|
15.11.2005 14:10:00
|
Merck/Schering-Plough Announces Update for the IMPROVE-IT Trial
IMPROVE-IT is a head-to-head study of VYTORIN 10/40mg as comparedto Zocor 40 mg. The primary endpoint of the trial is the composite ofcardiovascular death, myocardial infarction (MI), nonfatal stroke,rehospitalization for ACS or revascularization (occurring 30 days ormore after the initial event). The IMPROVE-IT study is designed tolower LDL cholesterol with VYTORIN below levels that have been studiedin prior large outcomes trials, which demonstrated that lower LDLcholesterol levels led to lower cardiovascular risk.
"This important new trial could add substantially to the body ofknowledge concerning how we can reduce the risk of coronary events bymanaging LDL cholesterol; including a determination of what impact LDLlowering may have in patients who present with ACS. It is importantthat the medical community continue to investigate how low we shouldgo in reducing LDL cholesterol in an effort to lower residual risk forthese patients," said Enrico Veltri, M.D., group vice president,Schering-Plough Research Institute.
Study Design
IMPROVE-IT is an international, multi-center, randomized,double-blind active comparator trial that will enroll approximately10,000 high risk patients with ACS, including unstable angina (UA),non-ST-segment elevation acute myocardial infarction (NSTEMI) andST-segment elevation acute myocardial infarction (STEMI). Patientswill be randomized to either VYTORIN 10/40 mg or simvastatin 40 mg perday. Patients will be followed for over two years. Clinical trialsites are opening throughout North America and Europe.
About Acute Coronary Syndromes
Acute coronary syndromes are generally caused by the buildup ofatherosclerotic plaque (deposits of fat-containing material) in thecoronary arteries of the heart. These plaques may tear or rupture,leading to the formation of a blood clot which may partly orcompletely block the blood flow in a coronary artery, abruptlylimiting the supply of oxygenated blood to a portion of heart muscle.Patients with unstable angina (UA) often experience chest painoccurring at rest, but testing does not show evidence of heart muscledamage. However, the development of angina is a warning sign that aheart attack may soon occur. NSTEMI, the most common form of heartattack, presents similarly to UA but is accompanied by evidence ofheart muscle damage. In STEMI, complete blockage of a coronary arterycauses more extensive damage to the heart muscle. Treatment of ACSincludes improving blood supply to the heart muscle, preventingfurther clot formation and, importantly, preventing future coronaryevents by slowing or arresting the underlying coronary diseaseprocess. According to the American Heart Association, it is estimatedthat approximately 1.5 million patients are annually admitted for ACSin the United States alone.
Full indications and contraindications for VYTORIN
VYTORIN is indicated as adjunctive therapy to diet for thereduction of elevated total cholesterol, LDL cholesterol, Apo B1,triglycerides and non-HDL cholesterol and to increase HDL cholesterolin patients with primary (heterozygous familial and non-familial)hypercholesterolemia or mixed hyperlipidemia. VYTORIN also isindicated for the reduction of elevated total cholesterol and LDLcholesterol 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 bypeople who are hypersensitive to any of its components. VYTORIN shouldnot be taken by anyone with active liver disease or unexplainedpersistent elevations of serum transaminases. Women who are ofchildbearing age (unless highly unlikely to conceive), are nursing orwho are pregnant should not take VYTORIN.
Selected cautionary information for VYTORIN
Muscle pain, tenderness or weakness in people taking VYTORINshould be reported to a doctor promptly because these could be signsof a serious side effect. VYTORIN should be discontinued if myopathyis diagnosed or suspected. To help avoid serious side effects,patients should talk to their doctor about medicine or food theyshould avoid while taking VYTORIN. In three placebo-controlled,12-week trials, the incidence of consecutive elevations ((Greater Thanor Equal to)3 X ULN) in serum transaminases were 1.7 percent overallfor patients treated with VYTORIN and 2.6 percent for patients treatedwith VYTORIN 10/80 mg. In controlled long-term (48 week) extensions,which included both newly-treated and previously-treated patients, theincidence of consecutive elevations ((Greater Than or Equal to)3 XULN) in serum transaminases was 1.8 percent overall and 3.6 percentfor patients treated with VYTORIN 10/80 mg. These elevations intransaminases were generally asymptomatic, not associated withcholestasis and returned to baseline after discontinuation of therapyor with continued treatment. Doctors should perform blood testsbefore, and periodically during treatment with VYTORIN when clinicallyindicated to check for liver problems. People taking VYTORIN 10/80 mgshould receive an additional liver function test prior to and threemonths after titration and periodically during the first year.
Due to the unknown effects of increased exposure to ezetimibe (aningredient in VYTORIN) in patients with moderate or severe hepaticinsufficiency, VYTORIN is not recommended in these patients. Thesafety and effectiveness of VYTORIN with fibrates have not beenestablished; therefore, co-administration with fibrates is notrecommended. Caution should be exercised when initiating VYTORIN inpatients treated with cyclosporine and in patients with severe renalinsufficiency.
In clinical studies VYTORIN was well tolerated with a lowincidence of adverse events
VYTORIN has been evaluated for safety in more than 3,800 patientsin 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 mostcommonly 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 (2.3percent).
About Merck/Schering-Plough Pharmaceuticals
Merck/Schering-Plough Pharmaceuticals is a joint venture betweenMerck & Co., Inc. and Schering-Plough Corporation formed to developand market in the United States new prescription medicines incholesterol management. The collaboration was expanded to includeworldwide markets (excluding Japan).
Merck Forward-Looking Statement
This press release contains "forward-looking statements" as thatterm is defined in the Private Securities Litigation Reform Act of1995. These statements involve risks and uncertainties, which maycause results to differ materially from those set forth in thestatements. The forward-looking statements may include statementsregarding product development, product potential or financialperformance. No forward-looking statement can be guaranteed, andactual results may differ materially from those projected. Merckundertakes no obligation to publicly update any forward-lookingstatement, whether as a result of new information, future events, orotherwise. Forward-looking statements in this press release should beevaluated together with the many uncertainties that affect Merck'sbusiness, particularly those mentioned in the cautionary statements inItem 1 of our Form 10-K for the year ended Dec. 31, 2004, and in ourperiodic reports on Form 10-Q and Form 8-K, which the companyincorporates by reference.
Schering-Plough Disclosure Notice
This press release contains "forward-looking statements" withinthe meaning of the Securities Litigation Reform Act of 1995, includingabout VYTORIN and the IMPROVE-IT clinical outcomes trial.Forward-looking statements relate to expectations or forecasts offuture events and not to historical information. Schering-Plough doesnot assume the obligation to update any forward-looking statement.There are no guarantees about the market performance of VYTORIN, theresults of the IMPROVE-IT clinical outcomes trial, Schering-Ploughstock or Schering-Plough's business. Actual results may varymaterially from forward-looking statements made here or in otherSchering-Plough written or spoken communications due to many factorsand uncertainties, which include the items discussed inSchering-Plough's Securities and Exchange Commission filings,including the 10-Q filed October 28, 2004.
Full prescribing information and patient product information forVYTORIN(TM) is attached.
(1)Apo B is the protein compound of lipoproteins, LDL and VLDL,which carry cholesterol in the blood.
VYTORIN is a trademark of MSP Singapore Company, LLC. All otherbrands are trademarks of their respective owners and are nottrademarks of MSP Singapore Company, LLC.
VYTORIN(R)(ezetimibe/simvastatin) 9619606
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 intestinalcholesterol and related phytosterol absorption, and simvastatin, a3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
The chemical name of ezetimibe is1-(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 verysoluble in ethanol, methanol, and acetone and practically insoluble inwater. Its structural formula is:
(OBJECT OMITTED)
Simvastatin, an inactive lactone, is hydrolyzed to thecorresponding (beta)-hydroxyacid form, which is an inhibitor ofHMG-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 molecularweight is 418.57.
Simvastatin is a white to off-white, nonhygroscopic, crystallinepowder that is practically insoluble in water, and freely soluble inchloroform, methanol and ethanol. Its structural formula is:
(OBJECT OMITTED)
VYTORIN is available for oral use as tablets containing 10 mg ofezetimibe, and 10 mg of simvastatin (VYTORIN 10/10), 20 mg ofsimvastatin (VYTORIN 10/20), 40 mg of simvastatin (VYTORIN 10/40), or80 mg of simvastatin (VYTORIN 10/80). Each tablet contains thefollowing inactive ingredients: butylated hydroxyanisole NF, citricacid monohydrate USP, croscarmellose sodium NF, hydroxypropylmethylcellulose 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 totalcholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) andapolipoprotein B (Apo B), the major protein constituent of LDL,promote human atherosclerosis. In addition, decreased levels ofhigh-density lipoprotein cholesterol (HDL-C) are associated with thedevelopment of atherosclerosis. Epidemiologic studies have establishedthat cardiovascular morbidity and mortality vary directly with thelevel of total-C and LDL-C and inversely with the level of HDL-C. LikeLDL, cholesterol-enriched triglyceride-rich lipoproteins, includingvery-low-density lipoproteins (VLDL), intermediate-densitylipoproteins (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 hasnot been determined.
Mode of Action
VYTORIN
Plasma cholesterol is derived from intestinal absorption andendogenous synthesis. VYTORIN contains ezetimibe and simvastatin, twolipid-lowering compounds with complementary mechanisms of action.VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, andincreases HDL-C through dual inhibition of cholesterol absorption andsynthesis.
Ezetimibe
Ezetimibe reduces blood cholesterol by inhibiting the absorptionof cholesterol by the small intestine. In a 2-week clinical study in18 hypercholesterolemic patients, ezetimibe inhibited intestinalcholesterol absorption by 54%, compared with placebo. Ezetimibe had noclinically meaningful effect on the plasma concentrations of thefat-soluble vitamins A, D, and E and did not impair adrenocorticalsteroid hormone production.
