implications for clinical use should be met with skepticism," said
Dr. Kim. "Given the broadly accepted, scientifically validated importance of
lowering LDL and the millions of people in the United States alone who are not
at their recommended treatment goals, VYTORIN and ZETIA remain effective options
for physicians to treat their appropriate patients." 

Both niacin and ezetimibe have established effects on lipids, as noted in the
prescribing information for these medicines. We look forward to the results from
IMPROVE-IT, the large, longer-term clinical outcomes trial underway to
understand whether additional LDL-lowering with ezetimibe reduces cardiovascular
outcomes. There are other separate large, longer-term clinical outcomes trials
being conducted to understand the role of raising HDL in reducing cardiovascular
outcomes. 

Physicians need multiple options to help manage their patients' cholesterol

There are millions of patients with high LDL cholesterol. There are also
millions of patients with elevated LDL cholesterol in addition to other lipid
abnormalities like elevated triglycerides. Physicians need multiple options like
ezetimibe and niacin to help manage patients' different lipid abnormalities.
Ezetimibe remains an effective medicine to do what it is approved by FDA and 89
other regulatory agencies to do: help lower LDL cholesterol as an adjunct to
diet when diet alone is not enough. 

According to Lipid Treatment Assessment Project 2 (Circulation 2009),
approximately 65 percent of very high-risk patients in the United States did not
reach their optimal LDL goal of less than 70 mg/dL. 

In separate head-to-head clinical studies, VYTORIN was shown to be more
effective than simvastatin, Lipitor, or Crestor at lowering LDL cholesterol at
the doses compared: VYTORIN provided >50 percent mean LDL cholesterol reduction.
In addition, in these separate studies, VYTORIN helped more patients achieve a
goal of <70 mg/dL than did simvastatin a, Lipitor b, or Crestor c 1. The
clinical impact of comparative differences in lipid changes between products is
not known. VYTORIN has not been shown to reduce heart attacks and strokes more
than simvastatin alone. 

Merck is well prepared to help our customers understand our position on the
ARBITER 6 study and that ZETIA and VYTORIN are effective options for physicians
to use to manage their patients' cholesterol. 

Merck's commitment to cardiovascular medicine

Following the merger of Merck with Schering-Plough, today's Merck has a robust
research effort aimed at cardiovascular disease. 

"No other health care company is doing more to study cardiovascular disease than
today's Merck," said Dr. Kim. 

Important information about VYTORIN

VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive
therapy to diet for the reduction of elevated total cholesterol, LDL
cholesterol, Apo B2 , triglycerides and non-HDL cholesterol and to increase HDL
cholesterol in patients with primary (heterozygous familial and non-familial)
hypercholesterolemia or mixed hyperlipidemia. 

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

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported
to a doctor promptly because these could be signs of a serious side effect.
VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help
avoid serious side effects, patients should talk to their doctor about medicine
or food they should avoid while taking VYTORIN. In three placebo-controlled,
12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum
transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6
percent for patients treated with VYTORIN 10/80 mg. In controlled long-term
(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 percent overall and 3.6 percent for patients treated with
VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic,
not associated with cholestasis and returned to baseline after discontinuation
of therapy or with continued treatment. Doctors should perform blood tests
before, and periodically during treatment with VYTORIN when clinically indicated
to check for liver problems. People taking VYTORIN 10/80 mg should receive an
additional liver function test prior to and three months after titration and
periodically during the first year. 

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

VYTORIN has been evaluated for safety in more than 10,100 patients in clinical
trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40
mg, 10/80 mg). In clinical trials, the most commonly reported side effects,
regardless of cause, included headache (5.8 percent), increased ALT (3.7
percent), myalgia (3.6 percent), upper respiratory tract infection (3.6
percent), and diarrhea (2.8 percent). 

VYTORIN is available as tablets containing 10 mg of ezetimibe combined with 10,
20, 40 or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40 or 10/80 mg,
respectively). 

Important information about ZETIA

ZETIA, along with diet, is indicated for use either by itself or together with
statins or fenofibrate in patients with high cholesterol to reduce LDL
cholesterol and total cholesterol when the response to diet and exercise has
been inadequate. 

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

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

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

In clinical trials, regardless of causality assessment, the most frequent side
effects for ZETIA co-administered with a statin vs. statin alone included
nasopharyngitis (3.7 percent vs. 3.3 percent), myalgia (3.2 percent vs. 2.7
percent), upper respiratory tract infection (2.9 percent vs. 2.8 percent),
arthralgia (2.6 percent vs. 2.4 percent), and diarrhea (2.5 percent vs. 2.2
percent); for ZETIA administered alone vs. placebo: upper respiratory tract
infection (4.3 percent vs. 2.5 percent), diarrhea (4.1 percent vs. 3.7 percent),
arthralgia (3.0 percent vs. 2.2 percent), sinusitis (2.8 percent vs. 2.2
percent), and pain in extremity (2.7 percent vs. 2.5 percent). 

Data

a Mean LDL-C decrease from baseline following treatment in a multicenter,
double-blind, placebo-controlled, 12-week trial (N=1,528) in patients with
hypercholesterolemia. Patients were randomized to receive 1 of 10 treatments:
placebo, ezetimibe (10 mg), simvastatin (10, 20, 40, or 80 mg), or VYTORIN
(10/10, 10/20, 10/40, or 10/80 mg). Mean baseline LDL-C was 176 mg/dL for all
doses of VYTORIN and 178 mg/dL for all doses of simvastatin.3 The mean percent
reduction in LDL-C for patients taking VYTORIN 10/10 mg was 45 percent vs. 33
percent for patients taking simvastatin 10 mg; VYTORIN 10/20 mg was 52 percent
vs. 34 percent for simvastatin 20 mg; VYTORIN 10/40 mg was 55 percent vs. 41
percent for simvastatin 40 mg; VYTORIN 10/80 mg was 60 percent vs. 49 percent
for simvastatin 80 mg (P<0.001). 13 percent of patients taking VYTORIN 10/10 mg
achieved LDL-C <70 mg/dL vs. 0 percent of patients taking simvastatin 10 mg; 33
percent for VYTORIN 10/20 mg vs. 2 percent for simvastatin 20 mg; 51 percent for
VYTORIN 10/40 mg vs. 4 percent for simvastatin 40 mg; 59 percent for VYTORIN
10/80 mg vs. 22 percent for simvastatin 80 mg (P<0.0001).4

b Mean percent change in LDL-C from untreated baseline in a multicenter,
double-blind, randomized, active-controlled, 8-arm, parallel-group study (6
weeks of active treatment) (N=1,902). Patients with hypercholesterolemia who had
not met their LDL-C goal as defined by NCEP ATP III were randomized to VYTORIN
10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg. Mean
pooled baseline LDL-C values for VYTORIN and atorvastatin were 178 mg/dL and 179
mg/dL, respectively.5 The mean percent reduction in LDL-C for patients taking
VYTORIN 10/10 mg was 47 percent vs. 36 percent for patients taking atorvastatin
10 mg; VYTORIN 10/20 mg was 51 percent vs. 44 percent for atorvastatin 20 mg;
VYTORIN 10/40 mg was 57 percent vs. 48 percent for atorvastatin 40 mg; VYTORIN
10/80 mg was 59 percent vs. 53 percent for atorvastatin 80 mg (P<0.05). Sixteen
percent of patients taking VYTORIN 10/10 mg achieved LDL-C <70 mg/dL vs. 4
percent of patients taking atorvastatin 10 mg; 29 percent for VYTORIN 10/20 mg
vs. 11 percent for atorvastatin 20 mg; 44 percent for VYTORIN 10/40 mg vs. 19
percent for atorvastatin 40 mg; 56 percent for VYTORIN 10/80 mg vs. 33 percent
for atorvastatin 80 mg (P<0.001).6

c Data from a multicenter, randomized, double-blind, active-controlled, 6-arm,
parallel-group study designed to evaluate the efficacy and safety of VYTORIN vs
rosuvastatin over a 6-week period. Patients with hypercholesterolemia (N=2,959)
were randomized to 1 of 6 treatment groups: VYTORIN 10/20, 10/40, or 10/80 mg or
rosuvastatin 10, 20, or 40 mg. Mean pooled baseline LDL-C levels for VYTORIN and
rosuvastatin were 172 mg/dL and 173 mg/dL, respectively. Mean baseline LDL-C
values for VYTORIN 10/20 mg (n=476), rosuvastatin 10 mg (n=475), VYTORIN 10/40
mg (n=477), rosuvastatin 20 mg (n=478), VYTORIN 10/80 mg (n=474), and
rosuvastatin 40 mg (n=475) were 172 mg/dL, 172 mg/dL, 173 mg/dL, 173 mg/dL, 172
mg/dL, and 173 mg/dL, respectively.7 The mean percent reduction in LDL-C for
patients taking VYTORIN 10/20 mg was 52 percent vs. 46 percent for patients
taking rosuvastatin 10 mg; VYTORIN 10/40 mg was 55 percent vs. 52 percent for
rosuvastatin 20 mg; VYTORIN 10/80 mg was 61 percent vs. 57 percent for
rosuvastatin 40 mg; (P<0.05). Twenty-four percent of patients taking VYTORIN
10/20 mg achieved LDL-C <70 mg/dL vs. 9 percent of patients taking rosuvastatin
10 mg; 41 percent for VYTORIN 10/40 mg vs. 30 percent for rosuvastatin 20 mg; 66
percent for VYTORIN 10/80 mg vs. 50 percent for rosuvastatin 40 mg (P<0.001) 7

About Merck

Today's Merck is working to help the world be well. Through our medicines,
vaccines, biologic therapies, and consumer and animal products, we work with
customers and operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to health
care through far-reaching programs that donate and deliver our products to the
people who need them. Merck. Be Well. For more information, visit www.merck.com.


Forward Looking Statement

This news release includes "forward-looking statements" within the meaning of
the safe harbor provisions of the United States Private Securities Litigation
Reform Act of 1995. Such statements may include, but are not limited to,
statements about the benefits of the merger between Merck and Schering-Plough,
including future financial and operating results, the combined company`s plans,
objectives, expectations and intentions and other statements that are not
historical facts. Such statements are based upon the current beliefs and
expectations of Merck`s management and are subject to significant risks and
uncertainties. Actual results may differ from those set forth in the
forward-looking statements. 

The following factors, among others, could cause actual results to differ from
those set forth in the forward-looking statements: the possibility that the
expected synergies from the merger of Merck and Schering-Plough will not be
realized, or will not be realized within the expected time period, due to, among
other things, the impact of pharmaceutical industry regulation and pending
legislation that could affect the pharmaceutical industry; the risk that the
businesses will not be integrated successfully; disruption from the merger
making it more difficult to maintain business and operational relationships;
Merck`s ability to accurately predict future market conditions; dependence on
the effectiveness of Merck`s patents and other protections for innovative
products; the risk of new and changing regulation and health policies in the
U.S. and internationally and the exposure to litigation and/or regulatory
actions. 

Merck undertakes no obligation to publicly update any forward-looking statement,
whether as a result of new information, future events or otherwise. Additional
factors that could cause results to differ materially from those described in
the forward-looking statements can be found in Merck`s 2008 Annual Report on
Form 10-K, Schering-Plough`s Quarterly Report on Form 10-Q for the quarterly
period ended Sept. 30, 2009, the proxy statement filed by Merck on June 25, 2009
and each company`s other filings with the Securities and Exchange Commission
(SEC) available at the SEC`s Internet site (www.sec.gov). 

1 See Data section for further information. 

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

3 Bays H, Ose L, Fraser N, et al; for Ezetimibe Study Group. A multicenter,
randomized, double-blind, placebo-controlled, factorial design study to evaluate
the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin
tablet compared with ezetimibe and simvastatin monotherapy in patients with
primary hypercholesterolemia. Clin Ther. 2004;26(11):1758-1773. 

4 Data available on request from Merck & Co., Inc., Professional Services-DAP,
WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package
20902252(1)-VYT. 

5 Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of
the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in
patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA)
study. Am Heart J. 2005;149(3):464-473. 

6 Data available on request from Merck & Co., Inc., Professional Services-DAP,
WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package
20902475(1)-VYT. 

7 Catapano AL, Davidson MH, Ballantyne CM, et al. Lipid-altering efficacy of the
ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic
patients. Curr Med Res Opin. 2006;22(10):2041-2053. 

Prescribing information and patient product information for VYTORIN and ZETIA
are attached.

ZETIA® and VYTORIN® are registered trademarks of MSP Singapore Company LLC.All
other brands are trademarks of their respective owners and are not trademarks of
MSP Singapore Company LLC.

9619513 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VYTORIN safely
and effectively. See full prescribing information for VYTORIN.

