Merck and Schering-Plough Resolve Previously Disclosed Investigation Under State Consumer Protection Statutes Related to VYTORIN® (ezetimibe/simvastatin) and ZETIA® (ezetimibe)

Merck & Co., Inc. and Schering-Plough Corporation and the companies' cholesterol joint venture, Merck/Schering-Plough Pharmaceuticals, today said they have reached a civil settlement with a multistate group of attorneys general representing 35 states and the District of Columbia who investigated whether the companies violated state consumer protection laws in connection with the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) clinical trial or by their promotion and marketing of VYTORIN and ZETIA.

As part of the resolution of the multistate investigation, the companies agreed to reimburse the investigative costs of the 35 states and the District of Columbia which totaled $5.4 million. The settlement agreement does not require the companies to make any other payment, and does not require or include any admission of misconduct or liability by the companies.

In the settlement, the companies agreed to continue to comply with the Food, Drug and Cosmetic Act, the U.S. Food and Drug Administration Amendments Act, and other laws requiring the truthful and non-misleading marketing of pharmaceutical products and made other voluntary assurances of compliance related to the promotion of VYTORIN and ZETIA.

"Today's agreement is consistent with our belief that the companies conducted the ENHANCE trial in good faith and that their promotion of VYTORIN and ZETIA was in compliance with the law," said Bruce N. Kuhlik, executive vice president and general counsel of Merck.

"Resolving these inquiries for an amount equal to the states' investigative costs is in the interests of all stakeholders," said Thomas J. Sabatino, executive vice president and general counsel of Schering-Plough.

In addition to the District of Columbia, the 35 states participating in the agreement are: Arizona, Arkansas, California, Colorado, Delaware, Florida, Hawaii, Idaho, Illinois, Iowa, Kentucky, Louisiana, Maine, Massachusetts, Michigan, Mississippi, Missouri, Montana, Nebraska, Nevada, New Jersey, New Mexico, North Carolina, North Dakota, Ohio, Oregon, Pennsylvania, South Carolina, South Dakota, Tennessee, Texas, Vermont, Washington, West Virginia, and Wisconsin.

The companies previously disclosed the multistate investigation in filings with the U.S. Securities and Exchange Commission.

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 B¹, 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 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

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%, and 4.5% in patients treated with fenofibrate alone. Caution should be exercised when initiating ZETIA in patients treated with cyclosporine, particularly in patients with severe renal insufficiency, due to increased blood levels of ZETIA.

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

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is also marketed as INEGY^® outside the U.S. ZETIA is marketed outside the U.S. as EZETROL^®.

Merck Forward-looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Schering-Plough Disclosure Notice

The information in this press release includes certain "forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to litigation and investigations concerning VYTORIN and ZETIA^® (ezetimibe) and the Merck Schering-Plough cholesterol joint venture's ENHANCE clinical trial. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough’s forward-looking statements, including economic factors, the government investigation process, the litigation process and the regulatory process, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough’s Securities and Exchange Commission filings, including Part I, Item IA. "Risk Factors” in Schering-Plough’s first quarter 2009 10-Q.

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

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

32147046T

REV 20

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: 05/2009

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

1.3 Homozygous Sitosterolemia

1.4 Limitations of Use

2 DOSAGE 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

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Use with Statins or Fenofibrate

5.2 Liver Enzymes

5.3 Myopathy/Rhabdomyolysis

5.4 Hepatic Impairment

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Cyclosporine

7.2 Fibrates

7.3 Fenofibrate

7.4 Cholestyramine

7.5 Coumarin Anticoagulants

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

14.3 Homozygous Sitosterolemia (Phytosterolemia)

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT 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

1 INDICATIONS 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.

1.1 Primary 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.

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

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

1.3 Homozygous Sitosterolemia

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

1.4 Limitations 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.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

The recommended dose of ZETIA is 10 mg once daily.

ZETIA can be administered with or without food.

2.2 Concomitant 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.

2.3 Co-Administration with Bile Acid Sequestrants

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

2.4 Patients with Hepatic Impairment

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

2.5 Patients with Renal Impairment

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

2.6 Geriatric Patients

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

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Use 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.

5.2 Liver 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.

5.3 Myopathy/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.

5.4 Hepatic 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)].

6 ADVERSE 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: 0-39 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: 0-112 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%).

6.1 Clinical 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: 0-39 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 Adverse Reaction	ZETIA 10 mg (%) n = 2396	Placebo (%) 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: 0-112 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 Adverse Reaction	All Statins* (%) n = 9361	ZETIA + All Statins* (%) 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.

