Merck/Schering-Plough Pharmaceuticals Provides Results of the ENHANCE Trial

WHITEHOUSE STATION, N.J. & KENILWORTH, N.J.--(BUSINESS WIRE)--Jan 14, 2008 - Merck/Schering-Plough Pharmaceuticals announced today the primary endpoint and other results of the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial. Merck/Schering-Plough has submitted an abstract on the ENHANCE trial for presentation at the American College of Cardiology meeting, which will be held in March 2008, and is awaiting notification of acceptance from the College.

ENHANCE was a surrogate endpoint trial conducted in 720 patients with Heterozygous Familial Hypercholesterolemia (HeFH), a rare condition that affects approximately 0.2 percent of the population. All analyses were conducted in accordance with the original statistical analysis plan. The primary endpoint was the mean change in 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.

There was no statistically significant difference between treatment groups on the primary endpoint. The change from baseline in the mean carotid IMT was 0.0111 mm for the ezetimibe/simvastatin 10/80 mg group versus 0.0058 mm for the simvastatin 80 mg group (p =0.29). At baseline, the mean carotid IMT measurement for ezetimibe/simvastatin was 0.68 mm and for simvastatin 80 mg was 0.69 mm. There was also no statistically significant difference between the treatment groups for each of the components of the primary endpoint, including the common carotid artery. Key secondary imaging endpoints showed no statistical difference between treatment groups.

The overall incidence rates of treatment-related adverse events, serious adverse events or adverse events leading to discontinuation were generally similar between treatment groups. The incidence of consecutive elevations of serum transaminases (greater than or equal to 3x ULN) was 10 out of 356 for ezetimibe/simvastatin (2.8 percent) as compared to 8 out of 360 for simvastatin (2.2 percent). Incidence of elevated creatine phosphokinase (greater than or equal to 10xULN) was 4 out of 356 (1.1 percent) in the ezetimibe/simvastatin group and 8 out of 360 (2.2 percent) in the simvastatin group and two cases (0.6 percent) of CPKgreater than or equal to 10xULN associated with muscle symptoms in the ezetimibe/simvastatin group and one case (0.3 percent) in the simvastatin group. There were no cases of rhabdomyolysis. Both medicines were generally well tolerated.

Overall, the safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels.

After washout, patients enrolled in the study had baseline LDL cholesterol levels of 319 mg/dL in the group randomized to ezetimibe/simvastatin and 318 mg/dL in the simvastatin group. Approximately eighty percent of the patients enrolled in the ENHANCE trial had previously been treated with statins.

In the trial, there was a significant difference in low-density lipoprotein (LDL) cholesterol lowering seen between the treatment groups -- 58 percent LDL cholesterol lowering at 24 months on ezetimibe/simvastatin 10/80 mg as compared to 41 percent at 24 months on simvastatin 80mg alone, (p<0.01).

The incidence rates of cardiovascular clinical events in ENHANCE for the ezetimibe/simvastatin and simvastatin groups, respectively, were as follows: cardiovascular death 2 out of 357 vs. 1 out of 363, non-fatal myocardial infarction 3 out of 357 vs. 2 out of 363, non-fatal stroke 1 out of 357 vs. 1 out of 363 and revascularization 6 out of 357 vs. 5 out of 363. There were no non-cardiovascular deaths or incidents of resuscitated cardiac arrests in the ENHANCE trial. This surrogate endpoint study was not powered nor designed to assess cardiovascular clinical event outcomes.

Merck/Schering-Plough Pharmaceuticals is currently conducting three large outcomes trials with ezetimibe/simvastatin, which involve more than 20,000 high-risk patients, including the more than 10,000 patient IMPROVE-IT trial. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

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 and 363 HeFH patients to simvastatin. The study collected more than 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.(1)

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(R) (ezetimibe/simvastatin)

VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B(2), 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).

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(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, 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.

(1) Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986;232:34-47.

(2) 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.

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

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 Level at

                              LDL Goal    Initiate        Which to

Risk Category                 (mg/dL)    Therapeutic   Consider Drug

                                          Lifestyle        Therapy

                                           Changesa       (mg/dL)

                                           (mg/dL)

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

CHD or CHD risk equivalentsb                              (>=)130

(10-year risk >20%)c            <100       (>=)100    (100-129: drug

                                                         optional)d

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

                                                      10-year risk 10-

2+ Risk factorse                <130       (>=)130      20%: (>=)130c

(10-year risk (<=)20%)c                                 10-year risk

                                                       <10%: (>=)160c

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

                                                          (>=)190

0-1 Risk factorf                <160       (>=)160     (160-189: LDL-

                                                       lowering drug

                                                          optional)

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


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

 intake of saturated fats (<7% of total calories) and cholesterol

 (<200 mg per day), and enhancing LDL lowering with plant

 stanols/sterols (2 g/d) and increased viscous (soluble) fiber (10-25

 g/d), 2) weight reduction, and 3) increased physical activity.

b CHD risk equivalents comprise: diabetes, multiple risk factors that

 confer a 10-year risk for CHD >20%, and other clinical forms of

 atherosclerotic disease (peripheral arterial disease, abdominal

 aortic aneurysm and symptomatic carotid artery disease).

c Risk assessment for determining the 10-year risk for developing CHD

 is carried out using the Framingham risk scoring. Refer to JAMA, May

 16, 2001; 285 (19): 2486-2497, or the NCEP website

 (http://www.nhlbi.nih.gov) for more details.