Ezetimibe localizes and appears to act at the brush border of thesmall intestine and inhibits the absorption of cholesterol, leading toa decrease in the delivery of intestinal cholesterol to the liver.This causes a reduction of hepatic cholesterol stores and an increasein clearance of cholesterol from the blood; this distinct mechanism iscomplementary to that of HMG-CoA reductase inhibitors (see CLINICALSTUDIES).
Simvastatin
Simvastatin reduces cholesterol by inhibiting the conversion ofHMG-CoA to mevalonate, an early step in the biosynthetic pathway forcholesterol. In addition, simvastatin reduces VLDL and TG andincreases HDL-C.
Pharmacokinetics
Absorption
VYTORIN
VYTORIN is bioequivalent to coadministered ezetimibe andsimvastatin.
Ezetimibe
After oral administration, ezetimibe is absorbed and extensivelyconjugated 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 noeffect on the extent of absorption of ezetimibe when administered as10-mg tablets. The Cmax value of ezetimibe was increased by 38% withconsumption of high-fat meals.
Simvastatin
Relative to the fasting state, the plasma profiles of both activeand total inhibitors of HMG-CoA reductase were not affected whensimvastatin was administered immediately before an American HeartAssociation recommended low-fat meal.
Distribution
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) tohuman plasma proteins.
Simvastatin
Both simvastatin and its (beta)-hydroxyacid metabolite are highlybound (approximately 95%) to human plasma proteins. When radiolabeledsimvastatin was administered to rats, simvastatin-derivedradioactivity crossed the blood-brain barrier.
Metabolism and Excretion
Ezetimibe
Ezetimibe is primarily metabolized in the small intestine andliver via glucuronide conjugation with subsequent biliary and renalexcretion. Minimal oxidative metabolism has been observed in allspecies evaluated.
In humans, ezetimibe is rapidly metabolized toezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are themajor drug-derived compounds detected in plasma, constitutingapproximately 10 to 20% and 80 to 90% of the total drug in plasma,respectively. Both ezetimibe and ezetimibe-glucuronide are slowlyeliminated from plasma with a half-life of approximately 22 hours forboth ezetimibe and ezetimibe-glucuronide. Plasma concentration-timeprofiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-ezetimibe (20 mg) to humansubjects, 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 inthe plasma.
Approximately 78% and 11% of the administered radioactivity wererecovered in the feces and urine, respectively, over a 10-daycollection period. Ezetimibe was the major component in feces andaccounted for 69% of the administered dose, whileezetimibe-glucuronide was the major component in urine and accountedfor 9% of the administered dose.
Simvastatin
Simvastatin is a lactone that is readily hydrolyzed in vivo to thecorresponding (beta)-hydroxyacid, a potent inhibitor of HMG-CoAreductase. Inhibition of HMG-CoA reductase is a basis for an assay inpharmacokinetic studies of the (beta)-hydroxyacid metabolites (activeinhibitors) and, following base hydrolysis, active plus latentinhibitors (total inhibitors) in plasma following administration ofsimvastatin. The major active metabolites of simvastatin present inhuman plasma are the (beta)-hydroxyacid of simvastatin and its6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.
Plasma concentrations of total radioactivity (simvastatin plus14C-metabolites) peaked at 4 hours and declined rapidly to about 10%of peak by 12 hours postdose. Since simvastatin undergoes extensivefirst-pass extraction in the liver, the availability of the drug tothe general circulation is low (<5%).
Following an oral dose of 14C-labeled simvastatin in man, 13% ofthe 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 for10 days, plasma concentrations for total ezetimibe were about 2-foldhigher in older ((>=)65 years) healthy subjects compared to youngersubjects.
Simvastatin
In a study including 16 elderly patients between 70 and 78 yearsof age who received simvastatin 40 mg/day, the mean plasma level ofHMG-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 for7 days, the absorption and metabolism of ezetimibe were similar inadolescents (10 to 18 years) and adults. Based on total ezetimibe,there are no pharmacokinetic differences between adolescents andadults. Pharmacokinetic data in the pediatric population <10 years ofage are not available.
Gender
Ezetimibe
In a multiple-dose study with ezetimibe given 10 mg once daily for10 days, plasma concentrations for total ezetimibe were slightlyhigher (<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 andCaucasians. There were too few patients in other racial or ethnicgroups to permit further pharmacokinetic comparisons.
Hepatic Insufficiency
Ezetimibe
After a single 10-mg dose of ezetimibe, the mean exposure (basedon area under the curve (AUC)) to total ezetimibe was increasedapproximately 1.7-fold in patients with mild hepatic insufficiency(Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUCvalues for total ezetimibe and ezetimibe increased approximately 3- to4-fold and 5- to 6-fold, respectively, in patients with moderate(Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pughscore 10 to 15). In a 14-day, multiple-dose study (10 mg daily) inpatients with moderate hepatic insufficiency, the mean AUC for totalezetimibe and ezetimibe increased approximately 4-fold compared tohealthy subjects.
Renal Insufficiency
Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severerenal disease (n=8; mean CrCl (<=)30 mL/min/1.73 m2), the mean AUC fortotal ezetimibe and ezetimibe increased approximately 1.5-fold,compared to healthy subjects (n=9).
Simvastatin
Pharmacokinetic studies with another statin having a similarprincipal route of elimination to that of simvastatin have suggestedthat for a given dose level higher systemic exposure may be achievedin patients with severe renal insufficiency (as measured by creatinineclearance).
Drug Interactions (See also PRECAUTIONS, Drug Interactions)
No clinically significant pharmacokinetic interaction was seenwhen ezetimibe was coadministered with simvastatin. Specificpharmacokinetic drug interaction studies with VYTORIN have not beenperformed.
Cytochrome P450: Ezetimibe had no significant effect on a seriesof probe drugs (caffeine, dextromethorphan, tolbutamide, and IVmidazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9and 3A4) in a "cocktail" study of twelve healthy adult males. Thisindicates that ezetimibe is neither an inhibitor nor an inducer ofthese cytochrome P450 isozymes, and it is unlikely that ezetimibe willaffect the metabolism of drugs that are metabolized by these enzymes.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dosehad no effect on the metabolism of the probe cytochrome P450 isoform3A4 (CYP3A4) substrates midazolam and erythromycin. This indicatesthat simvastatin is not an inhibitor of CYP3A4, and, therefore, is notexpected to affect the plasma levels of other drugs metabolized byCYP3A4.
Although the mechanism is not fully understood, cyclosporine hasbeen shown to increase the AUC of HMG-CoA reductase inhibitors. Theincrease in AUC for simvastatin acid is presumably due, in part, toinhibition of CYP3A4.
Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4can raise the plasma levels of HMG-CoA reductase inhibitory activityand increase the risk of myopathy. (See WARNINGS,Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions.)
Antacids: In a study of twelve healthy adults, a single dose ofantacid (Supralox(TM) 20 mL) administration had no significant effecton the oral bioavailability of total ezetimibe, ezetimibe-glucuronide,or ezetimibe based on AUC values. The Cmax value of total ezetimibewas decreased by 30%.
Cholestyramine: In a study of forty healthy hypercholesterolemic(LDL-C (>=)130 mg/dL) adult subjects, concomitant cholestyramine (4 gtwice daily) administration decreased the mean AUC of total ezetimibeand ezetimibe approximately 55% and 80%, respectively.
Cyclosporine: In a study of eight post-renal transplant patientswith 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 severerenal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) whowas receiving multiple medications, including cyclosporine,demonstrated a 12-fold greater exposure to total ezetimibe compared tohealthy subjects. In a two-period crossover study in twelve healthysubjects, daily administration of 20 mg ezetimibe for 8 days with asingle 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 (seePRECAUTIONS, Drug Interactions).
Fenofibrate: In a study of thirty-two healthy hypercholesterolemic(LDL-C (>=)130 mg/dL) adult subjects, concomitant fenofibrate (200 mgonce daily) administration increased the mean Cmax and AUC values oftotal ezetimibe approximately 64% and 48%, respectively.Pharmacokinetics of fenofibrate were not significantly affected byezetimibe (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) ofeither total HMG-CoA reductase inhibitory activity or fenofibric acid;there was a modest reduction (approximately 35%) of simvastatin acidwhich was not considered clinically significant (see WARNINGS,Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions).
Gemfibrozil: In a study of twelve healthy adult males, concomitantadministration of gemfibrozil (600 mg twice daily) significantlyincreased the oral bioavailability of total ezetimibe by a factor of1.7. Ezetimibe (10 mg once daily) did not significantly affect thebioavailability of gemfibrozil.
Coadministration of gemfibrozil (600 mg twice daily for 3 days)with simvastatin (40 mg daily) resulted in clinically significantincreases in simvastatin acid AUC (185%) and Cmax (112%), possibly dueto inhibition of simvastatin acid glucuronidation by gemfibrozil (seeWARNINGS, Myopathy/Rhabdomyolysis, PRECAUTIONS, Drug Interactions,DOSAGE AND ADMINISTRATION).
Grapefruit Juice: Grapefruit juice contains one or more componentsthat inhibit CYP3A4 and can increase the plasma concentrations ofdrugs metabolized by CYP3A4. In one study(1), 10 subjects consumed200 mL of double-strength grapefruit juice (one can of frozenconcentrate diluted with one rather than 3 cans of water) three timesdaily for 2 days and an additional 200 mL double-strength grapefruitjuice together with, and 30 and 90 minutes following, a single dose of60 mg simvastatin on the third day. This regimen of grapefruit juiceresulted in mean increases in the concentration (as measured by thearea under the concentration-time curve) of active and total HMG-CoAreductase inhibitory activity (measured using a radioenzyme inhibitionassay both before (for active inhibitors) and after (for totalinhibitors) base hydrolysis) of 2.4-fold and 3.6-fold, respectively,and of simvastatin and its (beta)-hydroxyacid metabolite (measuredusing a chemical assay -- liquid chromatography/tandem massspectrometry) of 16-fold and 7-fold, respectively. In a second study,16 subjects consumed one 8 oz glass of single-strength grapefruitjuice (one can of frozen concentrate diluted with 3 cans of water)with breakfast for 3 consecutive days and a single dose of 20 mgsimvastatin in the evening of the third day. This regimen ofgrapefruit juice resulted in a mean increase in the plasmaconcentration (as measured by the area under the concentration-timecurve) of active and total HMG-CoA reductase inhibitory activity(using a validated enzyme inhibition assay different from that used inthe first(1) study, both before (for active inhibitors) and after (fortotal 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 massspectrometry) of 1.88-fold and 1.31-fold, respectively. The effect ofamounts of grapefruit juice between those used in these two studies onsimvastatin pharmacokinetics has not been studied.