6.2 Post-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.

7 DRUG INTERACTIONS

[See Clinical Pharmacology (12.3).]

7.1 Cyclosporine

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

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

7.2 Fibrates

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.

7.3 Fenofibrate

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].

7.4 Cholestyramine

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.

7.5 Coumarin Anticoagulants

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 X the human exposure at 10 mg daily based on AUC_0-24hr 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 AUC_0-24hr 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)].

8.3 Nursing 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.

8.4 Pediatric 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 4 (3%) individuals in the ZETIA co-administered with simvastatin group and in 2 (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (=10 X ULN) occurred in 2 (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.

8.5 Geriatric 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)].

8.6 Hepatic 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)].

10 OVERDOSAGE

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

11 DESCRIPTION

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

[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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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 3 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)].

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Absorption: After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted adults, mean ezetimibe peak plasma concentrations (C_max) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (T_max). Ezetimibe-glucuronide mean C_max values of 45 to 71 ng/mL were achieved between 1 and 2 hours (T_max). 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 C_max 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 12 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 of Co-Administered Drug	Change in Cmax of Co-Administered Drug
Warfarin, 25 mg single dose on Day 7	10 mg QD, 11 days	decrease 2% (R-warfarin) decrease 4% (S-warfarin)	increase 3% (R-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 0% Levonorgestrel 0%	Ethinyl estradiol decrease 9% Levonorgestrel 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).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 X the human exposure at 10 mg daily based on AUC_0-24hr 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 AUC_0-24hr 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 AUC_0-24hr for total ezetimibe).

13.2 Animal 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 mcg/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 mcg/kg/day, respectively. These results are consistent with ZETIA being a potent cholesterol absorption inhibitor.

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

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

A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 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.

14 CLINICAL STUDIES

14.1 Primary 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 2 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 Ongoing 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 (Daily Dose)	N	Total-C	LDL-C	Apo B	TG†	HDL-C
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 4 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 8-11).

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

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

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

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

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

* 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.

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to 1 of 3 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%.

14.3 Homozygous Sitosterolemia (Phytosterolemia)

A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, 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 1 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.

16 HOW 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.

17 PATIENT 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.

17.1 Muscle 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.

17.2 Liver Enzymes

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

17.3 Pregnancy

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.

17.4 Breastfeeding

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.

17.5 FDA-approved Patient Labeling

32147046T

REV 20

Issued May 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.

29480877T

REV 20

ZETIA® (ezetimibe) Tablets

Patient Information about ZETIA (zet´-e-a)

Generic name: ezetimibe (e-zet´-e-mib)

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

What is ZETIA?

ZETIA is a medicine used to lower levels of total cholesterol and LDL (bad) cholesterol in the blood. 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 breastfeeding, 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 breastfeeding. 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.

29480877T

REV 20

Issued May 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.

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, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, fibrates		Avoid VYTORIN
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*

1 INDICATIONS AND USAGE

1.1 Primary Hyperlipidemia

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

1.3 Limitations of Use

2 DOSAGE 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

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/Rhabdomyolysis

5.2 Liver Enzymes

5.3 Hepatic Impairment

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG 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

8 USE 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

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT 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

1 INDICATIONS 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.

1.1 Primary 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.

1.2 Homozygous Familial Hypercholesterolemia (HoFH)

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

1.3 Limitations 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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended 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.

2.2 Patients with Homozygous Familial Hypercholesterolemia

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

2.3 Patients with Hepatic Impairment

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

2.4 Patients 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)].

2.5 Geriatric Patients

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

2.6 Coadministration 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).]

3 DOSAGE 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.

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy/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 Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Fibrates*		Avoid VYTORIN
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)

* 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.

5.2 Liver Enzymes

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

It is recommended that liver function tests be performed before the initiation of treatment with VYTORIN, and thereafter when clinically indicated. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 X ULN or greater persist, withdrawal of therapy with VYTORIN is recommended.

VYTORIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN.

5.3 Hepatic 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).]

6 ADVERSE 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)]

6.1 Clinical 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 Adverse Reaction		Placebo (%) n=371		Ezetimibe 10 mg (%) n=302		Simvastatin** (%) n=1234		VYTORIN** (%) n=1420
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 ?-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)].

6.2 Post-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.

7 DRUG INTERACTIONS

[See Clinical Pharmacology (12.3).]

VYTORIN

7.1 CYP3A4 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.

7.2 Lipid-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)].

7.3 Amiodarone 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)].

7.4 Cholestyramine

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

7.5 Cyclosporine 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).]

7.6 Digoxin

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.

7.7 Fibrates

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

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Animal 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).]

