From Merck:

New Analyses from the IMPROVE-IT Study with VYTORIN® (ezetimibe and simvastatin)

Further Analyses on the Long-Term Safety and Efficacy of VYTORIN® from the IMPROVE-IT Study Presented at the European Society of Cardiology (ESC) Meeting

Tuesday, September 1, 2015 9:00 am EDT

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KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD in the United States and Canada, today announced results from new analyses from the IMPROVE-IT study.

“IMPROVE-IT presents us with the opportunity to look at cardiovascular outcomes data for patients treated with the combination of simvastatin and ezetimibe (VYTORIN) and allows us to look at the important aspect of long-term safety and efficacy under controlled conditions,” said Dr. Michael A. Blazing, Duke Department of Medicine.

VYTORIN (ezetimibe and simvastatin) and ZETIA (ezetimibe) are currently indicated for use along with a healthy diet to reduce elevated LDL cholesterol in patients with hyperlipidemia. The current U.S. Prescribing Information for both products states that the effect of ezetimibe on cardiovascular morbidity and mortality, alone or incremental to statin therapy, has not been determined. Merck has submitted the data from the IMPROVE-IT study to the U.S. Food and Drug Administration to support a new indication for reduction of cardiovascular events for ZETIA and VYTORIN.

Incidence of New Onset Diabetes in the IMPROVE-IT Trial: Does Adding Ezetimibe to Simvastatin Increase Risk Compared to Simvastatin Alone?

The results of one of the analyses presented at ESC showed that patients treated with VYTORIN® – which combines simvastatin with the non-statin ZETIA® - showed a similar risk of new onset diabetes mellitus (DM) compared to simvastatin alone over a period of >5.5 years median follow-up. During the trial, 1,414 patients (13.3% of those without diabetes at enrollment) developed new onset DM defined as initiation of a diabetes medication or two consecutive fasting glucose levels ≥7 mmol/L (126 mg/dL). Of the new onset DM cases, 50.9% occurred in the VYTORIN (ezetimibe and simvastatin) arm and 49.1% in the simvastatin arm (hazard ratio 1.04; 95% CI 0.94-1.15).

Safety and Efficacy of Long-term Very Low Achieved LDL-C in the IMPROVE-IT Trial

This post-hoc analysis compared safety and efficacy data during the median six years follow-up in patients stratified by achieved LDL-C at month one of the trial. This analysis assessed patients achieving LDL-C levels <30 mg/dL, 30 - <50 mg/dL, 50 - <70 mg/dL and ≥70 mg/dL at month one of the trial. The nine selected safety events of special interest, which included hemorrhagic stroke and adverse events leading to treatment discontinuation, showed similar rates in patients with LDL-C <30 mg/dL at month one (achieved by 6% of patients) compared with patients with higher achieved LDL-C levels. For a complete list of all the safety parameters analyzed please visit the ESC website. In addition, this analysis concluded that cardiovascular events occurred less frequently in patients who achieved an LDL-C level <70 mg/dL at month 1 of the trial compared with LDL-C levels ≥70 mg/dL.

Achievement of Dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) Goals More Frequent with Addition of Ezetimibe and Associated with Better Outcomes in IMPROVE-IT

Additional evidence relating to the efficacy of VYTORIN comes from another IMPROVE-IT analysis, which assessed outcomes in subjects achieving specific levels of LDL-C and high sensitivity C-reactive protein (hs-CRP). CRP levels, a marker of inflammation, are associated with a higher cardiovascular risk in some settings. This analysis showed that patients achieving both LDL-C <70 mg/dL and hs-CRP <2 mg/L at one month had a lower rate of the primary composite endpoint of major CV events over the course of the trial compared with patients not achieving either level. Significantly more patients treated with VYTORIN met these specified dual levels at month one compared to patients treated with simvastatin alone (50% vs 29%, p<0.001).