VYTORIN (ezetimibe/simvastatin) Tablets

Initial U.S. Approval:2004

INDICATIONS AND USAGE

VYTORIN®, which contains a cholesterol absorption inhibitor and an HMG-CoA
reductase inhibitor (statin), is indicated as adjunctive therapy to diet to:

* reduce 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)
hyperlipidemia or mixed hyperlipidemia. (1.1) 
* reduce elevated total-C and LDL-C in patients with homozygous familial
hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments.
(1.2)

Limitations of Use (1.3)

* No incremental benefit of VYTORIN on cardiovascular morbidity and mortality
over and above that demonstrated for simvastatin has been established. VYTORIN
has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

DOSAGE AND ADMINISTRATION

* Dosage range is 10/10 mg/day through 10/80 mg/day. (2.1) 
* Recommended usual starting dose is 10/20 mg/day. (2.1) 
* Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after
administration of a bile acid sequestrant. (2.6, 7.4)

DOSAGE FORMS AND STRENGTHS

* Tablets (ezetimibe mg/simvastatin mg): 10/10, 10/20, 10/40, 10/80 (3)

CONTRAINDICATIONS

* Hypersensitivity to any component of this medication (4, 6.2) 
* Active liver disease or unexplained persistent elevations of hepatic
transaminase levels (4, 5.2) 
* Women who are pregnant or may become pregnant (4, 8.1) 
* Nursing mothers (4, 8.3)

WARNINGS AND PRECAUTIONS

* Patients should be advised to report promptly any symptoms of myopathy.
VYTORIN should be discontinued immediately if myopathy is diagnosed or
suspected. (5.1) 
* Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase
with higher doses and concomitant use of certain CYP3A4 inhibitors, gemfibrozil,
cyclosporine, danazol, amiodarone, and verapamil. Predisposing factors include
advanced age (≥65), uncontrolled hypothyroidism, and renal impairment. (5.1,
8.5, 8.6) 
* Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic
transaminase can occur. Monitor liver enzymes before and during treatment.
Patients titrated to the 10/80-mg dose should receive additional liver function
tests. (5.2) 
* VYTORIN is not recommended in patients with moderate or severe hepatic
impairment. (5.3, 12.3)

ADVERSE REACTIONS

* Common (incidence ≥2% and greater than placebo) adverse reactions in clinical
trials: headache, increased ALT, myalgia, upper respiratory tract infection, and
diarrhea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Merck/Schering-Plough
Pharmaceuticals at 1-866-637-2501 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.

DRUG INTERACTIONS

 Drug Interactions Associated with Increased                                             
 Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.5, 7.7)                     
 Interacting Agents                              Prescribing Recommendations           
 Itraconazole, ketoconazole, erythromycin,       Avoid VYTORIN                         
 clarithromycin, telithromycin, HIV protease                                           
 inhibitors, nefazodone, fibrates                                                      
 Cyclosporine, danazol                           Do not exceed 10/10 mg VYTORIN daily  
 Amiodarone, verapamil                           Do not exceed 10/20 mg VYTORIN daily  
 Grapefruit juice                                Avoid large quantities of grapefruit  
                                                 juice (>1 quart daily)                


* Cyclosporine: Combination increases exposure of ezetimibe and cyclosporine.
Cyclosporine concentrations should be monitored. (7.5, 12.3) 
* Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable INR prior to
starting VYTORIN. Monitor INR frequently until stable upon initiation or
alteration of VYTORIN therapy. (7.8) 
* Cholestyramine: Combination decreases exposure of ezetimibe. (2.6, 7.4)

USE IN SPECIFIC POPULATIONS

* Severe renal impairment: Caution should be exercised and the patient should be
closely monitored. (2.4, 8.6)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 05/2009

FULL PRESCRIBING INFORMATION: CONTENTS*

1INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia 

1.2 Homozygous Familial Hypercholesterolemia (HoFH) 

1.3 Limitations of Use 

2DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing 

2.2 Patients with Homozygous Familial Hypercholesterolemia 

2.3 Patients with Hepatic Impairment 

2.4 Patients with Renal Impairment 

2.5 Geriatric Patients 

2.6 Coadministration with Other Drugs 

3DOSAGE FORMS AND STRENGTHS

4CONTRAINDICATIONS

5WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis 

5.2 Liver Enzymes 

5.3 Hepatic Impairment 

6ADVERSE REACTIONS

6.1 Clinical Trials Experience 

6.2 Post-Marketing Experience 

7DRUG INTERACTIONS

7.1 CYP3A4 Interactions 

7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone 

7.3 Amiodarone or Verapamil 

7.4 Cholestyramine 

7.5 Cyclosporine or Danazol 

7.6 Digoxin 

7.7 Fibrates 

7.8 Coumarin Anticoagulants 

8USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

8.3 Nursing Mothers 

8.4 Pediatric Use 

8.5 Geriatric Use 

8.6 Renal Impairment 

8.7 Hepatic Impairment 

10OVERDOSAGE

11DESCRIPTION

12CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 

12.2 Pharmacodynamics 

12.3 Pharmacokinetics 

13NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 

13.2 Animal Toxicology and/or Pharmacology 

14CLINICAL STUDIES

14.1 Primary Hyperlipidemia 

14.2 Homozygous Familial Hypercholesterolemia (HoFH) 

16HOW SUPPLIED/STORAGE AND HANDLING

17PATIENT COUNSELING INFORMATION

17.1 Muscle Pain 

17.2 Liver Enzymes 

17.3 Pregnancy 

17.4 Breast-feeding 

17.5 FDA-Approved Patient Labeling 

*Sections or subsections omitted from the full prescribing information are not
listed. 

FULL PRESCRIBING INFORMATION

1INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk
factor intervention in individuals at significantly increased risk for
atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is
indicated as an adjunct to diet when the response to a diet restricted in
saturated fat and cholesterol and other nonpharmacologic measures alone has been
inadequate. 

1.1Primary Hyperlipidemia

VYTORIN is indicated for the reduction of elevated total cholesterol (total-C),
low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B),
triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C),
and to increase high-density lipoprotein cholesterol (HDL-C) in patients with
primary (heterozygous familial and non-familial) hyperlipidemia or mixed
hyperlipidemia. 

1.2Homozygous 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. 

1.3Limitations of Use

No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over
and above that demonstrated for simvastatin has been established. VYTORIN has
not been studied in Fredrickson type I, III, IV, and V dyslipidemias. 

2DOSAGE AND ADMINISTRATION

2.1Recommended Dosing

The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual
starting dose is 10/20 mg/day. VYTORIN should be taken as a single daily dose in
the evening, with or without food. 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. 

2.2Patients 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. 

2.3Patients with Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment [see
Warnings and Precautions (5.3)]. 

2.4Patients with Renal Impairment

No dosage adjustment is necessary in patients with mild or moderate renal
impairment. 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 Warnings and Precautions (5.1); Clinical Pharmacology (12.3)]. 

2.5Geriatric Patients

No dosage adjustment is necessary in geriatric patients [see Clinical
Pharmacology (12.3)]. 

2.6Coadministration with Other Drugs

[See Warnings and Precautions (5.1) and Drug Interactions (7).]

Bile Acid Sequestrants

Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours after
administration of a bile acid sequestrant [see Drug Interactions (7.4)]. 

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 [see
Drug Interactions (7.5)]. 

Amiodarone or Verapamil

In patients taking amiodarone or verapamil concomitantly with VYTORIN, the dose
should not exceed 10/20 mg/day [see Warnings and Precautions (5.1) and Drug
Interactions (7.3)]. 

Other Concomitant Lipid-Lowering Therapy

The safety and effectiveness of VYTORIN administered with fibrates have not been
established. Therefore, the combination of VYTORIN and fibrates should be
avoided [see Warnings and Precautions (5.1) and Drug Interactions (7.2 and
7.7)]. 

There is an increased risk of myopathy when simvastatin is used concomitantly
with fibrates (especially gemfibrozil). Combination therapy with gemfibrozil
should be avoided because of an increase in simvastatin exposure with
concomitant use. [See Warnings and Precautions (5.1) and Drug Interactions (7.2
and 7.7).]

3DOSAGE FORMS AND STRENGTHS

* VYTORIN® 10/10, (ezetimibe 10 mg/simvastatin 10 mg tablets) are white to
off-white capsule-shaped tablets with code "311" on one side. 
* VYTORIN® 10/20, (ezetimibe 10 mg/simvastatin 20 mg tablets) are white to
off-white capsule-shaped tablets with code "312" on one side. 
* VYTORIN® 10/40, (ezetimibe 10 mg/simvastatin 40 mg tablets) are white to
off-white capsule-shaped tablets with code "313" on one side. 
* VYTORIN® 10/80, (ezetimibe 10 mg/simvastatin 80 mg tablets) are white to
off-white capsule-shaped tablets with code "315" on one side.

4CONTRAINDICATIONS

Hypersensitivity to any component of this medication [see Adverse Reactions
(6.2)]. 

Active liver disease or unexplained persistent elevations in hepatic
transaminase levels [see Warnings and Precautions (5.2)]. 

Women who are pregnant or may become pregnant. Serum cholesterol and
triglycerides increase during normal pregnancy, and cholesterol or cholesterol
derivatives are essential for fetal development. Because HMG-CoA reductase
inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and
possibly the synthesis of other biologically active substances derived from
cholesterol, VYTORIN may cause fetal harm when administered to a pregnant woman.
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. There are no adequate and
well-controlled studies of VYTORIN use during pregnancy; however, in rare
reports congenital anomalies were observed following intrauterine exposure to
statins. In rat and rabbit animal reproduction studies, simvastatin revealed no
evidence of teratogenicity. 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 Use in Specific Populations (8.1)]. 

Nursing mothers. It is not known whether simvastatin is excreted into human
milk; however, a small amount of another drug in this class does pass into
breast milk. Because statins have the potential for serious adverse reactions in
nursing infants, women who require VYTORIN treatment should not breast-feed
their infants [see Use in Specific Populations (8.3)]. 

5WARNINGS AND PRECAUTIONS

5.1Myopathy/Rhabdomyolysis

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated
with ezetimibe compared with the relevant control arm (placebo or statin alone).
However, myopathy and rhabdomyolysis are known adverse reactions to statins 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, 0.6% for placebo, 0.0% for
ezetimibe, and 0.3% for all simvastatin doses. 

Simvastatin, like other statins, 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 statin activity in plasma.
Predisposing factors for myopathy include advanced age (≥65 years), uncontrolled
hypothyroidism, and renal impairment. 

As with other statins, 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. 

In post-marketing experience with ezetimibe, cases of myopathy and
rhabdomyolysis have been reported. 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. 

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. 

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by high levels of statin
activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform
3A4. Certain drugs that inhibit this metabolic pathway can raise the plasma
levels of simvastatin and may increase the risk of myopathy. These include
itraconazole, ketoconazole, and other antifungal azoles, the macrolide
antibiotics erythromycin and clarithromycin, and the ketolide antibiotic
telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large
quantities of grapefruit juice (>1 quart daily). The use of VYTORIN
concomitantly with these CYP3A4 inhibitors should be avoided. If treatment with
itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is
unavoidable, therapy with VYTORIN should be suspended during the course of
treatment. [See Drug Interactions (7).]

The benefits of the combined use of VYTORIN with the following drugs should be
carefully weighed against the potential risks of combinations: gemfibrozil,
other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), cyclosporine,
danazol, amiodarone, or verapamil. 

Caution should be used when prescribing other fibrates or lipid-lowering doses
(≥1 g/day) of niacin with VYTORIN, as these agents can cause myopathy when given
alone. 

Prescribing recommendations for interacting agents are summarized in Table 1
[see also Dosage and Administration (2.6), Drug Interactions (7), and Clinical
Pharmacology (12.3)].

 Table 1                                                             
 Drug Interactions Associated with Increased                         
 Risk of Myopathy/Rhabdomyolysis                                     
 Interacting Agents          Prescribing Recommendations           
 Itraconazole                Avoid VYTORIN                         
 Ketoconazole                                                      
 Erythromycin                                                      
 Clarithromycin                                                    
 Telithromycin                                                     
 HIV protease inhibitors                                           
 Nefazodone                                                        
 Fibrates*                                                         
 Cyclosporine†               Do not exceed 10/10 mg VYTORIN daily  
 Danazol†                                                          
 Amiodarone‡                 Do not exceed 10/20 mg VYTORIN daily  
 Verapamil‡                                                        
 Grapefruit juice            Avoid large quantities of grapefruit  
                             juice (>1 quart daily)                


* Combination therapy with fibrates should be avoided; however, although not
recommended, if VYTORIN is used in combination with gemfibrozil, the dose should
not exceed 10/10 mg daily. 

† The benefits of the use of VYTORIN in patients receiving cyclosporine or
danazol should be carefully weighed against the risks of these combinations. 

‡ 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. 

5.2Liver 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. 

5.3Hepatic Impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients
with moderate or severe hepatic impairment, VYTORIN is not recommended in these
patients. [See Clinical Pharmacology (12.3).]

6ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other
sections of the label:

* Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
* Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

6.1Clinical Trials Experience

VYTORIN

Because clinical studies are conducted under widely varying conditions, adverse
reaction rates observed in the clinical studies of a drug cannot be directly
compared to rates in the clinical studies of another drug and may not reflect
the rates observed in practice. 

In the VYTORIN (ezetimibe/simvastatin) placebo-controlled clinical trials
database of 1420 patients (age range 20-83 years, 52% women, 87% Caucasians, 3%
Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks,
5% of patients on VYTORIN and 2.2% of patients on placebo discontinued due to
adverse reactions. 

The most common adverse reactions in the group treated with VYTORIN that led to
treatment discontinuation and occurred at a rate greater than placebo were:

* Increased ALT (0.9%) 
* Myalgia (0.6%) 
* Increased AST (0.4%) 
* Back pain (0.4%)

The most commonly reported adverse reactions (incidence ≥2% and greater than
placebo) in controlled clinical trials were: headache (5.8%), increased ALT
(3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea
(2.8%). 

VYTORIN has been evaluated for safety in more than 10,189 patients in clinical
trials. 

Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2%
of patients treated with VYTORIN (n=1420) and at an incidence greater than
placebo, regardless of causality assessment, from four placebo-controlled
trials.