ANIMAL PHARMACOLOGY
Ezetimibe
The hypocholesterolemic effect of ezetimibe was evaluated incholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of humancholesterol metabolism. Ezetimibe was found to have an ED50 value of0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol levelsin monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and700 (mu)g/kg/day, respectively. These results are consistent withezetimibe being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe(ezetimibe-glucuronide) was administered intraduodenally, themetabolite was as potent as ezetimibe in inhibiting the absorption ofcholesterol, suggesting that the glucuronide metabolite had activitysimilar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 300mg/kg/day), the concentration of cholesterol in gallbladder bileincreased ~2- to 4-fold. However, a dose of 300 mg/kg/day administeredto dogs for one year did not result in gallstone formation or anyother adverse hepatobiliary effects. In a 14-day study in mice givenezetimibe (0.3 to 5 mg/kg/day) and fed a low-fat or cholesterol-richdiet, the concentration of cholesterol in gallbladder bile was eitherunaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determinethe selectivity of ezetimibe for inhibiting cholesterol absorption.Ezetimibe inhibited the absorption of 14C-cholesterol with no effecton 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 notinduce cytochrome P450 drug metabolizing enzymes. In toxicity studies,a pharmacokinetic interaction of ezetimibe with HMG-CoA reductaseinhibitors (parents or their active hydroxy acid metabolites) was seenin rats, dogs, and rabbits.
CLINICAL STUDIES
Primary Hypercholesterolemia
VYTORIN
VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, andincreases HDL-C in patients with hypercholesterolemia. Maximal to nearmaximal response is generally achieved within 2 weeks and maintainedduring chronic therapy.
VYTORIN is effective in men and women with hypercholesterolemia.Experience in non-Caucasians is limited and does not permit a preciseestimate 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 tentreatment groups: placebo, ezetimibe (10 mg), simvastatin (10 mg, 20mg, 40 mg, or 80 mg), or VYTORIN (10/10, 10/20, 10/40, or 10/80).
When patients receiving VYTORIN were compared to those receivingall doses of simvastatin, VYTORIN significantly lowered total-C,LDL-C, Apo B, TG, and non-HDL-C. The effects of VYTORIN on HDL-C weresimilar to the effects seen with simvastatin. Further analysis showedVYTORIN significantly increased HDL-C compared with placebo. (SeeTable 1.) The lipid response to VYTORIN was similar in patients withTG 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-
HDL-
(Daily Dose) N Total-C LDL-C Apo B HDL-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 reducedtotal-C, LDL-C, Apo B, TG, and non-HDL-C compared to simvastatin, andsignificantly increased HDL-C compared to placebo.
In a multicenter, double-blind, controlled, 23-week study, 710patients with known CHD or CHD risk equivalents, as defined by theNCEP ATP III guidelines, and an LDL-C (>=)130 mg/dL were randomized toone of four treatment groups: coadministered ezetimibe and simvastatinequivalent 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 dosetitrated at 6-week intervals to a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or10/40 were significantly larger than with simvastatin 20 mg (see Table2).
Table 2
Response to VYTORIN after 5 Weeks in Patients with CHD or CHD Risk
Equivalents and an LDL-C (>=)130 mg/dL
Simvastatin VYTORIN VYTORIN VYTORIN
20 mg 10/10 10/20 10/40
----------------------------------------------------------------------
N 253 251 109 97
----------------------------------------------------------------------
Mean baseline LDL-C 174 165 167 171
----------------------------------------------------------------------
Percent change LDL-C -38 -47 -53 -59
----------------------------------------------------------------------
In a multicenter, double-blind, 24-week, forced titration study,788 patients with primary hypercholesterolemia, who had not met theirNCEP ATP III target LDL-C goal, were randomized to receivecoadministered ezetimibe and simvastatin equivalent to VYTORIN (10/10and 10/20) or atorvastatin 10 mg. For all three treatment groups, thedose of the statin was titrated at 6-week intervals to 80 mg. At eachpre-specified dose comparison, VYTORIN lowered LDL-C to a greaterdegree than atorvastatin (see Table 3).
Table 3
Response to VYTORIN and Atorvastatin in
Patients with Primary Hypercholesterolemia
(Mean(a) % Change from Untreated Baseline(b))
Non-
HDL-
Treatment N Total-C LDL-C Apo B HDL-C TG(a) C
----------------------------------------------------------------------
Week 6
----------------------------------------------------------------------
Atorvastatin 10 mg(c) 262 -28 -37 -32 +5 -23 -35
----------------------------------------------------------------------
VYTORIN 10/10(d) 263 -34f -46f -38f +8f -26 -43f
----------------------------------------------------------------------
VYTORIN 10/20e 263 -36f -50f -41f +10f -25 -46f
----------------------------------------------------------------------
Week 12
----------------------------------------------------------------------
Atorvastatin 20 mg 246 -33 -44 -38 +7 -28 -42
----------------------------------------------------------------------
VYTORIN 10/20 250 -37f -50f -41f +9 -28 -46f
----------------------------------------------------------------------
VYTORIN 10/40 252 -39f -54f -45f +12f -31 -50f
----------------------------------------------------------------------
Week 18
----------------------------------------------------------------------
Atorvastatin 40 mg 237 -37 -49 -42 +8 -31 -47
----------------------------------------------------------------------
VYTORIN 10/40g 482 -40f -56f -45f +11f -32 -52f
----------------------------------------------------------------------
Week 24
----------------------------------------------------------------------
Atorvastatin 80 mg 228 -40 -53 -45 +6 -35 -50
----------------------------------------------------------------------
VYTORIN 10/80g 459 -43f -59f -49f +12f -35 -55f
----------------------------------------------------------------------
(a) For triglycerides, median % change from baseline
(b) Baseline - on no lipid-lowering drug
(c) Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and80 mg through Weeks 6, 12, 18, and 24
(d) VYTORIN: 10/10 start dose titrated to 10/20, 10/40, and 10/80through Weeks 6, 12, 18, and 24
(e) VYTORIN: 10/20 start dose titrated to 10/40, 10/40, and 10/80through Weeks 6, 12, 18, and 24
(f) p(<=)0.05 for difference with atorvastatin in the specifiedweek
(g) Data pooled for common doses of VYTORIN at Weeks 18 and 24.
In a multicenter, double-blind, 24-week trial, 214 patients withtype 2 diabetes mellitus treated with thiazolidinediones(rosiglitazone or pioglitazone) for a minimum of 3 months andsimvastatin 20 mg for a minimum of 6 weeks, were randomized to receiveeither simvastatin 40 mg or the coadministered active ingredientsequivalent to VYTORIN 10/20. The median LDL-C and HbA1c levels atbaseline were 89 mg/dL and 7.1%, respectively.
VYTORIN 10/20 was significantly more effective than doubling thedose of simvastatin to 40 mg. The median percent changes from baselinefor 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-Cand TG between the two treatment groups were not significantlydifferent.
Ezetimibe
In two multicenter, double-blind, placebo-controlled, 12-weekstudies in 1719 patients with primary hypercholesterolemia, ezetimibesignificantly lowered total-C (-13%), LDL-C (-19%), Apo B (-14%), andTG (-8%), and increased HDL-C (+3%) compared to placebo. Reduction inLDL-C was consistent across age, sex, and baseline LDL-C.
Simvastatin
In two large, placebo-controlled clinical trials, the ScandinavianSimvastatin Survival Study (N=4,444 patients) and the Heart ProtectionStudy (N=20,536 patients), the effects of treatment with simvastatinwere assessed in patients at high risk of coronary events because ofexisting coronary heart disease, diabetes, peripheral vessel disease,history of stroke or other cerebrovascular disease. Simvastatin wasproven to reduce: the risk of total mortality by reducing CHD deaths;the risk of non-fatal myocardial infarction and stroke; and the needfor coronary and non-coronary revascularization procedures.
No incremental benefit of VYTORIN on cardiovascular morbidity andmortality over and above that demonstrated for simvastatin has beenestablished.
Homozygous Familial Hypercholesterolemia (HoFH)
A double-blind, randomized, 12-week study was performed inpatients with a clinical and/or genotypic diagnosis of HoFH. Data wereanalyzed from a subgroup of patients (n=14) receiving simvastatin 40mg at baseline. Increasing the dose of simvastatin from 40 to 80 mg(n=5) produced a reduction of LDL-C of 13% from baseline onsimvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalentto VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction ofLDL-C of 23% from baseline on simvastatin 40 mg. In those patientscoadministered ezetimibe and simvastatin equivalent to VYTORIN (10/80,n=5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mgwas produced.
INDICATIONS AND USAGE
Primary Hypercholesterolemia
VYTORIN is indicated as adjunctive therapy to diet for thereduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and toincrease HDL-C in patients with primary (heterozygous familial andnon-familial) hypercholesterolemia or mixed hyperlipidemia.
Homozygous Familial Hypercholesterolemia (HoFH)
VYTORIN is indicated for the reduction of elevated total-C andLDL-C in patients with homozygous familial hypercholesterolemia, as anadjunct to other lipid-lowering treatments (e.g., LDL apheresis) or ifsuch treatments are unavailable.
