CLOPIDOGREL 75MG FILM-COATED TABLETS

Main information

  • Trade name:
  • CLOPIDOGREL 75MG FILM-COATED TABLETS
  • Dosage:
  • 75 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLOPIDOGREL 75MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1339/026/001
  • Authorization date:
  • 04-02-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clopidogrel75mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains75mgofclopidogrel(asclopidogrelhydrochloride).

Excipients:eachtabletcontains5.25mghydrogenatedcastoroil.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Pink,round,biconvextabletswithabevellededge,plainonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clopidogrelisindicatedinadultsforthepreventionofatherothromboticeventsin:

Patientssufferingfrommyocardialinfarction(fromafewdaysuntillessthan35days),ischaemicstroke(from7days

untillessthan6months)orestablishedperipheralarterialdisease.

Forfurtherinformationpleaserefertosection5.1.

4.2Posologyandmethodofadministration

Posology

Adultsandelderly

Clopidogrelshouldbegivenasasingledailydoseof75mg.

Ifadoseismissed:

Withinlessthan12hoursafterregularscheduledtime:patientsshouldtakethedoseimmediatelyandthentakethenext

doseattheregularscheduledtime.

Formorethan12hours:patientsshouldtakethenextdoseattheregularscheduledtimeandshouldnotdoublethedose.

Paediatricpopulation

Thesafetyandefficacyofclopidogrelinchildrenandadolescentsunder18yearsoldhavenotyetbeenestablished.

Renalimpairment

Therapeuticexperienceislimitedinpatientswithrenalimpairment(seesection4.4).

Hepaticimpairment

Therapeuticexperienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses(seesection4.4).

Methodofadministration

Fororaluse

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4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Severehepaticimpairment.

Activepathologicalbleedingsuchaspepticulcerorintracranialhaemorrhage.

4.4Specialwarningsandprecautionsforuse

Bleedingandhaematologicaldisorders

Duetotheriskofbleedingandhaematologicaladversereactions,bloodcellcountdeterminationand/orotherappropriatetesting

shouldbepromptlyconsideredwheneverclinicalsymptomssuggestiveofbleedingariseduringthecourseoftreatment(see

section4.8).Aswithotherantiplateletagents,clopidogrelshouldbeusedwithcautioninpatientswhomaybeatriskofincreased

bleedingfromtrauma,surgeryorotherpathologicalconditionsandinpatientsreceivingtreatmentwithASA,heparin,

glycoproteinIIb/IIIainhibitorsornonsteroidalanti-inflammatorydrugs(NSAIDs)includingCox-2inhibitors.Patientsshouldbe

followedcarefullyforanysignsofbleedingincludingoccultbleeding,especiallyduringthefirstweeksoftreatmentand/orafter

invasivecardiacproceduresorsurgery.Theconcomitantadministrationofclopidogrelwithoralanticoagulantsisnot

recommendedsinceitmayincreasetheintensityofbleedings(seesection4.5).

Ifapatientistoundergoelectivesurgeryandantiplateleteffectistemporarilynotdesirable,clopidogrelshouldbediscontinued7

dayspriortosurgery.Patientsshouldinformphysiciansanddentiststhattheyaretakingclopidogrelbeforeanysurgeryis

scheduledandbeforeanynewmedicinalproductistaken.Clopidogrelprolongsbleedingtimeandshouldbeusedwithcautionin

patientswhohavelesionswithapropensitytobleed(particularlygastrointestinalandintraocular).

Patientsshouldbetoldthatitmighttakelongerthanusualtostopbleedingwhentheytakeclopidogrel(aloneorincombination

withASA),andthattheyshouldreportanyunusualbleeding(siteorduration)totheirphysician.

ThromboticThrombocytopenicPurpura(TTP)

ThromboticThrombocytopenicPurpura(TTP)hasbeenreportedveryrarelyfollowingtheuseofclopidogrel,sometimesaftera

shortexposure.Itischaracterisedbythrombocytopeniaandmicroangiopathichaemolyticanaemiaassociatedwitheither

neurologicalfindings,renaldysfunctionorfever.TTPisapotentiallyfatalconditionrequiringprompttreatmentincluding

plasmapheresis.