d Some authorities recommend use of LDL-lowering drugs in this

 category if an LDL cholesterol <100 mg/dL cannot be achieved by

 therapeutic lifestyle changes. Others prefer use of drugs that

 primarily modify triglycerides and HDL, e.g., nicotinic acid or

 fibrate. Clinical judgment also may call for deferring drug therapy

 in this subcategory.

e Major risk factors (exclusive of LDL cholesterol) that modify LDL

 goals include cigarette smoking, hypertension (BP (>=)140/90 mm Hg or

 on anti-hypertensive medication), low HDL cholesterol (<40 mg/dL),

 family history of premature CHD (CHD in male first-degree relative

 <55 years; CHD in female first-degree relative <65 years), age (men

 (>=)45 years; women (>=)55 years). HDL cholesterol (>=)60 mg/dL

 counts as a "negative" risk factor; its presence removes one risk

 factor from the total count.

f Almost all people with 0-1 risk factor have a 10-year risk <10%;

 thus, 10-year risk assessment in people with 0-1 risk factor is not

 necessary.

Prior to initiating therapy with VYTORIN, secondary causes for dyslipidemia (i.e., diabetes, hypothyroidism, obstructive liver disease, chronic renal failure, and drugs that increase LDL-C and decrease HDL-C (progestins, anabolic steroids, and corticosteroids)), should be excluded or, if appropriate, treated. A lipid profile should be performed to measure total-C, LDL-C, HDL-C and TG. For TG levels >400 mg/dL (>4.5 mmol/L), LDL-C concentrations should be determined by ultracentrifugation.

At the time of hospitalization for an acute coronary event, lipid measures should be taken on admission or within 24 hours. These values can guide the physician on initiation of LDL-lowering therapy before or at discharge.

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

Active liver disease or unexplained persistent elevations in serum transaminases (see WARNINGS, Liver Enzymes).

Pregnancy and lactation. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as simvastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, VYTORIN is contraindicated during pregnancy and in nursing mothers. VYTORIN should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, VYTORIN should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).

WARNINGS

Myopathy/Rhabdomyolysis

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. In clinical trials, the incidence of CK >10 X the upper limit of normal (ULN) was 0.2% for VYTORIN. (See PRECAUTIONS, Skeletal Muscle.)

Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above 10 X ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,050 patients were treated with simvastatin with 24,747 (approximately 60%) treated for at least 4 years, the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

All patients starting therapy with VYTORIN or whose dose of VYTORIN is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. VYTORIN therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking VYTORIN merit closer monitoring. Therapy with VYTORIN should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.

Because VYTORIN contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of VYTORIN with the following:

Potent inhibitors of CYP3A4: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of cytochrome P450 3A4 (CYP3A4). When simvastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG-CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin.

The use of VYTORIN concomitantly with the potent CYP3A4 inhibitors itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. Concomitant use of other medicines labeled as having a potent inhibitory effect on CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN should be suspended during the course of treatment.

Other drugs:

Gemfibrozil, particularly with higher doses of VYTORIN: There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with gemfibrozil. Therefore, although not recommended, if VYTORIN is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily. (See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone, Other drug interactions, and DOSAGE AND ADMINISTRATION.)

Other lipid-lowering drugs (other fibrates or (>=)1 g/day of niacin): Caution should be used when prescribing other fibrates or lipid-lowering doses ((>=)1 g/day) of niacin with VYTORIN, as these agents can cause myopathy when given alone. The safety and effectiveness of VYTORIN administered with other fibrates or ((>=)1 g/day) of niacin have not been established. Therefore, the benefit of further alterations in lipid levels by the combined use of VYTORIN with other fibrates or niacin should be carefully weighed against the potential risks of these drug combinations. (See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone, Other drug interactions, and DOSAGE AND ADMINISTRATION.)

Cyclosporine or danazol with higher doses of VYTORIN: The dose of VYTORIN should not exceed 10/10 mg daily in patients receiving concomitant medication with cyclosporine or danazol. The benefits of the use of VYTORIN in patients receiving cyclosporine or danazol should be carefully weighed against the risks of these combinations. (See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Other drug interactions.)

Amiodarone or verapamil with higher doses of VYTORIN: The dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of VYTORIN at doses higher than 10/20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. (See PRECAUTIONS, Drug Interactions, Other drug interactions.) In an ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone. In an analysis of clinical trials involving 25,248 patients treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher in patients receiving verapamil and simvastatin (4/635; 0.63%) than in patients taking simvastatin without a calcium channel blocker (13/21,224; 0.061%).

Prescribing recommendations for interacting agents are summarized in Table 7 (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION). -0-

                               TABLE 7

         Drug Interactions Associated with Increased Risk of

                        Myopathy/Rhabdomyolysis

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

Interacting Agents            Prescribing Recommendations

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

Itraconazole                  Avoid VYTORIN

Ketoconazole

Erythromycin

Clarithromycin

Telithromycin

HIV protease inhibitors

Nefazodone

Fibrates*

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

Cyclosporine                  Do not exceed 10/10 mg VYTORIN daily

Danazol

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

Amiodarone                    Do not exceed 10/20 mg VYTORIN daily

Verapamil

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

Grapefruit juice              Avoid large quantities of grapefruit

                               juice (>1 quart daily)

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

*For additional information regarding gemfibrozil, see DOSAGE AND ADMINISTRATION.

Liver Enzymes

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations ((>=)3 X ULN) in serum transaminases was 1.7% overall for patients treated with VYTORIN and appeared to be dose-related with an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidenc

Posted: January 2008

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