CLOPIDOGREL

Main information

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

Documents

Localization

  • Available in:
  • CLOPIDOGREL Film Coated Tablet 75 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/060/001
  • Authorization date:
  • 20-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clopidogrel75mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains75mgofclopidogrel(asclopidogrelbase).

Excipient:eachfilm-coatedtabletcontains175mglactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Pink,film-coated,round,biconvextabletsdebossedwith«C»ononesideand«75»ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clopidogrelisindicatedinadultsforthepreventionofatherothromboticeventsin:

Patientssufferingfrommyocardialinfarction(fromafewdaysuntillessthan35days),ischaemicstroke(from7

daysuntillessthan6months)orestablishedperipheralarterialdisease.

Forfurtherinformationpleaserefertosection5.1.

4.2Posologyandmethodofadministration

Adultsandelderly

Clopidogrelshouldbegivenasasingledailydoseof75mgwithorwithoutfood.

Pharmacogenetics

CYP2C19poormetaboliserstatusisassociatedwithdiminishedresponsetoclopidogrel.

Theoptimaldoseregimenforpoormetabolisershasyettobedetermined

(seesection5.2).

Paediatricpatients

Thesafetyandefficacyofclopidogrelinchildrenandadolescentshavenotyetbeenestablished.

Renalimpairment

Therapeuticexperienceislimitedinpatientswithrenalimpairment(seesection4.4).

Hepaticimpairment

Therapeuticexperienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses

(seesection4.4).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Severeliverimpairment.

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4.4Specialwarningsandprecautionsforuse

Duetotheriskofbleedingandhaematologicalundesirableeffects,bloodcellcountdeterminationand/orother

appropriatetestingshouldbepromptlyconsideredwheneverclinicalsymptomssuggestiveofbleedingariseduringthe

courseoftreatment(seesection4.8).

Aswithotherantiplateletagents,clopidogrelshouldbeusedwithcautioninpatientswhomaybeatriskofincreased

bleedingfromtrauma,surgeryorotherpathologicalconditionsandinpatientsreceivingtreatmentwithASA,heparin,

glycoproteinIIb/IIIainhibitorsornon-steroidalanti-inflammatorydrugsincludingCox-2inhibitors.Patientsshouldbe

followedcarefullyforanysignsofbleedingincludingoccultbleeding,especiallyduringthefirstweeksoftreatment

and/orafterinvasivecardiacproceduresorsurgery.Theconcomitantadministrationofclopidogrelwithoral

anticoagulantsisnotrecommendedsinceitmayincreasetheintensityofbleedings(seesection4.5).

Ifapatientistoundergoelectivesurgeryandantiplateleteffectistemporarilynotdesirable,clopidogrelshouldbe

discontinued7dayspriortosurgery.Patientsshouldinformphysiciansanddentiststhattheyaretakingclopidogrel

beforeanysurgeryisscheduledandbeforeanynewmedicinalproductistaken.Clopidogrelprolongsbleedingtime

andshouldbeusedwithcautioninpatientswhohavelesionswithapropensitytobleed(particularlygastrointestinal

andintraocular).

Patientsshouldbetoldthatitmighttakelongerthanusualtostopbleedingwhentheytakeclopidogrel(aloneorin

combinationwithASA),andthattheyshouldreportanyunusualbleeding(siteorduration)totheirphysician.

ThromboticThrombocytopenicPurpura(TTP)hasbeenreportedveryrarelyfollowingtheuseofclopidogrel,

sometimesafterashortexposure.Itischaracterisedbythrombocytopeniaandmicroangiopathichaemolyticanaemia

associatedwitheitherneurologicalfindings,renaldysfunctionorfever.TTPisapotentiallyfatalconditionrequiring

prompttreatmentincludingplasmapheresis.

Inviewofthelackofdata,clopidogrelcannotberecommendedduringthefirst7daysafteracuteischaemicstroke.

Pharmacogenetics:Basedonliteraturedata,patientswithgeneticallyreducedCYP2C19functionhavelowersystemic

exposuretotheactivemetaboliteofclopidogrelanddiminishedantiplateletresponses,andgenerallyexhibithigher

cardiovasculareventratesfollowingmyocardialinfarctionthandopatientswithnormalCYP2C19function(seesection

5.2).

SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofdrugsthatinhibittheactivityof

thisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteofclopidogrelandareduction

inclinicalefficacy.ConcomitantuseofdrugsthatinhibitCYP2C19shouldbediscouraged(seesection4.5foralistof

CYP2C19inhibitors,seealsosection5.2).

AlthoughtheevidenceofCYP2C19inhibitionvarieswithintheclassofProtonPumpInhibitors,clinicalstudies

suggestaninteractionbetweenclopidogrelandpossiblyallmembersofthisclass.Therefore,concomitantuseofProton

PumpInhibitorsshouldbeavoidedunlessabsolutelynecessary.Thereisnoevidencethatotherdrugsthatreduce

stomachacidsuchasH

blockersorantacidsinterferewithantiplateletactivityofclopidogrel.

Therapeuticexperiencewithclopidogrelislimitedinpatientswithrenalimpairment.Thereforeclopidogrelshouldbe

usedwithcautioninthesepatients(seesection4.2).

Experienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses.Clopidogrelshould

thereforebeusedwithcautioninthispopulation(seesection4.2).

Clopidogrelcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants:theconcomitantadministrationofclopidogrelwithoralanticoagulantsisnotrecommendedsince

itmayincreasetheintensityofbleedings(seesection4.4).

GlycoproteinIIb/IIIainhibitors:clopidogrelshouldbeusedwithcautioninpatientswhomaybeatriskofincreased

bleedingfromtrauma,surgeryorotherpathologicalconditionsthatreceiveconcomitantglycoproteinIIb/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

4.8)

Non-SteroidalAnti-InflammatoryDrugs(NSAIDs):inaclinicalstudyconductedinhealthyvolunteers,theconcomitant

administrationofclopidogrelandnaproxenincreasedoccultgastrointestinalbloodloss.However,duetothelackof

interactionstudieswithotherNSAIDsitispresentlyunclearwhetherthereisanincreasedriskofgastrointestinal

bleedingwithallNSAIDs.Consequently,NSAIDsincludingCox-2inhibitorsandclopidogrelshouldbeco-

administeredwithcaution(seesection4.4).

Otherconcomitanttherapy:

SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofdrugsthatinhibittheactivityof

thisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteofclopidogrelandareduction

inclinicalefficacy.ConcomitantuseofdrugsthatinhibitCYP2C19shouldbediscouraged(seesections4.4and5.2).

DrugsthatinhibitCYP2C19includeomeprazoleandesomeprazole,fluvoxamine,fluoxetine,moclobemide,

voriconazole,fluconazole,ticlopidine,ciprofloxacin,cimetidine,carbamazepine,oxcarbazepineandchloramphenicol.

ProtonPumpInhibitors:

AlthoughtheevidenceofCYP2C19inhibitionvarieswithintheclassofProtonPumpInhibitors,clinicalstudies

suggestaninteractionbetweenclopidogrelandpossiblyallmembersofthisclass.Therefore,concomitantuseofProton

PumpInhibitorsshouldbeavoidedunlessabsolutelynecessary.Thereisnoevidencethatotherdrugsthatreduce

stomachacidsuchasH

blockersorantacidsinterferewithantiplateletactivityofclopidogrel.

Anumberofotherclinicalstudieshavebeenconductedwithclopidogrelandotherconcomitantmedicinalproductsto

investigatethepotentialforpharmacodynamicandpharmacokineticinteractions.Noclinicallysignificant

pharmacodynamicinteractionswereobservedwhenclopidogrelwasco-administeredwithatenolol,nifedipine,orboth

atenololandnifedipine.Furthermore,thepharmacodynamicactivityofclopidogrelwasnotsignificantlyinfluencedby

theco-administrationofphenobarbital,cimetidine,oroestrogen.

Thepharmacokineticsofdigoxinortheophyllinewerenotmodifiedbytheco-administrationofclopidogrel.Antacids

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Datafromstudieswithhumanlivermicrosomesindicatedthatthecarboxylicacidmetaboliteofclopidogrelcould

inhibittheactivityofCytochromeP4502C9.Thiscouldpotentiallyleadtoincreasedplasmalevelsofmedicinal

productssuchasphenytoinandtolbutamideandtheNSAIDs,whicharemetabolisedbyCytochromeP4502C9.Data

fromtheCAPRIEstudyindicatethatphenytoinandtolbutamidecanbesafelyco-administeredwithclopidogrel.

