Merck and Schering-Plough Respond To Issues Raised About Enhance Clinical Trial
VYTORIN(R) (ezetimibe/simvastatin) and ZETIA(R) (ezetimibe) have been studied extensively in patients with elevated cholesterol. Clinical studies conducted to date have demonstrated that VYTORIN and ZETIA significantly decreased LDL cholesterol in patients with elevated cholesterol, along with a healthy diet. In addition, the safety and tolerability profiles of VYTORIN and ZETIA are set forth in the approved labeling. The approval of VYTORIN and ZETIA in many markets around the world is based on their demonstrated safety and tolerability profiles, and ability to lower LDL-cholesterol.
"We stand behind VYTORIN and ZETIA and stand behind our science that has brought these cholesterol-lowering medications to millions of people around the world," said Peter S. Kim, Ph.D., president, Merck Research Laboratories.
Many patients with elevated cholesterol cannot achieve their cholesterol treatment goals with diet and exercise. Many of these patients also cannot achieve their treatment goals with statins alone.
Clinical studies, which are included in the attached prescribing information, have demonstrated that VYTORIN lowered patients' LDL cholesterol more than atorvastatin, rosuvastatin, or simvastatin at the doses studied. When added to a statin, ZETIA provided additional LDL-cholesterol lowering compared to the statin alone. Unlike some statins, ZETIA has not been shown to prevent heart disease or heart attacks. VYTORIN contains two medicines: ZETIA and Zocor(R) (simvastatin). It has not been shown to reduce heart attacks or strokes more than simvastatin alone.
"More than 20 years of clinical research has demonstrated that lowering LDL cholesterol, along with a healthy diet and other therapeutic lifestyle changes, is the cornerstone of lipid treatment for patients at risk for heart disease," said Dr. Koestler. "VYTORIN and ZETIA are important treatment options that can help appropriate patients lower their LDL cholesterol."
Regarding the ENHANCE trial
The ENHANCE study involved 720 patients with a rare form of inherited high cholesterol known as Heterozygous Familial Hypercholesterolemia (HeFH) that affects less than 0.2 percent of the population. This imaging trial looked at the effects of ezetimibe/simvastatin versus simvastatin on the intima media thickness (IMT) measured at three sites in the carotid arteries (the right and left common carotid, internal carotid and carotid bulb) between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a two-year period.
As indicated in the January 14, 2008 announcement, in ENHANCE, there was no statistically significant difference in the mean change in the primary measure of the study, between the maximum approved doses of ezetimibe/simvastatin and simvastatin alone. ENHANCE was not an outcomes trial; that is, it did not attempt to measure whether the combination of ezetimibe and simvastatin reduced the risk of heart attacks or strokes more than simvastatin alone. The IMPROVE-IT study, an ongoing outcomes trial, is being conducted to answer that question in patients with acute coronary syndrome.
In ENHANCE, ezetimibe/simvastatin achieved significantly greater LDL cholesterol reduction compared to simvastatin alone.
ENHANCE began in October 2002 and the last patient visit occurred in April 2006. Following the last patient visit, the study required the meticulous examination of approximately 30,000 ultrasound images of the carotid arteries and 10,000 ultrasound images of the femoral arteries.
The ENHANCE trial employed a novel non-invasive methodology to assess IMT using digital single-frame ultrasound imagery of the arteries. Examination of these images was a challenging process and the data analysis took significantly longer than expected. Numerous steps were taken in 2006 and 2007 to address quality issues and finalize the data analysis.
Until December 31, 2007, the study remained blinded; that is, neither the patients nor the researchers nor the companies knew the group of patients that received each therapy. On that date, statisticians for Schering-Plough Research Institute first became unblinded. Additional personnel at the companies were made aware of the findings during the first two weeks of January, 2008.
On January 14, 2008, the companies announced the results of the primary endpoint and other results.
An abstract has been submitted on the ENHANCE trial to the American College of Cardiology with the expectation that the data will be presented and discussed in an appropriate scientific context at their annual meeting in March, 2008.
The companies look forward to participating in rigorous scientific debates on this important issue in the months ahead. "We are committed to conducting clinical research with the highest integrity and quality, and reporting the results as quickly as possible," said Dr. Koestler.
