Merck/Schering-Plough Pharmaceuticals Comments on Results of the Enhance Study

CHICAGO--(BUSINESS WIRE)--Mar 30, 2008 - Results of ENHANCE (Ezetimibe aNd simvastatin in Hypercholesterolemia enhANces atherosClerosis rEgression), an imaging trial in 720 patients with heterozygous familial hypercholesterolemia (HeFH), a rare genetic condition that causes very high levels of LDL "bad" cholesterol and greatly increases the risk for premature coronary artery disease, were presented at the 57th annual scientific sessions of the American College of Cardiology and also were published on-line in The New England Journal of Medicine(i).

As previously reported on Jan. 14, 2008, despite the fact that ezetimibe/simvastatin 10/80 mg (VYTORIN(R) *) significantly lowered LDL "bad" cholesterol more than simvastatin 80 mg alone, there was no significant difference between treatment with ezetimibe/simvastatin and simvastatin alone on the pre-specified primary endpoint, a change in the thickness of carotid artery walls over two years as measured by ultrasound. There also were no significant differences between treatment with ezetimibe/simvastatin and simvastatin on the four pre-specified key secondary endpoints: percent of patients manifesting regression in the average carotid artery intima-media thickness (CA IMT); proportion of patients developing new carotid artery plaques >1.3 mm; changes in the average maximum CA IMT; and changes in the average CA IMT plus in the average common femoral artery IMT.

In ENHANCE, when compared to simvastatin alone, ezetimibe/simvastatin significantly lowered LDL "bad" cholesterol, as well as triglycerides and C-reactive protein (CRP). Ezetimibe/simvastatin is not indicated for the reduction of CRP. In the ENHANCE study, as previously reported, the overall safety profile of ezetimibe/simvastatin in the study was generally consistent with the product label.

"LDL cholesterol remains the primary target of lipid-modifying therapy and physicians should continue to lower patients' elevated LDL cholesterol and get their patients to their goals based on guidelines," said Michael Davidson, M.D., professor, director of preventive cardiology, The University of Chicago, Pritzker School of Medicine.

In the ENHANCE publication, the authors provided three theoretical explanations why, despite ezetimibe/simvastatin significantly lowering LDL "bad" cholesterol more than simvastatin (56 percent vs. 39 percent, p<0.01), there was no significant difference between treatment groups on the primary endpoint and four key secondary endpoints: (1) lowering of LDL cholesterol with non-statin therapy, such as ezetimibe, might affect IMT differently than statin therapy, (2) the imaging technology selected was not sensitive enough to detect a difference, or (3) that these HeFH patients were extensively pretreated with lipid-lowering therapy, thereby limiting the amount that CA IMT could change with further LDL cholesterol-lowering therapy, consequently limiting the ability to detect a differential response to the two treatments. The authors concluded that the reason for the failure to observe an incremental effect on CA IMT thickness in spite of a reduction of level of LDL cholesterol remains unknown.

In the publication, the authors addressed the premise that the lack of a difference in change of mean CA IMT between ezetimibe/simvastatin and simvastatin despite greater LDL cholesterol-lowering could be attributed to lipid-independent effects of statins on arteries. The authors presented several facts that argued against this concept, including a discussion of clinical studies involving statin and non-statin therapeutic approaches that demonstrated that cardiovascular risk reductions were associated with the degree of LDL-cholesterol lowering. The authors suggested that clinical outcomes data are needed to answer this question.

As for the hypothesis that the results may reflect the imaging technology, the authors noted this seems unlikely given the precision of the imaging measurement results seen in the ENHANCE trial.

With respect to the hypothesis that the ENHANCE results were due to the characteristics of the patients studied, the authors pointed out that in an earlier imaging study (extension of ASAP or Atorvastatin vs. Simvastatin on Atherosclerosis Progression study) use of potent lipid-lowering therapy in HeFH patients produced "regression" or "thinning" of CA IMT during the first one to two years of therapy, but further decreases during the following two years on the same therapy were not seen. In ENHANCE, approximately 80 percent of the enrolled patients reported taking statin treatment at the time of screening for the study, and had a mean baseline CA IMT of 0.69 to 0.70 mm. In another recent IMT study in HeFH patients (RADIANCE 1 or Rating Atherosclerotic Disease Change by Imaging with A New CETP Inhibitor study), the baseline CA IMT was also lower than in the earlier IMT study and similar to ENHANCE and, importantly, the pattern of change in CA IMT in this IMT study was very similar to that observed in both treatment groups in the ENHANCE study.

The authors noted that "these data raise the possibility that there may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima-media thickness in the context of previous statin therapy and a modest baseline intima-media thickness(ii)."

