EZETROL

Main information

  • Trade name:
  • EZETROL Tablets 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EZETROL Tablets 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/026/001
  • Authorization date:
  • 01-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ezetrol10mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgofezetimibe.

Excipient(s):Eachtabletcontains55mgoflactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromtheUK:

Whitetooff-white,capsule-shapedtabletsdebossedwith"414"ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

PrimaryHypercholesterolaemia

Ezetrolco-administeredwithanHMG-CoAreductaseinhibitor(statin)isindicatedasadjunctivetherapytodietforuse

inpatientswithprimary(heterozygousfamilialandnon-familial)hypercholesterolaemiawhoarenotappropriately

controlledwithastatinalone.

Ezetrolmonotherapyisindicatedasadjunctivetherapytodietforuseinpatientswithprimary(heterozygousfamilial

andnon-familial)hypercholesterolaemiainwhomastatinisconsideredinappropriateorisnottolerated.

HomozygousFamilialHypercholesterolaemia(HoFH)

Ezetrolco-administeredwithastatin,isindicatedasadjunctivetherapytodietforuseinpatientswithHoFH.Patients

mayalsoreceiveadjunctivetreatments(e.g.,LDLapheresis).

HomozygousSitosterolaemia(Phytosterolaemia)

Ezetrolisindicatedasadjunctivetherapytodietforuseinpatientswithhomozygousfamilialsitosterolaemia.

AbeneficialeffectofEzetroloncardiovascularmorbidityandmortalityhasnotyetbeendemonstrated.

4.2Posologyandmethodofadministration

Thepatientshouldbeonanappropriatelipid-loweringdietandshouldcontinueonthisdietduringtreatmentwith

Ezetrol.

Routeofadministrationisoral.TherecommendeddoseisoneEzetrol10mgtabletdaily.Ezetrolcanbeadministered

atanytimeoftheday,withorwithoutfood.

WhenEzetrolisaddedtoastatin,eithertheindicatedusualinitialdoseofthatparticularstatinorthealready

establishedhigherstatindoseshouldbecontinued.Inthissetting,thedosageinstructionsforthatparticularstatin

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Co-administrationwithbileacidsequestrants

DosingofEzetrolshouldoccureither 2hoursbeforeor 4hoursafteradministrationofabileacidsequestrant.

UseintheElderly

Nodosageadjustmentisrequiredforelderlypatients(seesection5.2).

UseinPaediatricPatients

Initiationoftreatmentmustbeperformedunderreviewofaspecialist.

Adolescents ≥10years(pubertalstatus:boys:TannerStageIIandabove;girls:atleastoneyearpost-menarche):no

dosageadjustmentisrequired(seesection5.2).Theclinicalexperienceinpaediatricandadolescentpatients(aged10-

17yearsold)is,however,limited.

WhenEzetrolisadministeredwithsimvastatin,thedosageinstructionsforsimvastatin,inadolescentsshouldbe

consulted.

Children<10years:Ezetrolisnotrecommendedforuseinchildrenbelowage10duetoinsufficientdataonsafety

andefficacy(seesection5.2).

UseinHepaticImpairment

Nodosageadjustmentisrequiredinpatientswithmildhepaticinsufficiency(Child-Pughscore5to6).Treatmentwith

Ezetrolisnotrecommendedinpatientswithmoderate(Child-Pughscore7to9)orsevere(Child-Pughscore>9)liver

dysfunction.(Seesections4.4and5.2.)

UseinRenalImpairment

Nodosageadjustmentisrequiredforrenallyimpairedpatients(seesection5.2).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

WhenEzetrolisco-administeredwithastatin,pleaserefertotheSPCforthatparticularmedicinalproduct.

TherapywithEzetrolco-administeredwithastatiniscontraindicatedduringpregnancyandlactation.

Ezetrolco-administeredwithastatiniscontraindicatedinpatientswithactiveliverdiseaseorunexplainedpersistent

elevationsinserumtransaminases.

4.4Specialwarningsandprecautionsforuse

WhenEzetrolisco-administeredwithastatin,pleaserefertotheSPCforthatparticularmedicinalproduct.

LiverEnzymes

Incontrolledco-administrationtrialsinpatientsreceivingEzetrolwithastatin,consecutivetransaminaseelevations

≥3Xtheupperlimitofnormal[ULN])havebeenobserved.WhenEzetrolisco-administeredwithastatin,liver

functiontestsshouldbeperformedatinitiationoftherapyandaccordingtotherecommendationsofthestatin.(See

section4.8.)

SkeletalMuscle

Inpost-marketingexperiencewithEzetrol,casesofmyopathyandrhabdomyolysishavebeenreported.Mostpatients

whodevelopedrhabdomyolysisweretakingastatinconcomitantlywithEzetrol.However,rhabdomyolysishasbeen

reportedveryrarelywithEzetrolmonotherapyandveryrarelywiththeadditionofEzetroltootheragentsknowntobe

associatedwithincreasedriskofrhabdomyolysis.