Therapy with lipid-altering agents should be a component ofmultiple risk-factor intervention in individuals at increased risk foratherosclerotic vascular disease due to hypercholesterolemia.Lipid-altering agents should be used in addition to an appropriatediet (including restriction of saturated fat and cholesterol) and whenthe response to diet and other non-pharmacological measures has beeninadequate. (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 Which
LDL Goal Initiate to
Risk Category (mg/dL) Therapeutic Consider Drug
Lifestyle Therapy
Changes(a) (mg/dL)
(mg/dL)
----------------------------------------------------------------------
CHD or CHD risk (greater than=)130
equivalents(b) less than100 (greater (100-129: drug
(10-year risk greater than=)100 optional)(d)
than20%)(c)
----------------------------------------------------------------------
10-year risk 10-
2+ Risk factors(e) 20%: (greater
(10-year risk (less less than130 (greater than=)130c
than=)20%)(c) than=)130 10-year risk less
than10%: (greater
than=)160c
----------------------------------------------------------------------
(greater than=)190
0-1 Risk factor(f) less than160 (greater (160-189: LDL-
than=)160 lowering drug
optional)
----------------------------------------------------------------------
(a) Therapeutic lifestyle changes include: 1) dietary changes:reduced intake of saturated fats (<7% of total calories) andcholesterol (<200 mg per day), and enhancing LDL lowering with plantstanols/sterols (2 g/d) and increased viscous (soluble) fiber (10-25g/d), 2) weight reduction, and 3) increased physical activity.
(b) CHD risk equivalents comprise: diabetes, multiple risk factorsthat confer a 10-year risk for CHD >20%, and other clinical forms ofatherosclerotic disease (peripheral arterial disease, abdominal aorticaneurysm and symptomatic carotid artery disease).
(c) Risk assessment for determining the 10-year risk fordeveloping CHD is carried out using the Framingham risk scoring. Referto 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 thiscategory if an LDL cholesterol <100 mg/dL cannot be achieved bytherapeutic lifestyle changes. Others prefer use of drugs thatprimarily modify triglycerides and HDL, e.g., nicotinic acid orfibrate. Clinical judgment also may call for deferring drug therapy inthis subcategory.
(e) Major risk factors (exclusive of LDL cholesterol) that modifyLDL goals include cigarette smoking, hypertension (BP (>=)140/90 mm Hgor on anti-hypertensive medication), low HDL cholesterol (<40 mg/dL),family history of premature CHD (CHD in male first-degree relative <55years; CHD in female first-degree relative <65 years), age (men (>=)45years; women (>=)55 years). HDL cholesterol (>=)60 mg/dL counts as a"negative" risk factor; its presence removes one risk factor from thetotal 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 isnot necessary.
Prior to initiating therapy with VYTORIN, secondary causes fordyslipidemia (i.e., diabetes, hypothyroidism, obstructive liverdisease, chronic renal failure, and drugs that increase LDL-C anddecrease HDL-C (progestins, anabolic steroids, and corticosteroids)),should be excluded or, if appropriate, treated. A lipid profile shouldbe 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 byultracentrifugation.
At the time of hospitalization for an acute coronary event, lipidmeasures should be taken on admission or within 24 hours. These valuescan guide the physician on initiation of LDL-lowering therapy beforeor at discharge.
CONTRAINDICATIONS
Hypersensitivity to any component of this medication.
Active liver disease or unexplained persistent elevations in serumtransaminases (see WARNINGS, Liver Enzymes).
Pregnancy and lactation. Atherosclerosis is a chronic process andthe discontinuation of lipid-lowering drugs during pregnancy shouldhave little impact on the outcome of long-term therapy of primaryhypercholesterolemia. Moreover, cholesterol and other products of thecholesterol biosynthesis pathway are essential components for fetaldevelopment, including synthesis of steroids and cell membranes.Because of the ability of inhibitors of HMG-CoA reductase such assimvastatin to decrease the synthesis of cholesterol and possiblyother products of the cholesterol biosynthesis pathway, VYTORIN iscontraindicated during pregnancy and in nursing mothers. VYTORINshould be administered to women of childbearing age only when suchpatients are highly unlikely to conceive. If the patient becomespregnant while taking this drug, VYTORIN should be discontinuedimmediately and the patient should be apprised of the potential hazardto the fetus (see PRECAUTIONS, Pregnancy).
WARNINGS
Myopathy/Rhabdomyolysis
In clinical trials, there was no excess of myopathy orrhabdomyolysis associated with ezetimibe compared with the relevantcontrol arm (placebo or HMG-CoA reductase inhibitor alone). However,myopathy and rhabdomyolysis are known adverse reactions to HMG-CoAreductase inhibitors and other lipid-lowering drugs. In clinicaltrials, the incidence of CK >10 X the upper limit of normal (ULN) was0.2% for VYTORIN. (See PRECAUTIONS, Skeletal Muscle.)
Simvastatin, like other inhibitors of HMG-CoA reductase,occasionally causes myopathy manifested as muscle pain, tenderness orweakness with creatine kinase above 10 X ULN. Myopathy sometimes takesthe form of rhabdomyolysis with or without acute renal failuresecondary to myoglobinuria, and rare fatalities have occurred. Therisk of myopathy is increased by high levels of HMG-CoA reductaseinhibitory activity in plasma.
As with other HMG-CoA reductase inhibitors, the risk ofmyopathy/rhabdomyolysis is dose related. In a clinical trial databasein which 41,050 patients were treated with simvastatin with 24,747(approximately 60%) treated for at least 4 years, the incidence ofmyopathy was approximately 0.02%, 0.08% and 0.53% at 20, 40 and 80mg/day, respectively. In these trials, patients were carefullymonitored and some interacting medicinal products were excluded.
All patients starting therapy with VYTORIN or whose dose ofVYTORIN is being increased, should be advised of the risk of myopathyand told to report promptly any unexplained muscle pain, tenderness orweakness. VYTORIN therapy should be discontinued immediately ifmyopathy is diagnosed or suspected. In most cases, muscle symptoms andCK increases resolved when simvastatin treatment was promptlydiscontinued. Periodic CK determinations may be considered in patientsstarting 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 therapywith simvastatin have had complicated medical histories, includingrenal insufficiency usually as a consequence of long-standing diabetesmellitus. Such patients taking VYTORIN merit closer monitoring.Therapy with VYTORIN should be temporarily stopped a few days prior toelective major surgery and when any major medical or surgicalcondition supervenes.
Because VYTORIN contains simvastatin, the risk ofmyopathy/rhabdomyolysis is increased by concomitant use of VYTORINwith the following:
Potent inhibitors of CYP3A4: Simvastatin, like several otherinhibitors 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 canincrease the risk of myopathy and rhabdomyolysis, particularly withhigher doses of simvastatin.
The use of VYTORIN concomitantly with the potent CYP3A4 inhibitorsitraconazole, ketoconazole, erythromycin, clarithromycin,telithromycin, HIV protease inhibitors, nefazodone, or largequantities of grapefruit juice (>1 quart daily) should be avoided.Concomitant use of other medicines labeled as having a potentinhibitory effect on CYP3A4 should be avoided unless the benefits ofcombined therapy outweigh the increased risk. If treatment withitraconazole, ketoconazole, erythromycin, clarithromycin ortelithromycin is unavoidable, therapy with VYTORIN should be suspendedduring the course of treatment.
Other drugs:
Gemfibrozil, particularly with higher doses of VYTORIN, and otherfibrates: The safety and effectiveness of ezetimibe administered withfibrates have not been established. Therefore, the concomitant use ofVYTORIN and fibrates should be avoided.
There is an increased risk of myopathy when simvastatin is usedconcomitantly with fibrates (especially gemfibrozil). The combined useof simvastatin with gemfibrozil should be avoided, unless the benefitsare likely to outweigh the increased risks of this drug combination.The dose of simvastatin should not exceed 10 mg daily in patientsreceiving concomitant medication with gemfibrozil. Therefore, althoughnot recommended, if VYTORIN is used in combination with gemfibrozil,the dose should not exceed 10/10 mg daily. (See PRECAUTIONS, DrugInteractions, Other drug interactions, Fibrates, and DOSAGE ANDADMINISTRATION.)
Niacin ((>=)1 g/day): Caution should be used when prescribinglipid-lowering doses ((>=)1 g/day) of niacin with VYTORIN, as niacincan cause myopathy when given alone. The benefit of furtheralterations in lipid levels by the combined use of VYTORIN with niacinshould be carefully weighed against the potential risks of this drugcombination (see PRECAUTIONS, Drug Interactions, Interactions withlipid-lowering drugs that can cause myopathy when given alone).
Cyclosporine or danazol with higher doses of VYTORIN: The dose ofVYTORIN should not exceed 10/10 mg daily in patients receivingconcomitant medication with cyclosporine or danazol. The benefits ofthe use of VYTORIN in patients receiving cyclosporine or danazolshould be carefully weighed against the risks of these combinations.(See CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, DrugInteractions, Other drug interactions).
Amiodarone or verapamil with higher doses of VYTORIN: The dose ofVYTORIN should not exceed 10/20 mg daily in patients receivingconcomitant medication with amiodarone or verapamil. The combined useof VYTORIN at doses higher than 10/20 mg daily with amiodarone orverapamil should be avoided unless the clinical benefit is likely tooutweigh the increased risk of myopathy. (See PRECAUTIONS, DrugInteractions, Other drug interactions). In an ongoing clinical trial,myopathy has been reported in 6% of patients receiving simvastatin 80mg and amiodarone. In an analysis of clinical trials involving 25,248patients treated with simvastatin 20 to 80 mg, the incidence ofmyopathy was higher in patients receiving verapamil and simvastatin(4/635; 0.63%) than in patients taking simvastatin without a calciumchannel blocker (13/21,224; 0.061%).
Prescribing recommendations for interacting agents are summarizedin 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 VYTORIN
Danazol daily
----------------------------------------------------------------------
Amiodarone Do not exceed 10/20 mg VYTORIN
Verapamil daily
----------------------------------------------------------------------
Grapefruit juice Avoid large quantities of
grapefruit juice (greater than1
quart daily)
----------------------------------------------------------------------
(*) For additional information regarding gemfibrozil, see DOSAGEAND ADMINISTRATION.
