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Study Showed VYTORIN-TM- -Ezetimibe/Simvastatin- Superior to Lipitor at Lowering LDL -Bad- Cholesterol

Posted on: Tuesday, 8 March 2005, 09:00 CST

Greater LDL Cholesterol Reduction with VYTORIN(TM) Compared to Lipitor Resulted in Greater Goal Attainment At Most Common Doses

Results from a clinical trial conducted in 1,902 patients with high cholesterol showed that VYTORIN(TM) (ezetimibe/simvastatin) provided greater reduction in LDL ("bad") cholesterol across the dosing ranges compared to Lipitor. At the most commonly used starting doses of these two therapies, VYTORIN 10/20 mg decreased LDL cholesterol by 51 percent compared with 36 percent for Lipitor 10 mg (p<0.001). The results were presented today at the American College of Cardiology's 2005 Annual Scientific Session.

In a subgroup of high risk patients (CHD or CHD risk equivalent), significant differences in LDL cholesterol reductions at these starting doses resulted in more patients achieving a goal of less than 100 mg/dL with VYTORIN as compared to Lipitor; specifically, 82 percent of high risk patients on VYTORIN 10/20 mg (n=106) achieved an LDL cholesterol goal of less than 100 mg/dL as compared to only 47 percent for patients on Lipitor 10 mg (n=106, p<0.001). High risk patients in the study with a goal of less than 100 mg/dL who were taking VYTORIN 10/20 mg had a baseline LDL cholesterol of 166 mg/dL as compared to patients taking Lipitor 10 mg who had a baseline of 169 mg/dL.

"There has been a good deal of discussion about achieving even lower LDL cholesterol goals especially in higher risk patients," said Christie Ballantyne, M.D., director of the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, Texas, and lead investigator of the study. "This study demonstrated that not only did more high risk patients taking VYTORIN 10/40 mg achieve the NCEP ATP III goal of less than 100 mg/dL as compared to Lipitor 40 mg, moreover the study also showed that a greater percentage, 57 percent, of these high risk patients on VYTORIN 10/40 mg also achieved an LDL cholesterol level of less than 70 mg/dL as compared to 23 percent of patients taking Lipitor."

Results from the study showed that VYTORIN 10/40 mg decreased LDL cholesterol by 59 percent compared to 49 percent for Lipitor 40 mg in the subgroup of high risk patients. These patients had a baseline LDL cholesterol values of 169 mg/dL and 175 mg/dL respectively (p<0.001). In this post-hoc analysis of the data, significant differences in LDL cholesterol reductions, at all doses compared, resulted in more high risk patients achieving an LDL cholesterol level of less than 70 mg/dL with VYTORIN as compared to Lipitor. In this study, 57 percent of high risk patients taking VYTORIN 10/40 mg (n=112) achieved a LDL cholesterol lowering of less than 70 mg/dL as compared to 23 percent of the patients (n=115) taking Lipitor 40 mg (p<0.001).

VYTORIN was approved by the FDA on July 23, 2004 for the treatment of high LDL cholesterol in patients with primary hypercholesterolemia or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. VYTORIN 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. The active ingredients in VYTORIN are ezetimibe and simvastatin. The recommended starting dose of VYTORIN is 10/20 mg (10 mg ezetimibe/20 mg simvastatin).

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.

Study results also demonstrated VYTORIN increased HDL cholesterol by a greater degree than Lipitor

In other results observed in the six week study, VYTORIN 10/40 mg and 10/80 mg also provided significantly greater increases in HDL ("good") cholesterol of 9.0 percent and 7.6 percent respectively as compared to the HDL cholesterol increase of 3.8 percent and 1.4 percent respectively seen in patients taking Lipitor 40 mg and 80 mg (p<0.001). Increased HDL cholesterol in patients treated with VYTORIN 10/10 mg (7.7 percent) and 10/20 mg (7.2 percent) was numerically higher compared to Lipitor 10 mg (6.9 percent) and 20 mg (5.1 percent). However, these differences did not reach statistical significance.

Study showed VYTORIN was well tolerated

Both VYTORIN and Lipitor were well tolerated in the study. The percentage of patients with clinical and laboratory adverse experiences was generally comparable between the two treatment groups. However, there was a significantly greater incidence of consecutive elevations in liver enzymes (ALT and/or AST) greater than or equal to three times the upper limit of normal in the pooled Lipitor group (1.2 percent, 11 out of 939 patients) compared with the pooled group of patients who took VYTORIN (0.1 percent, 1 out of 933 patients) (p<0.001). There were no clinically or statistically significant differences in the incidence of muscle enzyme elevations and no patients in the study were diagnosed with myopathy.