"We remain committed to the advancement of the study of high LDL cholesterol, its relationship to heart disease, and the availability of effective therapies in the interest of patients and healthcare providers everywhere," said Dr. Kim.
To further clarify issues surrounding the timeline of the ENHANCE study, a chronology of events is attached.
Additional background about the ENHANCE trial
ENHANCE was a multinational, randomized, double-blind, active comparator trial that used digitized single-frame ultrasound technology for imaging purposes. There were 357 HeFH patients randomized to ezetimibe/simvastatin 10/80 mg and 363 HeFH patients to simvastatin 80 mg. The study collected approximately 30,000 carotid artery and 10,000 femoral artery images from these patients. HeFH is characterized by markedly elevated plasma concentrations of LDL cholesterol; typically well above the 95th percentile for age and sex.
Single-frame ultrasound images were analyzed from the right and left carotid arteries at three sites (the common carotid, the internal carotid and the carotid bulb) and at numerous time points (baseline, 6, 12, 18 and 24 months). Images from the right and left common femoral arteries were analyzed at these same time points as well.
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(i) , 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 also 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 (greater than or equal to 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 (greater than or equal to 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 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).
Important information about ZETIA
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.
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, most frequent side effects for ZETIA alone vs. placebo included: back pain (4.1 percent vs. 3.9 percent), arthralgia (3.8 percent vs. 3.4 percent), and fatigue (2.2 percent vs. 1.8 percent); for ZETIA plus statin vs. statin or placebo alone: back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent), abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent), and fatigue (2.8 percent vs. 1.4 percent vs. 1.9 percent).
About Merck/Schering-Plough Pharmaceuticals
Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is also marketed as INEGY outside the U.S.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
Schering-Plough disclosure notice
The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to potential market for VYTORIN and ZETIA (ezetimibe). Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part II, Item 1A. "Risk Factors" in the Schering-Plough's third quarter 2007 10-Q.
Full prescribing information and patient product information for VYTORIN(R) and ZETIA(R) is attached.
(i) Apo B is the protein compound of lipoproteins, LDL and VLDL, which carry cholesterol in the blood
ZETIA(R) and VYTORIN(R) are registered trademarks of MSP Singapore Company LLC. All other brands are trademarks of their respective owners and are not trademarks of MSP Singapore Company LLC. ENHANCE Chronology
Late 2000 / Early 2001
-- Discussion of ENHANCE protocol as part of the ZETIA(R) (ezetimibe) clinical development program. Trial is designed to measure intima media thickness (IMT) using external ultrasound equipment. Consideration is also given to conducting an additional trial using intravascular ultrasound (IVUS) technology for imaging, but the decision is made subsequently not to conduct an IVUS trial. Approval of ZETIA is being sought on the strength of biomarkers (lowering total cholesterol, LDL, etc.). ENHANCE is intended as an intermediate post-market study with surrogate endpoints (relating to atherosclerosis), and it will be part of a broader development program with larger and longer term post-market studies focused on key cardiovascular clinical outcome endpoints. These include SEAS (patients with aortic stenosis) and SHARP (patients with chronic kidney disease), as well as IMPROVE-IT (discussed below).
April 2002
-- ENHANCE protocol is finalized. The study will compare ezetimibe/simvastatin 10/80 mg versus simvastatin 80 mg in patients with Heterozygous Familial Hypercholesterolemia (HeFH), a rare condition that affects approximately 0.2 percent of the population. The protocol defines the primary endpoint as the change in IMT seen in B-mode ultrasound images of the carotid artery, measured as the average far wall IMT of the right and left common carotid artery (CCA), carotid bulb, and internal carotid arteries on a per patient basis, between baseline and endpoint. (The study also involves analysis of B-mode images of the femoral arteries, a secondary endpoint, and M-mode ultrasound images of the common carotid artery, an exploratory endpoint, but the discussion that follows relates to B-mode carotid images and the primary endpoint.)
June 2002
-- First study site for ENHANCE is initiated.
August-September 2002
-- ENHANCE is announced at the 24th Congress of the European Society of Cardiology, which was held between August 31 and September 4, 2002, in Berlin.
October 2002
-- First patient randomized in ENHANCE.