Ifmyopathyissuspectedbasedonmusclesymptomsorisconfirmedbyacreatinephosphokinase(CPK)level>10

timestheULN,Ezetrol,anystatin,andanyoftheseotheragentsthatthepatientistakingconcomitantlyshouldbe

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AllpatientsstartingtherapywithEzetrolshouldbeadvisedoftheriskofmyopathyandtoldtoreportpromptlyany

unexplainedmusclepain,tendernessorweakness(seesection4.8).

HepaticInsufficiency

Duetotheunknowneffectsoftheincreasedexposuretoezetimibeinpatientswithmoderateorseverehepatic

insufficiency,Ezetrolisnotrecommended(seesection5.2).

Paediatric(10to17YearsofAge)Patients

EfficacyandsafetyofEzetrolco-administeredwithsimvastatininpatients10to17yearsofagewithheterozygous

familialhypercholesterolemiahavebeenevaluatedinacontrolledclinicaltrialinadolescentboys(TannerstageIIor

above)andingirlswhowereatleastoneyearpost-menarche..

Inthislimitedcontrolledstudy,therewasgenerallynodetectableeffectongrowthorsexualmaturationinthe

adolescentboysorgirls,oranyeffectonmenstrualcyclelengthingirls.However,theeffectsofezetimibefora

treatmentperiod>33weeksongrowthandsexualmaturationhavenotbeenstudied(Seesection4.2.and4.8.).

ThesafetyandefficacyofEzetrolco-administeredwithdosessimvastatinabove40mgdailyhavenotbeenstudiedin

pediatricpatients10to17yearsofage.

Ezetrolhasnotbeenstudiedinpatientsyoungerthan10yearsofageorinpre-menarchalgirls.(Seesections4.2and

4.8.)

Thelong-termefficacyoftherapywithEzetrolinpatientsbelow17yearsofagetoreduce

morbidityandmortalityinadulthoodhasnotbeenstudied.

Fibrates

ThesafetyandefficacyofEzetroladministeredwithfibrateshavenotbeenestablished.

IfcholelithiasisissuspectedinapatientreceivingEzetrolandfenofibrate,gallbladderinvestigationsareindicatedand

thistherapyshouldbediscontinued(seesections4.5and4.8).

Ciclosporin

CautionshouldbeexercisedwheninitiatingEzetrolinthesettingofciclosporin.Ciclosporinconcentrationsshouldbe

monitoredinpatientsreceivingEzetrolandciclosporin(seesection4.5).

Anticoagulants

IfEzetrolisaddedtowarfarin,anothercoumarinanticoagulant,orfluindione,theInternationalNormalisedRatio(INR)

shouldbeappropriatelymonitored(seesection4.5).

Excipient

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Inpreclinicalstudies,ithasbeenshownthatezetimibedoesnotinducecytochromeP450drugmetabolisingenzymes.

Noclinicallysignificantpharmacokineticinteractionshavebeenobservedbetweenezetimibeanddrugsknowntobe

metabolisedbycytochromesP4501A2,2D6,2C8,2C9,and3A4,orN-acetyltransferase.

Inclinicalinteractionstudies,ezetimibehadnoeffectonthepharmacokineticsofdapsone,dextromethorphan,digoxin,

oralcontraceptives(ethinylestradiolandlevonorgestrel),glipizide,tolbutamide,ormidazolamduringco-

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Antacids:Concomitantantacidadministrationdecreasedtherateofabsorptionofezetimibebuthadnoeffectonthe

bioavailabilityofezetimibe.Thisdecreasedrateofabsorptionisnotconsideredclinicallysignificant.

Cholestyramine:Concomitantcholestyramineadministrationdecreasedthemeanareaunderthecurve(AUC)oftotal

ezetimibe(ezetimibe+ezetimibeglucuronide)approximately55%.Theincrementallow-densitylipoprotein

cholesterol(LDL-C)reductionduetoaddingEzetroltocholestyraminemaybelessenedbythisinteraction(seesection

4.2).

Fibrates:InpatientsreceivingfenofibrateandEzetrol,physiciansshouldbeawareofthepossibleriskofcholelithiasis

andgallbladderdisease(seesections4.4and4.8).

IfcholelithiasisissuspectedinapatientreceivingEzetrolandfenofibrate,gallbladderinvestigationsareindicatedand

thistherapyshouldbediscontinued(seesection4.8).

Concomitantfenofibrateorgemfibroziladministrationmodestlyincreasedtotalezetimibeconcentrations

(approximately1.5-and1.7-foldrespectively).