Liver Enzymes
In three placebo-controlled, 12-week trials, the incidence ofconsecutive elevations ((>=)3 X ULN) in serum transaminases was 1.7%overall for patients treated with VYTORIN and appeared to bedose-related with an incidence of 2.6% for patients treated withVYTORIN 10/80. In controlled long-term (48-week) extensions, whichincluded both newly-treated and previously-treated patients, theincidence of consecutive elevations ((>=)3 X ULN) in serumtransaminases was 1.8% overall and 3.6% for patients treated withVYTORIN 10/80. These elevations in transaminases were generallyasymptomatic, not associated with cholestasis, and returned tobaseline after discontinuation of therapy or with continued treatment.
It is recommended that liver function tests be performed beforethe initiation of treatment with VYTORIN, and thereafter whenclinically indicated. Patients titrated to the 10/80-mg dose shouldreceive an additional test prior to titration, 3 months aftertitration to the 10/80-mg dose, and periodically thereafter (e.g.,semiannually) for the first year of treatment. Patients who developincreased transaminase levels should be monitored with a second liverfunction evaluation to confirm the finding and be followed thereafterwith frequent liver function tests until the abnormality(ies) returnto normal. Should an increase in AST or ALT of 3 X ULN or greaterpersist, withdrawal of therapy with VYTORIN is recommended.
VYTORIN should be used with caution in patients who consumesubstantial quantities of alcohol and/or have a past history of liverdisease. Active liver diseases or unexplained persistent transaminaseelevations are contraindications to the use of VYTORIN.
PRECAUTIONS
Information for Patients
Patients should be advised about substances they should not takeconcomitantly with VYTORIN and be advised to report promptlyunexplained muscle pain, tenderness, or weakness (see list below andWARNINGS, Myopathy/Rhabdomyolysis). Patients should also be advised toinform other physicians prescribing a new medication that they aretaking VYTORIN.
Skeletal Muscle
In post-marketing experience with ezetimibe, cases of myopathy andrhabdomyolysis have been reported regardless of causality. Mostpatients who developed rhabdomyolysis were taking a statin prior toinitiating ezetimibe. However, rhabdomyolysis has been reported veryrarely with ezetimibe monotherapy and very rarely with the addition ofezetimibe to agents known to be associated with increased risk ofrhabdomyolysis, such as fibrates.
Hepatic Insufficiency
Due to the unknown effects of the increased exposure to ezetimibein patients with moderate or severe hepatic insufficiency, VYTORIN isnot recommended in these patients. (See CLINICAL PHARMACOLOGY,Pharmacokinetics, Special Populations.)
Drug Interactions (See also CLINICAL PHARMACOLOGY, DrugInteractions)
VYTORIN
CYP3A4 Interactions
Potent inhibitors of CYP3A4 (below) increase the risk of myopathyby 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 myopathywhen given alone
See WARNINGS, Myopathy/Rhabdomyolysis.
The risk of myopathy is increased by gemfibrozil and to a lesserextent by other fibrates and niacin (nicotinic acid) ((>=)1 g/day).
Other drug interactions
Danazol: The risk of myopathy/rhabdomyolysis is increased byconcomitant administration of danazol particularly with higher dosesof VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS,Myopathy/Rhabdomyolysis).
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis isincreased by concomitant administration of amiodarone or verapamilwith higher doses of VYTORIN (see WARNINGS, Myopathy/Rhabdomyolysis).
Cholestyramine: Concomitant cholestyramine administrationdecreased the mean AUC of total ezetimibe approximately 55%. Theincremental LDL-C reduction due to adding VYTORIN to cholestyraminemay be reduced by this interaction.
Cyclosporine: The risk of myopathy/rhabdomyolysis is increased byconcomitant administration of cyclosporine particularly with higherdoses of VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics andWARNINGS, Myopathy/Rhabdomyolysis).
Caution should be exercised when using VYTORIN and cyclosporineconcomitantly due to increased exposure to both ezetimibe andcyclosporine (see DOSAGE AND ADMINISTRATION, Patients takingCyclosporine or Danazol). Cyclosporine concentrations should bemonitored in patients receiving VYTORIN and cyclosporine (see CLINICALPHARMACOLOGY, Drug Interactions).
The degree of increase in ezetimibe exposure may be greater inpatients with severe renal insufficiency. In patients treated withcyclosporine, the potential effects of the increased exposure toezetimibe from concomitant use should be carefully weighed against thebenefits of alterations in lipid levels provided by ezetimibe. In apharmacokinetic study in post-renal transplant patients with mildlyimpaired or normal renal function (creatinine clearance of >50mL/min), concomitant cyclosporine administration increased the meanAUC and Cmax of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and3.9-fold (range 3.0- to 4.4-fold), respectively. In a separate study,the total ezetimibe exposure increased 12-fold in one renal transplantpatient with severe renal insufficiency receiving multiplemedications, including cyclosporine. (See CLINICAL PHARMACOLOGY, DrugInteractions and WARNINGS, Myopathy/Rhabdomyolysis.)
Digoxin: Concomitant administration of a single dose of digoxin inhealthy male volunteers receiving simvastatin resulted in a slightelevation (less than 0.3 ng/mL) in plasma digoxin concentrationscompared to concomitant administration of placebo and digoxin.Patients taking digoxin should be monitored appropriately when VYTORINis initiated.
Fibrates: The safety and effectiveness of VYTORIN administeredwith fibrates have not been established.
Fibrates may increase cholesterol excretion into the bile, leadingto cholelithiasis. In a preclinical study in dogs, ezetimibe increasedcholesterol in the gallbladder bile (see ANIMAL PHARMACOLOGY).Coadministration of VYTORIN with fibrates is not recommended until usein patients is studied. (See WARNINGS, Myopathy/Rhabdomyolysis.)
Warfarin: Simvastatin 20-40 mg/day modestly potentiated the effectof coumarin anticoagulants: the prothrombin time, reported asInternational Normalized Ratio (INR), increased from a baseline of 1.7to 1.8 and from 2.6 to 3.4 in a normal volunteer study and in ahypercholesterolemic patient study, respectively. With other statins,clinically evident bleeding and/or increased prothrombin time has beenreported in a few patients taking coumarin anticoagulantsconcomitantly. In such patients, prothrombin time should be determinedbefore starting VYTORIN and frequently enough during early therapy toensure that no significant alteration of prothrombin time occurs. Oncea stable prothrombin time has been documented, prothrombin times canbe monitored at the intervals usually recommended for patients oncoumarin anticoagulants. If the dose of VYTORIN is changed ordiscontinued, the same procedure should be repeated. Simvastatintherapy has not been associated with bleeding or with changes inprothrombin time in patients not taking anticoagulants.
Concomitant administration of ezetimibe (10 mg once daily) had nosignificant effect on bioavailability of warfarin and prothrombin timein a study of twelve healthy adult males. There have beenpost-marketing reports of increased International Normalized Ratio(INR) in patients who had ezetimibe added to warfarin. Most of thesepatients were also on other medications.
The effect of VYTORIN on the prothrombin time has not beenstudied.
Ezetimibe
Fenofibrate: In a pharmacokinetic study, concomitant fenofibrateadministration increased total ezetimibe concentrations approximately1.5-fold.
Gemfibrozil: In a pharmacokinetic study, concomitant gemfibroziladministration increased total ezetimibe concentrations approximately1.7-fold.
Simvastatin
Propranolol: In healthy male volunteers there was a significantdecrease in mean Cmax, but no change in AUC, for simvastatin total andactive inhibitors with concomitant administration of single doses ofsimvastatin and propranolol. The clinical relevance of this finding isunclear. The pharmacokinetics of the enantiomers of propranolol werenot affected.
CNS Toxicity
Optic nerve degeneration was seen in clinically normal dogstreated with simvastatin for 14 weeks at 180 mg/kg/day, a dose thatproduced mean plasma drug levels about 12 times higher than the meanplasma drug level in humans taking 80 mg/day.
A chemically similar drug in this class also produced optic nervedegeneration (Wallerian degeneration of retinogeniculate fibers) inclinically normal dogs in a dose-dependent fashion starting at 60mg/kg/day, a dose that produced mean plasma drug levels about 30 timeshigher than the mean plasma drug level in humans taking the highestrecommended dose (as measured by total enzyme inhibitory activity).This same drug also produced vestibulocochlear Wallerian-likedegeneration and retinal ganglion cell chromatolysis in dogs treatedfor 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasmadrug level similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage andedema, mononuclear cell infiltration of perivascular spaces,perivascular fibrin deposits and necrosis of small vessels were seenin dogs treated with simvastatin at a dose of 360 mg/kg/day, a dosethat produced mean plasma drug levels that were about 14 times higherthan the mean plasma drug levels in humans taking 80 mg/day. SimilarCNS vascular lesions have been observed with several other drugs ofthis class.
There were cataracts in female rats after two years of treatmentwith 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day,respectively) and in dogs after three months at 90 mg/kg/day (19times) and at two years at 50 mg/kg/day (5 times).
Carcinogenesis, Mutagenesis, Impairment of Fertility
VYTORIN
No animal carcinogenicity or fertility studies have been conductedwith the combination of ezetimibe and simvastatin. The combination ofezetimibe with simvastatin did not show evidence of mutagenicity invitro in a microbial mutagenicity (Ames) test with Salmonellatyphimurium and Escherichia coli with or without metabolic activation.No evidence of clastogenicity was observed in vitro in a chromosomalaberration assay in human peripheral blood lymphocytes with ezetimibeand simvastatin with or without metabolic activation. There was noevidence of genotoxicity at doses up to 600 mg/kg with the combinationof ezetimibe and simvastatin (1:1) in the in vivo mouse micronucleustest.