-- FDA approves ZETIA. ZETIA is a lipid-lowering compound approved on the basis of clinical studies showing that it reduces total cholesterol (total C), low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (Apo B) in patients with hypercholesterolemia. Unlike statins, another class of lipid-lowering drug, which include simvastatin and which inhibit cholesterol synthesis in the liver, ZETIA inhibits the absorption of dietary cholesterol in the small intestine and reabsorption of cholesterol in the bile.
2002-2004
-- Patient enrollment and study visits continue. The last patient entered the study in April 2004.
July 2004
-- FDA approves VYTORIN(R) (ezetimibe/simvastatin), on the basis of clinical studies showing that it reduces total C, LDL-C, Apo B, and TG, and increases HDL-C, through dual inhibition of cholesterol synthesis absorption and synthesis in patients with hypercholesterolemia.
February 2005
-- ENHANCE methods article published in the American Heart Journal. This article, authored by Kastelein (the principal investigator), Philip Sager (then at Schering-Plough), Eric de Groot (a medical director working for the principal investigator), and Enrico Veltri (Schering-Plough) describes the design and the rationale for the study.
Summer through End of 2005
-- AHA Fall 2006 meeting is targeted for presentation of results, based on initiation of image reads at the reading laboratory in 2004 and anticipated completion of reads in May 2006.
-- In September 2005, Merck and Schering-Plough (MSP) register (on the NIH website) the IMPROVE-IT study, which is a post-market double-blind study comparing VYTORIN and simvastatin. The primary objective of IMPROVE-IT is to evaluate the clinical benefit of VYTORIN, compared with simvastatin, defining clinical benefit as the reduction in the risk of the occurrence of the composite endpoint of cardiovascular death, major coronary events, and stroke. Trial will continue until a minimum of 5,250 subjects have an primary endpoint event and each patient is followed for a minimum of 2.5 years. Enrollment begins immediately, study start date is February 2006, and estimated study completion date is January 2011.
-- Schering-Plough biostatisticians begin conducting routine data quality reviews of the initial blinded ENHANCE data, in anticipation of the completion of the study. These statistical reviews are performed for quality control/quality assurance purposes. The biostatisticians remain blinded as to treatment arm. In other words, they do not know whether a particular patient received ezetimibe/simvastatin or simvastatin, and they do not know how the group receiving ezetimibe/simvastatin compares to the group receiving simvastatin. The biostatisticians are unmasked as to patient and time sequence (i.e., they know that they are looking at the data for one particular patient and the proper time sequence for those data). The reviews are conducted batch by batch, and they identify concerns about the quality of the data based on the observations of results that appear biologically implausible. The initial concerns are raised by the review of the first batch and later confirmed by the review of the second and third batches.
January through April 2006
-- The study team considers remedial measures to address data quality concerns, including a modified ultrasound image reading process for the study (referred to as "synchronous" reading) and additional quality control steps. Synchronous reading meant the reader at the laboratory would have the ability to see all images at the same time for one patient and artery segment, in order to ensure that the same anatomical segment was measured each time. The reader would be blinded as to treatment arm and time sequence of patient visit. The reader would not know whether a particular patient had received ezetimibe/simvastatin or simvastatin. In March 2006, the Cholesterol Development Committee (CDC), a committee of the joint venture, reviews the data quality problems apparent from the Schering-Plough biostatisticians' review of data and the proposed remedial plan, including synchronous reading.
-- In March and April 2006, the director of an alternate reading laboratory is contacted regarding his laboratory's qualifications, and his feedback is sought on a selection of images from four patients. The laboratory is not retained, but the consultant will eventually serve as one of the expert panelists in November 2007.
-- In April 2006, the CDC approves the plan to read images using the synchronous reading process and to adopt other quality control steps. It approves a six-week pilot study (involving the original reading laboratory and an alternate laboratory) to assess the reproducibility and quality of reader measurements, at the end of which one lab will be selected to perform readings for the entire study.
-- Delays are incurred as a result of installation of new computer equipment required for synchronous reading and the training of readers on the new reading procedures.
-- April 2006, last patient last visit in ENHANCE study.
-- It is recognized that the AHA meeting deadline will not be met, and the ACC March 2007 meeting is identified as the target for presentation of the data.
