CLOPIDOGREL NICHE

Main information

  • Trade name:
  • CLOPIDOGREL NICHE
  • Dosage:
  • 75 Base Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLOPIDOGREL NICHE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/039/001
  • Authorization date:
  • 19-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClopidogrelNiche75mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains75mgofclopidogrelbase(asclopidogrelbesilate).

Excipients:eachfilm-coatedtabletcontains2.6mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Pink,round,biconvex,film-coated

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clopidogrelisindicatedinadultsforthepreventionofatherothromboticeventsin:

Patientssufferingfrommyocardialinfarction(fromafewdaysuntillessthan35days),ischaemicstroke(from7days

untillessthan6months)orestablishedperipheralarterialdisease.

Patientssufferingfromacutecoronarysyndrome:

Non-STsegmentelevationacutecoronarysyndrome(unstableanginaornon-Q-wavemyocardialinfarction),

includingpatientsundergoingastentplacementfollowingpercutaneouscoronaryintervention,incombination

withacetylsalicylicacid(ASA).

STsegmentelevationacutemyocardialinfarction,incombinationwithASAinmedicallytreatedpatients

eligibleforthrombolytictherapy.

Forfurtherinformationpleaserefertosection5.1.

4.2Posologyandmethodofadministration

Posology

Adultsandelderly

Clopidogrelshouldbegivenasasingledailydoseof75mg.

Inpatientssufferingfromacutecoronarysyndrome:

Non-STsegmentelevationacutecoronarysyndrome(unstableanginaornon-Q-wavemyocardialinfarction),

clopidogreltreatmentshouldbeinitiatedwithasingle300mgloadingdoseandthencontinuedat75mgoncea

day(withacetylsalicylicacid(ASA)75mg-325mgdaily).SincehigherdosesofASAwereassociatedwith

higherbleedingriskitisrecommendedthatthedoseofASAshouldnotbehigherthan100mg.Theoptimal

durationoftreatmenthasnotbeenformallyestablished.Clinicaltrialdatasupportuseupto12months,andthe

maximumbenefitwasseenat3months(seesection5.1).

STsegmentelevationacutemyocardialinfarction:clopidogrelshouldbegivenasasingledailydoseof75mg

initiatedwitha300-mgloadingdoseincombinationwithASAandwithorwithoutthrombolytics.Forpatients

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asearlyaspossibleaftersymptomsstartandcontinuedforatleastfourweeksThebenefitofthecombinationof

clopidogrelwithASAbeyondfourweekshasnotbeenstudiedinthissetting(seesection5.1).

Ifadoseismissed:

Withinlessthan12hoursafterregularscheduledtime:patientsshouldtakethedoseimmediatelyandthentakethe

nextdoseattheregularscheduledtime.

Formorethan12hours:patientsshouldtakethenextdoseattheregularscheduledtimeandshouldnotdoublethe

dose.

Paediatricpopulation

Thesafetyandefficacyofclopidogrelinchildrenandadolescentsunder18yearsoldhavenotyetbeenestablished.

Renalimpairment

Therapeuticexperienceislimitedinpatientswithrenalimpairment(seesection4.4).

Hepaticimpairment

Therapeuticexperienceislimitedinpatientswithmoderatehepaticdiseasewhomayhave

bleedingdiatheses(seesection4.4).

Methodofadministration

Fororaluse

Itmaybegivenwithorwithoutfood.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Severehepaticimpairment.

Activepathologicalbleedingsuchaspepticulcerorintracranialhaemorrhage.

4.4Specialwarningsandprecautionsforuse

Bleedingandhaematologicaldisorders

Duetotheriskofbleedingandhaematologicaladversereactions,bloodcellcountdeterminationand/orother

appropriatetestingshouldbepromptlyconsideredwheneverclinicalsymptomssuggestiveofbleedingariseduringthe

courseoftreatment(seesection4.8).Aswithotherantiplateletagents,clopidogrelshouldbeusedwithcautionin

patientswhomaybeatriskofincreasedbleedingfromtrauma,surgeryorotherpathologicalconditionsandinpatients

receivingtreatmentwithASA,heparin,glycoproteinIIb/IIIainhibitorsornon -steroidalanti-inflammatorydrugs

(NSAIDs)includingCox-2inhibitors.Patientsshouldbefollowedcarefullyforanysignsofbleedingincludingoccult

bleeding,especiallyduringthefirstweeksoftreatmentand/orafterinvasivecardiacproceduresorsurgery.The

concomitantadministrationofclopidogrelwithoralanticoagulantsisnotrecommendedsinceitmayincreasethe

intensityofbleedings(seesection4.5).

Ifapatientistoundergoelectivesurgeryandantiplateleteffectistemporarilynotdesirable,clopidogrelshouldbe

discontinued7dayspriortosurgery.Patientsshouldinformphysiciansanddentiststhattheyaretakingclopidogrel

beforeanysurgeryisscheduledandbeforeanynewmedicinalproductistaken.Clopidogrelprolongsbleedingtime

andshouldbeusedwithcautioninpatientswhohavelesionswithapropensitytobleed(particularlygastrointestinal

andintraocular).