Co-administrationofEzetrolwithotherfibrateshasnotbeenstudied.

Fibratesmayincreasecholesterolexcretionintothebile,leadingtocholelithiasis.Inanimalstudies,ezetimibe

sometimesincreasedcholesterolinthegallbladderbilebutnotinallspecies(seesection5.3).Alithogenicrisk

associatedwiththetherapeuticuseofEzetrolcannotberuledout.

Statins:Noclinicallysignificantpharmacokineticinteractionswereseenwhenezetimibewasco-administeredwith

atorvastatin,simvastatin,pravastatin,lovastatin,fluvastatin,orrosuvastatin.

Ciclosporin:Inastudyofeightpost-renaltransplantpatientswithcreatinineclearanceof >

50mL/minonastabledose

ofciclosporin,asingle10-mgdoseofEzetrolresultedina3.4-fold(range2.3-to7.9-fold)increaseinthemeanAUC

fortotalezetimibecomparedtoahealthycontrolpopulation,receivingezetimibealone,fromanotherstudy(n=17).Ina

differentstudy,arenaltransplantpatientwithsevererenalinsufficiencywhowasreceivingciclosporinandmultiple

othermedicationsdemonstrateda12-foldgreaterexposuretototalezetimibecomparedtoconcurrentcontrolsreceiving

ezetimibealone.Inatwo-periodcrossoverstudyintwelvehealthysubjects,dailyadministrationof20mgezetimibe

for8dayswithasingle100-mgdoseofciclosporinonDay7resultedinamean15%increaseinciclosporinAUC

(range10%decreaseto51%increase)comparedtoasingle100-mgdoseofciclosporinalone.Acontrolledstudyon

theeffectofco-administeredezetimibeonciclosporinexposureinrenaltransplantpatientshasnotbeenconducted.

CautionshouldbeexercisedwheninitiatingEzetrolinthesettingofciclosporin.Ciclosporinconcentrationsshouldbe

monitoredinpatientsreceivingEzetrolandciclosporin(seesection4.4).

Anticoagulants:Concomitantadministrationofezetimibe(10mgoncedaily)hadnosignificanteffecton

bioavailabilityofwarfarinandprothrombintimeinastudyoftwelvehealthyadultmales.However,therehavebeen

post-marketingreportsofincreasedInternationalNormalisedRatio(INR)inpatientswhohadEzetroladdedto

warfarinorfluindione.IfEzetrolisaddedtowarfarin,anothercoumarinanticoagulant,orfluindione,INRshouldbe

appropriatelymonitored(seesection4.4).

4.6Pregnancyandlactation

Ezetrolco-administeredwithastatiniscontraindicatedduringpregnancyandlactation(seesection4.3),pleasereferto

theSPCforthatparticularstatin.

Pregnancy:

Ezetrolshouldbegiventopregnantwomenonlyifclearlynecessary.Noclinicaldataareavailableontheuseof

Ezetrolduringpregnancy.Animalstudiesontheuseofezetimibeinmonotherapyhaveshownnoevidenceofdirector

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Lactation:

Ezetrolshouldnotbeusedduringlactation.Studiesonratshaveshownthatezetimibeissecretedintobreastmilk.Itis

notknownifezetimibeissecretedintohumanbreastmilk.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachines,itshouldbetakenintoaccountthatdizzinesshasbeenreported.

4.8Undesirableeffects

ClinicalStudies

Inclinicalstudiesofupto112weeksduration,Ezetrol10mgdailywasadministeredalonein2396patients,witha

statinin11,308patientsorwithfenofibratein185patients.Adversereactionswereusuallymildandtransient.The

overallincidenceofsideeffectswassimilarbetweenEzetrolandplacebo.Similarly,thediscontinuationratedueto

adverseexperienceswascomparablebetweenEzetrolandplacebo.

Ezetroladministeredaloneorco-administeredwithastatin:

ThefollowingadversereactionswereobservedinpatientstreatedwithEzetrol(N=2396)andatagreaterincidence

thanplacebo(N=1159)orinpatientstreatedwithEzetrolcoadministeredwithastatin(N=11308)andatagreater

incidencethanstatinadministeredalone(N=9361):

Frequenciesaredefinedas:verycommon( ≥1/10);common(≥1/100to<1/10);uncommon(≥1/1,000to<1/100);rare

≥1/10,000to<1/1,000)andveryrare(<1/10,000)