7.8 Coumarin 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 AUC_0-24hr 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 AUC_0-24hr 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.

8.3 Nursing 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)].

8.4 Pediatric 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.

8.5 Geriatric 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).]

8.6 Renal Impairment

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

8.7 Hepatic 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).]

10 OVERDOSAGE

VYTORIN

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

Ezetimibe

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

11 DESCRIPTION

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 ß-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-[1a,3a,7ß,8ß(2S^*,4S^*),-8aß]]. 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)

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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 ß-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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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 ß-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 C_max 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 ß-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 ß-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the ß-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 ß-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 C_max and AUC of niacin increased 9% and 22%, respectively. The mean C_max 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 C_max of total ezetimibe (1%), and simvastatin (2%), it increased the mean C_max 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 Dosage Regimen		Ezetimibe Dosage Regimen		Change in AUC of Coadministered Drug		Change in Cmax of Coadministered Drug
Warfarin, 25 mg single dose on Day 7		10 mg QD, 11 days		?2% (R-warfarin) ?4% (S-warfarin)		?3% (R-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 0% Levonorgestrel 0%		Ethinyl estradiol ?9% Levonorgestrel ?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‡ simvastatin		12 8.9		15 5.3
Nelfinavir†		1250 mg BID for 14 days		20 mg QD for 28 days		simvastatin acid‡ simvastatin		6		6.2
Itraconazole†		200 mg QD for 4 days		80 mg		simvastatin acid‡ simvastatin				13.1 13.1
Avoid >1 quart of grapefruit juice with VYTORIN [see Warnings and Precautions (5.1)]
Grapefruit Juice§ (high dose)		200 mL of double-strength TID		60 mg single dose		simvastatin acid simvastatin		7 16
Grapefruit Juice§ (low dose)		8 oz (about 237 mL) of single-strength#		20 mg single dose		simvastatin acid simvastatin		1.3 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 simvastatin		2.85 1.35		2.18 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 simvastatin		2.3 2.5		2.4 2.1
No dosing adjustments required for the following:
Fenofibrate		160 mg QD x14 days		80 mg QD on Days 8-14		simvastatin acid simvastatin		0.64 0.89		0.89 0.83
Diltiazem		120 mg BID for 10 days		80 mg on Day 10		simvastatin acid simvastatin		2.69 3.10		2.69 2.88
Amlodipine		10 mg QD x 10 days		80 mg on Day 10		simvastatin acid simvastatin		1.58 1.77		1.56 1.47
Propranolol		80 mg single dose		80 mg single dose		total inhibitor active inhibitor		0.79 0.79		? from 33.6 to 21.1 ng·eq/mL ? 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 ß-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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

VYTORIN

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

Ezetimibe

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC_0-24hr 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 AUC_0-24hr 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 AUC_0-24hr 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.

13.2 Animal 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.

14 CLINICAL STUDIES

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

^a For triglycerides, median % change from baseline

^b Baseline - on no lipid-lowering drug

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

In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C =130 mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10, 10/20, and 10/40) or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.

At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 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 20 mg		VYTORIN 10/10		VYTORIN 10/20		VYTORIN 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 (Daily Dose)		N		Total-Cc		LDL-Cc		Apo Bc		HDL-C		TGa		Non-HDL-Cc
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 VYTORIN doses pooled (10/10-10/80) provided significantly greater reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to atorvastatin doses pooled (10-80).

^d 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

VYTORIN 10/10d

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

VYTORIN 10/20

250

-37f

-50f

-41f

+9

-28

-46f

VYTORIN 10/40

252

-39f

-54f

-45f

+12f

-31

-50f

Week 18

Atorvastatin 40 mg

237

-37

-49

-42

+8

-31

-47

VYTORIN 10/40g

482

-40f

-56f

-45f

+11f

-32

-52f

Week 24

Atorvastatin 80 mg

228

-40

-53

-45

+6

-35

-50

VYTORIN 10/80g

459

-43f

-59f

-49f

+12f

-35

-55f

^a For triglycerides, median % change from baseline

^b Baseline - on no lipid-lowering drug

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

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

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

^f p=0.05 for difference with atorvastatin in the specified week

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

In a multicenter, double-blind, 6-week study, 2959 patients with 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 (Daily Dose)

N

Total-Cc

LDL-Cc

Apo Bc

HDL-C

TGa

Non-HDL-Cc

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

^d 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.

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

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

16 HOW 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.

17 PATIENT 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.

17.1 Muscle 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.

17.2 Liver 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.

17.3 Pregnancy

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.

17.4 Breast-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.

17.5 FDA-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

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