Patientsshouldbetoldthatitmighttakelongerthanusualtostopbleedingwhentheytakeclopidogrel(aloneorin

combinationwithASA),andthattheyshouldreportanyunusualbleeding(siteorduration)totheirphysician.

ThromboticThrombocytopenicPurpura(TTP)

ThromboticThrombocytopenicPurpura(TTP)hasbeenreportedveryrarelyfollowingtheuseofclopidogrel,

sometimesafterashortexposure.Itischaracterisedbythrombocytopeniaandmicroangiopathichemolyticanemia

associatedwitheitherneurologicalfindings,renaldysfunctionorfever.TTPisapotentiallyfatalconditionrequiring

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Recentischaemicstroke

Inviewofthelackofdata,clopidogrelcannotberecommendedduringthefirst7daysafteracuteischaemicstroke.

CytochromeP4502C19(CYP2C19)

Pharmacogenetics:InpatientswhoarepoorCYP2C19metabolisers,clopidogrelatrecommendeddosesformslessof

theactivemetaboliteofclopidogrelandhasasmallereffectonplateletfunction.Testsareavailabletoidentifya

patient'sCYP2C19genotype.

SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofmedicinalproductsthatinhibitthe

activityofthisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteofclopidogrel.The

clinicalrelevanceofthisinteractionisuncertain.AsaprecautionconcomitantuseofstrongormoderateCYP2C19

inhibitorsshouldbediscouraged(seesection4.5foralistofCYP2C19inhibitors,seealsosection5.2).

Renalimpairment

Therapeuticexperiencewithclopidogrelislimitedinpatientswithrenalimpairment.Thereforeclopidogrelshouldbe

usedwithcautioninthesepatients(seesection4.2).

Hepaticimpairment

Experienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses.Clopidogrelshould

thereforebeusedwithcautioninthispopulation(seesection4.2).

Excipients

ClopidogrelNichecontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants:theconcomitantadministrationofclopidogrelwithoralanticoagulantsisnotrecommendedsince

itmayincreasetheintensityofbleedings(seesection4.4).Althoughtheadministrationofclopidogrel75mg/daydid

notmodifythepharmacokineticsofS -warfarinorInternationalNormalisedRatio(INR)inpatientsreceiving

long -termwarfarintherapy,coadministrationofclopidogrelwithwarfarinincreasestheriskofbleedingbecauseof

independenteffectsonhemostasis.

GlycoproteinIIb/IIIainhibitors:clopidogrelshouldbeusedwithcautioninpatientswhoreceiveconcomitant

glycoproteinIIb/IIIainhibitors(seesection4.4).

Acetylsalicylicacid(ASA):ASAdidnotmodifytheclopidogrel-mediatedinhibitionofADP-inducedplatelet

aggregation,butclopidogrelpotentiatedtheeffectofASAoncollagen-inducedplateletaggregation.However,

concomitantadministrationof500mgofASAtwiceadayforonedaydidnotsignificantlyincreasetheprolongation

ofbleedingtimeinducedbyclopidogrelintake.Apharmacodynamicinteractionbetweenclopidogreland

acetylsalicylicacidispossible,leadingtoincreasedriskofbleeding.Therefore,concomitantuseshouldbeundertaken

withcaution(seesection4.4).However,clopidogrelandASAhavebeenadministeredtogetherforuptooneyear(see

section5.1).

Heparin:inaclinicalstudyconductedinhealthysubjects,clopidogreldidnotnecessitatemodificationoftheheparin

doseoraltertheeffectofheparinoncoagulation.Co-administrationofheparinhadnoeffectontheinhibitionof

plateletaggregationinducedbyclopidogrel.Apharmacodynamicinteractionbetweenclopidogrelandheparinis

possible,leadingtoincreasedriskofbleeding.Therefore,concomitantuseshouldbeundertakenwithcaution(see

section4.4).

Thrombolytics:thesafetyoftheconcomitantadministrationofclopidogrel,fibrinornon-fibrinspecificthrombolytic

agentsandheparinswasassessedinpatientswithacutemyocardialinfarction.Theincidenceofclinicallysignificant

bleedingwassimilartothatobservedwhenthrombolyticagentsandheparinareco-administeredwithASA(seesection

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NSAIDs:inaclinicalstudyconductedinhealthyvolunteers,theconcomitantadministrationofclopidogreland

naproxenincreasedoccultgastrointestinalbloodloss.However,duetothelackofinteractionstudieswithother

NSAIDsitispresentlyunclearwhetherthereisanincreasedriskofgastrointestinalbleedingwithallNSAIDs.

Consequently,NSAIDsincludingCox-2inhibitorsandclopidogrelshouldbeco-administeredwithcaution(seesection

4.4).

Otherconcomitanttherapy:SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useof

medicinalproductsthatinhibittheactivityofthisenzymewouldbeexpectedtoresultinreduceddruglevelsofthe

activemetaboliteofclopidogrel.Theclinicalrelevanceofthisinteractionisuncertain.Asaprecautionconcomitantuse

ofstrongormoderateCYP2C19inhibitorsshouldbediscouraged(seesections4.4and5.2).

