Merck Expresses Confidence In The Efficacy And Safety Profiles Of ZETIA (ezetimibe) And VYTORIN (ezetimibe/simvastatin) As Effective Medicines For Managing Elevated Cholesterol
At the American Heart Association meeting recently, Merck & Co., Inc. said it is confident in the safety and efficacy profiles of ZETIA (ezetimibe) and VYTORIN (ezetimibe/simvastatin), and issued the following comment in response to misinterpretation of results from a small 200-patient imaging study called ARBITER 6.
"The results of the small ARBITER 6 study do not, in any way, change our view of ZETIA and VYTORIN as effective medicines for fighting high LDL cholesterol," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "Nothing from this study, which a New England Journal of Medicine editorial says has 'several limitations,' changes the well established understanding that lowering LDL cholesterol is the primary target of therapy according to the guidelines. ZETIA and VYTORIN, when used as a supplement to a healthy diet, are effective in reducing LDL cholesterol," said Dr. Kim. "We encourage patients to continue taking their medication as prescribed by their physicians, and of course to speak to their physician if they have concerns."
The results of ARBITER 6 were widely predicted because the study design favored niacin as the patient population selected had well-controlled LDL cholesterol and relatively low HDL cholesterol. Also, it is important to remember that ARBITER 6 is not an outcomes study, and does not have the rigor or size to provide meaningful insight into the effect of either niacin or ezetimibe on clinical outcomes. Merck has reviewed the data from 43 completed shorter-term clinical trials involving approximately 2,400 patients who received ezetimibe alone and 13,600 patients who received ezetimibe with statins, as well as two longer-term studies, and is confident that the data support the safety profiles of ZETIA and VYTORIN as described in their labels.
"Any suggestion that the results of ARBITER 6 can definitively answer the question of the impact of ezetimibe on cardiovascular outcomes or that its results have implications for clinical use should be met with skepticism," said Dr. Kim. "Given the broadly accepted, scientifically validated importance of lowering LDL and the millions of people in the United States alone who are not at their recommended treatment goals, VYTORIN and ZETIA remain effective options for physicians to treat their appropriate patients."
Both niacin and ezetimibe have established effects on lipids, as noted in the prescribing information for these medicines. We look forward to the results from IMPROVE-IT, the large, longer-term clinical outcomes trial underway to understand whether additional LDL-lowering with ezetimibe reduces cardiovascular outcomes. There are other separate large, longer-term clinical outcomes trials being conducted to understand the role of raising HDL in reducing cardiovascular outcomes.
Physicians need multiple options to help manage their patients' cholesterol
There are millions of patients with high LDL cholesterol. There are also millions of patients with elevated LDL cholesterol in addition to other lipid abnormalities like elevated triglycerides. Physicians need multiple options like ezetimibe and niacin to help manage patients' different lipid abnormalities. Ezetimibe remains an effective medicine to do what it is approved by FDA and 89 other regulatory agencies to do: help lower LDL cholesterol as an adjunct to diet when diet alone is not enough.
According to Lipid Treatment Assessment Project 2 (Circulation 2009), approximately 65 percent of very high-risk patients in the United States did not reach their optimal LDL goal of less than 70 mg/dL.
In separate head-to-head clinical studies, VYTORIN was shown to be more effective than simvastatin, Lipitor, or Crestor at lowering LDL cholesterol at the doses compared: VYTORIN provided >50 percent mean LDL cholesterol reduction. In addition, in these separate studies, VYTORIN helped more patients achieve a goal of <70 mg/dL than did simvastatin a, Lipitor b, or Crestor c. The clinical impact of comparative differences in lipid changes between products is not known. VYTORIN has not been shown to reduce heart attacks and strokes more than simvastatin alone.
Merck is well prepared to help our customers understand our position on the ARBITER 6 study and that ZETIA and VYTORIN are effective options for physicians to use to manage their patients' cholesterol.
Merck's commitment to cardiovascular medicine
Following the merger of Merck with Schering-Plough, today's Merck has a robust research effort aimed at cardiovascular disease.
"No other health care company is doing more to study cardiovascular disease than today's Merck," said Dr. Kim.
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 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 10,100 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 (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).
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 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 co-administered with a statin vs. 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), and pain in extremity (2.7 percent vs. 2.5 percent).