Post-hoc analysis of C Reactive Protein (CRP) reduction showed VYTORIN achieved a 25 percent reduction, comparable to Lipitor

A post-hoc analysis of archived baseline and post-baseline blood samples was performed on 1,832 of the study's enrolled patients. Results from this analysis showed that averaged across all doses, both VYTORIN and Lipitor demonstrated a mean 25 percent reduction on CRP after six weeks of treatment.

"In addition to providing greater LDL cholesterol lowering than with Lipitor and in a pooled analysis, a greater increase in HDL cholesterol, VYTORIN was shown in this study to provide similar reductions in C-Reactive Protein," said Dr. Ballantyne. "While the exact meaning of CRP reduction is unknown, given the ongoing discussions around CRP, this is an interesting study finding. Further studies are needed to confirm these findings."

CRP is considered an emerging risk marker for CHD. In an American Heart Association/Centers for Disease Control Scientific Statement published in the January 2003 issue of Circulation, high-sensitivity CRP was recognized as a potentially valuable marker and an optional adjunct to major risk factors in the assessment of risk for coronary disease in patients at moderate cardiovascular risk.(1) The relationship between reductions in CRP and reduction of CHD risk has not been established.

Study design

The study was a multicenter, randomized, double-blind, active controlled parallel-group study of 1,902 patients designed to evaluate the efficacy and safety of VYTORIN as compared to Lipitor across their respective dosing ranges. The primary efficacy endpoint was the percent change from baseline to the end of the 6-week treatment period in LDL cholesterol for patients treated with VYTORIN or Lipitor averaged across all doses. The study enrolled men and women 18 to 79 years of age with an LDL cholesterol level at or above drug treatment thresholds established by the NCEP ATP III who were deemed eligible if they met the following criteria: established coronary heart disease (CHD) or CHD risk equivalent, or two or more risk factors conferring a 10-year risk for CHD greater than 20 percent (by Framingham score) with an LDL cholesterol greater than or equal to 130 mg/dL; no established CHD or CHD risk equivalent, with two or more risk factors conferring a 10-year risk for CHD greater than or equal to 10 percent and less than or equal to 20 percent with an LDL cholesterol greater than or equal to 130 mg/dL; no established CHD or CHD risk equivalent, with two or more risk factors conferring a 10-year risk for CHD less than 10 percent with an LDL cholesterol greater than or equal to 160 mg/dL; and no established CHD or CHD risk equivalent, with less than two risk factors, and with LDL cholesterol greater than or equal to 190 mg/dL. Other criteria included fasting serum triglyceride (TG) level less than or equal to 350 mg/dL, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatine kinase (CK) level less than or equal to 1.5 times the upper limit of normal, serum creatinine level less than or equal to 1.5 mg/dL, and a hemoglobin A1C less than nine percent in patients with diabetes.

Full indication for VYTORIN

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

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.

In clinical studies VYTORIN was well tolerated with a low incidence of adverse events

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 was expanded to include worldwide markets (excluding Japan).

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 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, 2003, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

Schering-Plough Disclosure Notice: This press release contains "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including the market for VYTORIN. Forward-looking statements relate to expectations or forecasts of future events and not to historical information. Schering-Plough does not assume the obligation to update any forward-looking statement. There are no guarantees about the market performance of VYTORIN, Schering-Plough stock or Schering-Plough's business. Actual results may vary materially from forward-looking statements made here or in other Schering-Plough written or spoken communications due to many factors and uncertainties, which include the market acceptance of VYTORIN, trade buying patterns, the introduction and performance of competitive products in the market, legislation that may impact the pricing/availability of VYTORIN and other items discussed in Schering-Plough's Securities and Exchange Commission filings, including the company's third quarter 10-Q.

Full prescribing information and patient product information for VYTORIN(TM) is attached.

