WHITEHOUSE STATION, N.J., Nov. 2, 2011 – Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) unanimously voted to recommend approval of Merck's VYTORIN® (ezetimibe/simvastatin) for use in patients with pre-dialysis chronic kidney disease. The Committee's vote was mixed (with the majority not in favor) regarding whether there is sufficient evidence to support approval specifically for patients with end-stage renal disease who are receiving dialysis. Merck is seeking indications for VYTORIN and for ZETIA® (ezetimibe) in combination with simvastatin to reduce the risk of major cardiovascular events in patients with chronic kidney disease based on the results of the Study of Heart and Renal Protection (SHARP) trial. Neither product is currently indicated for this use.
The Committee's recommendation will be considered by the FDA in its assessment of these investigational uses for VYTORIN and ZETIA. The FDA is not bound by the Committee's guidance, but takes its advice into account. Merck plans to discuss the results of today's Advisory Committee meeting with the FDA in the near future. Currently, the Company's supplemental new drug applications remain under review, with agency action expected in the first quarter of 2012.
"We are pleased with the panel's recommendation and will continue working with the FDA on its evaluation of the proposed new indications for VYTORIN and ZETIA. If approved for these uses, these medicines have the potential to help to address a significant, unmet need among people with chronic kidney disease," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "The Advisory Committee vote brings VYTORIN and ZETIA one step closer to being an option for these patients who are at increased risk for cardiovascular events and procedures, such as heart attacks, strokes and certain types of heart surgery."
The Committee reviewed the results of SHARP, which involved more than 9,000 patients, about two-thirds of whom were pre-dialysis and one-third was undergoing dialysis at study entry. SHARP studied the effect of the ezetimibe/simvastatin 10/20 mg combination tablet (VYTORIN) compared to placebo on the occurrence of major cardiovascular events in patients who, on average, had advanced or end stage chronic kidney disease and who did not have a history of heart attack or coronary revascularization, such as heart bypass surgery. The results of SHARP were published in the June 9 issue of The Lancet.
Important information about VYTORIN (ezetimibe/simvastatin)
VYTORIN contains 2 active ingredients: ezetimibe and simvastatin. VYTORIN is indicated as adjunctive therapy to diet for the reduction of total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non–HDL cholesterol and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia.
VYTORIN is not indicated to reduce major cardiovascular events in patients with chronic kidney disease. The prescribing information for VYTORIN currently states that no incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
VYTORIN is a prescription medicine and should not be taken with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone); with gemfibrozil, cyclosporine, or danazol; by anyone with active liver disease, unexplained persistent elevations of serum transaminases, or hypersensitivity to the product; or by women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant.
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 they already have tolerated treatment with simvastatin.
Selected cautionary information about VYTORIN
Muscle pain, tenderness, or weakness in people taking simvastatin should be reported to a doctor promptly because these could be signs of a serious side effect. Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness, or weakness with creatine phosphokinase (CK) levels above 10 × 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, including rhabdomyolysis, is dose related. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Therapy with VYTORIN should be discontinued immediately if markedly elevated CK levels occur or myopathy is diagnosed or suspected. VYTORIN also should be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis.
The risk of myopathy, including rhabdomyolysis, is greater in patients taking simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy, and with lower doses of simvastatin. Patients using VYTORIN 10/80 mg should be advised of this increased risk. Use of the 10/80 mg dose is restricted.
Because of the increased risk of myopathy/rhabdomyolysis, particularly at higher doses of simvastatin, concomitant use is contraindicated with drugs that are strong CYP3A4 inhibitors or with gemfibrozil, cyclosporine or danazol, and large quantities of grapefruit juice (>1 quart daily) should be avoided. The use of other fibrates with VYTORIN is not recommended. Use caution when prescribing VYTORIN with colchicine. The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving concomitant therapy with verapamil or diltiazem, and 10/20 mg daily in patients receiving amiodarone, amlodipine or ranolazine. The use of VYTORIN with these drugs, or with lipid-lowering doses of niacin, should be carefully weighed against the potential risk of myopathy/rhabdomyolysis with these combinations. Chinese patients should not receive VYTORIN 10/80 mg daily with niacin (≥1 g/day), and caution should be used when Chinese patients taking niacin are co-administered VYTORIN doses exceeding 10/20 mg/day. Adjustment of the VYTORIN dose may be needed when used with voriconazole. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN.
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.
Doctors should perform blood tests to check for liver problems before treatment and if symptoms of liver problems occur during treatment. In three placebo-controlled, 12 week trials, the incidence of consecutive elevations (≥3 × ULN) in serum transaminases was 1.7% overall and appeared to be dose related, with an incidence of 2.6% 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 × ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with 10/80 mg. These elevations were generally asymptomatic, not associated with cholestasis, and reversible whether treatment was maintained or discontinued.
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be promptly interrupted and should not be 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 of VYTORIN, the most commonly reported side effects, regardless of cause, included headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).
Selected additional dosage and administration information about VYTORIN
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). The recommended usual starting dose is 10/10 mg/day or 10/20 mg/day. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. The usual dosage range is 10/10 mg/day to 10/40 mg/day. Because the 10/80 mg dose of VYTORIN contains 80 mg of simvastatin, patients should not be titrated to the 10/80 mg dose. The 10/80 mg dose of VYTORIN should be restricted to patients who have been taking that dose chronically (eg, for 12 months or more) without evidence of muscle toxicity, and who do not need to be initiated on an interacting drug that is contraindicated or associated with a dose cap for simvastatin. See Dosage and Administration section of Prescribing Information for additional information.
Important information about ZETIA (ezetimibe)
ZETIA, along with diet, is indicated for use either by itself or together with statins or fenofibrate in patients with high cholesterol to reduce total cholesterol, LDL cholesterol, apolipoprotein B, and non-HDL cholesterol when the response to diet and exercise has been inadequate.
ZETIA is not indicated for use in reducing major cardiovascular events in patients with chronic kidney disease. The prescribing information for ZETIA currently states that its effect on cardiovascular morbidity and mortality has not been determined.
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. For people who have ever had liver problems or are pregnant or nursing, their doctor will decide if ZETIA is right for them. Refer to statin label for details about who should not take that statin.
Selected cautionary information about ZETIA
When using ZETIA with a statin, also follow the label recommendations for that specific statin.
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.
Doctors may do blood tests to check the patient's liver before the patient starts taking ZETIA with a statin, and during treatment according to the recommendations of the statin. 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 percent, and 4.5 percent 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, regardless of causality assessment, the most frequent side effects for ZETIA coadministered with a statin versus a statin alone included nasopharyngitis (3.7 percent versus 3.3 percent), myalgia (3.2 percent versus 2.7 percent), upper respiratory tract infection (2.9 percent versus 2.8 percent), arthralgia (2.6 percent versus 2.4 percent), and diarrhea (2.5 percent versus 2.2 percent); and for ZETIA administered alone versus placebo: upper respiratory tract infection (4.3 percent versus 2.5 percent), diarrhea (4.1 percent versus 3.7 percent), arthralgia (3.0 percent versus 2.2 percent), sinusitis (2.8 percent versus 2.2 percent), pain in extremity (2.7 percent versus 2.5 percent), and fatigue (2.4 percent versus 1.5 percent).