"Although a definitive explanation is never possible with a finding like this, we believe that the most likely explanation for the failure to see a significant difference between treatment groups in ENHANCE relates to the behavior of IMT in this population of HeFH patients," noted Thomas Musliner, M.D., executive director, Cardiovascular Disease, Clinical Research, Merck Research Laboratories. "The large majority of these patients were previously treated with LDL cholesterol-lowering therapy and presumably experienced an effect on CA IMT from that treatment, as reflected in the patients' relatively low CA IMT values when they began the study. The findings of the ASAP extension, RADIANCE 1 and ENHANCE suggest there are limits to how much IMT can be decreased in HeFH study cohorts in the context of the widespread and prolonged use of effective LDL cholesterol-lowering treatment starting at an earlier age, which is now the standard of care for these patients."

Endpoint data and cardiovascular events

ENHANCE investigators found no statistically significant difference between the two treatment groups on the primary endpoint, the change in the average CA IMT at three carotid artery locations. The change from baseline in the mean (average) CA IMT in the ezetimibe/simvastatin group was 0.0111 mm, which did not significantly differ from the simvastatin group's change of 0.0058 mm (P=0.29). The median data for the primary endpoint, which also showed no statistical difference between treatments, was 0.0058 mm in the ezetimibe/simvastatin group and 0.0095 mm for the simvastatin group. The treatment groups also did not have statistically significant differences for each of the three carotid artery locations that comprised the primary endpoint: the common carotid, the internal carotid and the carotid bulb. The data for these analyses, key secondary endpoints and cardiovascular events are included in the attachment.

The ENHANCE study was not designed nor powered to evaluate cardiovascular clinical events. IMPROVE-IT is underway and is designed to provide cardiovascular outcomes data for ezetimibe/simvastatin in patients with acute coronary syndrome. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Lipid parameters of LDL cholesterol, triglycerides and HDL cholesterol; and C-reactive protein

Over the two-year period of the ENHANCE study based upon the "last observation carried forward" endpoint approach, the group treated with ezetimibe/simvastatin had a 56 percent mean reduction of LDL cholesterol (from a baseline of 319 mg/dL) that was significantly greater than the 39 percent mean reduction of LDL cholesterol (from a baseline of 318 mg/dL) in the group treated with simvastatin alone (P<0.01). The LDL cholesterol-lowering observed in patients treated with ezetimibe/simvastatin in the ENHANCE trial was generally consistent with the LDL cholesterol-lowering of ezetimibe/simvastatin seen in separate head-to-head studies vs. simvastatin, vs. Crestor(R) and vs. Lipitor(R).

In addition, by study completion, the ezetimibe/simvastatin group had a 30 percent median reduction in triglycerides (from baseline 157 mg/dL), significantly more than the 23 percent median reduction (from baseline 160 mg/dL) in the simvastatin group (P<0.01). Also, the ezetimibe/simvastatin group had a 49 percent median reduction in CRP (from baseline 1.70 mg/L), significantly more than the 24 percent median reduction in CRP (from baseline 1.70 mg/L) in the simvastatin group (P<0.01). The ezetimibe/simvastatin group had a 10 percent increase (from baseline 46.7 mg/dL) in HDL "good" cholesterol; the simvastatin group had an 8 percent increase from baseline 47.4 mg/dL (P=0.05, no statistical significance).

Safety data

As previously reported, the overall safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels. Both medicines were generally well tolerated. Also, the overall incidence rates of treatment-related adverse events were 34 percent for ezetimibe/simvastatin (122/357) and 29 percent (107/363) for simvastatin only; the incidence rates for discontinuations due to adverse events were 8.1 percent for ezetimibe/simvastatin (29/357) and 9.4 percent for simvastatin only (34/363). Additional adverse event data are included in the attachment.

About the study design and methodology

The ENHANCE study was an international two-year, randomized, double-blind, controlled trial in 720 HeFH patients between the ages of 30 to 75. All of the ENHANCE patients had HeFH, which affects approximately 0.2 percent of the population. The rationale for studying HeFH patients is that these patients are known to be at increased risk for premature coronary artery disease and, if untreated, exhibit increased IMT progression rates beginning in childhood. Prior LDL cholesterol-lowering therapy of any kind was not an exclusion criterion for ENHANCE, although such therapies were discontinued at the start of the study. Also, there wasn't a minimum value for CA IMT specified for inclusion in study. Following a six-week, single blind, placebo lead-in/drug "wash-out" period, patients were randomized to receive either daily ezetimibe/simvastatin 10/80 mg (N=357) or daily simvastatin 80 mg (N=363).