June 2006
-- Six-week pilot synchronous reading study begins (referred to as the "Vanguard" study).
August 2006
-- The CDC reviews the results of the pilot synchronous reading study and selects the original laboratory to perform the readings for the entire study going forward.
August through December 2006
-- Reading of images using the synchronous process continues. Considerable effort is made to meet early January deadline for submission of abstract for presentation of study results at March 2007 ACC meeting.
-- In December 2006, primary reading process completed at the laboratory. Initial statistical review of the final received dataset (still blinded as to treatment arm) indicates that data quality problems still exist.
-- Two primary data issues are raised. The first is significant fluctuations in IMT (in individual patients) within short periods of time and over time, which would not be expected to occur in nature, and which some have referred to as "biologically implausible" data. The other primary issue relates to "missing" data, essentially data gaps because specific images were rejected for quality reasons -- for example, because the sonographer inaccurately captured the image, or because the reader deemed it outside the protocol or found it unreadable.
January 2007
-- Hiring of two independent contractors (a project manager and a data manager) to work with the laboratory on data management issues. Advice also sought from an independent consultant, who reviews the data and issues a report on January 26. Report considers data quality similar to that in other IMT trials, but acknowledges desire to improve data quality and recommends a number of ways to improve the data and reduce "missingness." This consultant will serve as one of the expert panelists in November 2007.
-- Schering-Plough begins the process of "querying" outlier data based on objectively defined criteria.
February through June 2007
-- Independent contractors perform assessment of data and quality control processes at the core laboratory. Procedures put in place to address data management concerns and institute an outlier data query process, with the assistance of an expert consultant.
-- Sponsor and consultants visit reading lab periodically to monitor activities.
-- Efforts to address missing images are tried as a pilot exercise, including through a so-called neighboring, or adjacent, image analysis. These efforts are determined not to be a productive approach.
-- The deadline for the March 2007 ACC meeting is not met, and the AHA November 2007 meeting is targeted for presentation of the data.
July 2007
-- Outlier querying process completed and reviewed. Data quality problems still exist. Data remain blinded as to treatment arm.
August 2007
-- MSP reviews data quality issues with the principal investigator and decides to convene an independent expert panel. Five experts, chosen primarily from a list supplied by the principal investigator, agree to sit on the panel. Principal investigator recuses himself from the meeting itself in order to help ensure that the panel members feel open to provide critical observations concerning the study, the principal investigator, and the core reading laboratory affiliated with the principal investigator.
November 2007
-- The deadline for the November AHA meeting is not met, and the March 2008 ACC meeting is targeted for presentation of the data.
-- On November 16, independent expert panel convenes. Consensus reached that despite significant methodological issues, total re-reading of the ENHANCE images is not recommended, since the assumption is that re-reading will not resolve problems in the ultrasound images themselves. Consensus also reached that the common carotid artery (CCA) provided the most reliable and consistent measurements in ENHANCE and that the sponsor should therefore consider changing the primary study endpoint to measurements of the CCA.
-- On November 19, the joint venture issues a press release describing the expert panel's recommendations.
-- On November 26, the CDC approves changing the primary endpoint and amending the study protocol. The original primary endpoint (the mean change in IMT measured at the three sites in the carotid arteries) would have been presented as a secondary endpoint.
-- On November 30, MSP meets with US and ex-US expert advisory boards. Some members of both boards express the view that the primary endpoint should not be changed.
December 2007
-- On December 11, MSP announces that it will not change the primary endpoint in the ENHANCE study. The primary endpoint and the protocol are not changed.
-- Data quality control reviews conclude and transmission of final carotid artery data from the imaging reading lab to the sponsors.
-- ENHANCE study is unblinded on December 31 to a small group of scientists.
January 2008
-- Additional personnel at the companies were made aware of the findings during the first two weeks of January, 2008.
-- On January 14, MSP issues press release announcing results from ENHANCE study. There was no statistically significant difference between the treatment groups on the primary endpoint. There was also no statistically significant difference between the treatment groups on each component of the primary endpoint, including the common carotid artery (CCA). The overall incidence of treatment-related adverse-events, serious adverse events, and adverse events leading to discontinuation were generally similar between treatment groups. The safety profiles of the two products (VYTORIN and simvastatin) were generally similar and consistent with their approved labeling. There was a significant difference in LDL cholesterol lowering between the treatment groups: 58 percent lowering at 24 months on VYTORIN 10/80, compared to 41 percent lowering at 24 months on simvastatin 80 mg.
