Vytorin (ezetimibe/simvastatin) Significantly Reduced Major Vascular Events in Patients With Chronic Kidney Disease in a New 9,000-Patient Investigational Study

SHARP is the First and Only Prospective Clinical Study in Patients With Chronic Kidney Disease to Show That an LDL Cholesterol-Lowering Medicine Reduced Major Vascular and Atherosclerotic Events

DENVER, Colo.--(BUSINESS WIRE)--Nov 20, 2010 - In a new investigational study of VYTORIN® (ezetimibe/simvastatin), the cholesterol-lowering medicine from Merck (known as MSD outside the US and Canada), VYTORIN 10/20 mg reduced the incidence of first major vascular events -- defined as non-fatal heart attacks or cardiac death, stroke or any revascularization procedure -- by a highly statistically significant 16.1 percent compared to placebo (p=0.0010). This was the pre-specified primary endpoint of the study. The SHARP (Study of Heart and Renal Protection) study involved more than 9,000 patients who, on average, had advanced or end-stage chronic kidney disease (CKD), and is the first prospective clinical study in patients with CKD to demonstrate the benefit of lowering LDL (bad) cholesterol on major vascular events. The results were presented today during Renal Week, the American Society of Nephrology's annual meeting, by Professor Colin Baigent, F.F.P.H., F.R.C.P., and Dr. Martin Landray, Ph.D., F.R.C.P., the principal investigators of SHARP, from the Oxford University Clinical Trial Service Unit (CTSU), Oxford, England.

"This is an important study," said Dr. Peter S. Kim, Ph.D., president, Merck Research Laboratories. "Patients with CKD have a high risk of ischemic vascular disease and increased rates of heart attack, stroke, other cardiovascular events and revascularization procedures. In SHARP, the investigational use of VYTORIN significantly reduced the risk of these events in a spectrum of patients with chronic kidney disease -- and this was the first demonstration that an LDL-cholesterol lowering medicine could do so."

Merck plans to seek regulatory approvals for the use of VYTORIN in patients with CKD based on the results from the SHARP study. VYTORIN is currently indicated as adjunctive therapy to diet for the reduction of LDL cholesterol in patients with primary 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.

SHARP is the largest prospective study of LDL-lowering in patients with CKD

SHARP is the largest clinical trial of VYTORIN conducted to date, and enrolled a total of 9,438 patients under the care of a nephrologist for chronic kidney disease. One-third of patients were undergoing dialysis therapy for end-stage kidney disease at the time of entry, and the remaining patients were pre-dialysis patients with advanced CKD with an average estimated glomerular filtration rate (a measure of kidney function) of 26.5 ml/min/1.73m2. Patients with a prior history of myocardial infarction or a revascularization procedure were excluded from the study. At randomization, the average LDL cholesterol of all patients enrolled in SHARP was 108 mg/dL.

Patients were initially randomized in a ratio of 4:4:1 to receive VYTORIN 10/20 mg daily versus placebo versus simvastatin 20 mg alone (for purposes of assessing drug safety). After one year, patients initially allocated to simvastatin alone were re-randomized to either VYTORIN 10/20 mg daily or placebo for the remainder of the study period. Patients were followed for a median of 4.9 years.

The protocol-specified primary endpoint for the study was the incidence of first major vascular events, defined as the composite of non-fatal heart attack or cardiac death, stroke or revascularization procedure in the two groups randomized to VYTORIN or placebo at study initiation. (This analysis did not include patients initially randomized to simvastatin alone for the first year.) In the intention-to-treat analysis, VYTORIN reduced first major vascular events by 16.1 percent compared to placebo (p=0.0010). In the group that received VYTORIN (n=4,193) 15.2 percent of patients had a major vascular event, compared to 17.9 percent of patients taking placebo (n=4,191).

In addition, in the full study population of patients, including patients who took simvastatin alone for the first year and were then re-randomized to either VYTORIN or placebo, VYTORIN reduced first major vascular events by 15.3 percent compared to placebo (p=0.0012). The rate of major vascular events in patients taking VYTORIN (n=4,650) was 15.1 percent, compared to 17.6 percent of patients taking placebo (n=4,620).

Results on Major Atherosclerotic Events Also Presented

Based on information from clinical studies of other LDL-lowering medicines that became available after the original SHARP study protocol was implemented in 2003 and before the study ended, the independent SHARP Steering Committee determined that the most relevant "key outcome" for the study should be the incidence of first "major atherosclerotic events." Major atherosclerotic events were defined as the combination of non-fatal heart attack, coronary death, ischemic stroke or any revascularization procedure; this analysis excluded non-coronary cardiac death and hemorrhagic stroke from the protocol-specified primary endpoint of major vascular events. (The Steering Committee's rationale and statistical analysis plan are discussed in a paper published on-line in the American Heart Journal). In the intention-to-treat analysis, VYTORIN also reduced first major atherosclerotic events by 16.5 percent compared to placebo (p=0.0022). The rate of first major atherosclerotic events in patients taking VYTORIN (n=4,650) was 11.3 percent, compared to 13.4 percent in patients taking placebo (n=4,620).

In the first year of the trial, VYTORIN 10/20 mg lowered LDL cholesterol by 40 percent compared to placebo, while simvastatin 20 mg lowered LDL cholesterol by 28 percent versus placebo; the reduction achieved by VYTORIN was 30 percent greater than that achieved by simvastatin alone. After two and half years of treatment, which was approximately mid-way through the study, VYTORIN lowered LDL cholesterol by 32 mg/dL, or 30 percent from baseline, compared to placebo.