ENHANCE investigators took digitized single-frame CA IMT images at the three locations of the patients' right and left carotid arteries, the main arteries in the neck that provide blood to the brain. These images were taken at several time points: study baseline, 6, 12, 18 and 24 months.

"Examination of the CA IMT collected during ENHANCE proved to be a far more challenging process than originally anticipated when the study design was drawn up. Therefore, preparation of the images for entry into a database took significantly longer than expected, as the blinded investigators and CA IMT evaluators took numerous steps in 2006 and 2007 to address image quality control and finalize the analysis," said Enrico P. Veltri, M.D., co-author of the ENHANCE study publication and group vice president, Global Clinical Research, Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute. "Our companies acted with integrity and good faith in connection with the trial," he said.

Important information about VYTORIN

Ezetimibe/simvastatin 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.

Ezetimibe/simvastatin 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.

Ezetimibe/simvastatin is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. Ezetimibe/simvastatin 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 ezetimibe/simvastatin.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking ezetimibe/simvastatin should be reported to a doctor promptly because these could be signs of a serious side effect. Ezetimibe/simvastatin 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 ezetimibe/simvastatin.

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 ezetimibe/simvastatin and 2.6 percent for patients treated with ezetimibe/simvastatin 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 ezetimibe/simvastatin 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 ezetimibe/simvastatin when clinically indicated to check for liver problems. People taking ezetimibe/simvastatin 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 in patients with moderate or severe hepatic insufficiency, ezetimibe/simvastatin is not recommended in these patients. The safety and effectiveness of ezetimibe/simvastatin with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating ezetimibe/simvastatin in patients treated with cyclosporine and in patients with severe renal insufficiency.

Ezetimibe/simvastatin 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).

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, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on 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 marketing for VYTORIN and ZETIA(R) (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 I, Item IA. "Risk Factors" in Schering-Plough's 2007 10-K/A.

* VYTORIN includes the two components (ezetimibe and simvastatin) in one tablet.

VYTORIN(R) is a trademark of MSP Singapore Company, LLC. All other brands are trademarks of their respective owners and are not trademarks of MSP Singapore Company, LLC.

Prescribing information and patient product information for VYTORIN is attached.

ZETIA(R) is a registered trademark of MSP Singapore Company, LLC.

(i) N Engl J Med 2008; 358:1431-43.

(ii) N Engl J Med 2008; 358:1431-43. -0-


Results From ENHANCE Study Presented at American College of Cardiology

   Scientific Sessions and Published in On-Line Version of The New

                      England Journal of Medicine


Data                              Drug                     P Value

(change from      -------------------------------------  (Mean only)

 study baseline)     Simvastatin     VYTORIN (10/80 mg     NS= not

                       (80 mg)           ezetimibe/      statistically

                                        simvastatin)      significant

                  -------------------------------------

                     Mean    Median     Mean    Median

----------------------------------------------------------------------

Baseline IMT

----------------------------------------------------------------------

Baseline CA IMT

 (mm)             0.70      0.69     0.69      0.68

----------------------------------------------------------------------

Primary Endpoint

----------------------------------------------------------------------

Change in CA IMT

 at three CA

 sites (mm)       0.0058    0.0095   0.0111    0.0058   =0.29 (NS)

----------------------------------------------------------------------

Individual

 Components of

 Primary Endpoint

----------------------------------------------------------------------

Far common

 carotid IMT (mm) 0.0024    0.0043   0.0019    0.0010   =0.93 (NS)

----------------------------------------------------------------------

Internal carotid

 IMT (mm)         -0.0007   0.0057   0.0099    0.0066   =0.21 (NS)

----------------------------------------------------------------------

Carotid bulb IMT

 (mm)             0.0062    0.0099   0.0144    0.0107   =0.37 (NS)

----------------------------------------------------------------------

Four Key

 Secondary

 Endpoints

----------------------------------------------------------------------

Patients

 manifesting      44.4               45.3

 regression in CA  percent            percent

 IMT               (142/320)          (146/322)         =0.92 (NS)

----------------------------------------------------------------------

Patients

 developing new

 CA plaques, pre-

 specified as

 lesions of 1.3   2.8                4.7

 mm or larger in   percent            percent

 thickness         (9/320)            (15/322)          =0.20 (NS)

----------------------------------------------------------------------

Change in the

 maximum CA IMT,

 pre-specified as

 the far wall

 maximum CA IMTs

 for the common

 carotids,

 carotid bulb,

 and internal

 carotids (mm)    0.0103    0.0103   0.0175    0.0160   =0.27 (NS)