-- Submission of "Late Breaker Place Holder Abstract" (a shell abstract, without the trial results) to ACC to reserve a spot for March 2008 meeting of the ACC.
ZETIA(R) and VYTORIN(R) are registered trademarks of MSP Singapore Company LLC.
VYTORIN (R) 10/10
(EZETIMIBE 10 MG/SIMVASTATIN 10 MG TABLETS)
VYTORIN (R) 10/20
(EZETIMIBE 10 MG/SIMVASTATIN 20 MG TABLETS)
VYTORIN (R) 10/40
(EZETIMIBE 10 MG/SIMVASTATIN 40 MG TABLETS)
VYTORIN (R) 10/80
(EZETIMIBE 10 MG/SIMVASTATIN 80 MG TABLETS)
DESCRIPTION
VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol and related phytosterol absorption, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)-3(S)-hydroxypropyl)-4(S) -(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3 and its molecular weight is 409.4.
Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Its structural formula is:
(Graphic Omitted)
Simvastatin, an inactive lactone, is hydrolyzed to the corresponding beta-hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)-ethyl)-1-naphthalenyl ester, (1S-(1alpha,3alpha,7beta,8beta(2S*,4S*),-8abeta)). The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57.
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Its structural formula is:
(Graphic Omitted)
VYTORIN is available for oral use as tablets containing 10 mg of ezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of simvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or 80 mg of simvastatin (VYTORIN 10/80). Each tablet contains the following inactive ingredients: butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hydroxypropyl methylcellulose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.
CLINICAL PHARMACOLOGY
Background
Clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B), the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of high-density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Mode of Action
VYTORIN
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis.
Ezetimibe
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production.
Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of HMG-CoA reductase inhibitors (see CLINICAL STUDIES).
Simvastatin
Simvastatin reduces cholesterol by inhibiting the conversion of HMG-CoA to mevalonate, an early step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.
Pharmacokinetics
Absorption
VYTORIN
VYTORIN is bioequivalent to coadministered ezetimibe and simvastatin.
Ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
Effect of Food on Oral Absorption
Ezetimibe
Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals.
Simvastatin
Relative to the fasting state, the plasma profiles of both active and total inhibitors of HMG-CoA reductase were not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
Simvastatin
Both simvastatin and its beta-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. When radiolabeled simvastatin was administered to rats, simvastatin-derived radioactivity crossed the blood-brain barrier.
Metabolism and Excretion
Ezetimibe
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.
Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Simvastatin
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic studies of the beta-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. The major active metabolites of simvastatin present in human plasma are the beta-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.
Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).
Special Populations
Geriatric Patients
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older ((>=)65 years) healthy subjects compared to younger subjects.
Simvastatin
In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age.
Pediatric Patients
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 7 days, the absorption and metabolism of ezetimibe were similar in adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population <10 years of age are not available.
Gender
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men.
Race
Ezetimibe
Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.
Hepatic Insufficiency
Ezetimibe
After a single 10-mg dose of ezetimibe, the mean exposure (based on area under the curve (AUC)) to total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency, the mean AUC for total ezetimibe and ezetimibe increased approximately 4-fold compared to healthy subjects.
Renal Insufficiency
Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl (<=)30 mL/min/1.73 m2), the mean AUC for total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to healthy subjects (n=9).
Simvastatin
Pharmacokinetic studies with another statin having a similar principal route of elimination to that of simvastatin have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).
Drug Interactions (See also PRECAUTIONS, Drug Interactions)
No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin. Specific pharmacokinetic drug interaction studies with VYTORIN have not been performed.
Cytochrome P450: Ezetimibe had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.
Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy. (See WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions.)
Antacids: In a study of twelve healthy adults, a single dose of antacid (Supralox(TM) 20 mL) administration had no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on AUC values. The Cmax value of total ezetimibe was decreased by 30%.