Ezetimibe
A 104-week dietary carcinogenicity study with ezetimibe wasconducted in rats at doses up to 1500 mg/kg/day (males) and 500mg/kg/day (females) (~20 times the human exposure at 10 mg daily basedon AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicitystudy with ezetimibe was also conducted in mice at doses up to 500mg/kg/day (>150 times the human exposure at 10 mg daily based onAUC0-24hr for total ezetimibe). There were no statisticallysignificant increases in tumor incidences in drug-treated rats ormice.
No evidence of mutagenicity was observed in vitro in a microbialmutagenicity (Ames) test with Salmonella typhimurium and Escherichiacoli with or without metabolic activation. No evidence ofclastogenicity was observed in vitro in a chromosomal aberration assayin human peripheral blood lymphocytes with or without metabolicactivation. In addition, there was no evidence of genotoxicity in thein vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats,there was no evidence of reproductive toxicity at doses up to 1000mg/kg/day in male or female rats (~7 times the human exposure at 10 mgdaily based on AUC0-24hr for total ezetimibe).
Simvastatin
In a 72-week carcinogenicity study, mice were administered dailydoses of simvastatin of 25, 100, and 400 mg/kg body weight, whichresulted in mean plasma drug levels approximately 1, 4, and 8 timeshigher than the mean human plasma drug level, respectively (as totalinhibitory activity based on AUC) after an 80-mg oral dose. Livercarcinomas were significantly increased in high-dose females and mid-and high-dose males with a maximum incidence of 90% in males. Theincidence of adenomas of the liver was significantly increased in mid-and high-dose females. Drug treatment also significantly increased theincidence of lung adenomas in mid- and high-dose males and females.Adenomas of the Harderian gland (a gland of the eye of rodents) weresignificantly higher in high-dose mice than in controls. No evidenceof a tumorigenic effect was observed at 25 mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to25 mg/kg/day, no evidence of a tumorigenic effect was observed (meanplasma drug levels were 1 times higher than humans given 80 mgsimvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was astatistically significant increase in the incidence of thyroidfollicular adenomas in female rats exposed to approximately 11 timeshigher levels of simvastatin than in humans given 80 mg simvastatin(as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and100 mg/kg/day produced hepatocellular adenomas and carcinomas (infemale rats at both doses and in males at 100 mg/kg/day). Thyroidfollicular cell adenomas were increased in males and females at bothdoses; thyroid follicular cell carcinomas were increased in females at100 mg/kg/day. The increased incidence of thyroid neoplasms appears tobe consistent with findings from other HMG-CoA reductase inhibitors.These treatment levels represented plasma drug levels (AUC) ofapproximately 7 and 15 times (males) and 22 and 25 times (females) themean human plasma drug exposure after an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbialmutagenicity (Ames) test with or without rat or mouse liver metabolicactivation. In addition, no evidence of damage to genetic material wasnoted in an in vitro alkaline elution assay using rat hepatocytes, aV-79 mammalian cell forward mutation study, an in vitro chromosomeaberration study in CHO cells, or an in vivo chromosomal aberrationassay in mouse bone marrow.
There was decreased fertility in male rats treated withsimvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximumhuman exposure level, based on AUC, in patients receiving 80 mg/day);however, this effect was not observed during a subsequent fertilitystudy in which simvastatin was administered at this same dose level tomale rats for 11 weeks (the entire cycle of spermatogenesis includingepididymal maturation). No microscopic changes were observed in thetestes of rats from either study. At 180 mg/kg/day, (which producesexposure levels 22 times higher than those in humans taking 80 mg/daybased on surface area, mg/m2), seminiferous tubule degeneration(necrosis and loss of spermatogenic epithelium) was observed. In dogs,there was drug-related testicular atrophy, decreased spermatogenesis,spermatocytic degeneration and giant cell formation at 10 mg/kg/day,(approximately 2 times the human exposure, based on AUC, at 80mg/day). The clinical significance of these findings is unclear.
Pregnancy
Pregnancy Category: X
See CONTRAINDICATIONS.
VYTORIN
As safety in pregnant women has not been established, treatmentshould be immediately discontinued as soon as pregnancy is recognized.VYTORIN should be administered to women of child-bearing potentialonly when such patients are highly unlikely to conceive and have beeninformed of the potential hazards.
Ezetimibe
In oral (gavage) embryo-fetal development studies of ezetimibeconducted in rats and rabbits during organogenesis, there was noevidence of embryolethal effects at the doses tested (250, 500, 1000mg/kg/day). In rats, increased incidences of common fetal skeletalfindings (extra pair of thoracic ribs, unossified cervical vertebralcentra, shortened ribs) were observed at 1000 mg/kg/day (~10 times thehuman exposure at 10 mg daily based on AUC0-24hr for total ezetimibe).In rabbits treated with ezetimibe, an increased incidence of extrathoracic ribs was observed at 1000 mg/kg/day (150 times the humanexposure at 10 mg daily based on AUC0-24hr for total ezetimibe).Ezetimibe crossed the placenta when pregnant rats and rabbits weregiven multiple oral doses.
Multiple-dose studies of ezetimibe coadministered with HMG-CoAreductase inhibitors (statins) in rats and rabbits duringorganogenesis result in higher ezetimibe and statin exposures.Reproductive findings occur at lower doses in coadministration therapycompared to monotherapy.
Simvastatin
Simvastatin was not teratogenic in rats at doses of 25 mg/kg/dayor in rabbits at doses up to 10 mg/kg daily. These doses resulted in 3times (rat) or 3 times (rabbit) the human exposure based on mg/m2surface area. However, in studies with another structurally-relatedHMG-CoA reductase inhibitor, skeletal malformations were observed inrats and mice.
Rare reports of congenital anomalies have been received followingintrauterine exposure to HMG-CoA reductase inhibitors. In a review(2)of approximately 100 prospectively followed pregnancies in womenexposed to simvastatin or another structurally related HMG-CoAreductase inhibitor, the incidences of congenital anomalies,spontaneous abortions and fetal deaths/stillbirths did not exceed whatwould be expected in the general population. The number of cases isadequate only to exclude a 3- to 4-fold increase in congenitalanomalies over the background incidence. In 89% of the prospectivelyfollowed pregnancies, drug treatment was initiated prior to pregnancyand was discontinued at some point in the first trimester whenpregnancy was identified.
Labor and Delivery
The effects of VYTORIN on labor and delivery in pregnant women areunknown.
Nursing Mothers
In rat studies, exposure to ezetimibe in nursing pups was up tohalf of that observed in maternal plasma. It is not known whetherezetimibe or simvastatin are excreted into human breast milk. Becausea small amount of another drug in the same class as simvastatin isexcreted in human milk and because of the potential for seriousadverse reactions in nursing infants, women who are nursing should nottake VYTORIN (see CONTRAINDICATIONS).
Pediatric Use
VYTORIN
There are insufficient data for the safe and effective use ofVYTORIN in pediatric patients. (See Ezetimibe and Simvastatin below.)
Ezetimibe
The pharmacokinetics of ezetimibe in adolescents (10 to 18 years)have been shown to be similar to that in adults. Treatment experiencewith ezetimibe in the pediatric population is limited to 4 patients (9to 17 years) with homozygous sitosterolemia and 5 patients (11 to 17years) with HoFH. Treatment with ezetimibe in children (<10 years) isnot recommended.
Simvastatin
Safety and effectiveness of simvastatin in patients 10-17 years ofage with heterozygous familial hypercholesterolemia have beenevaluated in a controlled clinical trial in adolescent boys and ingirls who were at least 1 year post-menarche. Patients treated withsimvastatin had an adverse experience profile generally similar tothat of patients treated with placebo. Doses greater than 40 mg havenot been studied in this population. In this limited controlled study,there was no detectable effect on growth or sexual maturation in theadolescent boys or girls, or any effect on menstrual cycle length ingirls. Adolescent females should be counseled on appropriatecontraceptive methods while on therapy with simvastatin (seeCONTRAINDICATIONS and PRECAUTIONS, Pregnancy). Simvastatin has notbeen studied in patients younger than 10 years of age, nor inpre-menarchal girls.
Geriatric Use
Of the patients who received VYTORIN in clinical studies, 792 were65 and older (this included 176 who were 75 and older). The safety ofVYTORIN was similar between these patients and younger patients.Greater sensitivity of some older individuals cannot be ruled out.(See CLINICAL PHARMACOLOGY, Special Populations and ADVERSEREACTIONS.)
ADVERSE REACTIONS
VYTORIN has been evaluated for safety in more than 3800 patientsin clinical trials. VYTORIN was generally well tolerated.
Table 6 summarizes the frequency of clinical adverse experiencesreported in (>=)2% of patients treated with VYTORIN (n=1236) and at anincidence greater than placebo regardless of causality assessment fromthree similarly designed, placebo-controlled trials.
Table 6*
Clinical Adverse Events Occurring in (greater than=)2% of Patients
Treated with VYTORIN and at an Incidence Greater than Placebo,
Regardless of Causality
----------------------------------------------------------------------
Body System/Organ Class Placebo Ezetimibe Simvastatin** VYTORIN**
10 mg
Adverse Event (%) (%) (%) (%)
n=311 n=302 n=1234 n=1236
----------------------------------------------------------------------
Body as a whole - general
disorders
Headache 6.4 6.0 5.9 6.8
Infection and infestations
Influenza 1.0 1.0 1.9 2.6
Upper respiratory
tract infection 2.6 5.0 5.0 3.9
Musculoskeletal and
connective tissue
disorders
Myalgia 2.9 2.3 2.6 3.5
Pain in extremity 1.3 3.0 2.0 2.3
----------------------------------------------------------------------
*Includes two placebo-controlled combination studies in which theactive ingredients equivalent to VYTORIN were coadministered and oneplacebo-controlled study in which VYTORIN was administered.
**All doses.
Post-marketing Experience
The adverse reactions reported for VYTORIN are consistent withthose previously reported with ezetimibe and/or simvastatin.
Ezetimibe
Other adverse experiences reported with ezetimibe inplacebo-controlled studies, regardless of causality assessment: Bodyas a whole - general disorders: fatigue; Gastrointestinal systemdisorders: abdominal pain, diarrhea; Infection and infestations:infection viral, pharyngitis, sinusitis; Musculoskeletal systemdisorders: arthralgia, back pain; Respiratory system disorders:coughing.