Apartfromthespecificmedicinalproductinteractioninformationdescribedabove,interactionstudieswithclopidogrel

andsomemedicinalproductscommonlyadministeredinpatientswithatherothromboticdiseasehavenotbeen

performed.

However,patientsenteredintoclinicaltrialswithclopidogrelreceivedavarietyofconcomitantmedicinalproducts

includingdiuretics,betablockers,ACEI,calciumantagonists,cholesterolloweringagents,coronaryvasodilators,

antidiabeticagents(includinginsulin),antiepilepticagents,andGPIIb/IIIaantagonistswithoutevidenceofclinically

significantadverseinteractions.

4.6Fertility,pregnancyandlactation

Asnoclinicaldataonexposuretoclopidogrelduringpregnancyareavailable,itispreferablenottouseclopidogrel

duringpregnancyasaprecautionarymeasure.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

development,parturitionorpostnataldevelopment(seesection5.3).

Itisunknownwhetherclopidogrelisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

clopidogrelinbreastmilk.Asaprecautionarymeasure,breast-feedingshouldnotbecontinuedduringtreatmentwith

Clopidogrel.

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

incidenceofseverecaseswas1.4%forclopidogreland1.6%forASA.

InCURE,themajorbleedingeventrateforclopidogrel+ASAwasdose-dependentonASA(<100mg:2.6%;100-

200mg:3.5%;>200mg:4.9%)aswasthemajorbleedingeventrateforplacebo+ASA(<100mg:2.0%;100-200mg:

2.3%;>200mg:4.0%).Theriskofbleeding(life-threatening,major,minor,other)decreasedduringthecourseofthe

trial:0-1months(clopidogrel:9.6%;placebo:6.6%),1-3months(clopidogrel:4.5%;placebo:2.3%),3-6months

(clopidogrel:3.8%;placebo:1.6%),6-9months(clopidogrel:3.2%;placebo:1.5%),9-12months(clopidogrel:1.9%;

placebo:1.0%).Therewasnoexcessinmajorbleedswithclopidogrel+ASAwithin7daysaftercoronarybypassgraft

surgeryinpatientswhostoppedtherapymorethanfivedayspriortosurgery(4.4%clopidogrel+ASAvs.5.3%

placebo+ASA).Inpatientswhoremainedontherapywithinfivedaysofbypassgraftsurgery,theeventratewas9.6%

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InCLARITY,therewasanoverallincreaseinbleedingintheclopidogrel+ASAgroup(17.4%)vs.theplacebo+ASA

group(12.9%).Theincidenceofmajorbleedingwassimilarbetweengroups(1.3%versus1.1%fortheclopidogrel+

ASAandtheplacebo+ASAgroups,respectively).Thiswasconsistentacrosssubgroupsofpatientsdefinedby

baselinecharacteristics,andtypeoffibrinolyticorheparintherapy.

InCOMMIT,theoverallrateofnoncerebralmajorbleedingorcerebralbleedingwaslowandsimilarinbothgroups

(0.6%versus0.5%intheclopidogrel+ASAandtheplacebo+ASAgroups,respectively).

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

drugreactionsarepresentedinorderofdecreasingseriousness.

SystemOrgan

Class Common Uncommon Rare Veryrare

Bloodandthe

lymphaticsystem

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

reportedwithfatal

outcome),

headache,

paraesthesia,

dizziness Tastedisturbances

Eyedisorders Eyebleeding

(conjunctival,

ocular,retinal)

