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REPEAT/New Study Showed VYTORIN(R) (Ezetimibe/Simvastatin) Superior to Lipitor in Reducing LDL ''Bad'' Cholesterol in Patients With Type II Diabetes at the Recommended Usual Starting Doses

Posted on: Monday, 12 June 2006, 09:00 CDT

Greater LDL Cholesterol Reduction with VYTORIN Compared to Lipitor

Resulted in Greater LDL Cholesterol Goal Attainment

Results from a new clinical study conducted in 1,229 patients with type 2 diabetes mellitus and high cholesterol showed that VYTORIN(R) (ezetimibe/simvastatin) provided superior reduction in LDL "bad" cholesterol compared to Lipitor(R) (atorvastatin) in comparisons of the recommended usual starting doses, according to data presented today at the American Diabetes Association's (ADA) 66th Annual Scientific Session. The primary efficacy endpoint was the percent change from baseline to the end of the six-week treatment period in LDL cholesterol.

VYTORIN, which contains ezetimibe and simvastatin, is the first and only product approved to treat the two sources of cholesterol by inhibiting the production of cholesterol in the liver and blocking the absorption of cholesterol in the intestine, including cholesterol from food. VYTORIN is marketed as INEGY in many countries outside the U.S.

At the recommended usual starting doses of both agents, VYTORIN 10/20 mg demonstrated a 53.6 mean percent reduction from baseline in LDL cholesterol as compared to a 38.3 percent reduction observed with Lipitor 10 mg and a 44.6 percent reduction with Lipitor 20 mg. At the alternative starting dose for patients requiring greater LDL lowering for the two agents (> 55 percent for VYTORIN and > 45 percent for Lipitor), VYTORIN 10/40 mg, decreased LDL cholesterol significantly more than Lipitor 40 mg -- 57.6 percent compared to 50.9 percent, respectively, (p<0.001 for all three comparisons).

"Patients with diabetes and high cholesterol are considered to be in the high risk category for heart disease, according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)," said Ronald Goldberg, M.D., co-director, Southeastern Florida Regional Diabetes Program, Miami. "This study showed that VYTORIN was significantly more effective than Lipitor in reducing LDL "bad" cholesterol when comparing the recommended usual starting doses and the alternative starting doses for those patients that need greater LDL cholesterol lowering."

In this study, the greater LDL cholesterol reductions with VYTORIN 10/20 mg helped more patients with type 2 diabetes (90.3 percent) achieve the LDL cholesterol treatment goal (<100 mg/dL) set by the NCEP ATP III guidelines versus patients taking Lipitor 10 mg (70.0 percent; p<0.001) and Lipitor 20 mg (82.1 percent; p<0.05). VYTORIN 10/40 mg versus Lipitor 40 mg resulted in 93.4 percent and 88.8 percent of patients, respectively, reaching a LDL cholesterol goal of <100 mg/dL (p=ns).

At the doses studied, significantly more patients treated with VYTORIN achieved LDL cholesterol of less than 70 mg/dL, than patients taking Lipitor. Specifically, 59.7 percent of patients taking VYTORIN 10/20 mg reached this LDL cholesterol level versus 21.5 percent of patients taking Lipitor 10 mg and 35.0 percent taking Lipitor 20 mg (p<0.001 for both comparisons). Additionally, 74.4 percent of patients taking VYTORIN 10/40 mg reached LDL cholesterol of <70 mg/dL as compared to 55.2 percent of patients taking Lipitor 40 mg (p<0.001).

Additional results from the study demonstrated that VYTORIN (10/20 and 10/40 mg) increased HDL "good" cholesterol by 8.0 and 6.3 percent, respectively, as compared to the HDL increases of 4.3 (p<0.0001), 4.5, (p<0.01) and 2.3 percent (p<0.001) seen in patients taking Lipitor (10, 20, and 40 mg) across the same dose comparisons.