Cholestyramine: In a study of forty healthy hypercholesterolemic (LDL-C (>=)130 mg/dL) adult subjects, concomitant cholestyramine (4 g twice daily) administration decreased the mean AUC of total ezetimibe and ezetimibe approximately 55% and 80%, respectively.
Cyclosporine: In a study of eight post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see PRECAUTIONS, Drug Interactions).
Fenofibrate: In a study of thirty-two healthy hypercholesterolemic (LDL-C (>=)130 mg/dL) adult subjects, concomitant fenofibrate (200 mg once daily) administration increased the mean Cmax and AUC values of total ezetimibe approximately 64% and 48%, respectively. Pharmacokinetics of fenofibrate were not significantly affected by ezetimibe (10 mg once daily).
Coadministration of fenofibrate (160 mg daily) with simvastatin (80 mg daily) for 7 days had no effect on plasma AUC (and Cmax) of either total HMG-CoA reductase inhibitory activity or fenofibric acid; there was a modest reduction (approximately 35%) of simvastatin acid which was not considered clinically significant (see WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions).
Gemfibrozil: In a study of twelve healthy adult males, concomitant administration of gemfibrozil (600 mg twice daily) significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7. Ezetimibe (10 mg once daily) did not significantly affect the bioavailability of gemfibrozil.
Coadministration of gemfibrozil (600 mg twice daily for 3 days) with simvastatin (40 mg daily) resulted in clinically significant increases in simvastatin acid AUC (185%) and Cmax (112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil (see WARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions, DOSAGE AND ADMINISTRATION).
Grapefruit Juice: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study(1), 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with, and 30 and 90 minutes following, a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity (measured using a radioenzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis) of 2.4-fold and 3.6-fold, respectively, and of simvastatin and its beta-hydroxyacid metabolite (measured using a chemical assay -- liquid chromatography/tandem mass spectrometry) of 16-fold and 7-fold, respectively. In a second study, 16 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity (using a validated enzyme inhibition assay different from that used in the first(1) study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis) of 1.13-fold and 1.18-fold, respectively, and of simvastatin and its beta-hydroxyacid metabolite (measured using a chemical assay -- liquid chromatography/tandem mass spectrometry) of 1.88-fold and 1.31-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
ANIMAL PHARMACOLOGY
Ezetimibe
The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 ug/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 ug/kg/day, respectively. These results are consistent with ezetimibe being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe (ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as potent as ezetimibe in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethyl estradiol, or the fat-soluble vitamins A and D.
In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase inhibitors (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
CLINICAL STUDIES
Primary Hypercholesterolemia
VYTORIN
VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with hypercholesterolemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
VYTORIN is effective in men and women with hypercholesterolemia. Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of VYTORIN.
Five multicenter, double-blind studies conducted with either VYTORIN or coadministered ezetimibe and simvastatin equivalent to VYTORIN in patients with primary hypercholesterolemia are reported: two were comparisons with simvastatin, two were comparisons with atorvastatin, and one was a comparison with rosuvastatin.
In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528 hypercholesterolemic patients were randomized to one of ten treatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80).
When patients receiving VYTORIN were compared to those receiving all doses of simvastatin, VYTORIN significantly lowered total-C, LDL-C, Apo B, TG, and non-HDL-C. The effects of VYTORIN on HDL-C were similar to the effects seen with simvastatin. Further analysis showed VYTORIN significantly increased HDL-C compared with placebo. (See Table 1.) The lipid response to VYTORIN was similar in patients with TG levels greater than or less than 200 mg/dL. -0-
Table 1
Response to VYTORIN in Patients with Primary Hypercholesterolemia
(Meana % Change from Untreated Baselineb)
Treatment
Non-
(Daily Dose) N Total-C LDL-C Apo B HDL-C TGa HDL-C
----------------------------------------------------------------------
Pooled data (All VYTORIN
doses)c 609 -38 -53 -42 +7 -24 -49
----------------------------------------------------------------------
Pooled data (All
simvastatin doses)c 622 -28 -39 -32 +7 -21 -36
----------------------------------------------------------------------
Ezetimibe 10 mg 149 -13 -19 -15 +5 -11 -18
----------------------------------------------------------------------
Placebo 148 -1 -2 0 0 -2 -2
----------------------------------------------------------------------
VYTORIN by dose
----------------------------------------------------------------------
10/10 152 -31 -45 -35 +8 -23 -41
----------------------------------------------------------------------
10/20 156 -36 -52 -41 +10 -24 -47
----------------------------------------------------------------------
10/40 147 -39 -55 -44 +6 -23 -51
----------------------------------------------------------------------
10/80 154 -43 -60 -49 +6 -31 -56
----------------------------------------------------------------------
Simvastatin by dose
----------------------------------------------------------------------
10 mg 158 -23 -33 -26 +5 -17 -30
----------------------------------------------------------------------
20 mg 150 -24 -34 -28 +7 -18 -32
----------------------------------------------------------------------
40 mg 156 -29 -41 -33 +8 -21 -38
----------------------------------------------------------------------
80 mg 158 -35 -49 -39 +7 -27 -45
----------------------------------------------------------------------
a For triglycerides, median % change from baseline
b Baseline - on no lipid-lowering drug
c VYTORIN doses pooled (10/10-10/80) significantly reduced total-C,
LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin, and
significantly increased HDL-C compared to placebo.