 Table 2*                                                                                                         
 Clinical Adverse Reactions Occurring in                                                                          
 
≥2% of Patients Treated with VYTORIN and at an Incidence Greater than Placebo,                                  
 
Regardless of Causality                                                                                         
                                                                                                          
 Body System/Organ Class                            Placebo    Ezetimibe    Simvastatin**     VYTORIN**   
 Adverse Reaction                                   (%)        10 mg        
(%)              
(%)        
                                                    n=371      (%)          n=1234            n=1420      
                                                               n=302                                      
 Body as a whole - general disorders                                                                      
 Headache                                           5.4        6.0          5.9               5.8         
 Gastrointestinal system disorders                                                                        
 Diarrhea                                           2.2        5.0          3.7               2.8         
 Infections and infestations                                                                              
 Influenza                                          0.8        1.0          1.9               2.3         
 Upper respiratory tract infection                  2.7        5.0          5.0               3.6         
 Musculoskeletal and connective tissue disorders                                                          
 Myalgia                                            2.4        2.3          2.6               3.6         
 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 two placebo-controlled
studies in which VYTORIN was administered. 

**All doses. 

Ezetimibe

Other adverse reactions reported with ezetimibe in placebo-controlled studies,
regardless of causality assessment: Musculoskeletal system disorders:
arthralgia; Infections and infestations: sinusitis; Body as a whole - general
disorders: fatigue. 

Simvastatin

Other adverse reactions reported with simvastatin in placebo-controlled clinical
studies, regardless of causality assessment: Cardiac disorders: atrial
fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders:
abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and
subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes
mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract
infections; Body as a whole - general disorders: asthenia, edema/swelling;
Psychiatric disorders: insomnia. 

Laboratory Tests

Marked persistent increases of hepatic serum transaminases have been noted [see
Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl
transpeptidase have been reported. 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 [see Warnings
and Precautions (5.1)]. 

6.2Post-Marketing Experience

Because the below reactions are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. 

The following adverse reactions have been reported in post-marketing experience
for VYTORIN or ezetimibe or simvastatin: pruritus; alopecia; erythema
multiforme; a variety of skin changes (e.g., nodules, discoloration, dryness of
skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps;
myalgia; arthralgia; pancreatitis; memory impairment; paresthesia; peripheral
neuropathy; vomiting; nausea; anemia; myopathy/rhabdomyolysis [see Warnings and
Precautions (5.1)]; hepatitis/jaundice; hepatic failure; depression;
cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver
transaminases; elevated creatine phosphokinase. 

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and
urticaria have been reported. 

In addition, an apparent hypersensitivity syndrome has been reported rarely that
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. 

7DRUG INTERACTIONS

[See Clinical Pharmacology(12.3).]

VYTORIN

7.1CYP3A4 Interactions

The risk of myopathy is increased by reducing the elimination of the simvastatin
component of VYTORIN. Hence when VYTORIN is used with an inhibitor of CYP3A4
(e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory
activity can increase the risk of myopathy and rhabdomyolysis, particularly with
higher doses of VYTORIN. [See Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3).]

Itraconazole, ketoconazole, and other antifungal azoles

Macrolide antibiotics erythromycin, clarithromycin, and the ketolide antibiotic
telithromycin

HIV protease inhibitors

Antidepressant nefazodone

Grapefruit juice in large quantities (>1 quart daily)

Concomitant use of these drugs and any medication labeled as having a strong
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. 

7.2Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

The risk of myopathy is increased by gemfibrozil and to a lesser extent by other
fibrates and niacin (nicotinic acid) (≥1 g/day) [see Warnings and Precautions
(5.1)]. 

7.3Amiodarone or Verapamil

The risk of myopathy/rhabdomyolysis is increased by concomitant administration
of amiodarone or verapamil with higher doses of VYTORIN [see Warnings and
Precautions (5.1)]. 

7.4Cholestyramine

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. 

7.5Cyclosporine or Danazol

The risk of myopathy/rhabdomyolysis is increased by concomitant administration
of cyclosporine or danazol particularly with higher doses of VYTORIN [see
Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. 

Caution should be exercised when using VYTORIN and cyclosporine concomitantly
due to increased exposure to both ezetimibe and cyclosporine [see Dosage and
Administration (2.6)]. Cyclosporine concentrations should be monitored in
patients receiving VYTORIN and cyclosporine [see Clinical Pharmacology (12.3)]. 

The degree of increase in ezetimibe exposure may be greater in patients with
severe renal impairment. 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. [See Warnings and Precautions (5.1) and Clinical Pharmacology
(12.3).]

7.6Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in
a slight elevation in plasma digoxin concentrations. Patients taking digoxin
should be monitored appropriately when VYTORIN is initiated. 

7.7Fibrates

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 Toxicology and/or Pharmacology (13.2)].
Coadministration of VYTORIN with fibrates is not recommended until use in
patients is studied. [See Warnings and Precautions (5.1).]

7.8Coumarin Anticoagulants

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 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. 

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

Pregnancy Category X.

[See Contraindications (4).]

VYTORIN

VYTORIN is contraindicated in women who are or may become pregnant.
Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and
cholesterol derivatives are needed for normal fetal development. Atherosclerosis
is a chronic process, and discontinuation of lipid-lowering drugs during
pregnancy should have little impact on long-term outcomes of primary
hypercholesterolemia therapy. There are no adequate and well-controlled studies
of VYTORIN use during pregnancy; however, there are rare reports of congenital
anomalies in infants exposed to statins in utero. Animal reproduction studies of
simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum
cholesterol and triglycerides increase during normal pregnancy, and cholesterol
or cholesterol derivatives are essential for fetal development. Because statins,
such as simvastatin, decrease cholesterol synthesis and possibly the synthesis
of other biologically active substances derived from cholesterol, VYTORIN may
cause fetal harm when administered to a pregnant woman. If VYTORIN is used
during pregnancy or if the patient becomes pregnant while taking this drug, the
patient should be apprised of the potential hazard to the fetus. 

Women of childbearing potential, who require VYTORIN treatment for a lipid
disorder, should be advised to use effective contraception. For women trying to
conceive, discontinuation of VYTORIN should be considered. If pregnancy occurs,
VYTORIN should be immediately discontinued. 

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 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 or rabbits at doses (25, 10 mg/kg/day,
respectively) that resulted in 3 times the human exposure based on mg/m2 surface
area. However, in studies with another structurally-related statin, skeletal
malformations were observed in rats and mice. 

There are rare reports of congenital anomalies following intrauterine exposure
to statins. In a review1 of approximately 100 prospectively followed pregnancies
in women exposed to simvastatin or another structurally-related statin, 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. 

1 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. 

8.3Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small
amount of another drug in this class is excreted in human milk and because of
the potential for serious adverse reactions in nursing infants, women taking
simvastatin should not nurse their infants. A decision should be made whether to
discontinue nursing or discontinue drug, taking into account the importance of
the drug to the mother [see Contraindications (4)]. 

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 (4)]. 

8.4Pediatric Use

The effects of ezetimibe coadministered with simvastatin (n=126) compared to
simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls
with heterozygous familial hypercholesterolemia (HeFH). In a multicenter,
double-blind, controlled study followed by an open-label phase, 142 boys and 106
postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females,
82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized
to receive either ezetimibe coadministered with simvastatin or simvastatin
monotherapy. Inclusion in the study required 1) a baseline LDL-C level between
160 and 400 mg/dL and 2) a medical history and clinical presentation consistent
with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161-351 mg/dL) in
the ezetimibe coadministered with simvastatin group compared to 219 mg/dL
(range: 149-336 mg/dL) in the simvastatin monotherapy group. The patients
received coadministered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or
simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered
ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27
weeks, and open-label coadministered ezetimibe and simvastatin (10 mg, 20 mg, or
40 mg) for 20 weeks thereafter. 

The results of the study at Week 6 are summarized in Table 3. Results at Week 33
were consistent with those at Week 6.

 Table 3                                                                                                                                             
 
Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Coadministered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia 
                                                                                                                                         
                                                     Total-C        LDL-C           Apo B          Non-HDL-C       TGa         HDL-C     
 Mean percent difference between treatment groups    -12%           -15%            -12%           -14%            -2%         +0.1%     
 95% Confidence Interval                             (-15%, -9%)    (-18%, -12%)    (-15%, -9%)    (-17%, -11%)    (-9, +4)    (-3, +3)  
 a For triglycerides, median % change from baseline                                                                                                  


From the start of the trial to the end of Week 33, discontinuations due to an
adverse reaction occurred in 7 (6%) patients in the ezetimibe coadministered
with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy
group. 

During the trial, hepatic transaminase elevations (two consecutive measurements
for ALT and/or AST ≥3 X ULN) occurred in four (3%) individuals in the ezetimibe
coadministered with simvastatin group and in two (2%) individuals in the
simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two
(2%) individuals in the ezetimibe coadministered with simvastatin group and in
zero individuals in the simvastatin monotherapy group. 

In this limited controlled study, there was no significant effect on growth or
sexual maturation in the adolescent boys or girls, or on menstrual cycle length
in girls. 

Coadministration of ezetimibe with simvastatin at doses greater than 40 mg/day
has not been studied in adolescents. Also, VYTORIN has not been studied in
patients younger than 10 years of age or in pre-menarchal girls. 

Ezetimibe

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide) there are no
pharmacokinetic differences between adolescents and adults. Pharmacokinetic data
in the pediatric population <10 years of age are not available. 

Simvastatin

The pharmacokinetics of simvastatin has not been studied in the pediatric
population. 

8.5Geriatric Use

Of the 10,189 patients who received VYTORIN in clinical studies, 3242 (32%) were
65 and older (this included 844 (8%) who were 75 and older). No overall
differences in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients but greater
sensitivity of some older individuals cannot be ruled out. Since advanced age
(≥65 years) is a predisposing factor for myopathy, VYTORIN should be prescribed
with caution in the elderly. [See Clinical Pharmacology (12.3).]

8.6Renal Impairment

Caution should be exercised when VYTORIN is administered to patients with severe
renal impairment. [See Dosage and Administration (2.4).]

8.7Hepatic Impairment

VYTORIN is contraindicated in patients with active liver disease or unexplained
persistent elevations of hepatic transaminases. VYTORIN is not recommended in
patients with moderate to severe hepatic impairment. [See Contraindications (4)
and Warnings and Precautions (5.2).]

10OVERDOSAGE

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
hyperlipidemia 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

Significant lethality was observed in mice after a single oral dose of 9 g/m2.
No evidence of lethality was observed in rats or dogs treated with doses of 30
and 100 g/m2, respectively. No specific diagnostic signs were observed in
rodents. At these doses the only signs seen in dogs were emesis and mucoid
stools. 

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. 

11DESCRIPTION

VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and
related phytosterol absorption, and simvastatin, an 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: 

(GRAPHIC OMITTED) 

Simvastatin, an inactive lactone, is hydrolyzed to the corresponding
β-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is
butanoic acid,
2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl
ester, [1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. 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: 

(GRAPHIC OMITTED) 

VYTORINis available for oral use as tablets containing 10 mg of ezetimibe, and
10 mg of simvastatin (VYTORIN10/10), 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, hypromellose USP, lactose
monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl
gallate NF. 

12CLINICAL PHARMACOLOGY

12.1Mechanism of Action

VYTORIN

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

Ezetimibe

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

Ezetimibe localizes at the brush border of the small intestine and inhibits the
absorption of cholesterol, leading to a decrease in the delivery of intestinal
cholesterol to the liver. This causes a reduction of hepatic cholesterol stores
and an increase in clearance of cholesterol from the blood; this distinct
mechanism is complementary to that of statins [see Clinical Studies (14)]. 

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form,
simvastatin acid, after administration. Simvastatin is a specific inhibitor of
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that
catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting
step in the biosynthetic pathway for cholesterol. In addition, simvastatin
reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C. 

12.2Pharmacodynamics

Clinical studies have demonstrated that elevated levels of total-C, LDL-C and
Apo B, the major protein constituent of LDL, promote human atherosclerosis. In
addition, decreased levels of 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 VLDL, intermediate-density
lipoproteins (IDL), and remnants, can also promote atherosclerosis. The
independent effect of raising HDL-C or lowering TG on the risk of coronary and
cardiovascular morbidity and mortality has not been determined. 

12.3Pharmacokinetics

The results of a bioequivalence study in healthy subjects demonstrated that the
VYTORIN (ezetimibe/simvastatin) 10 mg/10 mg to 10 mg/80 mg combination tablets
are bioequivalent to coadministration of corresponding doses of ezetimibe
(ZETIA®) and simvastatin (ZOCOR®) as individual tablets. 

Absorption

Ezetimibe

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

Simvastatin

The availability of the β-hydroxyacid to the systemic circulation following an
oral dose of simvastatin was found to be less than 5% of the dose, consistent
with extensive hepatic first-pass extraction. 

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 β-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 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
β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA
reductase is a basis for an assay in pharmacokinetic studies of the
β-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 β-hydroxyacid of simvastatin and its 6'-hydroxy,
6'-hydroxymethyl, and 6'-exomethylene derivatives. 

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was
excreted in urine and 60% in feces. Plasma concentrations of total radioactivity
(simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to
about 10% of peak by 12 hours postdose. 

Specific 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: [See Pediatric Use (8.4).]

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 Black and Caucasian subjects. Studies in
Asian subjects indicated that the pharmacokinetics of ezetimibe was similar to
those seen in Caucasian subjects. 

Hepatic Impairment

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 impairment (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 impairment, the mean AUC for total ezetimibe and ezetimibe
increased approximately 4-fold compared to healthy subjects. 

Renal Impairment

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
impairment (as measured by creatinine clearance). 

Drug Interactions [See also Drug Interactions (7).]