Ezetrolmonotherapy

Systemorganclass Adversereactions Frequency

Investigations ALTand/orASTincreased;bloodCPK

increased;gamma-glutamyltransferase

increased;liverfunctiontestabnormal Uncommon

Respiratory,Thoracicand

MediastinalDisorders cough Uncommon

GastrointestinalDisorders abdominalpain;diarrhoea;flatulence Common

dyspepsia;gastrooesophagealreflux

disease;nausea Uncommon

MusculoskeletalAndConnective

TissueDisorders arthralgia;musclespasms;neckpain Uncommon

MetabolismandNutrition

Disorders decreasedappetite Uncommon

VascularDisorders hotflush;hypertension Uncommon

GeneralDisordersAnd

AdministrationSiteCondition fatigue Common

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Ezetrolco-administeredwithfenofibrate:

Gastrointestinaldisorders:abdominalpain(common)

Inamulticentre,double-blind,placebo-controlled,clinicalstudyinpatientswithmixedhyperlipidaemia,625patients

weretreatedforupto12weeksand576patientsforupto1year.Inthisstudy,172patientstreatedwithEzetroland

fenofibratecompleted12weeksoftherapy,and230patientstreatedwithEzetrolandfenofibrate(including109who

receivedEzetrolaloneforthefirst12weeks)completed1yearoftherapy.Thisstudywasnotdesignedtocompare

treatmentgroupsforinfrequentevents.Incidencerates(95%CI)forclinicallyimportantelevations(>3XULN,

consecutive)inserumtransaminaseswere4.5%(1.9,8.8)and2.7%(1.2,5.4)forfenofibratemonotherapyandEzetrol

co-administeredwithfenofibrate,respectively,adjustedfortreatmentexposure.Correspondingincidenceratesfor

cholecystectomywere0.6%(0.0,3.1)and1.7%(0.6,4.0)forfenofibratemonotherapyandEzetrolco-administered

withfenofibrate,respectively(seesections4.4and4.5).

Paediatric(10to17yearsofage)Patients

Inastudyinvolvingadolescent(10to17yearsofage)patientswithheterozygousfamilialhypercholesterolaemia

(n=248),elevationsofALTand/orAST( ≥3XULN,consecutive)wereobservedin3%(4patients)ofthe

ezetimibe/simvastatinpatientscomparedto2%(2patients)inthesimvastatinmonotherapygroup;thesefigureswere

respectively2%(2patients)and0%forelevationofCPK( ≥10XULN)).Nocasesofmyopathywerereported.

Thistrialwasnotsuitedforcomparisonofrareadversedrugreactions.

Laboratoryvalues:

Incontrolledclinicalmonotherapytrials,theincidenceofclinicallyimportantelevationsinserumtransaminases(ALT

and/orAST 3XULN,consecutive)wassimilarbetweenEzetrol(0.5%)andplacebo(0.3%).Inco-administration

trials,theincidencewas1.3%forpatientstreatedwithEzetrolco-administeredwithastatinand0.4%forpatients

treatedwithastatinalone.Theseelevationsweregenerallyasymptomatic,notassociatedwithcholestasis,andreturned

tobaselineafterdiscontinuationoftherapyorwithcontinuedtreatment.(Seesection4.4.)

Inclinicaltrials,CPK>10XULNwasreportedfor4of1674(0.2%)patientsadministeredEzetrolalonevs1of786

(0.1%)patientsadministeredplacebo,andfor1of917(0.1%)patientsco-administeredEzetrolandastatinvs4of

929(0.4%)patientsadministeredastatinalone.Therewasnoexcessofmyopathyorrhabdomyolysisassociatedwith

AdditionaladversereactionswithEzetrolco-administeredwithastatin

Systemorganclass Adversereactions Frequency

Investigations ALTand/orASTincreased Common

NervousSystemDisorders headache Common

paraesthesia Uncommon

GastrointestinalDisorders drymouth;gastritis Uncommon

SkinAndSubcutaneousTissue

Disorders pruritus;rash;urticaria Uncommon

MusculoskeletalAndConnective

TissueDisorders myalgia Common

backpain;muscularweakness;painin

extremity Uncommon

GeneralDisordersAnd

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Post-marketingExperience

Thefollowingadditionaladversereactionshavebeenreportedinpost-marketingexperience.Becausetheseadverse

experienceshavebeenidentifiedfromspontaneousreports,theirtruefrequenciesarenotknownandcannotbe

estimated.

Bloodandlymphaticsystemdisorders:thrombocytopaenia

Nervoussystemdisorders:dizziness;paraesthesia

Respiratory,thoracicandmediastinaldisorders:dyspnoea

Gastrointestinaldisorders:pancreatitis;constipation

Skinandsubcutaneoustissuedisorders:erythemamultiforme

Musculoskeletalandconnectivetissuedisorders:myalgia;myopathy/rhabdomyolysis(seesection4.4)

Generaldisordersandadministrationsiteconditions:asthenia

Immunesystemdisorders:hypersensitivity,includingrash,urticaria,anaphylaxisandangio-oedema

Hepatobiliarydisorders:hepatitis;cholelithiasis;cholecystitis

Psychiatricdisorders:depression

4.9Overdose

Inclinicalstudies,administrationofezetimibe,50mg/dayto15healthysubjectsforupto14days,or40mg/dayto

18patientswithprimaryhypercholesterolaemiaforupto56days,wasgenerallywelltolerated.Inanimals,notoxicity

wasobservedaftersingleoraldosesof5000mg/kgofezetimibeinratsandmiceand3000mg/kgindogs.

