FDA approves VYTORIN, first and only to powerfully reduce LDL cholesterol through dual inhibition

07/23/04

VYTORIN lowered LDL cholesterol by 52 percent at the recommended starting dose (10/20 mg) and 60 percent at the maximum dose (10/80 mg)

WHITEHOUSE STATION and KENILWORTH, N.J., July 23, 2004 — Merck/Schering-Plough Pharmaceuticals announced today that the U.S. Food and Drug Administration has approved VYTORINTM (ezetimibe/simvastatin) for the treatment of high LDL cholesterol (LDL-C) in patients with primary hypercholesterolemia or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. VYTORIN is the first and only product approved to treat the two sources of cholesterol by inhibiting the production of cholesterol in the liver and blocking the absorption of cholesterol in the intestine, including cholesterol from food. The active ingredients in VYTORIN are ezetimibe and simvastatin. The recommended starting dose of VYTORIN is 10/20 mg (10 mg ezetimibe/20 mg simvastatin).

"Many patients who continue to have high cholesterol despite diet and other lifestyle modifications may require powerful LDL cholesterol-lowering agents and to do this we frequently look to highly efficacious medicines to provide the reduction they need," said Christie Ballantyne, M.D., director of the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, TX.

VYTORIN lowered LDL cholesterol by 52 percent at the recommended starting dose (10/20 mg) and 60 percent at the maximum dose (10/80 mg)

In a 12-week, multi-center, double-blind, placebo-controlled clinical study of 1,528 patients with LDL cholesterol levels of 145 mg/dL to 250 mg/dL, VYTORIN provided LDL cholesterol reductions of 52 percent at the recommended starting dose (10/20 mg), 55 percent at the 10/40 mg dose and 60 percent at the maximum dose (10/80 mg). VYTORIN is administered as a once-daily tablet and should be taken in the evening with or without food.

"VYTORIN is the first single cholesterol treatment to provide LDL cholesterol lowering through dual inhibition of cholesterol production and absorption. VYTORIN represents an important new treatment alternative for the millions of patients with elevated cholesterol for whom diet alone is not enough," said Raymond V. Gilmartin, chairman, president and chief executive officer of Merck & Co., Inc.

"With the approval of VYTORIN, physicians have a powerful new option that treats the two sources of cholesterol in one tablet," said Fred Hassan, chairman and chief executive officer of Schering-Plough. "VYTORIN represents an important new therapy that can provide patients with significant LDL cholesterol reductions."

In head-to-head trials, VYTORIN provided greater reductions in LDL cholesterol than atorvastatin (Lipitor) and simvastatin (Zocor) across the dosing range

In a 24-week, multi-center, randomized, double-blind, active-controlled, forced titration study of 788 patients, VYTORIN (doses ranging from 10/10 mg to 10/80 mg) was compared to atorvastatin monotherapy (doses ranging from 10 mg to 80 mg). The average LDL cholesterol levels at baseline across treatment groups ranged from 179 mg/dL to 181 mg/dL. At each pre-specified dose comparison, VYTORIN lowered LDL cholesterol to a significantly greater degree than atorvastatin. At the recommended usual starting doses, VYTORIN 10/20 mg lowered LDL cholesterol by 50 percent vs. 37 percent for atorvastatin 10 mg and 44 percent for atorvastatin 20 mg. The impact on clinical outcomes of these differences in lipid altering effects is unknown.

In the 12-week study of 1,528 patients with LDL cholesterol levels of 145 mg/dL to 250 mg/dL, those taking VYTORIN experienced significantly greater LDL cholesterol reductions compared to simvastatin. VYTORIN 10/20 mg achieved a 52 percent LDL cholesterol reduction compared to reductions of 34 percent and 41 percent, respectively, for simvastatin 20 mg and 40 mg (typical starting doses for simvastatin). No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

"The dual inhibition of cholesterol provided by VYTORIN delivers impressive LDL cholesterol reductions across the dosing range and offers physicians a unique and powerful new option in the evolving treatment of hyperlipidemia, especially in people who need more aggressive treatment to reach goal," said Margo Denke, M.D., clinical professor, University of Texas Health Science Center, San Antonio, TX.

In a clinical trial, greater LDL cholesterol reduction with VYTORIN compared to simvastatin (Zocor) resulted in greater goal attainment Results from a phase III, multi-center, randomized, double-blind controlled study of 710 patients showed that, after five weeks of treatment, VYTORIN 10/20 mg lowered LDL cholesterol by 53 percent compared to a 38 percent reduction with simvastatin 20 mg. This greater LDL cholesterol reduction resulted in 83 percent of patients treated with VYTORIN 10/20 mg achieving the study LDL cholesterol goal of less than 100 mg/dL as compared to 46 percent of patients taking simvastatin 20 mg.

Patients in this study were randomized to one of four treatment groups for 23 weeks: VYTORIN (10/10 mg, 10/20 mg or 10/40 mg) or simvastatin 20 mg. All 710 patients enrolled in the study had LDL cholesterol levels of 130 mg/dL or more (mean 165 mg/dL to 174 mg/dL across treatment arms) and coronary heart disease (CHD) or CHD risk equivalents as defined by the National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP) III.

"A medicine like VYTORIN, which provides dramatic LDL cholesterol-lowering efficacy and impressive goal attainment, is a welcome option for physicians and patients," said Dr. Ballantyne.

VYTORIN lowers cholesterol through dual inhibition of cholesterol production by the body and absorption in the small intestine

Cholesterol in the blood is derived from two sources – production by the body and absorption from the small intestine. The most widely prescribed cholesterol-lowering medications, called statins, work in the liver to reduce cholesterol production and increase clearance of cholesterol from the bloodstream. VYTORIN inhibits absorption of cholesterol in the small intestine, while also reducing cholesterol synthesis in the liver leading to clearance of cholesterol from the bloodstream.

Indications and contraindications for VYTORIN

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

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.

Selected cautionary information for 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 was 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 to be available in various doses

VYTORIN has been approved for use in patients at the following doses: 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg. Across the dosing range, the ezetimibe component of VYTORIN is held constant at 10 mg, while the simvastatin component ranges from 10 mg to 80 mg. The recommended starting dose for VYTORIN is 10/20 mg. Patients requiring LDL cholesterol reductions greater than 55 percent can be started on 10/40 mg. Patients requiring less aggressive LDL cholesterol reductions may be started at 10/10 mg. The dose of VYTORIN should be limited to 10/10 mg daily in patients on cyclosporine and 10/20 mg daily in patients on amiodarone or verapamil.

VYTORIN was well tolerated with a low incidence of adverse events

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).

Pricing and availability for VYTORIN

The price of VYTORIN will be $2.34 at all doses. This means that the significant LDL cholesterol reductions of VYTORIN are available to patients, physicians and payors at a price that is very competitive with other first-line agents in the marketplace. VYTORIN will be broadly available in pharmacies in the near future.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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