No clinically significant pharmacokinetic interaction was seen when ezetimibe
was coadministered with simvastatin. No specific pharmacokinetic drug
interaction studies with VYTORIN have been conducted other than the following
study with NIASPAN (Niacin extended-release tablets). 

Niacin: The effect of VYTORIN (10/20 mg daily for 7 days) on the
pharmacokinetics of NIASPAN extended-release tablets (1000 mg for 2 days and
2000 mg for 5 days following a low-fat breakfast) was studied in healthy
subjects. The mean Cmax and AUC of niacin increased 9% and 22%, respectively.
The mean Cmax and AUC of nicotinuric acid increased 10% and 19%, respectively
(N=13). In the same study, the effect of NIASPAN on the pharmacokinetics of
VYTORIN was evaluated (N=15). While concomitant NIASPAN decreased the mean Cmax
of total ezetimibe (1%), and simvastatin (2%), it increased the mean Cmax of
simvastatin acid (18%). In addition, concomitant NIASPAN increased the mean AUC
of total ezetimibe (26%), simvastatin (20%), and simvastatin acid (35%). 

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 statins. The increase in AUC for simvastatin acid is
presumably due, in part, to inhibition of CYP3A4. 

Simvastatin is a substrate for CYP3A4. Inhibitors of CYP3A4 can raise the plasma
levels of HMG-CoA reductase inhibitory activity and increase the risk of
myopathy. [See Warnings and Precautions (5.1); Drug Interactions (7.1).]

Ezetimibe

 Table 4                                                                                                        
 
Effect of Coadministered Drugs on Total Ezetimibe                                                             
 Coadministered Drug and Dosing Regimen                              Total Ezetimibe*                         
                                                                                                            
                                                                     Change in AUC          Change in Cmax  
 Cyclosporine-stable dose required (75-150 mg BID)†,**               ↑240%                  ↑290%           
 Fenofibrate, 200 mg QD, 14 days†                                    ↑48%                   ↑64%            
 Gemfibrozil, 600 mg BID, 7 days†                                    ↑64%                   ↑91%            
 Cholestyramine, 4 g BID, 14 days†                                   ↓55%                   ↓4%             
 Aluminum & magnesium hydroxide combination antacid, single dose§    ↓4%                    ↓30%            
 Cimetidine, 400 mg BID, 7 days                                      ↑6%                    ↑22%            
 Glipizide, 10 mg, single dose                                       ↑4%                    ↓8%             
 Statins                                                                                                    
 Lovastatin 20 mg QD, 7 days                                         ↑9%                    ↑3%             
 Pravastatin 20 mg QD, 14 days                                       ↑7%                    ↑23%            
 Atorvastatin 10 mg QD, 14 days                                      ↓2%                    ↑12%            
 Rosuvastatin 10 mg QD, 14 days                                      ↑13%                   ↑18%            
 Fluvastatin 20 mg QD, 14 days                                       ↓19%                   ↑7%             


* Based on 10 mg-dose of ezetimibe 

** Post-renal transplant patients with mild impaired or normal renal function.
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. 

† See 7. Drug Interactions 

§ Supralox®, 20 mL

 Table 5                                                                                                                                                                
 
Effect of Ezetimibe Coadministration on Systemic Exposure to Other Drugs                                                                                              
                                                                                                                                                                        
 Coadministered Drug and its                        Ezetimibe Dosage Regimen                                  Change in AUC              Change in Cmax           
 Dosage Regimen                                                                                               of Coadministered Drug     of Coadministered Drug   
 Warfarin, 25 mg single dose on Day 7               10 mg QD, 11 days                                         ↓2% (R-warfarin)           ↑3% (R-warfarin)         
                                                                                                              ↓4% (S-warfarin)           ↑1% (S-warfarin)         
 Digoxin, 0.5 mg single dose                        10 mg QD, 8 days                                          ↑2%                        ↓7%                      
 Gemfibrozil, 600 mg BID, 7 days†                   10 mg QD, 7 days                                          ↓1%                        ↓11%                     
 Ethinyl estradiol & Levonorgestrel, QD, 21 days    10 mg QD, Days 8-14 of 21 day oral contraceptive cycle    Ethinyl estradiol          Ethinyl estradiol        
                                                                                                              0%                         ↓9%                      
                                                                                                              
Levonorgestrel            
Levonorgestrel          
                                                                                                              
0%                        
↓5%                     
 Glipizide, 10 mg on Days 1 and 9                   10 mg QD, Days 2-9                                        ↓3%                        ↓5%                      
 Fenofibrate, 200 mg QD, 14 days†                   10 mg QD, 14 days                                         ↑11%                       ↑7%                      
 Cyclosporine, 100 mg single dose Day 7†            20 mg QD, 8 days                                          ↑15%                       ↑10%                     
 Statins                                                                                                                                                          
 Lovastatin 20 mg QD, 7 days                        10 mg QD, 7 days                                          ↑19%                       ↑3%                      
 Pravastatin 20 mg QD, 14 days                      10 mg QD, 14 days                                         ↓20%                       ↓24%                     
 Atorvastatin 10 mg QD, 14 days                     10 mg QD, 14 days                                         ↓4%                        ↑7%                      
 Rosuvastatin 10 mg QD, 14 days                     10 mg QD, 14 days                                         ↑19%                       ↑17%                     
 Fluvastatin 20 mg QD, 14 days                      10 mg QD, 14 days                                         ↓39%                       ↓27%                     


† See 7. Drug Interactions 

Simvastatin

 Table 6                                                                                                                                                                                            
 
Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure                                                                                                               
                                                                                                                                                                                                    
 Coadministered Drug or Grapefruit Juice    Dosing of Coadministered Drug or Grapefruit Juice    Dosing of Simvastatin       Geometric Mean Ratio                                             
                                                                                                                             (Ratio* with / without                                           
                                                                                                                             coadministered drug)                                             
                                                                                                                             
No Effect = 1.00                                                
                                                                                                                        AUC                     Cmax   
 Avoid taking with VYTORIN[see Warnings and Precautions (5.1)]                                                                                                                                      
 Telithromycin†                             200 mg QD for 4 days                                 80 mg                       simvastatin acid‡         12            15                   
                                                                                                                             simvastatin               
8.9          5.3                  
 Nelfinavir†                                1250 mg BID for 14 days                              20 mg QD for 28 days        simvastatin acid‡         6             6.2                  
                                                                                                                             simvastatin                                                  
 Itraconazole†                              200 mg QD for 4 days                                 80 mg                       simvastatin acid‡                       13.1                 
                                                                                                                             simvastatin                             13.1                 
 Avoid >1 quart of grapefruit juice with VYTORIN [see Warnings and Precautions (5.1)]                                                                                                               
 Grapefruit Juice§                          200 mL of double-strength TID¶                       60 mg single dose           simvastatin acid          7                                  
 (high dose)                                                                                                                 simvastatin               16                                 
 Grapefruit Juice§                          8 oz (about 237 mL) of single-strength#              20 mg single dose           simvastatin acid          1.3                                
 (low dose)                                                                                                                  simvastatin               1.9                                
 Avoid taking with VYTORIN. If VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily, based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)] 
 Gemfibrozil                                600 mg BID for 3 days                                40 mg                       simvastatin acid          2.85          2.18                 
                                                                                                                             simvastatin               1.35          0.91                 
 Avoid taking with >10/20 mg VYTORIN, based on clinical and/or post-marketing simvastatin experience [see Warnings and Precautions (5.1)]                                                           
 Verapamil SR                               240 mg QD Days 1-7 then 240 mg BID on Days 8-10      80 mg on Day 10             simvastatin acid          2.3           2.4                  
                                                                                                                             simvastatin               2.5           2.1                  
 No dosing adjustments required for the following:                                                                                                                                                  
 Fenofibrate                                160 mg QD x14 days                                   80 mg QD on Days 8-14       simvastatin acid          0.64          0.89                 
                                                                                                                             simvastatin               0.89          0.83                 
 Diltiazem                                  120 mg BID for 10 days                               80 mg on Day 10             simvastatin acid          2.69          2.69                 
                                                                                                                             simvastatin               3.10          2.88                 
 Amlodipine                                 10 mg QD x 10 days                                   80 mg on Day 10             simvastatin acid          1.58          1.56                 
                                                                                                                             simvastatin               1.77          1.47                 
 Propranolol                                80 mg single dose                                    80 mg single dose           total inhibitor           0.79          ↓ from 33.6 to 21.1  
                                                                                                                             
                         
             ng·eq/mL             
                                                                                                                             active inhibitor          0.79          
↓ from 7.0 to 4.7   
                                                                                                                                                                     ng·eq/mL             


* Results based on a chemical assay except results with propranolol as
indicated. 

† Results could be representative of the following CYP3A4 inhibitors:
ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and
nefazodone. 

‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. 

§ The effect of amounts of grapefruit juice between those used in these two
studies on simvastatin pharmacokinetics has not been studied. 

¶ Double-strength: one can of frozen concentrate diluted with one can of water.
Grapefruit juice was administered TID for 2 days, and 200 mL together with
single dose simvastatin and 30 and 90 minutes following single dose simvastatin
on Day 3. 

# Single-strength: one can of frozen concentrate diluted with 3 cans of water.
Grapefruit juice was administered with breakfast for 3 days, and simvastatin was
administered in the evening on Day 3. 

13NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 statins. 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-mg 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. 

13.2Animal Toxicology and/or Pharmacology

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). 

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 μg/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 μg/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, ethinyl 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 statins (parents or their active hydroxy acid
metabolites) was seen in rats, dogs, and rabbits. 

14CLINICAL STUDIES

14.1Primary Hyperlipidemia

VYTORIN

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

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

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

In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528
hyperlipidemic 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 7.) The lipid response to VYTORIN was similar
in patients with TG levels greater than or less than 200 mg/dL.

 Table 7                                                                                                              
 
Response to VYTORIN in Patients with Primary Hyperlipidemia                                                         
 
(Meana % Change from Untreated Baselineb)                                                                           
                                                                                                                      
 Treatment                               N      Total-C    LDL-C    Apo B    HDL-C    TGa    Non-HDL-C  
 (Daily Dose)                                                                                           
 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 VYTORINdoses 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 8).

 Table 8                                                                           
 
Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk Equivalents 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, 6-week study, 1902 patients with primary
hyperlipidemia, who had not met their NCEP ATP III target LDL-C goal, were
randomized to one of eight treatment groups: VYTORIN (10/10, 10/20, 10/40, or
10/80) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg). 

Across the dosage range, when patients receiving VYTORIN were compared to those
receiving milligram-equivalent statin doses of atorvastatin, VYTORIN lowered
total-C, LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only
the 10/40 mg and 10/80 mg VYTORIN doses increased HDL-C significantly more than
the corresponding milligram-equivalent statin dose of atorvastatin. The effects
of VYTORIN on TG were similar to the effects seen with atorvastatin. (See Table
9.)

 Table 9                                                                                                  
 
Response to VYTORIN and Atorvastatin in Patients with Primary Hyperlipidemia                            
 
(Meana % Change from Untreated Baselineb)                                                               
                                                                                            
 Treatment               N      Total-Cc    LDL-Cc    Apo Bc    HDL-C    TGa    Non-HDL-Cc  
 (Daily Dose)                                                                               
 VYTORIN by dose                                                                            
 10/10                   230    -34d        -47d      -37d      +8       -26    -43d        
 10/20                   233    -37d        -51d      -40d      +7       -25    -46d        
 10/40                   236    -41d        -57d      -46d      +9d      -27    -52d        
 10/80                   224    -43d        -59d      -48d      +8d      -31    -54d        
 Atorvastatin by dose                                                                       
 10 mg                   235    -27         -36       -31       +7       -21    -34         
 20 mg                   230    -32         -44       -37       +5       -25    -41         
 40 mg                   232    -36         -48       -40       +4       -24    -45         
 80 mg                   230    -40         -53       -44       +1       -32    -50         


a For triglycerides, median % change from baseline 

b Baseline - on no lipid-lowering drug 

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

d p<0.05 for difference with atorvastatin at equal mg doses of the simvastatin
component 

In a multicenter, double-blind, 24-week, forced-titration study, 788 patients
with primary hyperlipidemia, 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 10).

 Table 10                                                                                            
 
Response to VYTORIN and Atorvastatin in Patients with Primary Hyperlipidemia                       
 
(Meana % Change from Untreated Baselineb)                                                          
                                                                                                     
 Treatment              N      Total-C    LDL-C    Apo B    HDL-C    TGa    Non-HDL-C  
 Week 6                                                                                
 Atorvastatin 10 mgc    262    -28        -37      -32      +5       -23    -35        
 VYTORIN10/10d          263    -34f       -46f     -38f     +8f      -26    -43f       
 VYTORIN 10/20e         263    -36f       -50f     -41f     +10f     -25    -46f       
 Week 12                                                                               
 Atorvastatin 20 mg     246    -33        -44      -38      +7       -28    -42        
 VYTORIN10/20           250    -37f       -50f     -41f     +9       -28    -46f       
 VYTORIN10/40           252    -39f       -54f     -45f     +12f     -31    -50f       
 Week 18                                                                               
 Atorvastatin 40 mg     237    -37        -49      -42      +8       -31    -47        
 VYTORIN10/40g          482    -40f       -56f     -45f     +11f     -32    -52f       
 Week 24                                                                               
 Atorvastatin 80 mg     228    -40        -53      -45      +6       -35    -50        
 VYTORIN10/80g          459    -43f       -59f     -49f     +12f     -35    -55f       


a For triglycerides, median % change from baseline 

b Baseline - on no lipid-lowering drug 

cAtorvastatin: 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 VYTORINat Weeks 18 and 24. 

