Merck and Schering-Plough Resolve Previously Disclosed Civil Class Action Lawsuits Related to Vytorin (ezetimibe/simvastatin) and Zetia (ezetimibe)

WHITEHOUSE STATION, N.J. & KENILWORTH, N.J.--(BUSINESS WIRE)--Aug 5, 2009 - Merck & Co., Inc., Schering-Plough Corporation and the companies' cholesterol joint venture, Merck/Schering-Plough Pharmaceuticals (MSP), today announced that they have entered into agreements to resolve, for a total fixed amount of $41.5 million, civil class action litigation currently pending against the companies relating to the purchase or use of VYTORIN and ZETIA. The MSP joint venture recorded these charges in the second quarter 2009.

The agreements were reached with plaintiffs seeking to represent proposed classes of consumers, insurers and other entities and with a separate group of independently represented health plans that purchased, used or paid money towards the purchase of VYTORIN or ZETIA from the time of the products' introduction to the market.

"These agreements will allow the companies to avoid continuing defense costs and remain focused on discovering, developing and delivering novel medicines and vaccines," said Bruce N. Kuhlik, executive vice president and general counsel of Merck.

The settlement will resolve all of the class action lawsuits (including claims for attorneys' fees, costs and nongovernmental liens) that seek economic damages related to the purchase of VYTORIN and ZETIA. The companies have disclosed previously more than 140 such lawsuits pending in the United States District Court for the District of New Jersey. Those lawsuits make allegations regarding the safety and efficacy of VYTORIN and ZETIA based upon 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, the results of which were released by the companies in January of 2008.

The agreements are not an admission by the companies of any misconduct or liability in connection with the marketing or sale of VYTORIN or ZETIA or plaintiffs' allegations relating to the ENHANCE study. The agreement with the proposed classes is subject to court approval and certain conditions related to participation. The agreement with the independently represented health plans is not a class settlement and does not require court approval.

"We continue to believe that VYTORIN and ZETIA in addition to a healthy diet can provide important benefits for physicians in helping their patients with high cholesterol reach their cholesterol goals," said Thomas J. Sabatino, executive vice president and general counsel of Schering-Plough Corporation.

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 second 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.

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 γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions (5.1)].

6.2 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 a

Posted: August 2009


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