AfewcasesofoverdosagewithEzetrolhavebeenreported;mosthavenotbeenassociatedwithadverseexperiences.

Reportedadverseexperienceshavenotbeenserious.Intheeventofanoverdose,symptomaticandsupportivemeasures

shouldbeemployed.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherlipidmodifyingagents,ATCcode:C10AX09

Ezetrolisinanewclassoflipid-loweringcompoundsthatselectivelyinhibittheintestinalabsorptionofcholesteroland

relatedplantsterols.Ezetrolisorallyactiveandhasamechanismofactionthatdiffersfromotherclassesof

cholesterol-reducingcompounds(e.g.,statins,bileacidsequestrants[resins],fibricacidderivatives,andplantstanols).

Themoleculartargetofezetimibeisthesteroltransporter,Niemann-PickC1-Like1(NPC1L1),whichisresponsible

fortheintestinaluptakeofcholesterolandphytosterols.

Ezetimibelocalisesatthebrushborderofthesmallintestineandinhibitstheabsorptionofcholesterol,leadingtoa

decreaseinthedeliveryofintestinalcholesteroltotheliver;statinsreducecholesterolsynthesisintheliverand

togetherthesedistinctmechanismsprovidecomplementarycholesterolreduction.Ina2-weekclinicalstudyin

18hypercholesterolaemicpatients,Ezetrolinhibitedintestinalcholesterolabsorptionby54%,comparedwithplacebo.

Aseriesofpreclinicalstudieswasperformedtodeterminetheselectivityofezetimibeforinhibitingcholesterol

absorption.Ezetimibeinhibitedtheabsorptionof[ 14

C]-cholesterolwithnoeffectontheabsorptionoftriglycerides,

fattyacids,bileacids,progesterone,ethinylestradiol,orfatsolublevitaminsAandD.

Epidemiologicstudieshaveestablishedthatcardiovascularmorbidityandmortalityvarydirectlywiththeleveloftotal-

CandLDL-CandinverselywiththelevelofHDL-C.

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CLINICALTRIALS

Incontrolledclinicalstudies,Ezetroleitherasmonotherapyorco-administeredwithastatinsignificantlyreducedtotal

cholesterol(total-C),low-densitylipoproteincholesterol(LDL-C),apolipoproteinB(ApoB),andtriglycerides(TG)

andincreasedhigh-densitylipoproteincholesterol(HDL-C)inpatientswithhypercholesterolaemia.

PrimaryHypercholesterolaemia

Inadouble-blind,placebo-controlled,8-weekstudy,769patientswithhypercholesterolaemiaalreadyreceivingstatin

monotherapyandnotatNationalCholesterolEducationProgram(NCEP)LDL-Cgoal(2.6to4.1mmol/l[100to

160mg/dl],dependingonbaselinecharacteristics)wererandomisedtoreceiveeitherEzetrol10mgorplaceboin

additiontotheiron-goingstatintherapy.

Amongstatin-treatedpatientsnotatLDL-Cgoalatbaseline(~82%),significantlymorepatientsrandomisedtoEzetrol

achievedtheirLDL-Cgoalatstudyendpointcomparedtopatientsrandomisedtoplacebo,72%and19%,

respectively.ThecorrespondingLDL-Creductionsweresignificantlydifferent(25%and4%forEzetrolversus

placebo,respectively).Inaddition,Ezetrol,addedtoon-goingstatintherapy,significantlydecreasedtotal-C,ApoB,

TGandincreasedHDL-C,comparedwithplacebo.Ezetrolorplaceboaddedtostatintherapyreducedmedian

C-reactiveproteinby10%or0%frombaseline,respectively.

Intwo,double-blind,randomisedplacebo-controlled,12-weekstudiesin1719patientswithprimary

hypercholesterolaemia,Ezetrol10mgsignificantlyloweredtotal-C(13%),LDL-C(19%),ApoB(14%),andTG(8

%)andincreasedHDL-C(3%)comparedtoplacebo.Inaddition,Ezetrolhadnoeffectontheplasmaconcentrationsof

fat-solublevitaminsA,D,andE,noeffectonprothrombintime,and,likeotherlipidloweringagents,didnotimpair

adrenocorticalsteroidhormoneproduction.