MedicinalproductsthatinhibitCYP2C19includeomeprazoleandesomeprazole,fluvoxamine,fluoxetine,

moclobemide,voriconazole,fluconazole,ticlopidine,ciprofloxacin,cimetidine,carbamazepine,oxcarbazepineand

chloramphenicol.

ProtonPumpInhibitors(PPI):

Omeprazole80mgoncedailyadministeredeitheratthesametimeasclopidogrelorwith12hoursbetweenthe

administrationsofthetwodrugsdecreasedtheexposureoftheactivemetaboliteby45%(loadingdose)and40%

(maintenancedose).Thedecreasewasassociatedwitha39%(loadingdose)and21%(maintenancedose)reductionof

inhibitionofplateletaggregation.Esomeprazoleisexpectedtogiveasimilarinteractionwithclopidogrel.

Inconsistentdataontheclinicalimplicationsofthispharmacokinetic(PK)/pharmacodynamic(PD)interactioninterms

ofmajorcardiovasculareventshavebeenreportedfrombothobservationalandclinicalstudies.Asaprecaution,

concomitantuseofomeprazoleoresomeprazoleshouldbediscouraged(seesection4.4).

Lesspronouncedreductionsofmetaboliteexposurehasbeenobservedwithpantoprazoleorlansoprazole.

Theplasmaconcentrationsoftheactivemetabolitewas20%reduced(loadingdose)and14%reduced(maintenance

dose)duringconcomitanttreatmentwithpantoprazole80mgoncedaily.Thiswasassociatedwithareductionofthe

meaninhibitionofplateletaggregationby15%and11%,respectively.Theseresultsindicatethatclopidogrelcanbe

administeredwithpantoprazole.

ThereisnoevidencethatothermedicinalproductsthatreducestomachacidsuchasH2blockers(exceptcimetidine

whichisaCYP2C19inhibitor)orantacidsinterferewithantiplateletactivityofclopidogrel.

Othermedicinalproducts:Anumberofotherclinicalstudieshavebeenconductedwithclopidogrelandother

concomitantmedicinalproductstoinvestigatethepotentialforpharmacodynamicandpharmacokineticinteractions.No

clinicallysignificantpharmacodynamicinteractionswereobservedwhenclopidogrelwasco-administeredwith

atenolol,nifedipine,orbothatenololandnifedipine.Furthermore,thepharmacodynamicactivityofclopidogrelwasnot

significantlyinfluencedbythecoadministrationofphenobarbitaloroestrogen.

Thepharmacokineticsofdigoxinortheophyllinewerenotmodifiedbytheco-administrationofclopidogrel.Antacids

didnotmodifytheextentofclopidogrelabsorption.

DatafromtheCAPRIEstudyindicatethatphenytoinandtolbutamidewhicharemetabolisedbyCYP2C9canbesafely

co-administeredwithclopidogrel.

Apartfromthespecificmedicinalproductinteractioninformationdescribedabove,interactionstudieswithclopidogrel

andsomemedicinalproductscommonlyadministeredinpatientswithatherothromboticdiseasehavenotbeen

performed.However,patientsenteredintoclinicaltrialswithclopidogrelreceivedavarietyofconcomitantmedicinal

productsincludingdiuretics,betablockers,ACEI,calciumantagonists,cholesterolloweringagents,coronary

vasodilators,antidiabeticagents(includinginsulin),antiepilepticagentsandGPIIb/IIIaantagonistswithoutevidenceof

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4.6Fertility,pregnancyandlactation

Pregnancy

Asnoclinicaldataonexposuretoclopidogrelduringpregnancyareavailable,itispreferablenottouseclopidogrel

duringpregnancyasaprecautionarymeasure.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

development,parturitionorpostnataldevelopment(seesection5.3).

Breastfeeding

Itisunknownwhetherclopidogrelisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

clopidogrelinbreastmilk.Asaprecautionarymeasure,breast-feedingshouldnotbecontinuedduringtreatmentwith

ClopidogrelNiche.

Fertility

Clopidogrelwasnotshowntoalterfertilityinanimalstudies.

4.7Effectsonabilitytodriveandusemachines

Clopidogrelhasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Clopidogrelhasbeenevaluatedforsafetyinmorethan42,000patientswhohaveparticipatedinclinicalstudies,

includingover9,000patientstreatedfor1yearormore.Theclinicallyrelevantadversereactionsobservedinthe

CAPRIE,CURE,CLARITYandCOMMITstudiesarediscussedbelow.Overall,clopidogrel75mg/daywas

comparabletoASA325mg/dayinCAPRIEregardlessofage,genderandrace.Inadditiontoclinicalstudies

experience,adversereactionshavebeenspontaneouslyreported.

Bleedingisthemostcommonreactionreportedbothinclinicalstudiesaswellasinpost-marketingexperiencewhereit

wasmostlyreportedduringthefirstmonthoftreatment.

InCAPRIE,inpatientstreatedwitheitherclopidogrelorASA,theoverallincidenceofanybleedingwas9.3%.The

incidenceofseverecaseswassimilarforclopidogrelandASA.