Post-marketing Experience
The following adverse reactions have been reported inpost-marketing experience, regardless of causality assessment:
Hypersensitivity reactions, including angioedema, rash, andurticaria; arthralgia; elevations in liver transaminases; hepatitis;thrombocytopenia; pancreatitis; nausea; cholelithiasis; cholecystitis;elevated creatine phosphokinase; and, very rarely,myopathy/rhabdomyolysis (see WARNINGS, Myopathy/Rhabdomyolysis).
Simvastatin
Other adverse experiences reported with simvastatin inplacebo-controlled clinical studies, regardless of causalityassessment: Body as a whole - general disorders: asthenia; Eyedisorders: cataract; Gastrointestinal system disorders: abdominalpain, constipation, diarrhea, dyspepsia, flatulence, nausea; Skin andsubcutaneous tissue disorders: eczema, pruritus, rash.
The following effects have been reported with other HMG-CoAreductase inhibitors. Not all the effects listed below havenecessarily been associated with simvastatin therapy.
Musculoskeletal system disorders: muscle cramps, myalgia,myopathy, rhabdomyolysis, arthralgias.
Nervous system disorders: dysfunction of certain cranial nerves(including alteration of taste, impairment of extra-ocular movement,facial paresis), tremor, dizziness, memory loss, paresthesia,peripheral neuropathy, peripheral nerve palsy, psychic disturbances.
Ear and labyrinth disorders: vertigo.
Psychiatric disorders: anxiety, insomnia, depression, loss oflibido.
Hypersensitivity Reactions: An apparent hypersensitivity syndromehas been reported rarely which has included one or more of thefollowing features: anaphylaxis, angioedema, lupus erythematous-likesyndrome, polymyalgia rheumatica, dermatomyositis, vasculitis,purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA,ESR increase, eosinophilia, arthritis, arthralgia, urticaria,asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea,toxic epidermal necrolysis, erythema multiforme, includingStevens-Johnson syndrome.
Gastrointestinal system disorders: pancreatitis, vomiting.
Hepatobiliary disorders: hepatitis, including chronic activehepatitis, cholestatic jaundice, fatty change in liver, and, rarely,cirrhosis, fulminant hepatic necrosis, and hepatoma.
Metabolism and nutrition disorders: anorexia.
Skin and subcutaneous tissue disorders: alopecia, pruritus. Avariety of skin changes (e.g., nodules, discoloration, dryness ofskin/mucous membranes, changes to hair/nails) have been reported.
Reproductive system and breast disorders: gynecomastia, erectiledysfunction.
Eye disorders: progression of cataracts (lens opacities),ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkalinephosphatase, (gamma)-glutamyl transpeptidase, and bilirubin; thyroidfunction abnormalities.
Laboratory Tests
Marked persistent increases of serum transaminases have been noted(see WARNINGS, Liver Enzymes). About 5% of patients taking simvastatinhad elevations of CK levels of 3 or more times the normal value on oneor more occasions. This was attributable to the noncardiac fraction ofCK. Muscle pain or dysfunction usually was not reported (see WARNINGS,Myopathy/Rhabdomyolysis).
Concomitant Lipid-Lowering Therapy
In controlled clinical studies in which simvastatin wasadministered concomitantly with cholestyramine, no adverse reactionspeculiar to this concomitant treatment were observed. The adversereactions that occurred were limited to those reported previously withsimvastatin or cholestyramine.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys and girls whowere at least 1 year post-menarche, 10-17 years of age withheterozygous familial hypercholesterolemia (n=175), the safety andtolerability profile of the group treated with simvastatin (10-40 mgdaily) was generally similar to that of the group treated withplacebo, with the most common adverse experiences observed in bothgroups being upper respiratory infection, headache, abdominal pain,and nausea (see CLINICAL PHARMACOLOGY, Special Populations andPRECAUTIONS, Pediatric Use).
OVERDOSAGE
VYTORIN
No specific treatment of overdosage with VYTORIN can berecommended. In the event of an overdose, symptomatic and supportivemeasures should be employed.
Ezetimibe
In clinical studies, administration of ezetimibe, 50 mg/day to 15healthy subjects for up to 14 days, or 40 mg/day to 18 patients withprimary hypercholesterolemia for up to 56 days, was generally welltolerated.
A few cases of overdosage have been reported; most have not beenassociated with adverse experiences. Reported adverse experiences havenot been serious.
Simvastatin
A few cases of overdosage with simvastatin have been reported; themaximum dose taken was 3.6 g. All patients recovered without sequelae.
The dialyzability of simvastatin and its metabolites in man is notknown at present.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-loweringdiet before receiving VYTORIN and should continue on this diet duringtreatment with VYTORIN. The dosage should be individualized accordingto the baseline LDL-C level, the recommended goal of therapy, and thepatient's response. (See NCEP Adult Treatment Panel (ATP) IIIGuidelines, summarized in Table 4.) VYTORIN should be taken as asingle daily dose in the evening, with or without food.
The dosage range is 10/10 mg/day through 10/80 mg/day. Therecommended usual starting dose is 10/20 mg/day. Initiation of therapywith 10/10 mg/day may be considered for patients requiring lessaggressive LDL-C reductions. Patients who require a larger reductionin LDL-C (greater than 55%) may be started at 10/40 mg/day. Afterinitiation or titration of VYTORIN, lipid levels may be analyzed after2 or more weeks and dosage adjusted, if needed. See below for dosagerecommendations for patients receiving certain concomitant therapiesand for those with renal insufficiency.
Patients with Homozygous Familial Hypercholesterolemia
The recommended dosage for patients with homozygous familialhypercholesterolemia is VYTORIN 10/40 mg/day or 10/80 mg/day in theevening. VYTORIN should be used as an adjunct to other lipid-loweringtreatments (e.g., LDL apheresis) in these patients or if suchtreatments are unavailable.
Patients with Hepatic Insufficiency
No dosage adjustment is necessary in patients with mild hepaticinsufficiency (see PRECAUTIONS, Hepatic Insufficiency).
Patients with Renal Insufficiency
No dosage adjustment is necessary in patients with mild ormoderate renal insufficiency. However, for patients with severe renalinsufficiency, VYTORIN should not be started unless the patient hasalready tolerated treatment with simvastatin at a dose of 5 mg orhigher. Caution should be exercised when VYTORIN is administered tothese patients and they should be closely monitored (see CLINICALPHARMACOLOGY, Pharmacokinetics and WARNINGS, Myopathy/Rhabdomyolysis).
Geriatric Patients
No dosage adjustment is necessary in geriatric patients (seeCLINICAL PHARMACOLOGY, Special Populations).
Coadministration with Bile Acid Sequestrants
Dosing of VYTORIN should occur either (>=)2 hours before or (>=)4hours after administration of a bile acid sequestrant (seePRECAUTIONS, Drug Interactions).
Patients taking Cyclosporine or Danazol
Caution should be exercised when initiating VYTORIN in the settingof cyclosporine. In patients taking cyclosporine or danazol, VYTORINshould not be started unless the patient has already toleratedtreatment with simvastatin at a dose of 5 mg or higher. The dose ofVYTORIN should not exceed 10/10 mg/day.
Patients taking Amiodarone or Verapamil
In patients taking amiodarone or verapamil concomitantly withVYTORIN, the dose should not exceed 10/20 mg/day (see WARNINGS,Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions, Other druginteractions).
Patients taking other Concomitant Lipid-Lowering Therapy
The safety and effectiveness of ezetimibe administered withfibrates have not been established. Therefore, the combination ofVYTORIN and fibrates should be avoided (see WARNINGS,Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions, Otherdrug interactions).
There is an increased risk of myopathy when simvastatin is usedconcomitantly with fibrates (especially gemfibrozil). Therefore,although not recommended, if VYTORIN is used in combination withgemfibrozil, the dose should not exceed 10/10 mg daily (see WARNINGS,Myopathy/Rhabdomyolysis, and PRECAUTIONS, Drug Interactions, Otherdrug interactions).
HOW SUPPLIED
No. 3873 -- Tablets VYTORIN 10/10 are white to off-whitecapsule-shaped tablets with code "311" on one side.
They are supplied as follows:
NDC 66582-311-31 bottles of 30
NDC 66582-311-54 bottles of 90
NDC 66582-311-82 bottles of 1000 (If repackaged in blisters, thenopaque or light-resistant blisters should be used.)
NDC 66582-311-87 bottles of 10,000 (If repackaged in blisters,then opaque or light-resistant blisters should be used.)
NDC 66582-311-28 unit dose packages of 100.
No. 3874 -- Tablets VYTORIN 10/20 are white to off-whitecapsule-shaped tablets with code "312" on one side.
They are supplied as follows:
NDC 66582-312-31 bottles of 30
NDC 66582-312-54 bottles of 90
NDC 66582-312-82 bottles of 1000 (If repackaged in blisters, thenopaque or light-resistant blisters should be used.)
NDC 66582-312-87 bottles of 10,000 (If repackaged in blisters,then opaque or light-resistant blisters should be used.)
NDC 66582-312-28 unit dose packages of 100.
No. 3875 -- Tablets VYTORIN 10/40 are white to off-whitecapsule-shaped tablets with code "313" on one side.
They are supplied as follows:
NDC 66582-313-31 bottles of 30
NDC 66582-313-54 bottles of 90
NDC 66582-313-74 bottles of 500 (If repackaged in blisters, thenopaque or light-resistant blisters should be used.)
NDC 66582-313-52 unit dose packages of 50.
No. 3876 -- Tablets VYTORIN 10/80 are white to off-whitecapsule-shaped tablets with code "315" on one side.
They are supplied as follows:
NDC 66582-315-31 bottles of 30
NDC 66582-315-54 bottles of 90
NDC 66582-315-74 bottles of 500 (If repackaged in blisters, thenopaque or light-resistant blisters should be used.)