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

The effects of VYTORIN and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C
and HDL-C are shown in Table 11.

 Table 11                                                                                                  
 
Response to VYTORIN and Rosuvastatin in Patients with Primary Hyperlipidemia                             
 
(Meana % Change from Untreated Baselineb)                                                                
                                                                                             
 Treatment               N      Total-Cc    LDL-Cc    Apo Bc    HDL-C    TGa     Non-HDL-Cc  
 (Daily Dose)                                                                                
 VYTORIN by dose                                                                             
 10/20                   476    -37d        -52d      -42d      +7       -23d    -47d        
 10/40                   477    -39e        -55e      -44e      +8       -27     -50e        
 10/80                   474    -44f        -61f      -50f      +8       -30f    -56f        
 Rosuvastatin by dose                                                                        
 10 mg                   475    -32         -46       -37       +7       -20     -42         
 20 mg                   478    -37         -52       -43       +8       -26     -48         
 40 mg                   475    -41         -57       -47       +8       -28     -52         


a For triglycerides, median % change from baseline 

b Baseline - on no lipid-lowering drug 

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

d p<0.05 vs. rosuvastatin 10 mg 

e p<0.05 vs. rosuvastatin 20 mg 

f p<0.05 vs. rosuvastatin 40 mg 

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

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

Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719
patients with primary hyperlipidemia, 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. 

14.2Homozygous 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. 

16HOW SUPPLIED/STORAGE AND HANDLING

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°C (68-77°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°C (68-77°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. 

17PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling (17.5).]

Patients should be advised to adhere to their National Cholesterol Education
Program (NCEP)-recommended diet, a regular exercise program, and periodic
testing of a fasting lipid panel. 

Patients should be advised about substances they should not take concomitantly
with VYTORIN [see Warnings and Precautions (5.1)]. Patients should also be
advised to inform other physicians prescribing a new medication that they are
taking VYTORIN.

17.1Muscle Pain

All patients starting therapy with VYTORIN should be advised of the risk of
myopathy and told to report promptly any unexplained muscle pain, tenderness or
weakness. The risk of this occurring is increased when taking certain types of
medication or consuming larger quantities of grapefruit juice. They should
discuss all medication, both prescription and over the counter, with their
healthcare professional. 

17.2Liver Enzymes

It is recommended that liver function tests be performed before the initiation
of 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. 

17.3Pregnancy

Women of childbearing age should be advised to use an effective method of birth
control to prevent pregnancy while using VYTORIN. Discuss future pregnancy plans
with your patients, and discuss when to stop taking VYTORIN if they are trying
to conceive. Patients should be advised that if they become pregnant they should
stop taking VYTORIN and call their healthcare professional. 

17.4Breast-feeding

Women who are breast-feeding should be advised to not use VYTORIN. Patients who
have a lipid disorder and are breast-feeding should be advised to discuss the
options with their healthcare professional. 

17.5FDA-Approved Patient Labeling

Issued May 2009 

9619513 

Manufactured for: 

MERCK/Schering-Plough Pharmaceuticals 

North Wales, PA 19454, USA 

By: 

MSD Technology Singapore Pte. Ltd. 

Singapore 637766 

Or 

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

Via Emilia, 21 

27100 - Pavia, Italy 

Or 

Merck Sharp & Dohme Ltd. 

Cramlington, Northumberland, UK NE23 3JU 

Or 

Jointly manufactured by: 

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

Via Emilia, 21 

27100 - Pavia, Italy 

and 

MSD Technology Singapore Pte. Ltd. 

Singapore 637766 

VYTORIN® (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. VYTORIN is for
patients who cannot control their cholesterol levels by diet and exercise 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. VYTORIN has not been shown to
reduce heart attacks or strokes more than simvastatin alone. 

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. 
* If you are a woman of childbearing age, you should use an effective method of
birth control to prevent pregnancy while using VYTORIN.

VYTORIN has not been studied 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, muscle pain, and diarrhea (see What should I tell my
doctor before and while taking VYTORIN?). 

The following side effects have been reported in general use with VYTORIN or
with 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; raised red rash, sometimes with
target-shaped lesions; joint pain; muscle pain; alterations in some laboratory
blood tests; liver problems (sometimes serious); inflammation of the pancreas;
nausea; dizziness; tingling sensation; depression; gallstones; inflammation of
the gallbladder; trouble sleeping; poor memory.

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 one of the causes for 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, hypromellose USP, lactose monohydrate NF, magnesium stearate NF,
microcrystalline cellulose NF, and propyl gallate NF. 

Issued May 2009 

9619513 

Manufactured for: 

Merck/Schering-Plough Pharmaceuticals 

North Wales, PA 19454, USA 

By: 

MSD Technology Singapore Pte. Ltd. 

Singapore 637766 

Or 

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

Via Emilia, 21 

27100 - Pavia, Italy 

Or 

Merck Sharp & Dohme Ltd. 

Cramlington, Northumberland, UK NE23 3JU 

Or 

Jointly manufactured by: 

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

Via Emilia, 21 

27100 - Pavia, Italy 

and 

MSD Technology Singapore Pte. Ltd. 

Singapore 637766

 32147054T  
 REV 21     


HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZETIA safely
and effectively. See full prescribing information for ZETIA.

 ZETIA (ezetimibe) Tablets    
 Initial U.S. Approval: 2002  


INDICATIONS AND USAGE

ZETIA is an inhibitor of intestinal cholesterol (and related phytosterol)
absorption indicated as an adjunct to diet to: 

-- Reduce elevated total-C, LDL-C, and Apo B in patients with primary
hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor
(statin) (1.1) 

-- Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed
hyperlipidemia in combination with fenofibrate (1.1) 

-- Reduce elevated total-C and LDL-C in patients with homozygous familial
hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin
(1.2) 

-- Reduce elevated sitosterol and campesterol in patients with homozygous
sitosterolemia (phytosterolemia) (1.3) 

Limitations of Use (1.4) 

-- The effect of ZETIA on cardiovascular morbidity and mortality has not been
determined. 

-- ZETIA has not been studied in Fredrickson Type I, III, IV, and V
dyslipidemias. 

DOSAGE AND ADMINISTRATION

-- One 10-mg tablet once daily, with or without food (2.1) 

-- Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after
administration of a bile acid sequestrant. (2.3, 7.4) 

DOSAGE FORMS AND STRENGTHS

-- Tablets: 10 mg (3) 

CONTRAINDICATIONS

-- Statin contraindications apply when ZETIA is used with a statin: 

-- Active liver disease, which may include unexplained persistent elevations in
hepatic transaminase levels (4, 5.2) 

-- Women who are pregnant or may become pregnant (4, 8.1) 

-- Nursing mothers (4, 8.3) 

-- Known hypersensitivity to product components (4, 6.2) 

WARNINGS AND PRECAUTIONS

-- ZETIA is not recommended in patients with moderate or severe hepatic
impairment. (5.4, 8.6, 12.3) 

-- Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic
transaminase can occur when ZETIA is added to a statin. Therefore, when ZETIA is
added to statin therapy, monitor hepatic transaminase levels before and during
treatment according to the recommendations for the individual statin used. (5.2)


-- Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): 

-- Cases of myopathy and rhabdomyolysis have been reported in patients treated
with ZETIA co-administered with a statin and with ZETIA administered alone. Risk
for skeletal muscle toxicity increases with higher doses of statin, advanced age
(>65), hypothyroidism, renal impairment, and depending on the statin used,
concomitant use of other drugs. (5.3, 6.2) 

ADVERSE REACTIONS

-- Common adverse reactions in clinical trials: 

-- ZETIA co-administered with a statin (incidence ≥2% and greater than statin
alone): 

-- nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and
diarrhea (6) 

-- ZETIA administered alone (incidence ≥2% and greater than placebo): 

-- upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain
in extremity (6) 

To report SUSPECTED ADVERSE REACTIONS, contact Merck/Schering-Plough
Pharmaceuticals at 1-866-637-2501 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.

DRUG INTERACTIONS

-- Cyclosporine: Combination increases exposure of ZETIA and cyclosporine.
Cyclosporine concentrations should be monitored in patients taking ZETIA
concomitantly. (7.1, 12.3) 

-- Fenofibrate: Combination increases exposure of ZETIA.If cholelithiasis is
suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are
indicated and alternative lipid-lowering therapy should be considered. (6.1,
7.3) 

-- Fibrates: Co-administration of ZETIA with fibrates other than fenofibrate is
not recommended until use in patients is adequately studied. (7.2) 

-- Cholestyramine: Combination decreases exposure of ZETIA. (2.3, 7.4, 12.3) 

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 07/2009

FULL PRESCRIBING INFORMATION: CONTENTS*

1INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia 

1.2 Homozygous Familial Hypercholesterolemia (HoFH) 

1.3 Homozygous Sitosterolemia 

1.4 Limitations of Use 

2DOSAGE AND ADMINISTRATION

2.1 General Dosing Information 

2.2 Concomitant Lipid-Lowering Therapy 

2.3 Co-Administration with Bile Acid Sequestrants 

2.4 Patients with Hepatic Impairment 

2.5 Patients with Renal Impairment 

2.6 Geriatric Patients 

3DOSAGE FORMS AND STRENGTHS

4CONTRAINDICATIONS

5WARNINGS AND PRECAUTIONS

5.1 Use with Statins or Fenofibrate 

5.2 Liver Enzymes 

5.3 Myopathy/Rhabdomyolysis 

5.4 Hepatic Impairment 

6ADVERSE REACTIONS

6.1 Clinical Trials Experience 

6.2 Post-Marketing Experience 

7DRUG INTERACTIONS

7.1 Cyclosporine 

7.2 Fibrates 

7.3 Fenofibrate 

7.4 Cholestyramine 

7.5 Coumarin Anticoagulants 

8USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 

8.3 Nursing Mothers 

8.4 Pediatric Use 

8.5 Geriatric Use 

8.6 Hepatic Impairment 

10OVERDOSAGE

11DESCRIPTION

12CLINICAL PHARMACOLOGY

12.1 Mechanism of Action 

12.2 Pharmacodynamics 

12.3 Pharmacokinetics 

13NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 

13.2 Animal Toxicology and/or Pharmacology 

14CLINICAL STUDIES

14.1 Primary Hyperlipidemia 

14.2 Homozygous Familial Hypercholesterolemia (HoFH) 

14.3 Homozygous Sitosterolemia (Phytosterolemia) 

16HOW SUPPLIED/STORAGE AND HANDLING

17PATIENT COUNSELING INFORMATION

17.1 Muscle Pain 

17.2 Liver Enzymes 

17.3 Pregnancy 

17.4 Breastfeeding 

17.5 FDA-approved Patient Labeling 

*Sections or subsections omitted from the full prescribing information are not
listed. 

FULL PRESCRIBING INFORMATION

1INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk
factor intervention in individuals at significantly increased risk for
atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is
indicated as an adjunct to diet when the response to a diet restricted in
saturated fat and cholesterol and other nonpharmacologic measures alone has been
inadequate. 

1.1Primary Hyperlipidemia

Monotherapy

ZETIA1 , administered alone, is indicated as adjunctive therapy to diet for the
reduction of elevated total cholesterol (total-C), low-density lipoprotein
cholesterol (LDL-C), and apolipoprotein B (Apo B) in patients with primary
(heterozygous familial and non-familial) hyperlipidemia.Combination Therapy with
HMG-CoA Reductase Inhibitors (Statins)

ZETIA, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to
diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with
primary (heterozygous familial and non-familial) hyperlipidemia.Combination
Therapy with Fenofibrate

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

1.2Homozygous Familial Hypercholesterolemia (HoFH)

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

1.3Homozygous Sitosterolemia

ZETIA is indicated as adjunctive therapy to diet for the reduction of elevated
sitosterol and campesterol levels in patients with homozygous familial
sitosterolemia. 

1.4Limitations of Use

The effect of ZETIA on cardiovascular morbidity and mortality has not been
determined. 

ZETIA has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. 

2DOSAGE AND ADMINISTRATION

2.1General Dosing Information

The recommended dose of ZETIA is 10 mg once daily. 

ZETIA can be administered with or without food. 

2.2Concomitant Lipid-Lowering Therapy

ZETIA may be administered with a statin (in patients with primary
hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for
incremental effect. For convenience, the daily dose of ZETIA may be taken at the
same time as the statin or fenofibrate, according to the dosing recommendations
for the respective medications. 

2.3Co-Administration with Bile Acid Sequestrants

Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after
administration of a bile acid sequestrant [see Drug Interactions (7.4)]. 

2.4Patients with Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment [see
Warnings and Precautions (5.4)]. 

2.5Patients with Renal Impairment

No dosage adjustment is necessary in patients with renal impairment [see
Clinical Pharmacology (12.3)].

2.6Geriatric Patients

No dosage adjustment is necessary in geriatric patients [see Clinical
Pharmacology (12.3)]. 

3DOSAGE FORMS AND STRENGTHS

10-mg tablets are white to off-white, capsule-shaped tablets debossed with "414"
on one side. 

4CONTRAINDICATIONS

ZETIA is contraindicated in the following conditions: 

-- The combination of ZETIA with a statin is contraindicated in patients with
active liver disease or unexplained persistent elevations in hepatic
transaminase levels. 

-- Women who are pregnant or may become pregnant. Because statins decrease
cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol, ZETIA in combination with a statin may
cause fetal harm when administered to pregnant women. Additionally, there is no
apparent benefit to therapy during pregnancy, and safety in pregnant women has
not been established. If the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus and the lack
of known clinical benefit with continued use during pregnancy. [See Use in
Specific Populations (8.1).]