InCURE,therewasnoexcessinmajorbleedswithclopidogrelplusASAwithin7daysaftercoronarybypassgraft

surgeryinpatientswhostoppedtherapymorethanfivedayspriortosurgery.Inpatientswhoremainedontherapy

withinfivedaysofbypassgraftsurgery,theeventratewas9.6%forclopidogrelplusASAand6.3%forplaceboplus

ASA.

InCLARITY,therewasanoverallincreaseinbleedingintheclopidogrelplusASAgroupvs.theplaceboplusASA

group.Theincidenceofmajorbleedingwassimilarbetweengroups.Thiswasconsistentacrosssubgroupsofpatients

definedbybaselinecharacteristics,andtypeoffibrinolyticorheparintherapy.

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Adversereactionsthatoccurredeitherduringclinicalstudiesorthatwerespontaneouslyreportedarepresentedinthe

tablebelow.Theirfrequencyisdefinedusingthefollowingconventions:common(1/100to<1/10);uncommon

(1/1,000to<1/100);rare(1/10,000to<1/1,000);veryrare(<1/10,000).Withineachsystemorganclass,adverse

reactionsarepresentedinorderofdecreasingseriousness.

System

Organ

Class Common Uncommon Rare Veryrare

Bloodandthe

lymphatic

system

disorders Thrombocytopenia,

leucopenia,

eosinophilia Neutropenia,

including

severe

neutropenia Thrombotic

thrombocytopenic

purpura(TTP)(see

section4.4),aplastic

anaemia,

pancytopenia,

agranulocytosis,

severe

thrombocytopenia,

granulocytopenia,

anaemia

Immunesystem

disorders Serumsickness,

anaphylactoid

reactions

Psychiatric

disorders Hallucinations,

confusion

Nervoussystem

disorders Intracranial

bleeding(some

caseswere

reportedwith

fataloutcome),

headache,

paraesthesia,

dizziness Tastedisturbances

Eyedisorders Eyebleeding

(conjunctival,

ocular,

retinal)

Earandlabyrinth

disorders Vertigo

VasculardisordersHaematoma Serioushaemorrhage,

haemorrhageof

operativewound,

vasculitis,

hypotension

Respiratory,

thoracic

mediastinal

disorders Epistaxis Respiratorytract

bleeding

(haemoptysis,

pulmonary

haemorrhage),

bronchospasm,

interstitial

pneumonitis

Gastrointestinal

disorders Gastrointestinal

haemorrhage,

diarrhoea,

abdominal

pain, Gastriculcerand

duodenalulcer,

gastritis,

vomiting,nausea,

constipation, Retroperitoneal

haemorrhage Gastrointestinaland

retroperitoneal

haemorrhagewith

fataloutcome,

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4.9Overdose

Overdosefollowingclopidogreladministrationmayleadtoprolongedbleedingtimeandsubsequentbleeding

complications.Appropriatetherapyshouldbeconsideredifbleedingsareobserved.

Noantidotetothepharmacologicalactivityofclopidogrelhasbeenfound.Ifpromptcorrectionofprolongedbleeding

timeisrequired,platelettransfusionmayreversetheeffectsofclopidogrel.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:plateletaggregationinhibitorsexcl.Heparin,ATCCode:BO1AC-04

dyspepsia flatulence (includingulcerative

orlymphocytic

colitis),stomatitis

Hepato-biliary

disorders Acuteliverfailure,

hepatitis,

abnormalliver

functiontest

System

Organ

Class Common Uncommon Rare Veryrare

Skinand

subcutaneous

tissuedisorders Bruising Rash,pruritus,

skin

bleeding(purpura) Bullousdermatitis

(toxicepidermal

necrolysis,Stevens

JohnsonSyndrome,

erythema

multiforme),

angioedema,rash

erythematous,

urticaria,

eczema,lichen

planus

Musculoskeletal,

connectivetissue

andbone

disorders Musculo-skeletal

bleeding

(haemarthrosis),

arthritis,

arthralgia,

myalgia

Renalandurinary

disorders Haematuria Glomerulonephritis,

blood

creatinine

increased

Generaldisorders

administration

siteconditions Bleedingat

puncturesite Fever

Investigations Bleedingtime

prolonged,

neutrophilcount

decreased,

plateletcount

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metabolisedbyCYP450enzymestoproducetheactivemetabolitethatinhibitsplateletaggregation.Theactive

metaboliteofclopidogrelselectivelyinhibitsthebindingofadenosinediphosphate(ADP)toitsplateletP2Y

receptor

andthesubsequentADP-mediatedactivationoftheglycoproteinGPIIb/IIIacomplex,therebyinhibitingplatelet

aggregation.Duetotheirreversiblebinding,plateletsexposedareaffectedfortheremainderoftheirlifespan

(approximately7-10days)andrecoveryofnormalplateletfunctionoccursatarateconsistentwithplateletturnover.

PlateletaggregationinducedbyagonistsotherthanADPisalsoinhibitedbyblockingtheamplificationofplatelet

activationbyreleasedADP.

BecausetheactivemetaboliteisformedbyCYP450enzymes,someofwhicharepolymorphicorsubjecttoinhibition

byothermedicinalproducts,notallpatientswillhaveadequateplateletinhibition.