In a multicenter, double-blind, controlled, 23-week study, 710 patients with known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines, and an LDL-C (>=)130 mg/dL were randomized to one of four treatment groups: coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10, 10/20, and 10/40), or simvastatin 20 mg. Patients not reaching an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were significantly larger than with simvastatin 20 mg (see Table 2). -0-
Table 2
Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk
Equivalents and an LDL-C (>=)130 mg/dL
Simvastatin VYTORIN VYTORIN VYTORIN
20 mg 10/10 10/20 10/40
----------------------------------------------------------------------
N 253 251 109 97
----------------------------------------------------------------------
Mean baseline LDL-C 174 165 167 171
----------------------------------------------------------------------
Percent change LDL-C -38 -47 -53 -59
----------------------------------------------------------------------
In a multicenter, double-blind, 6-week study, 1902 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of eight treatment groups: VYTORIN (10/10, 10/20, 10/40, or 10/80) or atorvastatin (10 mg, 20 mg, 40 mg, or 80 mg).
Across the dosage range, when patients receiving VYTORIN were compared to those receiving milligram-equivalent statin doses of atorvastatin, VYTORIN lowered total-C, LDL-C, Apo B, and non-HDL-C significantly more than atorvastatin. Only the 10/40 mg and 10/80 mg VYTORIN doses increased HDL-C significantly more than the corresponding milligram-equivalent statin dose of atorvastatin. The effects of VYTORIN on TG were similar to the effects seen with atorvastatin. (See Table 3.) -0-
Table 3
Response to VYTORIN and Atorvastatin in Patients with Primary
Hypercholesterolemia
(Meana % Change from Untreated Baselineb)
Treatment
Non-
Total- LDL- Apo HDL- HDL-
(Daily Dose) N Cc Cc Bc C TGa Cc
----------------------------------------------------------------------
VYTORIN by dose
----------------------------------------------------------------------
10/10 230 -34d -47d -37d +8 -26 -43d
----------------------------------------------------------------------
10/20 233 -37d -51d -40d +7 -25 -46d
----------------------------------------------------------------------
10/40 236 -41d -57d -46d +9d -27 -52d
----------------------------------------------------------------------
10/80 224 -43d -59d -48d +8d -31 -54d
----------------------------------------------------------------------
Atorvastatin by dose
----------------------------------------------------------------------
10 mg 235 -27 -36 -31 +7 -21 -34
----------------------------------------------------------------------
20 mg 230 -32 -44 -37 +5 -25 -41
----------------------------------------------------------------------
40 mg 232 -36 -48 -40 +4 -24 -45
----------------------------------------------------------------------
80 mg 230 -40 -53 -44 +1 -32 -50
----------------------------------------------------------------------
a For triglycerides, median % change from baseline
b Baseline - on no lipid-lowering drug
c VYTORIN doses pooled (10/10-10/80) provided significantly greater
reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to
atorvastatin doses pooled (10-80).