Significantly greater reductions in triglycerides (TG) were observed for those patients treated with VYTORIN 10/20 mg (25.7 percent) versus patients taking Lipitor 10 mg (22.7 percent; p<0.05). Additionally greater reductions in high sensitivity C-reactive protein (hs-CRP) were observed in patients treated with VYTORIN 10/20 mg (23.3 percent) versus Lipitor 10 mg (13.7 percent p<0.05). No significant differences were seen in triglycerides and hs-CRP changes at the other dose comparisons.

High triglycerides and low HDL cholesterol are both risk factors for cardiovascular disease (CVD); CRP is considered an emerging risk factor for CVD. The relationship between treatment-induced changes in triglycerides, HDL, and CRP and reduction of CVD risk has not been established.

About the Study

The clinical study was a randomized double-blind, six week, parallel-group study of 1,229 patients with type 2 diabetes and high cholesterol designed to evaluate the lipid modifying efficacy and safety of VYTORIN as compared to Lipitor across the recommended usual starting dose and alternative starting dose for people requiring greater reductions in LDL cholesterol comparisons. Baseline LDL cholesterol ranged from 144-147 mg/dL.

Patients were randomized to receive VYTORIN 10/20 mg, 10/40 mg or Lipitor 10 mg, 20 mg or 40 mg. This study enrolled patients with type II diabetes mellitus including those patients with cardiovascular disease or other forms of atherosclerosis. Both VYTORIN and Lipitor were generally well tolerated in this study.

Important information about VYTORIN

VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B(1), 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.

VYTORIN is available as tablets containing 10 mg of ezetimibe combined with 10, 20, 40 or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40 or 10/80 mg, respectively).

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 (=>3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (=>3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.

VYTORIN has been evaluated for safety in more than 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 marketed as INEGY in many countries 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 cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, 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 Securities Litigation Reform Act of 1995, including statements relating to VYTORIN and the potential market for VYTORIN. 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 Item 1A. Risk Factors in the Company's 2005 10-K.

Prescribing information and patient product information for VYTORIN(R) is attached.

(1) Apo B is the protein compound of lipoproteins, LDL and VLDL, which carry cholesterol in the blood.

VYTORIN (R) is a trademark of MSP Marketing Services (C) LLC. All other brands are trademarks of their respective owners and are not trademarks of MSP Marketing Services (C) LLC.

9619607 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: (OBJECT 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-naphthalenylester, (1S-(1(alpha) ,3(alpha),7(beta),8(beta)(2S*,4S*),-8a(beta))). 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: (OBJECT 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. 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 and appears to act 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