Data
a Mean LDL-C decrease from baseline following treatment in a multicenter, double-blind, placebo-controlled, 12-week trial (N=1,528) in patients with hypercholesterolemia. Patients were randomized to receive 1 of 10 treatments: placebo, ezetimibe (10 mg), simvastatin (10, 20, 40, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80 mg). Mean baseline LDL-C was 176 mg/dL for all doses of VYTORIN and 178 mg/dL for all doses of simvastatin. The mean percent reduction in LDL-C for patients taking VYTORIN 10/10 mg was 45 percent vs. 33 percent for patients taking simvastatin 10 mg; VYTORIN 10/20 mg was 52 percent vs. 34 percent for simvastatin 20 mg; VYTORIN 10/40 mg was 55 percent vs. 41 percent for simvastatin 40 mg; VYTORIN 10/80 mg was 60 percent vs. 49 percent for simvastatin 80 mg (P<0.001). 13 percent of patients taking VYTORIN 10/10 mg achieved LDL-C <70 mg/dL vs. 0 percent of patients taking simvastatin 10 mg; 33 percent for VYTORIN 10/20 mg vs. 2 percent for simvastatin 20 mg; 51 percent for VYTORIN 10/40 mg vs. 4 percent for simvastatin 40 mg; 59 percent for VYTORIN 10/80 mg vs. 22 percent for simvastatin 80 mg (P<0.0001).
b Mean percent change in LDL-C from untreated baseline in a multicenter, double-blind, randomized, active-controlled, 8-arm, parallel-group study (6 weeks of active treatment) (N=1,902). Patients with hypercholesterolemia who had not met their LDL-C goal as defined by NCEP ATP III were randomized to VYTORIN 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg. Mean pooled baseline LDL-C values for VYTORIN and atorvastatin were 178 mg/dL and 179 mg/dL, respectively. The mean percent reduction in LDL-C for patients taking VYTORIN 10/10 mg was 47 percent vs. 36 percent for patients taking atorvastatin 10 mg; VYTORIN 10/20 mg was 51 percent vs. 44 percent for atorvastatin 20 mg; VYTORIN 10/40 mg was 57 percent vs. 48 percent for atorvastatin 40 mg; VYTORIN 10/80 mg was 59 percent vs. 53 percent for atorvastatin 80 mg (P<0.05). Sixteen percent of patients taking VYTORIN 10/10 mg achieved LDL-C <70 mg/dL vs. 4 percent of patients taking atorvastatin 10 mg; 29 percent for VYTORIN 10/20 mg vs. 11 percent for atorvastatin 20 mg; 44 percent for VYTORIN 10/40 mg vs. 19 percent for atorvastatin 40 mg; 56 percent for VYTORIN 10/80 mg vs. 33 percent for atorvastatin 80 mg (P<0.001).
c Data from a multicenter, randomized, double-blind, active-controlled, 6-arm, parallel-group study designed to evaluate the efficacy and safety of VYTORIN vs rosuvastatin over a 6-week period. Patients with hypercholesterolemia (N=2,959) were randomized to 1 of 6 treatment groups: VYTORIN 10/20, 10/40, or 10/80 mg or rosuvastatin 10, 20, or 40 mg. Mean pooled baseline LDL-C levels for VYTORIN and rosuvastatin were 172 mg/dL and 173 mg/dL, respectively. Mean baseline LDL-C values for VYTORIN 10/20 mg (n=476), rosuvastatin 10 mg (n=475), VYTORIN 10/40 mg (n=477), rosuvastatin 20 mg (n=478), VYTORIN 10/80 mg (n=474), and rosuvastatin 40 mg (n=475) were 172 mg/dL, 172 mg/dL, 173 mg/dL, 173 mg/dL, 172 mg/dL, and 173 mg/dL, respectively. The mean percent reduction in LDL-C for patients taking VYTORIN 10/20 mg was 52 percent vs. 46 percent for patients taking rosuvastatin 10 mg; VYTORIN 10/40 mg was 55 percent vs. 52 percent for rosuvastatin 20 mg; VYTORIN 10/80 mg was 61 percent vs. 57 percent for rosuvastatin 40 mg; (P<0.05). Twenty-four percent of patients taking VYTORIN 10/20 mg achieved LDL-C <70 mg/dL vs. 9 percent of patients taking rosuvastatin 10 mg; 41 percent for VYTORIN 10/40 mg vs. 30 percent for rosuvastatin 20 mg; 66 percent for VYTORIN 10/80 mg vs. 50 percent for rosuvastatin 40 mg (P<0.001)
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SOURCE: Merck