The researchers noted that the reduction in major vascular events and major atherosclerotic events based on the LDL-cholesterol reduction achieved with VYTORIN in SHARP was consistent with reduction of outcomes that would be predicted based on the recently published Cholesterol Treatment Trialists' (CTT) meta-analysis of large-scale statin trials. The CTT analysis, published online in The Lancet, examined the relationship between LDL-cholesterol lowering and reduced rates of cardiovascular events.

One of the secondary endpoints for SHARP was the progression to end-stage renal disease (ESRD) among patients who were not yet on dialysis at the start of the study. A patient was considered to have progressed to ESRD if they started long-term dialysis or proceeded to kidney transplantation following randomization. On this endpoint, there was no difference between VYTORIN and placebo; 33.9 percent of patients receiving VYTORIN (n=3,117) proceeded to ESRD, compared to 34.6 percent of patients on placebo (n=3,130).

VYTORIN 10/20 mg Safety Profile Over the Nearly Five Years of Follow-up

In terms of assessing safety in SHARP, the researchers assessed reports of serious adverse events as well as adverse events that were pre-specified: cancer, myopathy with levels of creatine phosphokinase (CK) >10 x but ‰¤40 x upper limit of normal (ULN), and reports of myopathy with CK >40 x ULN, hepatitis, persistently elevated liver enzymes (ALT/AST >3 x ULN), complications of gallstones, other hospitalizations for gallstones, and pancreatitis without gallstones.

Overall, the safety profile of VYTORIN 10/20 mg in this study was consistent with the profile described in the current approved label.

VYTORIN (n=4,650) was comparable to placebo (n=4,620) in the incidence of cancer and cancer-related deaths: cancer was reported in 9.4 percent of patients taking VYTORIN versus 9.5 percent of patients taking placebo (p=0.89); mortality due to cancer was reported in 3.2 percent of patients taking VYTORIN versus 2.8 percent of patients taking placebo (p=0.20).

For other safety analyses that were pre-specified, VYTORIN was also comparable to placebo in the incidence of CK > 10 x but ‰¤ 40 x ULN (0.4 percent for VYTORIN versus 0.3 percent for placebo), CK >40 x ULN (0.1 percent in each group), hepatitis (0.5 percent for VYTORIN versus 0.4 percent for placebo), persistently elevated ALT/AST>3 x ULN (0.6 percent in each group), complications of gallstones (1.8 percent for VYTORIN versus 1.6 percent for placebo), other hospitalizations for gallstones (0.5 percent for VYTORIN versus 0.6 percent for placebo) and pancreatitis without gallstones (0.3 percent for VYTORIN versus 0.4 percent for placebo).

"Merck is proud to support clinical trials such as SHARP and we thank the Oxford University and the thousands of patients and health care professionals who participated in SHARP for their contributions to this study to address this important medical question for patients with CKD," Kim said.

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 B, 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 not indicated to reduce major vascular events or atherosclerotic events in patients with chronic kidney disease. The prescribing information for VYTORIN states that it has not been shown to reduce heart attacks or strokes more than simvastatin alone.

No dosage adjustment is necessary in patients with mild or moderate renal impairment. Caution should be exercised when VYTORIN is administered to patients with severe renal insufficiency. VYTORIN should not be initiated in such patients unless the patient has already tolerated treatment with simvastatin.

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.

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

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (‰¥3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (‰¥3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

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

VYTORIN has been evaluated for safety in more than 10,100 patients in clinical trials. In clinical trials, the most commonly reported side effects, regardless of cause, included headache (5.8 percent), increased ALT (3.7 percent), myalgia (3.6 percent), upper respiratory tract infection (3.6 percent), and diarrhea (2.8 percent).

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

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

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

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

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2009 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Prescribing Information and Patient Product Information for VYTORIN® is available at
http://www.msppharma.com/msppharma/documents/vytorin_pi.pdf and http://www.msppharma.com/msppharma/documents/vytorin_ppi.pdf.

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

RECENT MAJOR CHANGES

Dosage and Administration    
Chinese Patients Taking Lipid-Modifying Doses (‰¥1 g/day Niacin) of
Niacin-Containing Products (2.6)

 

  03/2010
Coadministration with Other Drugs (2.7)   03/2010
Warnings and Precautions    
Myopathy/Rhabdomyolysis (5.1)   03/2010
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. (2.7, 7.5)

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, verapamil, and diltiazem. 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 (2.7, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8)
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
Diltiazem   Do not exceed 10/40 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. (7.6, 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. (7.9)
  • Cholestyramine: Combination decreases exposure of ezetimibe. (2.7, 7.5)

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: 05/2010

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   Chinese Patients Taking Lipid-Modifying Doses (‰¥1 g/day Niacin) of Niacin-Containing Products
    2.7   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, Verapamil, or Diltiazem
    7.4   Niacin
    7.5   Cholestyramine
    7.6   Cyclosporine or Danazol
    7.7   Digoxin
    7.8   Fibrates
    7.9   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 Chinese Patients Taking Lipid-Modifying Doses (‰¥1 g/day Niacin) of Niacin-Containing Products

Because of an increased risk for myopathy, caution should be used when treating Chinese patients with VYTORIN coadministered with lipid-modifying doses (‰¥1 g/day niacin) of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings and Precautions (5.1).]

2.7 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 (7.5)].

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 (7.6)].

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)].

Diltiazem

The dose of VYTORIN should not exceed 10/40 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

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 7.8)].

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 7.8).]

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, verapamil, or diltiazem.

Caution should be used when prescribing other fibrates with VYTORIN, as these agents can cause myopathy when given alone.

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (‰¥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg coadministered with lipid-modifying doses of a niacin-containing product. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients.

Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.7), 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
Diltiazem§   Do not exceed 10/40 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.

 

§

 

  The combined use of VYTORIN at doses higher than 10/40 mg daily with diltiazem 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 consecut

Posted: November 2010

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