Repeateddosesof75mgperdayproducedsubstantialinhibitionofADP-inducedplateletaggregationfromthefirst

day;thisincreasedprogressivelyandreachedsteadystatebetweenDay3andDay7.Atsteadystate,theaverage

inhibitionlevelobservedwithadoseof75mgperdaywasbetween40%and60%.Plateletaggregationandbleeding

timegraduallyreturnedtobaselinevalues,generallywithin5daysaftertreatmentwasdiscontinued.

Thesafetyandefficacyofclopidogrelhavebeenevaluatedin4double-blindstudiesinvolvingover80,000patients:the

CAPRIEstudy,acomparisonofclopidogreltoASA,andtheCURE,CLARITYandCOMMITstudiescomparing

clopidogreltoplacebo,bothmedicinalproductsgivenincombinationwithASAandotherstandardtherapy.

Recentmyocardialinfarction(MI),recentstrokeorestablishedperipheralarterialdisease

TheCAPRIEstudyincluded19,185patientswithatherothrombosisasmanifestedbyrecentmyocardialinfarction(<35

days),recentischaemicstroke(between7daysand6months)orestablishedperipheralarterialdisease(PAD).Patients

wererandomisedtoclopidogrel75mg/dayorASA325mg/day,andwerefollowedfor1to3years.Inthemyocardial

infarctionsubgroup,mostofthepatientsreceivedASAforthefirstfewdaysfollowingtheacutemyocardialinfarction.

Clopidogrelsignificantlyreducedtheincidenceofnewischaemicevents(combinedendpointofmyocardialinfarction,

ischaemicstrokeandvasculardeath)whencomparedtoASA.Intheintentiontotreatanalysis,939eventswere

observedintheclopidogrelgroupand1,020eventswithASA(relativeriskreduction(RRR)8.7%,[95%CI:0.2to

16.4];p=0.045),whichcorresponds,forevery1000patientstreatedfor2years,to10[CI:0to20]additionalpatients

beingpreventedfromexperiencinganewischaemicevent.Analysisoftotalmortalityasasecondaryendpointdidnot

showanysignificantdifferencebetweenclopidogrel(5.8%)andASA(6.0%).

Inasubgroupanalysisbyqualifyingcondition(myocardialinfarction,ischaemicstroke,andPAD)thebenefitappeared

tobestrongest(achievingstatisticalsignificanceatp=0.003)inpatientsenrolledduetoPAD(especiallythosewhoalso

hadahistoryofmyocardialinfarction)(RRR=23.7%;CI:8.9to36.2)andweaker(notsignificantlydifferentfrom

ASA)instrokepatients(RRR=7.3%;CI:-5.7to18.7[p=0.258]).Inpatientswhowereenrolledinthetrialonthesole

basisofarecentmyocardialinfarction,clopidogrelwasnumericallyinferior,butnotstatisticallydifferentfromASA

(RRR=-4.0%;CI:-22.5to11.7[p=0.639]).Inaddition,asubgroupanalysisbyagesuggestedthatthebenefitof

clopidogrelinpatientsover75yearswaslessthanthatobservedinpatients75years.

SincetheCAPRIEtrialwasnotpoweredtoevaluateefficacyofindividualsubgroups,itisnotclearwhetherthe

differencesinrelativeriskreductionacrossqualifyingconditionsarereal,oraresultofchance.

Acutecoronarysyndrome

TheCUREstudyincluded12,562patientswithnon-STsegmentelevationacutecoronarysyndrome(unstableanginaor

non-Q-wavemyocardialinfarction),andpresentingwithin24hoursofonsetofthemostrecentepisodeofchestpainor

symptomsconsistentwithischaemia.PatientswererequiredtohaveeitherECGchangescompatiblewithnew

ischaemiaorelevatedcardiacenzymesortroponinIorTtoatleasttwicetheupperlimitofnormal.Patientswere

randomisedtoclopidogrel(300mgloadingdosefollowedby75mg/day,N=6,259)orplacebo(N=6,303),bothgiven

incombinationwithASA(75-325mgoncedaily)andotherstandardtherapies.Patientsweretreatedforuptooneyear.

InCURE,823(6.6%)patientsreceivedconcomitantGPIIb/IIIareceptorantagonisttherapy.Heparinswere

administeredinmorethan90%ofthepatientsandtherelativerateofbleedingbetweenclopidogrelandplacebowas

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Thenumberofpatientsexperiencingtheprimaryendpoint[cardiovascular(CV)death,myocardialinfarction(MI),or

stroke]was582(9.3%)intheclopidogrel-treatedgroupand719(11.4%)intheplacebo-treatedgroup,a20%relative

riskreduction(95%CIof10%-28%;p=0.00009)fortheclopidogrel-treatedgroup(17%relativeriskreductionwhen

patientsweretreatedconservatively,29%whentheyunderwentpercutaneoustransluminalcoronaryangioplasty

(PTCA)withorwithoutstentand10%whentheyunderwentcoronaryarterybypassgraft(CABG)).New

cardiovascularevents(primaryendpoint)wereprevented,withrelativeriskreductionsof22%(CI:8.6,33.4),32%

(CI:12.8,46.4),4%(CI:-26.9,26.7),6%(CI:-33.5,34.3)and14%(CI:-31.6,44.2),duringthe0-1,1-3,3-6,6-9and

9-12monthstudyintervals,respectively.Thus,beyond3monthsoftreatment,thebenefitobservedintheclopidogrel+

ASAgroupwasnotfurtherincreased,whereastheriskofhaemorrhagepersisted(seesection4.4).