----------------------------------------------------------------------

Change in the CA

 IMT plus the

 common femoral

 artery IMT (mm)  0.0033             0.0182             =0.15 (NS)

----------------------------------------------------------------------

Lipid Parameters:

 LDL-C,

 Triglycerides,

 HDL-C; and C-

 reactive Protein

----------------------------------------------------------------------

LDL-C             -39.1

                   percent           -55.6

                   (317.8             percent

                  +/- 66.1            (319.0+/-

                   to                 65.0 to

                   192.7+/-           141.3+/-

                   60.3               52.6

                   mg/dL)             mg/dL)            <0.01

----------------------------------------------------------------------

Triglycerides               -23.2              - 29.8

                             percent            percent

                             (160 to            (157 to

                             120                108

                             mg/dL)             mg/dL)  <0.01 (median)

----------------------------------------------------------------------

HDL-C             +7.8               +10.2

                   percent            percent

                   (47.4+/-          (46.7+/-

                   13.2 to            11.3 to

                   50.7+/-            50.9+/-

                   14.7               12.8

                   mg/dL)             mg/dL)            =0.05

----------------------------------------------------------------------

C-reactive                  -23.5              -49.2

 Protein                     percent            percent

                             (1.70              (1.70

                             to 1.20            to 0.90

                             mg/dL)             mg/dL)  <0.01 (median)

----------------------------------------------------------------------

Pre-Specified

 Cardiovascular

 Events

----------------------------------------------------------------------

Cardiovascular

 deaths           1/363              2/357

----------------------------------------------------------------------

Nonfatal heart

 attacks          2/363              3/357

----------------------------------------------------------------------

Nonfatal strokes  1/363              1/357

----------------------------------------------------------------------

Revascularization 5/363              6/357

----------------------------------------------------------------------

Adverse Events

----------------------------------------------------------------------

Incidence of

 consecutive

 elevations of

 serum

 transaminases    2.2 percent        2.8 percent

 (=> 3x ULN)      (8/360)            (10/356)

----------------------------------------------------------------------

Incidence of

 elevated

 creatine

 phosphokinase

 (CPK) (=> 10x    2.2 percent        1.1 percent

 ULN)             (8/360)            (4/356)

----------------------------------------------------------------------

Cases of elevated

 CPK associated

 with muscle      0.3 percent (1     0.6 percent (2

 symptoms          case)              cases)

----------------------------------------------------------------------

VYTORIN (R) (ezetimibe/simvastatin)

9619509

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 C(24)H(21)F(2)NO(3) 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-(1(alpha),3(alpha),7(beta),8(beta)(2S*,4S*),-8a(beta))). The empirical formula of simvastatin is C(25)H(38)O(5) 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 C(max) 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 (14)C-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 (14)C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus (14)C-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 m(2)), 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 C(max) 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 C(max) 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 m(2)) 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 C(max) 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 C(max)) 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 C(max) (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 ED(50) value of 0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED(50) values in dogs, rats, and mice were 7, 30, and 700 (mu)g/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 (tilde)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 (14)C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl 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

            (Mean(a) % Change from Untreated Baseline(b))


       Treatment

      (Daily Dose)        N  Total-C LDL-C Apo B HDL-C TG(a) Non-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

            (Mean(a) % Change from Untreated Baseline(b))


 Treatment

(Daily Dose)  N  Total-C(c) LDL-C(c) Apo B(c) HDL-C TG(a) Non-HDL-C(c)

----------------------------------------------------------------------

VYTORIN by

 dose

10/10        230   -34(d)    -47(d)   -37(d)   +8    -26     -43(d)

----------------------------------------------------------------------

10/20        233   -37(d)    -51(d)   -40(d)   +7    -25     -46(d)

----------------------------------------------------------------------

10/40        236   -41(d)    -57(d)   -46(d)  +9(d)  -27     -52(d)

----------------------------------------------------------------------

10/80        224   -43(d)    -59(d)   -48(d)  +8(d)  -31     -54(d)

----------------------------------------------------------------------

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

            (Mean(a) % Change from Untreated Baseline(b))


      Treatment        N  Total-C LDL-C  Apo B  HDL-C  TG(a) Non-HDL-C

----------------------------------------------------------------------

Week 6

----------------------------------------------------------------------

Atorvastatin 10 mg(c) 262   -28    -37    -32     +5    -23     -35

----------------------------------------------------------------------

VYTORIN 10/10(d)      263 -34(f)  -46(f) -38(f) +8(f)   -26   -43(f)