-- Nursing mothers. Because statins may pass into breast milk, and because
statins have the potential to cause serious adverse reactions in nursing
infants, women who require ZETIA treatment in combination with a statin should
be advised not to nurse their infants [see Use in Specific Populations (8.3)].

-- Patients with a known hypersensitivity to any component of this product.
Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria
have been reported with ZETIA [see Adverse Reactions (6.2)]. 

5WARNINGS AND PRECAUTIONS

5.1Use with Statins or Fenofibrate

Concurrent administration of ZETIA with a specific statin or fenofibrate should
be in accordance with the product labeling for that medication. 

5.2Liver Enzymes

In controlled clinical monotherapy studies, the incidence of consecutive
elevations (≥3 X the upper limit of normal [ULN]) in hepatic transaminase levels
was similar between ZETIA (0.5%) and placebo (0.3%). 

In controlled clinical combination studies of ZETIA initiated concurrently with
a statin, the incidence of consecutive elevations (≥3 X ULN) in hepatic
transaminase levels was 1.3% for patients treated with ZETIA administered with
statins and 0.4% for patients treated with statins alone. These elevations in
transaminases were generally asymptomatic, not associated with cholestasis, and
returned to baseline after discontinuation of therapy or with continued
treatment. When ZETIA is co-administered with a statin, liver tests should be
performed at initiation of therapy and according to the recommendations of the
statin. Should an increase in ALT or AST ≥3 X ULN persist, consider withdrawal
of ZETIA and/or the statin. 

5.3Myopathy/Rhabdomyolysis

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated
with ZETIA compared with the relevant control arm (placebo or statin alone).
However, myopathy and rhabdomyolysis are known adverse reactions to statins and
other lipid-lowering drugs. In clinical trials, the incidence of creatine
phosphokinase (CPK) >10 X ULN was 0.2% for ZETIA vs 0.1% for placebo, and 0.1%
for ZETIA co-administered with a statin vs 0.4% for statins alone. Risk for
skeletal muscle toxicity increases with higher doses of statin, advanced age
(>65), hypothyroidism, renal impairment, and depending on the statin used,
concomitant use of other drugs. 

In post-marketing experience with ZETIA, cases of myopathy and rhabdomyolysis
have been reported. Most patients who developed rhabdomyolysis were taking a
statin prior to initiating ZETIA. However, rhabdomyolysis has been reported with
ZETIA monotherapy and with the addition of ZETIA to agents known to be
associated with increased risk of rhabdomyolysis, such as fibrates. ZETIA and
any statin or fibrate that the patient is taking concomitantly should be
immediately discontinued if myopathy is diagnosed or suspected. The presence of
muscle symptoms and a CPK level >10 X the ULN indicates myopathy. 

5.4Hepatic Impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients
with moderate to severe hepatic impairment, ZETIA is not recommended in these
patients. [See Clinical Pharmacology (12.3).]

6ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other
sections of the label: 

-- Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

-- Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3)]

Monotherapy Studies: 

In the ZETIA controlled clinical trials database (placebo-controlled) of 2396
patients with a median treatment duration of 12 weeks (range 0 to 39 weeks),
3.3% of patients on ZETIA and 2.9% of patients on placebo discontinued due to
adverse reactions. The most common adverse reactions in the group of patients
treated with ZETIA that led to treatment discontinuation and occurred at a rate
greater than placebo were: 

-- Arthralgia (0.3%) 

-- Dizziness (0.2%) 

-- Gamma-glutamyltransferase increased (0.2%) 

The most commonly reported adverse reactions (incidence ≥2% and greater than
placebo) in the ZETIA monotherapy controlled clinical trial database of 2396
patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%),
arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). 

Statin Co-Administration Studies: 

In the ZETIA + statin controlled clinical trials database of 11,308 patients
with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of
patients on ZETIA + statin and 3.3% of patients on statin alone discontinued due
to adverse reactions. The most common adverse reactions in the group of patients
treated with ZETIA + statin that led to treatment discontinuation and occurred
at a rate greater than statin alone were: 

-- Alanine aminotransferase increased (0.6%) 

-- Myalgia (0.5%) 

-- Fatigue, aspartate aminotransferase increased, headache, and pain in
extremity (each at 0.2%) 

The most commonly reported adverse reactions (incidence ≥2% and greater than
statin alone) in the ZETIA + statin controlled clinical trial database of 11,308
patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract
infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%). 

6.1Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse
reaction rates observed in the clinical studies of a drug cannot be directly
compared to rates in the clinical studies of another drug and may not reflect
the rates observed in clinical practice. 

Monotherapy

In 10 double-blind, placebo-controlled clinical trials, 2396 patients with
primary hyperlipidemia (age range 9-86 years, 50% women, 90% Caucasians, 5%
Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with ZETIA 10
mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks). 

Adverse reactions reported in ≥2% of patients treated with ZETIA and at an
incidence greater than placebo in placebo-controlled studies of ZETIA,
regardless of causality assessment, are shown in Table 1.

 TABLE 1: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with ZETIA and at an Incidence Greater than Placebo, Regardless of Causality 
 Body System/Organ Class                               ZETIA 10 mg   Placebo    
 Adverse Reaction                                      (%)           (%)        
                                                       
n = 2396     
n = 1159  
 Gastrointestinal disorders                                                     
 Diarrhea                                              4.1           3.7        
 General disorders and administration site conditions                           
 Fatigue                                               2.4           1.5        
 Infections and infestations                                                    
 Influenza                                             2.0           1.5        
 Sinusitis                                             2.8           2.2        
 Upper respiratory tract infection                     4.3           2.5        
 Musculoskeletal and connective tissue disorders                                
 Arthralgia                                            3.0           2.2        
 Pain in extremity                                     2.7           2.5        


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

Combination with a Statin

In 28 double-blind, controlled (placebo or active-controlled) clinical trials,
11,308 patients with primary hyperlipidemia (age range 10-93 years, 48% women,
85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were
treated with ZETIA 10 mg/day concurrently with or added to on-going statin
therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks). 

The incidence of consecutive increased transaminases (≥3 X ULN) was higher in
patients receiving ZETIA administered with statins (1.3%) than in patients
treated with statins alone (0.4%). [See Warnings and Precautions (5.2).]

Clinical adverse reactions reported in ≥2% of patients treated with ZETIA +
statin and at an incidence greater than statin, regardless of causality
assessment, are shown in Table 2.

 TABLE 2: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with ZETIA Co-Administered with a Statin and at an Incidence Greater than Statin, Regardless of Causality 
 Body System/Organ Class                               All Statins*   ZETIA + All Statins*   
 Adverse Reaction                                      (%)            (%)                    
                                                       
n = 9361      
n = 11,308            
 Gastrointestinal disorders                                                                  
 Diarrhea                                              2.2            2.5                    
 General disorders and administration site conditions                                        
 Fatigue                                               1.6            2.0                    
 Infections and infestations                                                                 
 Influenza                                             2.1            2.2                    
 Nasopharyngitis                                       3.3            3.7                    
 Upper respiratory tract infection                     2.8            2.9                    
 Musculoskeletal and connective tissue disorders                                             
 Arthralgia                                            2.4            2.6                    
 Back pain                                             2.3            2.4                    
 Myalgia                                               2.7            3.2                    
 Pain in extremity                                     1.9            2.1                    


* All Statins = all doses of all statins 

Combination with Fenofibrate

This clinical study involving 625 patients with mixed dyslipidemia (age range
20-76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians)
treated for up to 12 weeks and 576 patients treated for up to an additional 48
weeks evaluated co-administration of ZETIA and fenofibrate. This study was not
designed to compare treatment groups for infrequent events. Incidence rates (95%
CI) for clinically important elevations (≥3 X ULN, consecutive) in hepatic
transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate
monotherapy (n=188) and ZETIA co-administered with fenofibrate (n=183),
respectively, adjusted for treatment exposure. Corresponding incidence rates for
cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for
fenofibrate monotherapy and ZETIA co-administered with fenofibrate, respectively
[see Drug Interactions (7.3)]. The numbers of patients exposed to
co-administration therapy as well as fenofibrate and ezetimibe monotherapy were
inadequate to assess gallbladder disease risk. There were no CPK elevations >10
X ULN in any of the treatment groups. 

6.2Post-Marketing Experience

Because the reactions below are reported voluntarily from a population of
uncertain size, it is generally not possible to reliably estimate their
frequency or establish a causal relationship to drug exposure. 

The following additional adverse reactions have been identified during
post-approval use of ZETIA: 

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and
urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine
phosphokinase; myopathy/rhabdomyolysis [see Warnings and Precautions (5.3)];
elevations in liver transaminases; hepatitis; abdominal pain; thrombocytopenia;
pancreatitis; nausea; dizziness; paresthesia; depression; headache;
cholelithiasis; cholecystitis. 

7DRUG INTERACTIONS

[See Clinical Pharmacology (12.3).]

7.1Cyclosporine

Caution should be exercised when using ZETIA and cyclosporine concomitantly due
to increased exposure to both ezetimibe and cyclosporine. Cyclosporine
concentrations should be monitored in patients receiving ZETIA and cyclosporine.


The degree of increase in ezetimibe exposure may be greater in patients with
severe renal insufficiency. In patients treated with cyclosporine, the potential
effects of the increased exposure to ezetimibe from concomitant use should be
carefully weighed against the benefits of alterations in lipid levels provided
by ezetimibe. 

7.2Fibrates

The efficacy and safety of co-administration of ezetimibe with fibrates other
than fenofibrate have not been studied. 

Fibrates may increase cholesterol excretion into the bile, leading to
cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol
in the gallbladder bile [see Nonclinical Toxicology (13.2)]. Co-administration
of ZETIA with fibrates other than fenofibrate is not recommended until use in
patients is adequately studied. 

7.3Fenofibrate

If cholelithiasis is suspected in a patient receiving ZETIA and fenofibrate,
gallbladder studies are indicated and alternative lipid-lowering therapy should
be considered [see Adverse Reactions (6.1) and the product labeling for
fenofibrate]. 

7.4Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the
curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C
reduction due to adding ezetimibe to cholestyramine may be reduced by this
interaction. 

7.5Coumarin Anticoagulants

If ezetimibe is added to warfarin, a coumarin anticoagulant, the International
Normalized Ratio (INR) should be appropriately monitored. 

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of ezetimibe in pregnant
women. Ezetimibe should be used during pregnancy only if the potential benefit
justifies the risk to the fetus. 

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

Multiple-dose studies of ezetimibe given in combination with statins in rats and
rabbits during organogenesis result in higher ezetimibe and statin exposures.
Reproductive findings occur at lower doses in combination therapy compared to
monotherapy. 

All statins are contraindicated in pregnant and nursing women. When ZETIA is
administered with a statin in a woman of childbearing potential, refer to the
pregnancy category and product labeling for the statin. [See Contraindications
(4).]

8.3Nursing Mothers

It is not known whether ezetimibe is excreted into human breast milk. In rat
studies, exposure to total ezetimibe in nursing pups was up to half of that
observed in maternal plasma. Because many drugs are excreted in human milk,
caution should be exercised when ZETIA is administered to a nursing woman. ZETIA
should not be used in nursing mothers unless the potential benefit justifies the
potential risk to the infant. 

8.4Pediatric Use

The effects of ZETIA co-administered with simvastatin (n=126) compared to
simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls
with heterozygous familial hypercholesterolemia (HeFH). In a multicenter,
double-blind, controlled study followed by an open-label phase, 142 boys and 106
postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females,
82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized
to receive either ZETIA co-administered with simvastatin or simvastatin
monotherapy. Inclusion in the study required 1) a baseline LDL-C level between
160 and 400 mg/dL and 2) a medical history and clinical presentation consistent
with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161-351 mg/dL) in
the ZETIA co-administered with simvastatin group compared to 219 mg/dL (range:
149-336 mg/dL) in the simvastatin monotherapy group. The patients received
co-administered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin
monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ZETIA and 40
mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and
open-label co-administered ZETIA and simvastatin (10 mg, 20 mg, or 40 mg) for 20
weeks thereafter. 

The results of the study at Week 6 are summarized in Table 3. Results at Week 33
were consistent with those at Week 6.

 TABLE 3: Mean Percent Difference at Week 6 Between the Pooled ZETIA Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia 
                                                   Total-C      LDL-C         Apo B        Non-HDL-C     TG*         HDL-C       
 Mean percent difference between treatment groups  -12%         -15%          -12%         -14%          -2%         +0.1%       
 95% Confidence Interval                           (-15%, -9%)  (-18%, -12%)  (-15%, -9%)  (-17%, -11%)  (-9%, +4%)  (-3%, +3%)  


* For triglycerides, median % change from baseline 

From the start of the trial to the end of Week 33, discontinuations due to an
adverse reaction occurred in 7 (6%) patients in the ZETIA co-administered with
simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group. 

During the trial, hepatic transaminase elevations (two consecutive measurements
for ALT and/or AST ≥3 X ULN) occurred in four (3%) individuals in the ZETIA
co-administered with simvastatin group and in two (2%) individuals in the
simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two
(2%) individuals in the ZETIA co-administered with simvastatin group and in zero
individuals in the simvastatin monotherapy group. 

In this limited controlled study, there was no significant effect on growth or
sexual maturation in the adolescent boys or girls, or on menstrual cycle length
in girls. 