TheuseofclopidogrelinCUREwasassociatedwithadecreaseintheneedofthrombolytictherapy(RRR=43.3%;CI:

24.3%,57.5%)andGPIIb/IIIainhibitors(RRR=18.2%;CI:6.5%,28.3%).

Thenumberofpatientsexperiencingtheco-primaryendpoint(CVdeath,MI,strokeorrefractoryischaemia)was1035

(16.5%)intheclopidogrel-treatedgroupand1187(18.8%)intheplacebo-treatedgroup,a14%relativeriskreduction

(95%CIof6%-21%,p=0.0005)fortheclopidogrel-treatedgroup.Thisbenefitwasmostlydrivenbythestatistically

significantreductionintheincidenceofMI[287(4.6%)intheclopidogreltreatedgroupand363(5.8%)intheplacebo

treatedgroup].Therewasnoobservedeffectontherateofrehospitalisationforunstableangina.

Theresultsobtainedinpopulationswithdifferentcharacteristics(e.g.unstableanginaornon-Q-waveMI,lowtohigh

risklevels,diabetes,needforrevascularisation,age,gender,etc.)wereconsistentwiththeresultsoftheprimary

analysis.Inparticular,inapost-hocanalysisin2172patients(17%ofthetotalCUREpopulation)whounderwentstent

placement(Stent-CURE),thedatashowedthatclopidogrelcomparedtoplacebo,demonstratedasignificantRRRof

26.2%favouringclopidogrelfortheco-primaryendpoint(CVdeath,MI,stroke)andalsoasignificantRRRof23.9%

forthesecondco-primaryendpoint(CVdeath,MI,strokeorrefractoryischaemia).Moreover,thesafetyprofileof

clopidogrelinthissubgroupofpatientsdidnotraiseanyparticularconcern.Thus,theresultsfromthissubsetarein

linewiththeoveralltrialresults.

Thebenefitsobservedwithclopidogrelwereindependentofotheracuteandlong-termcardiovasculartherapies(such

asheparin/LMWH,GPIIb/IIIaantagonists,lipidloweringmedicinalproducts,betablockers,andACE-inhibitors).The

efficacyofclopidogrelwasobservedindependentlyofthedoseofASA(75-325mgoncedaily).

InpatientswithacuteST-segmentelevationMI,safetyandefficacyofclopidogrelhavebeenevaluatedin2

randomised,placebo-controlled,double-blindstudies,CLARITYandCOMMIT.

TheCLARITYtrialincluded3,491patientspresentingwithin12hoursoftheonsetofaSTelevationMIandplanned

forthrombolytictherapy.Patientsreceivedclopidogrel(300mgloadingdose,followedby75mg/day,n=1752)or

placebo(n=1739),bothincombinationwithASA(150to325mgasaloadingdose,followedby75to162mg/day),a

fibrinolyticagentand,whenappropriate,heparin.Thepatientswerefollowedfor30days.Theprimaryendpointwas

theoccurrenceofthecompositeofanoccludedinfarctrelatedarteryonthepredischargeangiogram,ordeathor

recurrentMIbeforecoronaryangiography.Forpatientswhodidnotundergoangiography,theprimaryendpointwas

deathorrecurrentmyocardialinfarctionbyDay8orbyhospitaldischarge.Thepatientpopulationincluded19.7%

womenand29.2%patients 65years.Atotalof99.7%ofpatientsreceivedfibrinolytics(fibrinspecific:68.7%,

nonfibrinspecific:31.1%),89.5%heparin,78.7%betablockers,54.7%ACEinhibitorsand63%statins.

Fifteenpercent(15.0%)ofpatientsintheclopidogrelgroupand21.7%intheplacebogroupreachedtheprimary

endpoint,representinganabsolutereductionof6.7%anda36%oddsreductioninfavourofclopidogrel(95%CI:24,

47%;p<0.001),mainlyrelatedtoareductioninoccludedinfarct-relatedarteries.Thisbenefitwasconsistentacrossall

prespecifiedsubgroupsincludingpatients’ageandgender,infarctlocation,andtypeoffibrinolyticorheparinused.

The2x2factorialdesignCOMMITtrialincluded45,852patientspresentingwithin24hoursoftheonsetofthe

symptomsofsuspectedMIwithsupportingECGabnormalities(i.e.STelevation,STdepressionorleftbundle-branch

block).Patientsreceivedclopidogrel(75mg/day,n=22,961)orplacebo(n=22,891),incombinationwithASA(162

mg/day),for28daysoruntilhospitaldischarge.Theco-primaryendpointsweredeathfromanycauseandthefirst

occurrenceofre-infarction,strokeordeath.Thepopulationincluded27.8%women,58.4%patients 60years(26%

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Clopidogrelsignificantlyreducedtherelativeriskofdeathfromanycauseby7%(p=0.029),andtherelativeriskof

thecombinationofre-infarction,strokeordeathby9%(p=0.002),representinganabsolutereductionof0.5%and

0.9%,respectively.Thisbenefitwasconsistentacrossage,genderandwithorwithoutfibrinolytics,andwasobserved

asearlyas24hours.