. 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%). Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. 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 Blacks and Caucasians. There were too few patients in other racial or ethnic groups to permit further pharmacokinetic comparisons. 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 (mu)g/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 (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 ~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. 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. Table 1 Response to VYTORIN in Patients with Primary Hypercholesterolemia (Mean(a) % Change from Untreated Baseline(b)) Treatment Non- Total-LDL-Apo HDL- HDL- (Daily Dose) N C C B C TG(a) 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). Table 2 Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk quivalents 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, 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 3). Table 3 Response to VYTORIN and Atorvastatin in Patients with Primary Hypercholesterolemia (Mean(a) % Change from Untreated Baseline(b)) Total- Non- Treatment N C LDL-C Apo B HDL-C TG(a) 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, 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 4.) Table 4 Summary of NCEP ATP III Guidelines LDL Level at Which to LDL Level at LDL Goal Initiate Which to Risk Category (mg/dL) TherapeuticConsider Drug Lifestyle Therapy Changes(a) (mg/dL) (mg/dL) ---------------------------------------------------------------------- (greater CHD or CHD risk equivalents(b) less (greater than=)130 (10-year risk greater than20%)(c) than100 than=)100 (100-129: drug optional)(d) ---------------------------------------------------------------------- 10-year risk 10-20%: (greater 2+ Risk factors(e) less (greater than=)130(c) (10-year risk (less than=)20%)(c) than130 than=)130 10-year risk less than10%: (greater than=)160(c) ---------------------------------------------------------------------- (greater than=)190 0-1 Risk factor(f) less (greater (160-189: than160 than=)160 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, and other fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Therefore, the concomitant use of VYTORIN and fibrates should be avoided. 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 PRECAUTIONS, Drug Interactions, Other drug interactions, Fibrates, and DOSAGE AND ADMINISTRATION.) Niacin ((>=)1 g/day): Caution should be used when prescribing lipid-lowering doses ((>=)1 g/day) of niacin with VYTORIN, as niacin can cause myopathy when given alone. The benefit of further alterations in lipid levels by the combined use of VYTORIN with niacin should be carefully weighed against the potential risks of this drug combination (see PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone). 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 5 (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions; DOSAGE AND ADMINISTRATION). TABLE 5 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 Danazol VYTORIN daily ------------------------------------------------------ Amiodarone Do not exceed 10/20 mg Verapamil VYTORIN daily ------------------------------------------------------ Grapefruit juice Avoid large quantities of grapefruit juice (greater than1 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 incidence of consecutive elevations ((>=)3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with VYTORIN 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. It is recommended that liver function tests be performed before the initiation of treatment with VYTORIN, and thereafter when clinically indicated. Patients titrated to the 10/80-mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80-mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 X ULN or greater persist, withdrawal of therapy with VYTORIN is recommended. VYTORIN should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of VYTORIN. PRECAUTIONS Information for Patients Patients should be advised about substances they should not take concomitantly with VYTORIN and be advised to report promptly unexplained muscle pain, tenderness, or weakness (see list below and WARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised to inform other physicians prescribing a new medication that they are taking VYTORIN. Skeletal Muscle In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Hepatic Insufficiency Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations.) Drug Interactions (See also CLINICAL PHARMACOLOGY, Drug Interactions) VYTORIN CYP3A4 Interactions Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by reducing the elimination of the simvastatin component of VYTORIN. See WARNINGS, Myopathy/Rhabdomyolysis, and CLINICAL PHARMACOLOGY, Pharmacokinetics, Drug Interactions. Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Large quantities of grapefruit juice (>1 quart daily) Interactions with lipid-lowering drugs that can cause myopathy when given alone See WARNINGS, Myopathy/Rhabdomyolysis. The risk of myopathy is increased by gemfibrozil and to a lesser extent by other fibrates and niacin (nicotinic acid) ((>=)1 g/day). Other drug interactions Danazol: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of danazol particularly with higher doses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS, Myopathy/Rhabdomyolysis). Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of VYTORIN (see WARNINGS, Myopathy/Rhabdomyolysis). Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be reduced by this interaction. Cyclosporine: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine particularly with higher doses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis). Caution should be exercised when using VYTORIN and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine (see DOSAGE AND ADMINISTRATION, Patients taking Cyclosporine or Danazol). Cyclosporine concentrations should be monitored in patients receiving VYTORIN and cyclosporine (see CLINICAL PHARMACOLOGY, Drug Interactions). The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe. In a pharmacokinetic study in post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), concomitant cyclosporine administration increased the mean AUC and Cmax 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. In a separate study, the total ezetimibe exposure increased 12-fold in one renal transplant patient with severe renal insufficiency receiving multiple medications, including cyclosporine. (See CLINICAL PHARMACOLOGY, Drug Interactions and WARNINGS, Myopathy/Rhabdomyolysis.) Digoxin: Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in plasma digoxin concentrations compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when VYTORIN is initiated. Fibrates: The safety and effectiveness of VYTORIN administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see ANIMAL PHARMACOLOGY). Coadministration of VYTORIN with fibrates is not recommended until use in patients is studied. (See WARNINGS, Myopathy/Rhabdomyolysis.) Warfarin: Simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in a normal volunteer study and in a hypercholesterolemic patient study, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting VYTORIN and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased International Normalized Ratio (INR) in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications. The effect of VYTORIN on the prothrombin time has not been studied. Ezetimibe Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. Simvastatin Propranolol: In hea

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