Recentischaemicstroke

Inviewofthelackofdata,clopidogrelcannotberecommendedduringthefirst7daysafteracuteischaemicstroke.

CytochromeP4502C19(CYP2C19)

Pharmacogenetics:InpatientswhoarepoorCYP2C19metabolisers,clopidogrelatrecommendeddosesformslessoftheactive

metaboliteofclopidogrelandhasasmallereffectonplateletfunction.Testsareavailabletoidentifyapatient'sCYP2C19

genotype.

SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofmedicinalproductsthatinhibittheactivityof

thisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteofclopidogrel.Theclinicalrelevanceof

thisinteractionisuncertain.AsaprecautionconcomitantuseofstrongormoderateCYP2C19inhibitorsshouldbediscouraged

(seesection4.5foralistofCYP2C19inhibitors,seealsosection5.2).

Renalimpairment

Therapeuticexperiencewithclopidogrelislimitedinpatientswithrenalimpairment.Thereforeclopidogrelshouldbeusedwith

cautioninthesepatients(seesection4.2).

Hepaticimpairment

Experienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses.Clopidogrelshouldthereforebe

usedwithcautioninthispopulation(seesection4.2).

Excipients

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants:theconcomitantadministrationofclopidogrelwithoralanticoagulantsisnotrecommendedsinceitmay

increasetheintensityofbleedings(seesection4.4).Althoughtheadministrationofclopidogrel75mg/daydidnotmodifythe

pharmacokineticsofS -warfarinorInternationalNormalisedRatio(INR)inpatientsreceivinglong-termwarfarintherapy,

coadministrationofclopidogrelwithwarfarinincreasestheriskofbleedingbecauseofindependenteffectsonhemostasis.

GlycoproteinIIb/IIIainhibitors:clopidogrelshouldbeusedwithcautioninpatientswhoreceiveconcomitantglycoproteinIIb/IIIa

inhibitors(seesection4.4).

Acetylsalicylicacid(ASA):ASAdidnotmodifytheclopidogrel-mediatedinhibitionofADP-inducedplateletaggregation,but

clopidogrelpotentiatedtheeffectofASAoncollagen-inducedplateletaggregation.However,concomitantadministrationof500

mgofASAtwiceadayforonedaydidnotsignificantlyincreasetheprolongationofbleedingtimeinducedbyclopidogrelintake.

Apharmacodynamicinteractionbetweenclopidogrelandacetylsalicylicacidispossible,leadingtoincreasedriskofbleeding.

Therefore,concomitantuseshouldbeundertakenwithcaution(seesection4.4).However,clopidogrelandASAhavebeen

administeredtogetherforuptooneyear(seesection5.1).

Heparin:inaclinicalstudyconductedinhealthysubjects,clopidogreldidnotnecessitatemodificationoftheheparindoseoralter

theeffectofheparinoncoagulation.Co-administrationofheparinhadnoeffectontheinhibitionofplateletaggregationinduced

byclopidogrel.Apharmacodynamicinteractionbetweenclopidogrelandheparinispossible,leadingtoincreasedriskofbleeding.

Therefore,concomitantuseshouldbeundertakenwithcaution(seesection4.4).

Thrombolytics:thesafetyoftheconcomitantadministrationofclopidogrel,fibrinornon-fibrinspecificthrombolyticagentsand

heparinswasassessedinpatientswithacutemyocardialinfarction.Theincidenceofclinicallysignificantbleedingwassimilarto

thatobservedwhenthrombolyticagentsandheparinareco-administeredwithASA(seesection4.8).

NSAIDs:inaclinicalstudyconductedinhealthyvolunteers,theconcomitantadministrationofclopidogrelandnaproxenincreased

occultgastrointestinalbloodloss.However,duetothelackofinteractionstudieswithotherNSAIDsitispresentlyunclear

whetherthereisanincreasedriskofgastrointestinalbleedingwithallNSAIDs.Consequently,NSAIDsincludingCox-2inhibitors

andclopidogrelshouldbeco-administeredwithcaution(seesection4.4).