5.2Pharmacokineticproperties

Absorption

Aftersingleandrepeatedoraldosesof75mgperday,clopidogrelisrapidlyabsorbed.Meanpeakplasmalevelsof

unchangedclopidogrel(approximately2.2-2.5ng/mlafterasingle75mgoraldose)occurredapproximately45

minutesafterdosing.Absorptionisatleast50%,basedonurinaryexcretionofclopidogrelmetabolites.

Distribution

Clopidogrelandthemaincirculating(inactive)metabolitebindreversiblyinvitrotohumanplasmaproteins(98%and

94%respectively).Thebindingisnon-saturableinvitrooverawideconcentrationrange.

Metabolism

Clopidogrelisextensivelymetabolisedbytheliver.Invitroandinvivo,clopidogrelismetabolizedaccordingtotwo

mainmetabolicpathways:onemediatedbyesterasesandleadingtohydrolysisintoitsinactivecarboxylicacid

derivative(85%ofcirculatingmetabolites),andonemediatedbymultiplecytochromesP450.Clopidogrelisfirst

metabolisedtoa2-oxo-clopidogrelintermediatemetabolite.Subsequentmetabolismofthe2-oxo-clopidogrel

intermediatemetaboliteresultsinformationoftheactivemetabolite,athiolderivativeofclopidogrel.Invitro,this

metabolicpathwayismediatedbyCYP3A4,CYP2C19,CYP1A2andCYP2B6.Theactivethiolmetabolitewhichhas

beenisolatedinvitro,bindsrapidlyandirreversiblytoplateletreceptors,thusinhibitingplateletaggregation.

TheC

oftheactivemetaboliteistwiceashighfollowingasingle300 -mgclopidogrelloadingdoseasitisafterfour

daysof75-mgmaintenancedose.C

occursapproximately30to60minutesafterdosing.

Elimination

Followinganoraldoseof 14

C-labelledclopidogrelinman,approximately50%wasexcretedintheurineand

approximately46%inthefaecesinthe120-hourintervalafterdosing.Afterasingleoraldoseof75mg,clopidogrel

hasahalf-lifeofapproximately6hours.Theeliminationhalf-lifeofthemaincirculating(inactive)metabolitewas8

hoursaftersingleandrepeatedadministration.

Pharmacogenetics

CYP2C19isinvolvedintheformationofboththeactivemetaboliteandthe2-oxo-clopidogrelintermediatemetabolite.

Clopidogrelactivemetabolitepharmacokineticsandantiplateleteffects,asmeasuredbyexvivoplateletaggregation

assays,differaccordingtoCYP2C19genotype.

TheCYP2C19*1allelecorrespondstofullyfunctionalmetabolismwhiletheCYP2C19*2andCYP2C19*3allelesare

nonfunctional.TheCYP2C19*2andCYP2C19*3allelesaccountforthemajorityofreducedfunctionallelesin

Caucasian(85%)andAsian(99%)poormetabolisers.Otherallelesassociatedwithabsentorreducedmetabolismare

lessfrequentandincludeCYP2C19*4,*5,*6,*7,and*8.Apatientwithpoormetaboliserstatuswillpossesstwoloss-

of-functionallelesasdefinedabove.PublishedfrequenciesforthepoorCYP2C19metabolisergenotypesare

approximately2%forCaucasians,4%forBlacksand14%forChinese.Testsareavailabletodetermineapatient’s

CYP2C19genotype.

Acrossoverstudyin40healthysubjects,10eachinthefourCYP2C19metabolisergroups(ultrarapid,extensive,

intermediateandpoor),evaluatedpharmacokineticandantiplateletresponsesusing300mgfollowedby75mg/dayand

600mgfollowedby150mg/day,eachforatotalof5days(steadystate).Nosubstantialdifferencesinactivemetabolite

exposureandmeaninhibitionofplateletaggregation(IPA)wereobservedbetweenultrarapid,extensiveand

intermediatemetabolisers.Inpoormetabolisers,activemetaboliteexposurewasdecreasedby63 -71%comparedto

extensivemetabolisers.Afterthe300mg/75mgdoseregimen,antiplateletresponsesweredecreasedinthepoor

metaboliserswithmeanIPA(5µMADP)of24%(24hours)and37%(Day5)ascomparedtoIPAof39%(24hours)

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Whenpoormetabolisersreceivedthe600mg/150mgregimen,activemetaboliteexposurewasgreaterthanwiththe

300mg/75mgregimen.Inaddition,IPAwas32%(24hours)and61%(Day5),whichweregreaterthaninthepoor

metabolisersreceivingthe300mg/75mgregimen,andweresimilartotheotherCYP2C19metabolisergroups

receivingthe300mg/75mgregimen.Anappropriatedoseregimenforthispatientpopulationhasnotbeenestablished

inclinicaloutcometrials.