Inamulticenter,double-blind,controlledclinicalstudy(ENHANCE),720patientswithheterozygousfamilial

hypercholesterolemiawererandomizedtoreceiveezetimibe10mgincombinationwithsimvastatin80mg(n=357)or

simvastatin80mg(n=363)for2years.Theprimaryobjectiveofthestudywastoinvestigatetheeffectofthe

ezetimibe/simvastatincombinationtherapyoncarotidarteryintima-mediathickness(IMT)comparedtosimvastatin

monotherapy.Theimpactofthissurrogatemarkeroncardiovascularmorbidityandmortalityisstillnotdemonstrated.

Theprimaryendpoint,thechangeinthemeanIMTofallsixcarotidsegments,didnotdiffersignificantly(p=0.29)

betweenthetwotreatmentgroupsasmeasuredbyB-modeultrasound.Withezetimibe10mgincombinationwith

simvastatin80mgorsimvastatin80mgalone,intima-medialthickeningincreasedby0.0111mmand0.0058mm,

respectively,overthestudy’s2yearduration(baselinemeancarotidIMT0.68mmand0.69mmrespectively.

Ezetimibe10mgincombinationwithsimvastatin80mgloweredLDL-C,total-C,ApoB,andTGsignificantlymore

thansimvastatin80mg.ThepercentincreaseinHDL-Cwassimilarforthetwotreatmentgroups.Theadverse

reactionsreportedforezetimibe10mgincombinationwithsimvastatin80mgwereconsistentwithitsknownsafety

profile.

ClinicalStudiesinPaediatricPatients(10to17yearsofage)

Inamulticentre,double-blind,controlledstudy,142boys(TannerstageIIandabove)and106postmenarchalgirls,10

to17yearsofage(meanage14.2years)withheterozygousfamilialhypercholesterolaemia(HeFH)withbaselineLDL-

Clevelsbetween4.1and10.4mmol/lwererandomisedtoeitherEzetrol10mgco-administeredwithsimvastatin(10,

20or40mg)orsimvastatin(10,20or40mg)alonefor6weeks,co-administeredEzetroland40mgsimvastatinor40

mgsimvastatinaloneforthenext27weeks,andopen-labelco-administeredEzetrolandsimvastatin(10mg,20mg,or

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AtWeek6,Ezetrolco-administeredwithsimvastatin(alldoses)significantlyreducedtotal-C(38%vs26%),LDL-C

(49%vs34%),ApoB(39%vs27%),andnon-HDL-C(47%vs33%)comparedtosimvastatin(alldoses)alone.

ResultsforthetwotreatmentgroupsweresimilarforTGandHDL-C(-17%vs-12%and+7%vs+6%,

respectively).AtWeek33,resultswereconsistentwiththoseatWeek6andsignificantlymorepatientsreceiving

Ezetroland40mgsimvastatin(62%)attainedtheNCEPAAPidealgoal(<2.8mmol/L[110mg/dL])forLDL-C

comparedtothosereceiving40mgsimvastatin(25%).AtWeek53,theendoftheopenlabelextension,theeffectson

lipidparametersweremaintained.

ThesafetyandefficacyofEzetrolco-administeredwithdosesofsimvastatinabove40mgdailyhavenotbeenstudied

inpaediatricpatients10to17yearsofage.Thelong-termefficacyoftherapywithEzetrolinpatientsbelow17yearsof

agetoreducemorbidityandmortalityinadulthoodhasnotbeenstudied.

HomozygousFamilialHypercholesterolaemia(HoFH)

Adouble-blind,randomised,12-weekstudyenrolled50patientswithaclinicaland/orgenotypicdiagnosisofHoFH,

whowerereceivingatorvastatinorsimvastatin(40mg)withorwithoutconcomitantLDLapheresis.Ezetrol

co-administeredwithatorvastatin(40or80mg)orsimvastatin(40or80mg),significantlyreducedLDL-Cby15%

comparedwithincreasingthedoseofsimvastatinoratorvastatinmonotherapyfrom40to80mg.

HomozygousSitosterolaemia(Phytosterolaemia)

Inadouble-blind,placebo-controlled,8-weektrial,37patientswithhomozygoussitosterolaemiawererandomisedto

receiveEzetrol10mg(n=30)orplacebo(n=7).Somepatientswerereceivingothertreatments(e.g.,statins,resins).

Ezetrolsignificantlyloweredthetwomajorplantsterols,sitosterolandcampesterol,by21%and24%frombaseline,

respectively.Theeffectsofdecreasingsitosterolonmorbidityandmortalityinthispopulationarenotknown.