Earandlabyrinth

disorders Vertigo

Vasculardisorders Haematoma Serioushaemorrhage,

haemorrhageof

operativewound,

vasculitis,

hypotension

Respiratory,

thoracicand

mediastinal

disorders Epistaxis Respiratorytract

bleeding

(haemoptysis,

pulmonary

haemorrhage),

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4.9Overdose

Overdosefollowingclopidogreladministrationmayleadtoprolongedbleedingtimeandsubsequentbleeding

complications.Appropriatetherapyshouldbeconsideredifbleedingsareobserved.Noantidotetothepharmacological

activityofclopidogrelhasbeenfound.Ifpromptcorrectionofprolongedbleedingtimeisrequired,platelettransfusion

interstitial

pneumonitis

Gastrointestinal

disorders Gastrointestinal

haemorrhage,

diarrhoea,

abdominal

pain,dyspepsia Gastriculcerand

duodenalulcer,

gastritis,vomiting,

nausea,

constipation,

flatulence Retroperitoneal

haemorrhage Gastrointestinaland

retroperitoneal

haemorrhagewith

fataloutcome,

pancreatitis,colitis

(includingulcerative

orlymphocytic

colitis),stomatitis

Hepato-

biliary

disorders Acuteliverfailure,

hepatitis,abnormal

liverfunctiontest

Skinand

subcutaneous

tissue

disorders Bruising Rash,pruritus,

skinbleeding

(purpura) Bullousdermatitis

(toxicepidermal

necrolysis,Stevens

JohnsonSyndrome,

erythema

multiforme),

angioedema,rash

erythematous,

urticaria,eczema,

lichenplanus

Musculoskeletal,

connective

tissueand

bone

disorders Musculo-skeletal

bleeding

(haemarthrosis),

arthritis,arthralgia,

myalgia

Renaland

urinary

disorders Haematuria Glomerulonephritis,

bloodcreatinine

increased

General

disordersand

administration

site

conditions Bleedingat

puncturesite Fever

Investigations Bleedingtime

prolonged,

neutrophilcount

decreased,platelet

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:plateletaggregationinhibitorsexcl.heparin,ATCCode:B01AC04.

Clopidogrelisaprodrug,oneofwhosemetabolitesisaninhibitorofplateletaggregation.Clopidogrelmustbe

metabolisedbyCYP450enzymestoproducetheactivemetabolitethatinhibitsplateletaggregation.Theactive

metaboliteofclopidogrelselectivelyinhibitsthebindingofadenosinediphosphate(ADP)toitsplateletP2Y

receptor

andthesubsequentADP -mediatedactivationoftheglycoproteinGPIIb/IIIacomplex,therebyinhibitingplatelet

aggregation.Duetotheirreversiblebinding,plateletsexposedareaffectedfortheremainderoftheirlifespan

(approximately7-10days)andrecoveryofnormalplateletfunctionoccursatarateconsistentwithplateletturnover.

PlateletaggregationinducedbyagonistsotherthanADPisalsoinhibitedbyblockingtheamplificationofplatelet

activationbyreleasedADP.

BecausetheactivemetaboliteisformedbyCYP450enzymes,someofwhicharepolymorphicorsubjecttoinhibition

byotherdrugs,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,forevery1,000patientstreatedfor2years,to10[CI:0to20]additionalpatients

beingpreventedfromexperiencinganewischaemicevent.Analysisoftotalmortalityasasecondaryendpointdidnot

showanysignificantdifferencebetweenclopidogrel(5.8%)andASA(6.0%).

Inasubgroupanalysisbyqualifyingcondition(myocardialinfarction,ischaemicstroke,andPAD)thebenefitappeared

tobestrongest(achievingstatisticalsignificanceatp=0.003)inpatientsenrolledduetoPAD(especiallythosewho

alsohadahistoryofmyocardialinfarction)(RRR=23.7%;CI:8.9to36.2)andweaker(notsignificantlydifferent

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

thesolebasisofarecentmyocardialinfarction,clopidogrelwasnumericallyinferior,butnotstatisticallydifferentfrom

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

clopidogrelinpatientsover75yearswaslessthanthatobservedinpatients75years.

SincetheCAPRIEtrialwasnotpoweredtoevaluateefficacyofindividualsubgroups,itisnotclearwhetherthe

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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

notsignificantlyaffectedbytheconcomitantheparintherapy.