Co-administration of ZETIA with simvastatin at doses greater than 40 mg/day has
not been studied in adolescents. Also, ZETIA has not been studied in patients
younger than 10 years of age or in pre-menarchal girls. 

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no
pharmacokinetic differences between adolescents and adults. Pharmacokinetic data
in the pediatric population <10 years of age are not available. 

8.5Geriatric Use

Monotherapy Studies

Of the 2396 patients who received ZETIA in clinical studies, 669 (28%) were 65
and older, and 111 (5%) were 75 and older. 

Statin Co-Administration Studies

Of the 11,308 patients who received ZETIA + statin in clinical studies, 3587
(32%) were 65 and older, and 924 (8%) were 75 and older. 

No overall differences in safety and effectiveness were observed between these
patients and younger patients, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out [see
Clinical Pharmacology (12.3)]. 

8.6Hepatic Impairment

ZETIA is not recommended in patients with moderate to severe hepatic impairment
[see Warnings and Precautions(5.4) and Clinical Pharmacology(12.3)]. 

ZETIA given concomitantly with a statin is contraindicated in patients with
active liver disease or unexplained persistent elevations of hepatic
transaminase levels [see Contraindications(4); Warnings and Precautions(5.2) and
Clinical Pharmacology(12.3)]. 

10OVERDOSAGE

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
hyperlipidemia for up to 56 days, was generally well tolerated. 

A few cases of overdosage with ZETIA have been reported; most have not been
associated with adverse experiences. Reported adverse experiences have not been
serious. In the event of an overdose, symptomatic and supportive measures should
be employed. 

11DESCRIPTION

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

[GRAPHIC OMITTED] 

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

12CLINICAL PHARMACOLOGY

12.1Mechanism of Action

Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol
by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic
patients, ZETIA inhibited intestinal cholesterol absorption by 54%, compared
with placebo. ZETIA had no clinically meaningful effect on the plasma
concentrations of the fat-soluble vitamins A, D, and E (in a study of 113
patients), and did not impair adrenocortical steroid hormone production (in a
study of 118 patients). 

The cholesterol content of the liver is derived predominantly from three
sources. The liver can synthesize cholesterol, take up cholesterol from the
blood from circulating lipoproteins, or take up cholesterol absorbed by the
small intestine. Intestinal cholesterol is derived primarily from cholesterol
secreted in the bile and from dietary cholesterol. 

Ezetimibe has a mechanism of action that differs from those of other classes of
cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric
acid derivatives, and plant stanols). The molecular target of ezetimibe has been
shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is
involved in the intestinal uptake of cholesterol and phytosterols. 

Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile
acid excretion. Instead, ezetimibe localizes at the brush border of the small
intestine and inhibits the absorption of cholesterol, leading to a decrease in
the delivery of intestinal cholesterol to the liver. This causes a reduction of
hepatic cholesterol stores and an increase in clearance of cholesterol from the
blood; this distinct mechanism is complementary to that of statins and of
fenofibrate [see Clinical Studies (14.1)]. 

12.2Pharmacodynamics

Clinical studies have demonstrated that elevated levels of total-C, LDL-C and
Apo B, the major protein constituent of LDL, promote human atherosclerosis. In
addition, decreased levels of 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 TG on the
risk of coronary and cardiovascular morbidity and mortality has not been
determined. 

ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients
with hyperlipidemia. Administration of ZETIA with a statin is effective in
improving serum total-C, LDL-C, Apo B, TG, and HDL-C beyond either treatment
alone. Administration of ZETIA with fenofibrate is effective in improving serum
total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as
compared to either treatment alone. The effects of ezetimibe given either alone
or in addition to a statin or fenofibrate on cardiovascular morbidity and
mortality have not been established. 

12.3Pharmacokinetics

Absorption

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

Effect of Food on Oral Absorption

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

Distribution

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

Metabolism and Excretion

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

In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe
and ezetimibe-glucuronide are the major drug-derived compounds detected in
plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in
plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are 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. 

Specific Populations

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

Pediatric Patients:[See Use in Specific Populations (8.4).]

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

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

Hepatic Impairment:After a single 10-mg dose of ezetimibe, the mean AUC for
total ezetimibe was increased approximately 1.7-fold in patients with mild
hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The
mean AUC values for total ezetimibe and ezetimibe were increased approximately
3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate
(Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to
15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate
hepatic impairment, the mean AUC values for total ezetimibe and ezetimibe were
increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects.
Due to the unknown effects of the increased exposure to ezetimibe in patients
with moderate or severe hepatic impairment, ZETIA is not recommended in these
patients [see Warnings and Precautions (5.4)]. 

Renal Impairment:After a single 10-mg dose of ezetimibe in patients with severe
renal disease (n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total
ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately
1.5-fold, compared to healthy subjects (n=9).Drug Interactions [See also Drug
Interactions (7)]

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

 TABLE 4: Effect of Co-Administered Drugs on Total Ezetimibe                                        
 Co-Administered Drug and Dosing Regimen                           Total Ezetimibe*                
                                                                   Change in AUC  Change in Cmax  
 Cyclosporine-stable dose required (75-150 mg BID)†, ‡             increase 240%  increase 290%   
 Fenofibrate, 200 mg QD, 14 days‡                                  increase 48%   increase 64%    
 Gemfibrozil, 600 mg BID, 7 days‡                                  increase 64%   increase 91%    
 Cholestyramine, 4 g BID, 14 days‡                                 decrease 55%   decrease 4%     
 Aluminum & magnesium hydroxide combination antacid, single dose§  decrease 4%    decrease 30%    
 Cimetidine, 400 mg BID, 7 days                                    increase 6%    increase 22%    
 Glipizide, 10 mg, single dose                                     increase 4%    decrease 8%     
 Statins                                                                                          
 Lovastatin 20 mg QD, 7 days                                       increase 9%    increase 3%     
 Pravastatin 20 mg QD, 14 days                                     increase 7%    increase 23%    
 Atorvastatin 10 mg QD, 14 days                                    decrease 2%    increase 12%    
 Rosuvastatin 10 mg QD, 14 days                                    increase 13%   increase 18%    
 Fluvastatin 20 mg QD, 14 days                                     decrease 19%   increase 7%     


* Based on 10 mg dose of ezetimibe 

† Post-renal transplant patients with mild impaired or normal renal function. 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. 

‡ See Drug Interactions (7) 

§ Supralox, 20 mL

 TABLE 5: Effect of Ezetimibe Co-Administration on Systemic Exposure to Other Drugs                                                                             
 Co-Administered Drug and its Dosage Regimen      Ezetimibe Dosage Regimen                             Change in AUC              Change in Cmax             
                                                                                                       of Co-Administered Drug    of Co-Administered Drug    
 Warfarin, 25 mg single dose on day 7             10 mg QD, 11 days                                    decrease 2% (R-warfarin)   increase 3% (R-warfarin)   
                                                                                                       decrease 4% (S-warfarin)   increase 1% (S-warfarin)   
 Digoxin, 0.5 mg single dose                      10 mg QD, 8 days                                     increase 2%                decrease 7%                
 Gemfibrozil, 600 mg BID, 7 days*                 10 mg QD, 7 days                                     decrease 1%                decrease 11%               
 Ethinyl estradiol & Levonorgestrel, QD, 21 days  10 mg QD, days 8-14 of 21d oral contraceptive cycle  Ethinyl estradiol          Ethinyl estradiol          
                                                                                                       0%                         decrease 9%                
                                                                                                       
Levonorgestrel            
Levonorgestrel            
                                                                                                       
0%                        
decrease 5%               
 Glipizide, 10 mg on days 1 and 9                 10 mg QD, days 2-9                                   decrease 3%                decrease 5%                
 Fenofibrate, 200 mg QD, 14 days*                 10 mg QD, 14 days                                    increase 11%               increase 7%                
 Cyclosporine, 100 mg single dose day 7*          20 mg QD, 8 days                                     increase 15%               increase 10%               
 Statins                                                                                                                                                     
 Lovastatin 20 mg QD, 7 days                      10 mg QD, 7 days                                     increase 19%               increase 3%                
 Pravastatin 20 mg QD, 14 days                    10 mg QD, 14 days                                    decrease 20%               decrease 24%               
 Atorvastatin 10 mg QD, 14 days                   10 mg QD, 14 days                                    decrease 4%                increase 7%                
 Rosuvastatin 10 mg QD, 14 days                   10 mg QD, 14 days                                    increase 19%               increase 17%               
 Fluvastatin 20 mg QD, 14 days                    10 mg QD, 14 days                                    decrease 39%               decrease 27%               


* See Drug Interactions (7) 

13NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at
doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 X 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 X 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 X the human exposure at 10 mg daily based on AUC0-24hr for total
ezetimibe). 

13.2Animal Toxicology and/or Pharmacology

The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed
Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism.
Ezetimibe was found to have an ED50 value of 0.5 μg/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 μg/kg/day, respectively. These results are consistent
with ZETIA being a potent cholesterol absorption inhibitor. 

In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was
administered intraduodenally, the metabolite was as potent as the parent
compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting
that the glucuronide metabolite had activity similar to the parent drug. 

In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the
concentration of cholesterol in gallbladder bile increased ~2- to 4-fold.
However, a dose of 300 mg/kg/day administered to dogs for one year did not
result in gallstone formation or any other adverse hepatobiliary effects. In a
14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or
cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was
either unaffected or reduced to normal levels, respectively. 

A series of acute preclinical studies was performed to determine the selectivity
of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the
absorption of 14C-cholesterol with no effect on the absorption of triglycerides,
fatty acids, bile acids, progesterone, ethinyl 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 statins (parents or their active hydroxy acid
metabolites) was seen in rats, dogs, and rabbits. 

14CLINICAL STUDIES

14.1Primary Hyperlipidemia

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

Monotherapy

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719
patients with primary hyperlipidemia, ZETIA significantly lowered total-C,
LDL-C, Apo B, and TG, and increased HDL-C compared to placebo (see Table 6).
Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

 TABLE 6: Response to ZETIA in Patients with Primary Hyperlipidemia(Mean* % Change from Untreated Baseline†) 
                               Treatment Group  N    Total-C  LDL-C  Apo B  TG*  HDL-C      
 Study 1‡                      Placebo          205  +1       +1     -1     -1         -1   
 Ezetimibe                     622              -12  -18      -15    -7           +1   
 Study 2‡                      Placebo          226  +1       +1     -1     +2         -2   
 Ezetimibe                     666              -12  -18      -16    -9           +1   
 Pooled Data‡ (Studies 1 & 2)  Placebo          431  0        +1     -2     0          -2   
 Ezetimibe                     1288             -13  -18      -16    -8           +1   


* For triglycerides, median % change from baseline 

† Baseline - on no lipid-lowering drug 

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

Combination with Statins

ZETIA Added to On-going Statin Therapy

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients
with primary hyperlipidemia, known coronary heart disease or multiple
cardiovascular risk factors who were already receiving statin monotherapy, but
who had not met their NCEP ATP II target LDL-C goal were randomized to receive
either ZETIA or placebo in addition to their on-going statin. 

ZETIA, added to on-going statin therapy, significantly lowered total-C, LDL-C,
Apo B, and TG, and increased HDL-C compared with a statin administered alone
(see Table 7). LDL-C reductions induced by ZETIA were generally consistent
across all statins.

 TABLE 7: Response to Addition of ZETIA to On-Going Statin Therapy* in Patients with Hyperlipidemia(Mean† % Change from Treated Baseline‡) 
 Treatment                   N    Total-C  LDL-C  Apo B  TG†  HDL-C  
 (Daily Dose)                                                        
 On-going Statin + Placebo§  390  -2       -4     -3     -3   +1     
 On-going Statin + ZETIA§    379  -17      -25    -19    -14  +3     


* Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others
(pravastatin, fluvastatin, cerivastatin, lovastatin) 

† For triglycerides, median % change from baseline 

‡ Baseline - on a statin alone. 

§ ZETIA + statin significantly reduced total-C, LDL-C, Apo B, and TG, and
increased HDL-C compared to statin alone. 

ZETIA Initiated Concurrently with a Statin

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382
hyperlipidemic patients, ZETIA or placebo was administered alone or with various
doses of atorvastatin, simvastatin, pravastatin, or lovastatin. 

When all patients receiving ZETIA with a statin were compared to all those
receiving the corresponding statin alone, ZETIA significantly lowered total-C,
LDL-C, Apo B, and TG, and, with the exception of pravastatin, increased HDL-C
compared to the statin administered alone. LDL-C reductions induced by ZETIA
were generally consistent across all statins. (See footnote ‡, Tables 8 to 11.)