Consistentwiththeaboveresults,inameta -analysisincluding6studiesof335clopidogrel-treatedsubjectsatsteady

state,itwasshownthatactivemetaboliteexposurewasdecreasedby28%forintermediatemetabolisers,and72%for

poormetaboliserswhileplateletaggregationinhibition(5µMADP)wasdecreasedwithdifferencesinIPAof5.9%and

21.4%,respectively,whencomparedtoextensivemetabolisers.

TheinfluenceofCYP2C19genotypeonclinicaloutcomesinpatientstreatedwithclopidogrelhasnotbeenevaluatedin

prospective,randomised,controlledtrials.Therehavebeenanumberofretrospectiveanalyses,however,toevaluate

thiseffectinpatientstreatedwithclopidogrelforwhomtherearegenotypingresults:CURE(n=2721),CHARISMA

(n=2428),CLARITY -TIMI28(n=227),TRITON-TIMI38(n=1477),andACTIVE-A(n=601),aswellasanumber

ofpublishedcohortstudies.

InTRITON -TIMI38and3ofthecohortstudies(Collet,Sibbing,Giusti)thecombinedgroupofpatientswitheither

intermediateorpoormetaboliserstatushadahigherrateofcardiovascularevents(death,myocardialinfarction,and

stroke)orstentthrombosiscomparedtoextensivemetabolisers.

InCHARISMAandonecohortstudy(Simon),anincreasedeventratewasobservedonlyinpoormetaboliserswhen

comparedtoextensivemetabolisers.

InCURE,CLARITY,ACTIVE -Aandoneofthecohortstudies(Trenk),noincreasedeventratewasobservedbased

onmetaboliserstatus.

Noneoftheseanalyseswereadequatelysizedtodetectdifferencesinoutcomeinpoormetabolisers.

Thepharmacokineticsoftheactivemetaboliteofclopidogrelisnotknowninthesespecialpopulations.

Renalimpairment

Afterrepeateddosesof75mgclopidogrelperdayinsubjectswithsevererenaldisease(creatinineclearancefrom5

to15ml/min),inhibitionofADP-inducedplateletaggregationwaslower(25%)thanthatobservedinhealthy

subjects,however,theprolongationofbleedingtimewas similartothatseeninhealthysubjectsreceiving75mgof

clopidogrelperday.Inaddition,clinicaltolerancewasgoodinallpatients.

Hepaticimpairment

Afterrepeateddosesof75mgclopidogrelperdayfor10daysinpatientswithseverehepaticimpairment,

inhibitionofADP-inducedplateletaggregationwassimilartothatobservedinhealthysubjects.Themean

bleedingtimeprolongationwasalsosimilarinthetwogroups.

Race

TheprevalenceofCYP2C19allelesthatresultinintermediateandpoorCYP2C19metabolismdiffersaccordingto

race/ethnicity(seePharmacogenetics).Fromliterature,limiteddatainAsianpopulationsareavailabletoassessthe

clinicalimplicationofgenotypingofthisCYPonclinicaloutcomeevents.

5.3Preclinicalsafetydata

Duringnonclinicalstudiesinratandbaboon,themostfrequentlyobservedeffectswereliverchanges.Theseoccurred

atdosesrepresentingatleast25timestheexposureseeninhumansreceivingtheclinicaldoseof75mg/dayandwerea

consequenceofaneffectonhepaticmetabolisingenzymes.Noeffectonhepaticmetabolisingenzymeswasobserved

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Atveryhighdoses,apoorgastrictolerability(gastritis,gastricerosionsand/orvomiting)ofclopidogrelwasalso

reportedinratandbaboon.

Therewasnoevidenceofcarcinogeniceffectwhenclopidogrelwasadministeredfor78weekstomiceand104weeks

toratswhengivenatdosesupto77mg/kgperday(representingatleast25timestheexposureseeninhumans

receivingtheclinicaldoseof75mg/day).

Clopidogrelhasbeentestedinarangeofinvitroandinvivogenotoxicitystudies,andshowednogenotoxicactivity.

Clopidogrelwasfoundtohavenoeffectonthefertilityofmaleandfemaleratsandwasnotteratogenicineitherratsor

rabbits.Whengiventolactatingrats,clopidogrelcausedaslightdelayinthedevelopmentoftheoffspring.Specific

pharmacokineticstudiesperformedwithradiolabelledclopidogrelhaveshownthattheparentcompoundorits

metabolitesareexcretedinthemilk.Consequently,adirecteffect(slighttoxicity),oranindirecteffect(low

palatability)cannotbeexcluded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Microcrystallinecellulose

Spray-driedMannitol

Hydroxypropylcellulose

Crospovidone

Citricacid

Macrogol6000

Stearicacid

Talc

Coating:

OpadryIIPink32K14834

Hypromellose(E421)

Ironoxidered(E172)

Lactosemonohydrate

Triacetin(E1518)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

InPVC/PVDC/aluminiumblisters,storebelow30°C.

InPA/ALL/PVC-aluminiumblisters,thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

14,28,30,50,84,90or100film-coatedtabletspackedinPVC/PVDC/AluminiumblistersorinPA/ALL/PVC-

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Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1,TheCamCentre

WilburyWay

Hitchin

HertfordshireSG4OTW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/39/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19November2010

10DATEOFREVISIONOFTHETEXT

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