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),duringthe0-1,1-3,3-6,6-9and9-12

monthstudyintervals,respectively.Thus,beyond3monthsoftreatment,thebenefitobservedintheclopidogrel+ASA

groupwasnotfurtherincreased,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)was1,035

(16.5%)intheclopidogrel-treatedgroupand1,187(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-hocanalysisin2,172patients(17%ofthetotalCUREpopulation)whounderwent

stentplacement(Stent-CURE),thedatashowedthatclopidogrelcomparedtoplacebo,demonstratedasignificantRRR

of26.2%favouringclopidogrelfortheco-primaryendpoint(CVdeath,MI,stroke)andalsoasignificantRRRof

23.9%forthesecondco-primaryendpoint(CVdeath,MI,strokeorrefractoryischaemia).Moreover,thesafetyprofile

ofclopidogrelinthissubgroupofpatientsdidnotraiseanyparticularconcern.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=1,752)or

placebo(n=1,739),bothincombinationwithASA(150to325mgasaloadingdose,followedby75to162mg/day),a

fibrinolyticagentand,whenappropriate,heparin.Thepatientswerefollowedfor30days.Theprimaryendpointwas

theoccurrenceofthecompositeofanoccludedinfarct-relatedarteryonthepredischargeangiogram,ordeathor

recurrentMIbeforecoronaryangiography.Forpatientswhodidnotundergoangiography,theprimaryendpointwas

deathorrecurrentmyocardialinfarctionbyDay8orbyhospitaldischarge.Thepatientpopulationincluded19.7%

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

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Fifteenpercent(15.0%)ofpatientsintheclopidogrelgroupand21.7%intheplacebogroupreachedtheprimary

endpoint,representinganabsolutereductionof6.7%anda36%oddsreductioninfavorofclopidogrel(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%

70years)and54.5%patientswhoreceivedfibrinolytics.

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)occurredapproximately

45minutesafterdosing.Absorptionisatleast50%,basedonurinaryexcretionofclopidogrelmetabolites.

Distribution

Clopidogrelandthemaincirculating(inactive)metabolitebindreversiblyinvitrotohumanplasmaproteins(98%and

94%respectively).Thebindingisnon -saturableinvitrooverawideconcentrationrange.

Metabolism

Clopidogrelisextensivelymetabolisedbytheliver.Invitroandinvivo,clopidogrelismetabolisedaccordingtotwo

mainmetabolicpathways:onemediatedbyesterasesandleadingtohydrolysisintoitsinactivecarboxylicacid

derivative(85%ofcirculatingmetabolites),andonemediatedbymultiplecytochromesP450.Clopidogrelisfirst

metabolisedtoa2-oxo-clopidogrelintermediatemetabolite.Subsequentmetabolismofthe2-oxo-clopidogrel

intermediatemetaboliteresultsinformationoftheactivemetabolite,athiolderivativeofclopidogrel.Invitro,this

metabolicpathwayismediatedbyCYP3A4,CYP2C19,CYP1A2andCYP2B6.Theactivethiolmetabolitewhichhas

beenisolatedinvitro,bindsrapidlyandirreversiblytoplateletreceptors,thusinhibitingplateletaggregation.

Elimination

Followinganoraldoseof 14

C-labelledclopidogrelinman,approximately50%wasexcretedintheurineand

approximately46%inthefaecesinthe120-hourintervalafterdosing.Afterasingleoraldoseof75mg,clopidogrel

hasahalf -lifeofapproximately6hours.Theeliminationhalf-lifeofthemaincirculating(inactive)metabolitewas

8hoursaftersingleandrepeatedadministration.

Pharmacogenetics

SeveralpolymorphicCYP450enzymesactivateclopidogrel.CYP2C19isinvolvedintheformationofboththeactive

metaboliteandthe2-oxo-clopidogrelintermediatemetabolite.Clopidogrelactivemetabolitepharmacokineticsand

antiplateleteffects,asmeasuredbyexvivoplateletaggregationassays,differaccordingtoCYP2C19genotype.The

CYP2C19*1allelecorrespondstofullyfunctionalmetabolismwhiletheCYP2C19*2andCYP2C19*3alleles

correspondtoreducedmetabolism.TheCYP2C19*2andCYP2C19*3allelesaccountfor85%ofreducedfunction

allelesinwhitesand99%inAsians.OtherallelesassociatedwithreducedmetabolismincludeCYP2C19*4,*5,*6,*7,

and*8,butthesearelessfrequentinthegeneralpopulation.PublishedfrequenciesforthecommonCYP2C19