 TABLE 8: Response to ZETIA and Atorvastatin Initiated Concurrentlyin Patients with Primary Hyperlipidemia(Mean* % Change from Untreated Baseline†) 
 Treatment                              N    Total-C  LDL-C  Apo B  TG*  HDL-C  
 (Daily Dose)                                                                   
 Placebo                                60   +4       +4     +3     -6   +4     
 ZETIA                                  65   -14      -20    -15    -5   +4     
 Atorvastatin 10 mg                     60   -26      -37    -28    -21  +6     
 ZETIA +                                65   -38      -53    -43    -31  +9     
 Atorvastatin 10 mg                                                             
 Atorvastatin 20 mg                     60   -30      -42    -34    -23  +4     
 ZETIA +                                62   -39      -54    -44    -30  +9     
 Atorvastatin 20 mg                                                             
 Atorvastatin 40 mg                     66   -32      -45    -37    -24  +4     
 ZETIA +                                65   -42      -56    -45    -34  +5     
 Atorvastatin 40 mg                                                             
 Atorvastatin 80 mg                     62   -40      -54    -46    -31  +3     
 ZETIA +                                63   -46      -61    -50    -40  +7     
 Atorvastatin 80 mg                                                             
 Pooled data (All Atorvastatin Doses)‡  248  -32      -44    -36    -24  +4     
 Pooled data (All ZETIA +               255  -41      -56    -45    -33  +7     
 Atorvastatin Doses)‡                                                           


* For triglycerides, median % change from baseline 

† Baseline - on no lipid-lowering drug 

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

 TABLE 9: Response to ZETIA and Simvastatin Initiated Concurrentlyin Patients with Primary Hyperlipidemia(Mean* % Change from Untreated Baseline†) 
 Treatment                             N    Total-C  LDL-C  Apo B  TG*  HDL-C  
 (Daily Dose)                                                                  
 Placebo                               70   -1       -1     0      +2   +1     
 ZETIA                                 61   -13      -19    -14    -11  +5     
 Simvastatin 10 mg                     70   -18      -27    -21    -14  +8     
 ZETIA +                               67   -32      -46    -35    -26  +9     
 Simvastatin 10 mg                                                             
 Simvastatin 20 mg                     61   -26      -36    -29    -18  +6     
 ZETIA +                               69   -33      -46    -36    -25  +9     
 Simvastatin 20 mg                                                             
 Simvastatin 40 mg                     65   -27      -38    -32    -24  +6     
 ZETIA +                               73   -40      -56    -45    -32  +11    
 Simvastatin 40 mg                                                             
 Simvastatin 80 mg                     67   -32      -45    -37    -23  +8     
 ZETIA +                               65   -41      -58    -47    -31  +8     
 Simvastatin 80 mg                                                             
 Pooled data (All Simvastatin Doses)‡  263  -26      -36    -30    -20  +7     
 Pooled data (All ZETIA +              274  -37      -51    -41    -29  +9     
 Simvastatin Doses)‡                                                           


* For triglycerides, median % change from baseline 

† Baseline - on no lipid-lowering drug 

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

 TABLE 10: Response to ZETIA and Pravastatin Initiated Concurrentlyin Patients with Primary Hyperlipidemia(Mean* % Change from Untreated Baseline†) 
 Treatment                             N    Total-C  LDL-C  Apo B  TG*  HDL-C  
 (Daily Dose)                                                                  
 Placebo                               65   0        -1     -2     -1   +2     
 ZETIA                                 64   -13      -20    -15    -5   +4     
 Pravastatin 10 mg                     66   -15      -21    -16    -14  +6     
 ZETIA +                               71   -24      -34    -27    -23  +8     
 Pravastatin 10 mg                                                             
 Pravastatin 20 mg                     69   -15      -23    -18    -8   +8     
 ZETIA +                               66   -27      -40    -31    -21  +8     
 Pravastatin 20 mg                                                             
 Pravastatin 40 mg                     70   -22      -31    -26    -19  +6     
 ZETIA +                               67   -30      -42    -32    -21  +8     
 Pravastatin 40 mg                                                             
 Pooled data (All Pravastatin Doses)‡  205  -17      -25    -20    -14  +7     
 Pooled data (All ZETIA +              204  -27      -39    -30    -21  +8     
 Pravastatin Doses)‡                                                           


* For triglycerides, median % change from baseline 

† Baseline - on no lipid-lowering drug 

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

 TABLE 11: Response to ZETIA and Lovastatin Initiated Concurrentlyin Patients with Primary Hyperlipidemia(Mean* % Change from Untreated Baseline†) 
 Treatment                            N    Total-C  LDL-C  Apo B  TG*  HDL-C  
 (Daily Dose)                                                                 
 Placebo                              64   +1       0      +1     +6   0      
 ZETIA                                72   -13      -19    -14    -5   +3     
 Lovastatin 10 mg                     73   -15      -20    -17    -11  +5     
 ZETIA +                              65   -24      -34    -27    -19  +8     
 Lovastatin 10 mg                                                             
 Lovastatin 20 mg                     74   -19      -26    -21    -12  +3     
 ZETIA +                              62   -29      -41    -34    -27  +9     
 Lovastatin 20 mg                                                             
 Lovastatin 40 mg                     73   -21      -30    -25    -15  +5     
 ZETIA +                              65   -33      -46    -38    -27  +9     
 Lovastatin 40 mg                                                             
 Pooled data (All Lovastatin Doses)‡  220  -18      -25    -21    -12  +4     
 Pooled data (All ZETIA +             192  -29      -40    -33    -25  +9     
 Lovastatin Doses)‡                                                           


* For triglycerides, median % change from baseline 

† Baseline - on no lipid-lowering drug 

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

Combination with Fenofibrate

In a multicenter, double-blind, placebo-controlled, clinical study in patients
with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576
for up to an additional 48 weeks. Patients were randomized to receive placebo,
ZETIA alone, 160 mg fenofibrate alone, or ZETIA and 160 mg fenofibrate in the
12-week study. After completing the 12-week study, eligible patients were
assigned to ZETIA co-administered with fenofibrate or fenofibrate monotherapy
for an additional 48 weeks. 

ZETIA co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo
B, and non-HDL-C compared to fenofibrate administered alone. The percent
decrease in TG and percent increase in HDL-C for ZETIA co-administered with
fenofibrate were comparable to those for fenofibrate administered alone (see
Table 12).

 TABLE 12: Response to ZETIA and Fenofibrate Initiated Concurrentlyin Patients with Mixed Hyperlipidemia(Mean* % Change from Untreated Baseline† at 12 weeks) 
 Treatment                   N    Total-C  LDL-C  Apo B  TG*  HDL-C  Non-HDL-C  
 (Daily Dose)                                                                   
 Placebo                     63   0        0      -1     -9   +3     0          
 ZETIA                       185  -12      -13    -11    -11  +4     -15        
 Fenofibrate 160 mg          188  -11      -6     -15    -43  +19    -16        
 ZETIA + Fenofibrate 160 mg  183  -22      -20    -26    -44  +19    -30        


* For triglycerides, median % change from baseline 

† Baseline - on no lipid-lowering drug 

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

14.2Homozygous Familial Hypercholesterolemia (HoFH)

A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH.
This double-blind, randomized, 12-week study enrolled 50 patients with a
clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL
apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were
randomized to one of three treatment groups, atorvastatin or simvastatin (80
mg), ZETIA administered with atorvastatin or simvastatin (40 mg), or ZETIA
administered with atorvastatin or simvastatin (80 mg). Due to decreased
bioavailability of ezetimibe in patients concomitantly receiving cholestyramine
[see Drug Interactions (7.1)], ezetimibe was dosed at least 4 hours before or
after administration of resins. Mean baseline LDL-C was 341 mg/dL in those
patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316
mg/dL in the group randomized to ZETIA plus atorvastatin 40 or 80 mg or
simvastatin 40 or 80 mg. ZETIA, administered with atorvastatin or simvastatin
(40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared
with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to
80 mg (7%). In those treated with ZETIA plus 80 mg atorvastatin or with ZETIA
plus 80 mg simvastatin, LDL-C was reduced by 27%. 

14.3Homozygous Sitosterolemia (Phytosterolemia)

A study was conducted to assess the efficacy of ZETIA in the treatment of
homozygous sitosterolemia. In this multicenter, double-blind,
placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia
with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic
regimen (diet, bile-acid-binding resins, statins, ileal bypass surgery and/or
LDL apheresis), were randomized to receive ZETIA (n=30) or placebo (n=7). Due to
decreased bioavailability of ezetimibe in patients concomitantly receiving
cholestyramine [see Drug Interactions (7.1)], ezetimibe was dosed at least 2
hours before or 4 hours after resins were administered. Excluding the one
subject receiving LDL apheresis, ZETIA significantly lowered plasma sitosterol
and campesterol, by 21% and 24% from baseline, respectively. In contrast,
patients who received placebo had increases in sitosterol and campesterol of 4%
and 3% from baseline, respectively. For patients treated with ZETIA, mean plasma
levels of plant sterols were reduced progressively over the course of the study.
The effects of reducing plasma sitosterol and campesterol on reducing the risks
of cardiovascular morbidity and mortality have not been established. 

Reductions in sitosterol and campesterol were consistent between patients taking
ZETIA concomitantly with bile acid sequestrants (n=8) and patients not on
concomitant bile acid sequestrant therapy (n=21). 

Limitations of Use

The effect of ZETIA on cardiovascular morbidity and mortality has not been
determined. 

16HOW SUPPLIED/STORAGE AND HANDLING

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

NDC 66582-414-31 bottles of 30 

NDC 66582-414-54 bottles of 90 

NDC 66582-414-74 bottles of 500 

NDC 66582-414-76 bottles of 5000 

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

Storage

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

17PATIENT COUNSELING INFORMATION

[See FDA-approved Patient Labeling (17.5).]

Patients should be advised to adhere to their National Cholesterol Education
Program (NCEP)-recommended diet, a regular exercise program, and periodic
testing of a fasting lipid panel. 

17.1Muscle Pain

All patients starting therapy with ezetimibe should be advised of the risk of
myopathy and told to report promptly any unexplained muscle pain, tenderness or
weakness. The risk of this occurring is increased when taking certain types of
medication. Patients should discuss all medication, both prescription and
over-the-counter, with their physician. 

17.2Liver Enzymes

Liver tests should be performed when ZETIA is added to statin therapy and
according to statin recommendations. 

17.3Pregnancy

Women of childbearing age should be advised to use an effective method of birth
control to prevent pregnancy while using ZETIA added to statin therapy. Discuss
future pregnancy plans with your patients, and discuss when to stop combination
ZETIA and statin therapy if they are trying to conceive. Patients should be
advised that if they become pregnant they should stop taking combination ZETIA
and statin therapy and call their healthcare professional. 

17.4Breastfeeding

Women who are breastfeeding should be advised to not use ZETIA added to statin
therapy. Patients who have a lipid disorder and are breastfeeding should be
advised to discuss the options with their healthcare professionals. 

17.5FDA-approved Patient Labeling

 32147054T                                            
 REV 21                                               
                                                      
 Issued July 2009                                     
                                                      
 Printed in USA.                                      
 U.S. Patent Nos. 5,846,966; 7,030,106 and RE37,721.  


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


1 COPYRIGHT © 2001, 2002, 2005, 2007, 2008 Merck/Schering-Plough
Pharmaceuticals. All rights reserved.

 29480885T  
 REV 21     


 ZETIA (ezetimibe) Tablets                   
                                             
 Patient Information about ZETIA (zĕt´-ē-ă)  
 Generic name: ezetimibe (ĕ-zĕt´-ĕ-mīb)      


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

What is ZETIA?

ZETIA is a medicine used to lower levels of total cholesterol and LDL (bad)
cholesterol in the blood. ZETIA is for patients who cannot control their
cholesterol levels by diet and exercise alone. It can be used by itself or with
other medicines to treat high cholesterol. You should stay on a
cholesterol-lowering diet while taking this medicine. 

ZETIA works to reduce the amount of cholesterol your body absorbs. ZETIA does
not help you lose weight. ZETIA has not been shown to prevent heart disease or
heart attacks. 

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

Who should not take ZETIA?

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

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

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

-- If you are a woman of childbearing age, you should use an effective method of
birth control to prevent pregnancy while using ZETIA added to statin therapy. 

ZETIA has not been studied in children under age 10. 

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

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

Tell your doctor about all your medical conditions including allergies. 

Tell your doctor if you: 

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

-- are pregnant or plan to become pregnant. Your doctor will discuss with you
whether ZETIA is right for you. 

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

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

How should I take ZETIA?

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

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

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

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

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

What are the possible side effects of ZETIA?

In clinical studies patients reported few side effects while taking ZETIA. These
included diarrhea, joint pains, and feeling tired. 

Patients have experienced severe muscle problems while taking ZETIA, usually
when ZETIA was added to a statin drug. If you experience unexplained muscle
pain, tenderness, or weakness while taking ZETIA, contact your doctor
immediately. You need to do this promptly, because on rare occasions, these
muscle problems can be serious, with muscle breakdown resulting in kidney
damage. 

Additionally, the following side effects have been reported in general use:
allergic reactions (which may require treatment right away) including swelling
of the face, lips, tongue, and/or throat that may cause difficulty in breathing
or swallowing, rash, and hives; raised red rash, sometimes with target-shaped
lesions; joint pain; muscle aches; alterations in some laboratory blood tests;
liver problems; stomach pain; inflammation of the pancreas; nausea; dizziness;
tingling sensation; depression; headache; gallstones; inflammation of the
gallbladder. 

Tell your doctor if you are having these or any other medical problems while on
ZETIA. For a complete list of side effects, ask your doctor or pharmacist. 

What should I know about high cholesterol?

Cholesterol is a type of fat found in your blood. Your total cholesterol is made
up of LDL and HDL cholesterol. 

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

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

Triglycerides also are fats found in your blood. 

General information about ZETIA

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

This summarizes the most important information about ZETIA. If you would like
more information, talk with your doctor. You can ask your pharmacist or doctor
for information about ZETIA that is written for health professionals. 

Inactive ingredients:

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

 29480885T                                            
 REV 21                                               
                                                      
 Issued July 2009                                     
 Printed in USA.                                      
 U.S. Patent Nos. 5,846,966; 7,030,106 and RE37,721.  


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


 COPYRIGHT © 2001, 2002, 2007, 2008 Merck/Schering-Plough Pharmaceuticals.  
 All rights reserved.                                                       
 Printed in USA.                                                            


Merck
Media:
Ron Rogers, 908-423-6449
Cell: 908-391-4302
or
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