AorticStenosis

TheSimvastatinandEzetimibefortheTreatmentofAorticStenosis(SEAS)studywasamulti-center,double-blind,

placebo-controlledstudywithamediandurationof4.4yearsconductedin1873patientswithasymptomaticaortic

stenosis(AS),documentedbyDoppler-measuredaorticpeakflowvelocitywithintherangeof2.5to4.0m/s.Only

patientswhowereconsiderednottorequirestatintreatmentforpurposesofreducingatheroscleroticcardiovascular

diseaseriskwereenrolled.Patientswererandomized1:1toreceiveplaceboorco-administeredezetimibe10mgand

simvastatin40mgdaily.

Theprimaryendpointwasthecompositeofmajorcardiovascularevents(MCE)consistingofcardiovasculardeath,

aorticvalvereplacement(AVR)surgery,congestiveheartfailure(CHF)asaresultofprogressionofAS,nonfatal

myocardialinfarction,coronaryarterybypassgrafting(CABG),percutaneouscoronaryintervention(PCI),

hospitalizationforunstableangina,andnonhemorrhagicstroke.Thekeysecondaryendpointswerecompositesof

subsetsoftheprimaryendpointeventcategories.

Comparedtoplacebo,ezetimibe/simvastatin10/40mgdidnotsignificantlyreducetheriskofMCE.

Theprimaryoutcomeoccurredin333patients(35.3%)intheezetimibe/simvastatingroupandin355patients(38.2%)

intheplacebogroup(hazardratiointheezetimibe/simvastatingroup,0.96;95%confidenceinterval,0.83to1.12;p=

0.59).Aorticvalvereplacementwasperformedin267patients(28.3%)intheezetimibe/simvastatingroupandin278

patients(29.9%)intheplacebogroup(hazardratio,1.00;95%CI,0.84to1.18;p=0.97).Fewerpatientshadischemic

cardiovasculareventsintheezetimibe/simvastatingroup(n=148)thanintheplacebogroup(n=187)(hazardratio,

0.78;95%CI,0.63to0.97;p=0.02),mainlybecauseofthesmallernumberofpatientswhounderwentcoronaryartery

bypassgrafting.

Canceroccurredmorefrequentlyintheezetimibe/simvastatingroup(105versus70,p=0.01).Theclinicalrelevance

ofthisobservationisuncertain.Inameta-analysisincludinginterimresultsfromtwolarge,long-term,ongoingstudies

withezetimibe/simvastatin(n=10,319activelytreated,10,298controltreated;patient-years=18,246activelytreated,

18,255controltreated)therewasnotanincreasedrateofcancer(313activetreatment,326control;riskratio,0.96;

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5.2Pharmacokineticproperties

Absorption:Afteroraladministration,ezetimibeisrapidlyabsorbedandextensivelyconjugatedtoa

pharmacologicallyactivephenolicglucuronide(ezetimibe-glucuronide).Meanmaximumplasmaconcentrations(C

occurwithin1to2hoursforezetimibe-glucuronideand4to12hoursforezetimibe.Theabsolutebioavailabilityof

ezetimibecannotbedeterminedasthecompoundisvirtuallyinsolubleinaqueousmediasuitableforinjection.

Concomitantfoodadministration(highfatornon-fatmeals)hadnoeffectontheoralbioavailabilityofezetimibewhen

administeredasEzetrol10-mgtablets.Ezetrolcanbeadministeredwithorwithoutfood.

Distribution:Ezetimibeandezetimibe-glucuronidearebound99.7%and88to92%tohumanplasmaproteins,

respectively.

Biotransformation:Ezetimibeismetabolisedprimarilyinthesmallintestineandliverviaglucuronideconjugation(a

phaseIIreaction)withsubsequentbiliaryexcretion.Minimaloxidativemetabolism(aphaseIreaction)hasbeen

observedinallspeciesevaluated.Ezetimibeandezetimibe-glucuronidearethemajordrug-derivedcompoundsdetected

inplasma,constitutingapproximately10to20%and80to90%ofthetotaldruginplasma,respectively.Both

ezetimibeandezetimibe-glucuronideareslowlyeliminatedfromplasmawithevidenceofsignificantenterohepatic

recycling.Thehalf-lifeforezetimibeandezetimibe-glucuronideisapproximately22hours.

Elimination:Followingoraladministrationof 14

C-ezetimibe(20mg)tohumansubjects,totalezetimibeaccountedfor

approximately93%ofthetotalradioactivityinplasma.Approximately78%and11%oftheadministered

radioactivitywererecoveredinthefaecesandurine,respectively,overa10-daycollectionperiod.After48hours,there

werenodetectablelevelsofradioactivityintheplasma.

SpecialPopulations:

PaediatricPatients

Theabsorptionandmetabolismofezetimibearesimilarbetweenchildrenandadolescents(10to18years)andadults.