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Todate,theimpactofCYP2C19genotypeonthepharmacokineticsoftheactivemetaboliteofclopidogrelhasbeen

evaluatedin227subjectsfrom7reportedstudies.ReducedCYP2C19metabolisminintermediateandpoor

metabolisersdecreasedtheC

andAUCoftheactivemetaboliteby30 -50%following300-or600-mgloading

dosesand75 -mgmaintenancedoses.Loweractivemetaboliteexposureresultsinlessplateletinhibitionorhigher

residualplateletreactivity.Todate,diminishedantiplateletresponsestoclopidogrelhavebeendescribedfor

intermediateandpoormetabolisersin21reportedstudiesinvolving4,520subjects.Therelativedifferencein

antiplateletresponsebetweengenotypegroupsvariesacrossstudiesdependingonthemethodusedtoevaluate

response,butistypicallygreaterthan30%.

TheassociationbetweenCYP2C19genotypeandclopidogreltreatmentoutcomewasevaluatedin2posthocclinical

trialanalyses(substudiesofCLARITY[n=465]andTRITON -TIMI38[n=1,477])and5cohortstudies(total

n=6,489).InCLARITYandoneofthecohortstudies(n=765;Trenk),cardiovasculareventratesdidnotdiffer

significantlybygenotype.InTRITON -TIMI38and3ofthecohortstudies(n=3,516;Collet,Sibbing,Giusti),patients

withanimpairedmetaboliserstatus(intermediateandpoorcombined)hadahigherrateofcardiovascularevents(death,

myocardialinfarction,andstroke)orstentthrombosiscomparedtoextensivemetabolisers.Inthefifthcohortstudy

(n=2,208;Simon),theincreasedeventratewasobservedonlyinpoormetabolisers.

PharmacogenetictestingcanidentifygenotypesassociatedwithvariabilityinCYP2C19activity.

TheremaybegeneticvariantsofotherCYP450enzymeswitheffectsontheabilitytoformtheactivemetaboliteof

clopidogrel.

Specialpopulations

Thepharmacokineticsoftheactivemetaboliteofclopidogrelisnotknowninthesespecialpopulations.

Renalimpairment

Afterrepeateddosesof75mgclopidogrelperdayinsubjectswithsevererenaldisease(creatinineclearancefrom5to

15ml/min),inhibitionofADP -inducedplateletaggregationwaslower(25%)thanthatobservedinhealthysubjects,

however,theprolongationofbleedingtimewassimilartothatseeninhealthysubjectsreceiving75mgofclopidogrel

perday.Inaddition,clinicaltolerancewasgoodinallpatients.

Hepaticimpairment

Afterrepeateddosesof75mgclopidogrelperdayfor10daysinpatientswithseverehepaticimpairment,inhibitionof

-inducedplateletaggregationwassimilartothatobservedinhealthysubjects.Themeanbleedingtime

prolongationwasalsosimilarinthetwogroups.

Race

TheprevalenceofCYP2C19allelesthatresultinintermediateandpoorCYP2C19metabolismdiffersaccordingto

race/ethnicity(seePharmacogenetics).Fromliterature,limiteddatainAsianpopulationsareavailabletoassessthe

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5.3Preclinicalsafetydata

Duringnonclinicalstudiesinratandbaboon,themostfrequentlyobservedeffectswereliverchanges.Theseoccurred

atdosesrepresentingatleast25timestheexposureseeninhumansreceivingtheclinicaldoseof75mg/dayandwerea

consequenceofaneffectonhepaticmetabolisingenzymes.Noeffectonhepaticmetabolisingenzymeswasobservedin

humansreceivingclopidogrelatthetherapeuticdose.

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:

Mannitol(E421),

Lactoseanhydrous,

Cellulose,microcrystalline,

Butylhydroxyanisole(E320),

Silicacolloidalanhydrous,

Croscarmellosesodium,

Sodiumstearylfumarate

Coating:

Polyvinylalcohol,

Talc,

Titaniumdioxide(E171),

Macrogol3350,

Lecithin(soya),

redironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

14,15,28,30,50,50x1,56,60,84,90,98and100film-coatedtabletspackedinoPA-Aluminium-PVC/Aluminium

blisters.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

8MARKETINGAUTHORISATIONNUMBER

PA822/60/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20thMay2011

10DATEOFREVISIONOFTHETEXT

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