----------------------------------------------------------------------

VYTORIN 10/20(e)      263 -36(f)  -50(f) -41(f) +10(f)  -25   -46(f)

----------------------------------------------------------------------

Week 12

----------------------------------------------------------------------

Atorvastatin 20 mg    246   -33    -44    -38     +7    -28     -42

----------------------------------------------------------------------

VYTORIN 10/20         250 -37(f)  -50(f) -41(f)   +9    -28   -46(f)

----------------------------------------------------------------------

VYTORIN 10/40         252 -39(f)  -54(f) -45(f) +12(f)  -31   -50(f)

----------------------------------------------------------------------

Week 18

----------------------------------------------------------------------

Atorvastatin 40 mg    237   -37    -49    -42     +8    -31     -47

----------------------------------------------------------------------

VYTORIN 10/40(g)      482 -40(f)  -56(f) -45(f) +11(f)  -32   -52(f)

----------------------------------------------------------------------

Week 24

----------------------------------------------------------------------

Atorvastatin 80 mg    228   -40    -53    -45     +6    -35     -50

----------------------------------------------------------------------

VYTORIN 10/80(g)      459 -43(f)  -59(f) -49(f) +12(f)  -35   -55(f)

----------------------------------------------------------------------


(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

            (Mean(a) % Change from Untreated Baseline(b))


 Treatment

(Daily Dose) N  Total-C(c) LDL-C(c) Apo B(c) HDL-C TG(a)  Non-HDL-C(c)

----------------------------------------------------------------------

VYTORIN by

 dose

10/20       476   -37(d)    -52(d)   -42(d)   +7   -23(d)    -47(d)

----------------------------------------------------------------------

10/40       477   -39(e)    -55(e)   -44(e)   +8    -27      -50(e)

----------------------------------------------------------------------

10/80       474   -44(f)    -61(f)   -50(f)   +8   -30(f)    -56(f)

----------------------------------------------------------------------

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

(e) p<0.05 vs. rosuvastatin 20 mg

(f) p<0.05 vs. rosuvastatin 40 mg

In a multicenter, double-blind, 24-week trial, 214 patients with type 2 diabetes mellitus treated with thiazolidinediones (rosiglitazone or pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6 weeks, were randomized to receive either simvastatin 40 mg or the coadministered active ingredients equivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels at baseline were 89 mg/dL and 7.1%, respectively.

VYTORIN 10/20 was significantly more effective than doubling the dose of simvastatin to 40 mg. The median percent changes from baseline for VYTORIN vs simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%; and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment groups were not significantly different.

Ezetimibe

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), and TG (-8%), and increased HDL-C (+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

Simvastatin

In two large, placebo-controlled clinical trials, the Scandinavian Simvastatin Survival Study (N=4,444 patients) and the Heart Protection Study (N=20,536 patients), the effects of treatment with simvastatin were assessed in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease. Simvastatin was proven to reduce: the risk of total mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction and stroke; and the need for coronary and non-coronary revascularization procedures.

No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Homozygous Familial Hypercholesterolemia (HoFH)

A double-blind, randomized, 12-week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n=14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/80, n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.

INDICATIONS AND USAGE

Primary Hypercholesterolemia

VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.

Homozygous Familial Hypercholesterolemia (HoFH)

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

Therapy with lipid-altering agents should be a component of multiple risk-factor intervention in individuals at increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to an appropriate diet (including restriction of saturated fat and cholesterol) and when the response to diet and other non-pharmacological measures has been inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines, summarized in Table 6.) -0-

                               Table 6

                  Summary of NCEP ATP III Guidelines


                            LDL Level at

                              Which to

                     LDL      Initiate       LDL Level at Which to

Risk Category         Goal   Therapeutic     Consider Drug Therapy

                    (mg/dL)  Lifestyle              (mg/dL)

                             Changes(a)

                              (mg/dL)

----------------------------------------------------------------------

CHD or CHD risk

 equivalents(b)      <100      >=100                 >=130

(10-year risk                             (100-129: drug optional)(d)

 >20%)(c)

----------------------------------------------------------------------

2+ Risk factors(e)                       10-year risk 10-20%: >=130(c)

(10-year risk        <130      >=130      10-year risk <10%: >=160(c)

 <=20%)(c)

----------------------------------------------------------------------

                                                     >=190

0-1 Risk factor(f)   <160      >=160     (160-189: LDL-lowering drug

                                                   optional)

----------------------------------------------------------------------


(a) Therapeutic lifestyle changes include: 1) dietary changes: reduced

 intake of saturated fats (<7% of

Posted: March 2008

View comments

Hide
(web4)