About the IMPROVE-IT Trial

IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy International Trial) was led by the Thrombolysis In Myocardial Infarction (TIMI) Study Group of Brigham and Women’s Hospital and the Duke Clinical Research Institute (DCRI) and was sponsored by Merck. IMPROVE-IT was an international, multi-center, randomized, double-blind, active comparator trial of 18,144 high-risk patients presenting with acute coronary syndromes (ACS), including unstable angina (UA), non-ST-segment elevation acute myocardial infarction (NSTEMI) and ST-segment elevation acute myocardial infarction (STEMI). The study assessed the incidence of major CV events, as measured by a composite of CV death, non-fatal MI, non-fatal stroke, re-hospitalization for ACS or coronary revascularization (occurring 30 days or more after the initial event), in patients treated with ezetimibe/simvastatin (VYTORIN) compared with patients treated with simvastatin alone.

All patients in the trial were started at doses of ezetimibe and simvastatin 10/40 mg or simvastatin 40 mg. Prior to a 2011 protocol amendment, the dose could be titrated to ezetimibe/simvastatin 10/80 mg or simvastatin 80 mg if successive LDL-C values exceeded 79 mg/dL. The study enrolled patients within 10 days of ACS hospitalization who had sufficient risk as defined in the protocol and who had an initial LDL-C of ≤125 mg/dL if lipid-lowering drug naïve or <100 mg/dL if on a prior prescription lipid-lowering therapy identified as no more potent than simvastatin 40 mg/day. The LDL-C entry limitations were designed to enroll patients reasonably anticipated to achieve LDL-C levels of 70 mg/dL or less in the simvastatin only cohort, which was the optional recommended target set in the 2004 update to the Adult Treatment Panel (ATP) III guidelines.

About VYTORIN® (ezetimibe and simvastatin)

VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non–HDL cholesterol, and to increase HDL cholesterol in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia when diet alone is not enough.

The Prescribing Information for VYTORIN states that no incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. VYTORIN is not indicated to reduce cardiovascular events in patients who have presented with acute coronary syndromes.

VYTORIN (ezetimibe and simvastatin) should not be taken with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products); or with gemfibrozil, cyclosporine, or danazol. VYTORIN also should not be taken by anyone with active liver disease, unexplained persistent elevations of hepatic transaminase levels, or hypersensitivity to the product; or by women who are pregnant, nursing or may become pregnant.

Selected Cautionary Information About VYTORIN (ezetimibe and simvastatin)

All patients starting therapy with VYTORIN, or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing VYTORIN. VYTORIN should be discontinued immediately if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. VYTORIN contains simvastatin, which occasionally causes myopathy manifested as muscle pain, tenderness, or weakness with CK levels above 10 times ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy, including rhabdomyolysis, is dose related.

The 10/80 mg dose of VYTORIN should not be started in new patients. The risk of myopathy, including rhabdomyolysis, is greater in patients taking simvastatin 80 mg compared with other statin therapies with similar or greater LDL cholesterol lowering efficacy, and with lower doses of simvastatin. The 10/80 mg dose of VYTORIN should be used only in patients who have been taking that dose chronically (e.g., for 12 months or more) without evidence of muscle toxicity. If a patient who is currently tolerating the 10/80 mg dose needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Please read Warnings and Precautions in the Prescribing Information for additional information.

In addition to drugs that are contraindicated because of an increased risk of myopathy/rhabdomyolysis, grapefruit juice should be avoided. Use caution when prescribing VYTORIN with a fenofibrate, and immediately discontinue both drugs if myopathy is diagnosed or suspected. Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be used when prescribing VYTORIN (ezetimibe and simvastatin) with colchicine.

The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving verapamil, diltiazem or dronedarone, and 10/20 mg daily in patients receiving amiodarone, amlodipine or ranolazine. For patients with homozygous familial hypercholesterolemia (HoFH) taking lomitapide, the dose should not exceed 10/20 mg/day (or 10/40 mg/day for patients who have previously taken simvastatin 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity); patients initiating lomitapide should have their dose of VYTORIN (ezetimibe and simvastatin) reduced by 50%. The benefits of combined use of VYTORIN with these drugs, other fenofibrates, or niacin (≥1 g/day) should be carefully weighed against the potential risk of myopathy/rhabdomyolysis. Caution should be used when Chinese patients taking niacin (≥1 g/day) are coadministered doses of VYTORIN exceeding 10/20 mg/day; Chinese patients should not receive VYTORIN 10/80 mg with niacin.

Persistent elevations in hepatic transaminase can occur. Liver function tests should be performed at treatment initiation and thereafter when clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be interrupted promptly and not restarted unless an alternate etiology is found.

Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin.

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 tablets contain ezetimibe and simvastatin: 10 mg of ezetimibe and 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40, or 10/80 mg, respectively). The usual dosage range is 10/10 mg/day to 10/40 mg/day; patients should not be titrated to the restricted 10/80-mg dose.

About ZETIA® (ezetimibe)

ZETIA, administered alone or in combination with a statin, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, and non-HDL cholesterol in patients with primary (heterozygous familial and non-familial) hyperlipidemia when diet alone is not enough.

The Prescribing Information for ZETIA states that the effect of ZETIA on cardiovascular morbidity and mortality has not been determined. ZETIA is not indicated for use with a statin to further reduce cardiovascular events in patients who have presented with acute coronary syndromes.

ZETIA (ezetimibe) should not be taken by people with hypersensitivity to any component of the medication. Statin contraindications also apply when ZETIA is used with these drugs: statins are contraindicated in patients with active liver disease, unexplained persistent elevations in hepatic transaminase levels and in pregnant and nursing women. Refer to individual statin labels for details about who should not take that statin.

Selected Cautionary Information About ZETIA (ezetimibe)

When using ZETIA with a statin, also follow the label recommendations for that specific statin.

When ZETIA was coadministered with a statin, consecutive elevations in hepatic transaminase levels (greater than or equal to 3 times ULN) were slightly higher (1.3 percent) than those of statins alone (0.4 percent). Liver function tests should be performed when ZETIA is added to statin therapy and according to statin recommendations. Should an increase in ALT or AST greater than or equal to 3 times ULN persist, consider withdrawal of ZETIA and/or the statin.

Patients should be advised to promptly report muscle pain, tenderness, or weakness. Risk for skeletal muscle toxicity increases with higher statin doses, advanced age (>65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. Discontinue drug if myopathy is diagnosed or suspected.

ZETIA is not recommended in patients with moderate to severe hepatic impairment.

The coadministration of ZETIA with fibrates other than fenofibrate is not recommended until use in patients is adequately studied. Exercise caution when using ZETIA and cyclosporine concomitantly because exposure to both drugs is increased. Cyclosporine concentrations should be monitored in these patients.

ZETIA should be used in pregnant or nursing women only if the benefit outweighs the risk.

In clinical trials, regardless of causality assessment, the most frequent side effects for ZETIA coadministered with a statin versus a statin alone included nasopharyngitis (3.7 percent vs 3.3 percent), myalgia (3.2 percent vs 2.7 percent), upper respiratory tract infection (2.9 percent vs 2.8 percent), arthralgia (2.6 percent vs 2.4 percent), and diarrhea (2.5 percent vs 2.2 percent); for ZETIA administered alone vs placebo: upper respiratory tract infection (4.3 percent vs 2.5 percent), diarrhea (4.1 percent vs 3.7 percent), arthralgia (3.0 percent vs 2.2 percent), sinusitis (2.8 percent vs 2.2 percent), pain in extremity (2.7 percent vs 2.5 percent), and fatigue (2.4 percent vs 1.5 percent).

Additional Information About the IMPROVE-IT Trial

IMPROVE-IT was a multi-center, randomized, double-blind active comparator trial of 18,144 high-risk patients presenting with acute coronary syndromes (ACS), including unstable angina (UA), non-ST-segment elevation acute myocardial infarction (NSTEMI) and ST-segment elevation acute myocardial infarction (STEMI). Patients were randomized to receive ezetimibe and simvastatin (VYTORIN) or simvastatin alone, and were followed for up to nine years, with a median clinical follow-up of approximately six years. The primary efficacy endpoint was the composite of cardiovascular death, non-fatal MI, non-fatal stroke, re-hospitalization for ACS or coronary revascularization (occurring 30 days or more after the initial event).

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 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 and connect with us on Twitter, Facebook and YouTube.

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Please see Prescribing Information for VYTORIN® (ezetimibe and simvastatin) athttp://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf and the Patient Information for VYTORIN athttp://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_ppi.pdf.

Please see Prescribing Information for ZETIA® (ezetimibe) athttp://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf and the Patient Information for ZETIA athttp://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_ppi.pdf.