NDC 66582-315-52 unit dose packages of 50.
Storage
Store at 20-25(degree)C (68-77(degree)F). (See USP Controlled RoomTemperature.) Keep container tightly closed.
Storage of 10,000 count bottles
Store bottle of 10,000 VYTORIN 10/10 and 10/20 capsule-shapedtablets at 20-25(degree)C (68-77(degree)F). (See USP Controlled RoomTemperature.) Store in original container until time of use. Whenproduct container is subdivided, repackage into a tightly-closed,light-resistant container. Entire contents must be repackagedimmediately upon opening.
Issued September 2005
Printed in USA
Manufactured for:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Or
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia
Italy
(1) Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther1998;64(5):477-83.
(2) Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson,W.P., Postmarketing Surveillance of Lovastatin and SimvastatinExposure During Pregnancy, Reproductive Toxicology, 10(6):439-446,1996.
9621003
VYTORIN(R) (ezetimibe/simvastatin) Tablets
Patient Information about VYTORIN (VI-tor-in)
Generic name: ezetimibe/simvastatin tablets
Read this information carefully before you start taking VYTORIN.Review this information each time you refill your prescription forVYTORIN as there may be new information. This information does nottake the place of talking with your doctor about your medicalcondition or your treatment. If you have any questions about VYTORIN,ask your doctor. Only your doctor can determine if VYTORIN is rightfor you.
What is VYTORIN?
VYTORIN contains two cholesterol-lowering medications, ezetimibeand simvastatin, available as a tablet in four strengths:
-- VYTORIN 10/10 (ezetimibe 10 mg/simvastatin 10 mg)
-- VYTORIN 10/20 (ezetimibe 10 mg/simvastatin 20 mg)
-- VYTORIN 10/40 (ezetimibe 10 mg/simvastatin 40 mg)
-- VYTORIN 10/80 (ezetimibe 10 mg/simvastatin 80 mg)
VYTORIN is a medicine used to lower levels of total cholesterol,LDL (bad) cholesterol, and fatty substances called triglycerides inthe blood. In addition, VYTORIN raises levels of HDL (good)cholesterol. It is used for patients who cannot control theircholesterol levels by diet alone. You should stay on acholesterol-lowering diet while taking this medicine.
VYTORIN works to reduce your cholesterol in two ways. It reducesthe cholesterol absorbed in your digestive tract, as well as thecholesterol your body makes by itself. VYTORIN does not help you loseweight.
For more information about cholesterol, see the section called"What should I know about high cholesterol?"
Who should not take VYTORIN?
Do not take VYTORIN:
-- If you are allergic to ezetimibe or simvastatin, the active ingredients in VYTORIN, or to the inactive ingredients. For a list of inactive ingredients, see the "Inactive ingredients" section at the end of this information sheet.
-- If you have active liver disease or repeated blood tests indicating possible liver problems.
-- If you are pregnant, or think you may be pregnant, or planning to become pregnant or breast-feeding.
VYTORIN is not recommended for use in children under 10 years ofage.
What should I tell my doctor before and while taking VYTORIN?
Tell your doctor right away if you experience unexplained musclepain, tenderness, or weakness. This is because on rare occasions,muscle problems can be serious, including muscle breakdown resultingin kidney damage.
The risk of muscle breakdown is greater at higher doses ofVYTORIN.
The risk of muscle breakdown is greater in patients with kidneyproblems.
Taking VYTORIN with certain substances can increase the risk ofmuscle problems. It is particularly important to tell your doctor ifyou are taking any of the following:
-- cyclosporine
-- danazol
-- antifungal agents (such as itraconazole or ketoconazole)
-- fibric acid derivatives (such as gemfibrozil, bezafibrate, or fenofibrate)
-- the antibiotics erythromycin, clarithromycin, and telithromycin
-- HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and saquinavir)
-- the antidepressant nefazodone
-- amiodarone (a drug used to treat an irregular heartbeat)
-- verapamil (a drug used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions)
-- large doses ((>=)1 g/day) of niacin or nicotinic acid
-- large quantities of grapefruit juice (>1 quart daily)
It is also important to tell your doctor if you are takingcoumarin anticoagulants (drugs that prevent blood clots, such aswarfarin).
Tell your doctor about any prescription and nonprescriptionmedicines you are taking or plan to take, including natural or herbalremedies.
Tell your doctor about all your medical conditions includingallergies.
Tell your doctor if you:
-- drink substantial quantities of alcohol or ever had liver problems. VYTORIN may not be right for you.
-- are pregnant or plan to become pregnant. Do not use VYTORIN if you are pregnant, trying to become pregnant or suspect that you are pregnant. If you become pregnant while taking VYTORIN, stop taking it and contact your doctor immediately.
-- are breast-feeding. Do not use VYTORIN if you are breast-feeding.
Tell other doctors prescribing a new medication that you aretaking VYTORIN.
How should I take VYTORIN?
Your doctor has prescribed your dose of VYTORIN. The availabledoses of VYTORIN are 10/10, 10/20, 10/40, and 10/80. The usual dailystarting dose is VYTORIN 10/20.
-- Take VYTORIN once a day, in the evening, with or without food.
-- Try to take VYTORIN as prescribed. If you miss a dose, do not take an extra dose. Just resume your usual schedule.
-- Continue to follow a cholesterol-lowering diet while taking VYTORIN. Ask your doctor if you need diet information.
-- Keep taking VYTORIN unless your doctor tells you to stop. If you stop taking VYTORIN, your cholesterol may rise again.
What should I do in case of an overdose?
Contact your doctor immediately.
What are the possible side effects of VYTORIN?
See your doctor regularly to check your cholesterol level and tocheck for side effects. Your doctor may do blood tests to check yourliver before you start taking VYTORIN and during treatment.
In clinical studies patients reported the following common sideeffects while taking VYTORIN: headache and muscle pain (see Whatshould I tell my doctor before and while taking VYTORIN?).
The following side effects have been reported in general use witheither ezetimibe or simvastatin tablets (tablets that contain theactive ingredients of VYTORIN):
-- allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing (which may require treatment right away), rash, hives; joint pain; alterations in some laboratory blood tests; liver problems; inflammation of the pancreas; nausea; gallstones; inflammation of the gallbladder.
Tell your doctor if you are having these or any other medicalproblems while on VYTORIN. This is not a complete list of sideeffects. For a complete list, ask your doctor or pharmacist.
What should I know about high cholesterol?
Cholesterol is a type of fat found in your blood. Cholesterolcomes from two sources. It is produced by your body and it comes fromthe food you eat. Your total cholesterol is made up of both LDL andHDL cholesterol.
LDL cholesterol is called "bad" cholesterol because it can buildup in the wall of your arteries and form plaque. Over time, plaquebuild-up can cause a narrowing of the arteries. This narrowing canslow or block blood flow to your heart, brain, and other organs. HighLDL cholesterol is a major cause of heart disease and stroke.
HDL cholesterol is called "good" cholesterol because it keeps thebad cholesterol from building up in the arteries.
Triglycerides also are fats found in your body.
General Information about VYTORIN
Medicines are sometimes prescribed for conditions that are notmentioned in patient information leaflets. Do not use VYTORIN for acondition for which it was not prescribed. Do not give VYTORIN toother people, even if they have the same condition you have. It mayharm them.
This summarizes the most important information about VYTORIN. Ifyou would like more information, talk with your doctor. You can askyour pharmacist or doctor for information about VYTORIN that iswritten for health professionals. For additional information, visitthe following web site: vytorin.com.
Inactive ingredients:
Butylated hydroxyanisole NF, citric acid monohydrate USP,croscarmellose sodium NF, hydroxypropyl methylcellulose USP, lactosemonohydrate NF, magnesium stearate NF, microcrystalline cellulose NF,and propyl gallate NF.
Issued June 2005
Manufactured for:
Merck/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
Singapore 637766
Or
Merck Sharp & Dohme (Italia) S.p.A.
Via Emilia, 21
27100 - Pavia
Italy
Der finanzen.at Ratgeber für Aktien!
Wenn Sie mehr über das Thema Aktien erfahren wollen, finden Sie in unserem Ratgeber viele interessante Artikel dazu!
Jetzt informieren!
Nachrichten zu Merck Co.mehr Nachrichten
|
08.01.25 |
Schwacher Handel in New York: Dow Jones verbucht Abschläge (finanzen.at) | |
|
08.01.25 |
Dow Jones-Handel aktuell: Dow Jones verbucht Gewinne (finanzen.at) | |
|
08.01.25 |
Schwacher Handel in New York: Dow Jones beginnt die Mittwochssitzung im Minus (finanzen.at) | |
|
07.01.25 |
Börse New York: Dow Jones legt zum Handelsende den Rückwärtsgang ein (finanzen.at) | |
|
07.01.25 |
Dow Jones-Handel aktuell: Dow Jones verbucht Verluste (finanzen.at) | |
|
07.01.25 |
Dow Jones-Handel aktuell: Dow Jones mit Abgaben (finanzen.at) | |
|
07.01.25 |
Dow Jones 30 Industrial-Titel Merck-Aktie: So viel Gewinn hätte ein Investment in Merck von vor 5 Jahren eingefahren (finanzen.at) | |
|
07.01.25 |
Börse New York: Börsianer lassen Dow Jones zum Start steigen (finanzen.at) |
Analysen zu Merck Co.mehr Analysen
Aktien in diesem Artikel
| Merck Co. | 97,70 | 1,14% |
|
Indizes in diesem Artikel
| Dow Jones | 41 995,22 | -1,50% | |
| S&P 500 | 5 837,99 | -1,36% | |
| S&P 100 | 2 863,11 | -1,38% | |
| NYSE US 100 | 16 447,86 | 0,76% |
Nachrichten
ETF-Sparplan
Oskar ist der einfache und intelligente ETF-Sparplan. Er übernimmt die ETF-Auswahl, ist steuersmart, transparent und kostengünstig.