Basedontotalezetimibe,therearenopharmacokineticdifferencesbetweenadolescentsandadults.Pharmacokinetic

datainthepaediatricpopulation<10yearsofagearenotavailable.Clinicalexperienceinpaediatricandadolescent

patientsincludespatientswithHoFHorHeFHorsitosterolaemia.

GeriatricPatients

Plasmaconcentrationsfortotalezetimibeareabout2-foldhigherintheelderly(65years)thanintheyoung(18to

45years).LDL-CreductionandsafetyprofilearecomparablebetweenelderlyandyoungsubjectstreatedwithEzetrol.

Therefore,nodosageadjustmentisnecessaryintheelderly.

HepaticInsufficiency

Afterasingle10-mgdoseofezetimibe,themeanAUCfortotalezetimibewasincreasedapproximately1.7-foldin

patientswithmildhepaticinsufficiency(Child-Pughscore5or6),comparedtohealthysubjects.Ina14-day,multiple-

dosestudy(10mgdaily)inpatientswithmoderatehepaticinsufficiency(Child-Pughscore7to9),themeanAUCfor

totalezetimibewasincreasedapproximately4-foldonDay1andDay14comparedtohealthysubjects.Nodosage

adjustmentisnecessaryforpatientswithmildhepaticinsufficiency.Duetotheunknowneffectsoftheincreased

exposuretoezetimibeinpatientswithmoderateorsevere(Child-Pughscore>9)hepaticinsufficiency,Ezetrolisnot

recommendedinthesepatients(seesection4.4).

RenalInsufficiency

Afterasingle10-mgdoseofezetimibeinpatientswithsevererenaldisease(n=8;meanCrCl ≤30ml/min/1.73m 2

themeanAUCfortotalezetimibewasincreasedapproximately1.5-fold,comparedtohealthysubjects(n=9).This

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Anadditionalpatientinthisstudy(post-renaltransplantandreceivingmultiplemedications,includingciclosporin)had

a12-foldgreaterexposuretototalezetimibe.

Gender

Plasmaconcentrationsfortotalezetimibeareslightlyhigher(approximately20%)inwomenthaninmen.LDL-C

reductionandsafetyprofilearecomparablebetweenmenandwomentreatedwithEzetrol.Therefore,nodosage

adjustmentisnecessaryonthebasisofgender.

5.3Preclinicalsafetydata

Animalstudiesonthechronictoxicityofezetimibeidentifiednotargetorgansfortoxiceffects.Indogstreatedforfour

weekswithezetimibe( ≥0.03mg/kg/day)thecholesterolconcentrationinthecysticbilewasincreasedbyafactorof

2.5to3.5.However,inaone-yearstudyondogsgivendosesofupto300mg/kg/daynoincreasedincidenceof

cholelithiasisorotherhepatobiliaryeffectswereobserved.Thesignificanceofthesedataforhumansisnotknown.A

lithogenicriskassociatedwiththetherapeuticuseofEzetrolcannotberuledout.

Inco-administrationstudieswithezetimibeandstatinsthetoxiceffectsobservedwereessentiallythosetypically

associatedwithstatins.Someofthetoxiceffectsweremorepronouncedthanobservedduringtreatmentwithstatins

alone.Thisisattributedtopharmacokineticandpharmacodynamicinteractionsinco-administrationtherapy.Nosuch

interactionsoccurredintheclinicalstudies.Myopathiesoccurredinratsonlyafterexposuretodosesthatwereseveral

timeshigherthanthehumantherapeuticdose(approximately20timestheAUClevelforstatinsand500to2000times

theAUClevelfortheactivemetabolites).

Inaseriesofinvivoandinvitroassaysezetimibe,givenaloneorco-administeredwithstatins,exhibitednogenotoxic

potential.Long-termcarcinogenicitytestsonezetimibewerenegative.

Ezetimibehadnoeffectonthefertilityofmaleorfemalerats,norwasitfoundtobeteratogenicinratsorrabbits,nor

diditaffectprenatalorpostnataldevelopment.Ezetimibecrossedtheplacentalbarrierinpregnantratsandrabbits

givenmultipledosesof1000mg/kg/day.Theco-administrationofezetimibeandstatinswasnotteratogenicinrats.In

pregnantrabbitsasmallnumberofskeletaldeformities(fusedthoracicandcaudalvertebrae,reducednumberofcaudal

vertebrae)wereobserved.Theco-administrationofezetimibewithlovastatinresultedinembryolethaleffects.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Croscarmellosesodium

Lactosemonohydrate

Magnesiumstearate

Microcrystallinecellulose

Povidone(K29-32)

Sodiumlaurilsulfate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

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6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

PushthroughblistersofclearpolychlorotrifluoroethylenelPVCsealedtovinylcoatedaluminiuminpackscontaining

28tablets.Inanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialinstructions.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton,Oldham

LancashireOL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/26/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1 st

October2010

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