(1) Pearson TA, Mensah G, Alexander RW, et al. AHA/CDC Scientific Statement: Markers of Inflammation and Cardiovascular Disease, Application to Clinical and Public Health Practice. Circulation. (2003;107:499-511)

VYTORIN is a trademark of MSP Singapore Company, LLC. All other brands are trademarks of their respective owners and are not trademarks of MSP Singapore Company, LLC. -0- *T VYTORIN(TM)(ezetimibe/simvastatin) 9619602 VYTORIN TM 10/10 (ezetimibe 10 mg/SIMVASTATIN 10 mg TABLETS) VYTORIN TM 10/20 (ezetimibe 10 mg/SIMVASTATIN 20 mg TABLETS) VYTORIN TM 10/40 (ezetimibe 10 mg/SIMVASTATIN 40 mg TABLETS) VYTORIN TM 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-naphthalenyl ester, (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: (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. 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. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of simvastatin (estimated to be >60% in man), the availability of drug to the general circulation is low. Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reaches the general circulation as active inhibitors. 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. 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. 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). 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. 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 (Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998;64(5):477-83), 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 first1 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 (0.03-300 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 (0.3-5 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 (Daily Dose) N Total-C LDL-C Apo B ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- Pooled data (All VYTORIN 609 -38 -53 -42 doses)(c) ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- Pooled data (All 622 -28 -39 -32 simvastatin doses)(c) ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- Ezetimibe 10 mg 149 -13 -19 -15 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- Placebo 148 -1 -2 0 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- VYTORIN by dose 10/10 152 -31 -45 -35 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- 10/20 156 -36 -52 -41 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- 10/40 147 -39 -55 -44 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- 10/80 154 -43 -60 -49 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- Simvastatin by dose 10 mg 158 -23 -33 -26 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- 20 mg 150 -24 -34 -28 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- 40 mg 156 -29 -41 -33 ---------------------------- ---------- ---------- ---------- -------- ---------------------------- ---------- ---------- ---------- -------- 80 mg 158 -35 -49 -39 ---------------------------- ---------- ---------- ---------- -------- Treatment (Daily Dose) HDL-C TG(a) Non-HDL-C ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- Pooled data (All VYTORIN +7 -24 -49 doses)(c) ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- Pooled data (All +7 -21 -36 simvastatin doses)(c) ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- Ezetimibe 10 mg +5 -11 -18 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- Placebo 0 -2 -2 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- VYTORIN by dose 10/10 +8 -23 -41 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- 10/20 +10 -24 -47 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- 10/40 +6 -23 -51 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- 10/80 +6 -31 -56 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- Simvastatin by dose 10 mg +5 -17 -30 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- 20 mg +7 -18 -32 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- 40 mg +8 -21 -38 ---------------------------- ---------- ---------- ----------- ---------------------------- ---------- ---------- ----------- 80 mg +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 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 174 165 167 171 LDL-C ------------------ ------------- -------- ------------ ------------- ------------------ ------------- -------- ------------ ------------- Percent change -38 -47 -53 -59 LDL-C ------------------ ------------- -------- ------------ ------------- 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)) Treatment N Total-C LDL-C Apo B -------------------- ----------- ----------- ------------ ----------- -------------------- ----------- ----------- ------------ ----------- Week 6 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... Atorvastatin 10 mg(c) 262 -28 -37 -32 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... VYTORIN 10/10(d) 263 -34(f) -46(f) -38(f) .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... VYTORIN 10/20(e) 263 -36(f) -50(f) -41(f) -------------------- ----------- ----------- ------------ ----------- -------------------- ----------- ----------- ------------ ----------- Week 12 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... Atorvastatin 20 mg 246 -33 -44 -38 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... VYTORIN 10/20 250 -37(f) -50(f) -41(f) .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... VYTORIN 10/40 252 -39(f) -54(f) -45(f) -------------------- ----------- ----------- ------------ ----------- -------------------- ----------- ----------- ------------ ----------- Week 18 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... Atorvastatin 40 mg 237 -37 -49 -42 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... VYTORIN 10/40g 482 -40(f) -56(f) -45(f) -------------------- ----------- ----------- ------------ ----------- -------------------- ----------- ----------- ------------ ----------- Week 24 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... Atorvastatin 80 mg 228 -40 -53 -45 .................... ........... ........... ............ ........... .................... ........... ........... ............ ........... VYTORIN 10/80(g) 459 -43(f) -59(f) -49(f) -------------------- ----------- ----------- ------------ ----------- Treatment HDL-C TG(a) Non-HDL-C -------------------- ----------- ------------ ----------- -------------------- ----------- ------------ ----------- Week 6 .................... ........... ............ ........... .................... ........... ............ ........... Atorvastatin 10 mg(c) +5 -23 -35 .................... ........... ............ ........... .................... ........... ............ ........... VYTORIN 10/10(d) +8(f) -26 -43(f) .................... ........... ............ ........... .................... ........... ............ ........... VYTORIN 10/20(e) +10(f) -25 -46(f) -------------------- ----------- ------------ ----------- -------------------- ----------- ------------ ----------- Week 12 .................... ........... ............ ........... .................... ........... ............ ........... Atorvastatin 20 mg +7 -28 -42 .................... ........... ............ ........... .................... ........... ............ ........... VYTORIN 10/20 +9 -28 -46(f) .................... ........... ............ ........... .................... ........... ............ ........... VYTORIN 10/40 +12(f) -31 -50(f) -------------------- ----------- ------------ ----------- -------------------- ----------- ------------ ----------- Week 18 .................... ........... ............ ........... .................... ........... ............ ........... Atorvastatin 40 mg +8 -31 -47 .................... ........... ............ ........... .................... ........... ............ ........... VYTORIN 10/40g +11(f) -32 -52(f) -------------------- ----------- ------------ ----------- -------------------- ----------- ------------ ----------- Week 24 .................... ........... ............ ........... .................... ........... ............ ........... Atorvastatin 80 mg +6 -35 -50 .................... ........... ............ ........... .................... ........... ............ ........... VYTORIN 10/80(g) +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 Risk Category LDL Goal LDL Level at Which to Initiate Therapeutic Lifestyle Changes(a) (mg/dL) (mg/dL) ------------------------------ -------------- ------------------------ CHD or CHD risk equivalents(b) <100 =>100 (10-year risk >20%)(c) ------------------------------ -------------- ------------------------ ------------------------------ -------------- ------------------------ 2+ Risk factors(e) <130 =>130 (10-year risk <=20%)(c) ------------------------------ -------------- ------------------------ ------------------------------ -------------- ------------------------ 0-1 Risk factor(f) <160 =>160 ------------------------------ -------------- ------------------------ Risk Category LDL level at Which to Consider Drug Therapy (mg/dL) ------------------------------ --------------------------- CHD or CHD risk equivalentsb =>130 (10-year risk >20%)(c) (100-129: drug optional)(d) ------------------------------ --------------------------- ------------------------------ --------------------------- 2+ Risk factors(e) 10-year risk 10-20%: (10-year risk <=20%)(c) =>130(c) 10-year risk <10%: =>160(c) ------------------------------ --------------------------- ------------------------------ --------------------------- 0-1 Risk factor(f) =>190 (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. 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. -- Because VYTORIN contains simvastatin, the risk of myopathy/rhabdomyolysis is increased by concomitant use of VYTORIN with the following: - Potent inhibitors of CYP3A4: Cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily), particularly with higher doses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, CYP3A4 Interactions). Other drugs: - Gemfibrozil, particularly with higher doses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone). - Other lipid-lowering drugs (other fibrates or =>1 g/day of niacin) that can cause myopathy when given alone (see PRECAUTIONS, Drug Interactions, Interactions with lipid-lowering drugs that can cause myopathy when given alone). - Danazol particularly with higher doses of VYTORIN (see below; CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Other drug interactions). - Amiodarone or verapamil with higher doses of VYTORIN (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%). -- The risk of myopathy/rhabdomyolysis is dose related for simvastatin. The incidence in clinical trials, in which patients were carefully monitored and some interacting drugs were excluded, has been approximately 0.02% at 20 mg, 0.07% at 40 mg and 0.3% at 80 mg. Consequently: 1. Use of VYTORIN concomitantly with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, or large quantities of grapefruit juice (>1 quart daily) should be avoided. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN should be suspended during the course of treatment. Concomitant use with other medicines labeled as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk. 2. There is an increased risk of myopathy when simvastatin is used concomitantly with gemfibrozil or 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. (See PRECAUTIONS, Drug Interactions, Other Drug Interactions, Fibrates.) 3. 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. 4. 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 PRECAUTIONS, Drug Interactions, Other Drug Interactions, Cyclosporine.) 5. 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. 6. 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. The presence of these symptoms, and/or a CK level >10 times the ULN indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increases resolved. Periodic CK determinations may be considered in patients starting therapy with VYTORIN or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. 7. 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. 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 ha

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