d p<0.05 for difference with atorvastatin at equal mg doses of the
simvastatin component
In a multicenter, double-blind, 24-week, forced titration study, 788 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to receive coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10 and 10/20) or atorvastatin 10 mg. For all three treatment groups, the dose of the statin was titrated at 6-week intervals to 80 mg. At each pre-specified dose comparison, VYTORIN lowered LDL-C to a greater degree than atorvastatin (see Table 4). -0-
Table 4
Response to VYTORIN and Atorvastatin in Patients with Primary
Hypercholesterolemia
(Meana % Change from Untreated Baselineb)
Non-
Total- LDL- Apo HDL- HDL-
Treatment N C C B C TGa C
----------------------------------------------------------------------
Week 6
----------------------------------------------------------------------
Atorvastatin 10 mgc 262 -28 -37 -32 +5 -23 -35
----------------------------------------------------------------------
VYTORIN 10/10d 263 -34f -46f -38f +8f -26 -43f
----------------------------------------------------------------------
VYTORIN 10/20e 263 -36f -50f -41f +10f -25 -46f
----------------------------------------------------------------------
Week 12
----------------------------------------------------------------------
Atorvastatin 20 mg 246 -33 -44 -38 +7 -28 -42
----------------------------------------------------------------------
VYTORIN 10/20 250 -37f -50f -41f +9 -28 -46f
----------------------------------------------------------------------
VYTORIN 10/40 252 -39f -54f -45f +12f -31 -50f
----------------------------------------------------------------------
Week 18
----------------------------------------------------------------------
Atorvastatin 40 mg 237 -37 -49 -42 +8 -31 -47
----------------------------------------------------------------------
VYTORIN 10/40g 482 -40f -56f -45f +11f -32 -52f
----------------------------------------------------------------------
Week 24
----------------------------------------------------------------------
Atorvastatin 80 mg 228 -40 -53 -45 +6 -35 -50
----------------------------------------------------------------------
VYTORIN 10/80g 459 -43f -59f -49f +12f -35 -55f
----------------------------------------------------------------------
a For triglycerides, median % change from baseline
b Baseline - on no lipid-lowering drug
c Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg
through Weeks 6, 12, 18, and 24
d VYTORIN: 10/10 start dose titrated to 10/20, 10/40, and 10/80
through Weeks 6, 12, 18, and 24
e VYTORIN: 10/20 start dose titrated to 10/40, 10/40, and 10/80
through Weeks 6, 12, 18, and 24
f p(<=)0.05 for difference with atorvastatin in the specified week
g Data pooled for common doses of VYTORIN at Weeks 18 and 24.
In a multicenter, double-blind, 6-week study, 2959 patients with primary hypercholesterolemia, who had not met their NCEP ATP III target LDL-C goal, were randomized to one of six treatment groups: VYTORIN (10/20, 10/40, or 10/80) or rosuvastatin (10 mg, 20 mg, or 40 mg).
The effects of VYTORIN and rosuvastatin on total-C, LDL-C, Apo B, TG, non-HDL-C and HDL-C are shown in Table 5. -0-
Table 5
Response to VYTORIN and Rosuvastatin in Patients with Primary
Hypercholesterolemia
(Meana % Change from Untreated Baselineb)
Treatment
Non-
Total- LDL- Apo HDL- HDL-
(Daily Dose) N Cc Cc Bc C TGa Cc
----------------------------------------------------------------------
VYTORIN by dose
----------------------------------------------------------------------
10/20 476 -37d -52d -42d +7 -23d -47d
----------------------------------------------------------------------
10/40 477 -39e -55e -44e +8 -27 -50e
----------------------------------------------------------------------
10/80 474 -44f -61f -50f +8 -30f -56f
----------------------------------------------------------------------
Rosuvastatin by dose
----------------------------------------------------------------------
10 mg 475 -32 -46 -37 +7 -20 -42
----------------------------------------------------------------------
20 mg 478 -37 -52 -43 +8 -26 -48
----------------------------------------------------------------------
40 mg 475 -41 -57 -47 +8 -28 -52
----------------------------------------------------------------------
a For triglycerides, median % change from baseline
b Baseline - on no lipid-lowering drug
c VYTORIN doses pooled (10/20-10/80) provided significantly greater
reductions in total-C, LDL-C, Apo B, and non-HDL-C compared to
rosuvastatin doses pooled (10-40 mg).
d p<0.05 vs. rosuvastatin 10 mg
Posted: January 2008