Otherconcomitanttherapy:SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofmedicinal

productsthatinhibittheactivityofthisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteof

clopidogrel.Theclinicalrelevanceofthisinteractionisuncertain.Asaprecautionconcomitantuseofstrongormoderate

CYP2C19inhibitorsshouldbediscouraged(seeSections4.4and5.2).

MedicinalproductsthatinhibitCYP2C19includeomeprazoleandesomeprazole,fluvoxamine,fluoxetine,moclobemide,

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

ProtonPumpInhibitors(PPI):

Omeprazole80mgoncedailyadministeredeitheratthesametimeasclopidogrelorwith12hoursbetweentheadministrationsof

thetwodrugsdecreasedtheexposureoftheactivemetaboliteby45%(loadingdose)and40%(maintenancedose).Thedecrease

wasassociatedwitha39%(loadingdose)and21%(maintenancedose)reductioninhibitionofplateletaggregation.Esomeprazole

isexpectedtogiveasimilarinteractionwithclopidogrel.

Inconsistentdataontheclinicalimplicationsofthispharmacokinetic(PK)/pharmacodynamic(PD)interactionintermsofmajor

cardiovasculareventshavebeenreportedfrombothobservationalandclinicalstudies.Asaprecaution,concomitantuseof

omeprazoleoresomeprazoleshouldbediscouraged(seesection4.4

Lesspronouncedreductionsofmetaboliteexposurehasbeenobservedwithpantoprazoleorlansoprazole.

Theplasmaconcentrationsoftheactivemetabolitewas20%reduced(loadingdose)and14%reduced(maintenancedose)during

concomitanttreatmentwithpantoprazole80mgoncedaily.Thiswasassociatedwithareductionofthemeaninhibitionofplatelet

aggregationby15%and11%,respectively.Theseresultsindicatethatclopidogrelcanbeadministeredwithpantoprazole.

ThereisnoevidencethatothermedicinalproductsthatreducestomachacidsuchasH2blockers(exceptcimetidinewhichisa

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Othermedicinalproducts:Anumberofotherclinicalstudieshavebeenconductedwithclopidogrelandotherconcomitant

medicinalproductstoinvestigatethepotentialforpharmacodynamicandpharmacokineticinteractions.Noclinicallysignificant

pharmacodynamicinteractionswereobservedwhenclopidogrelwasco-administeredwithatenolol,nifedipine,orbothatenolol

andnifedipine.Furthermore,thepharmacodynamicactivityofclopidogrelwasnotsignificantlyinfluencedbytheco-

administrationofphenobarbitaloroestrogen.

Thepharmacokineticsofdigoxinortheophyllinewerenotmodifiedbytheco-administrationofclopidogrel.Antacidsdidnot

modifytheextentofclopidogrelabsorption.

DatafromtheCAPRIEstudyindicatethatphenytoinandtolbutamidewhicharemetabolisedbyCYP2C9canbesafelyco-

administeredwithclopidogrel.

Apartfromthespecificmedicinalproductinteractioninformationdescribedabove,interactionstudieswithclopidogrelandsome

medicinalproductscommonlyadministeredinpatientswithatherothromboticdiseasehavenotbeenperformed.However,patients

enteredintoclinicaltrialswithclopidogrelreceivedavarietyofconcomitantmedicinalproductsincludingdiuretics,betablockers,

ACEI,calciumantagonists,cholesterolloweringagents,coronaryvasodilators,antidiabeticagents(includinginsulin),

antiepilepticagents,andGPIIb/IIIaantagonistswithoutevidenceofclinicallysignificantadverseinteractions.

4.6Fertility,pregnancyandlactation

Pregnancy

Asnoclinicaldataonexposuretoclopidogrelduringpregnancyareavailable,itispreferablenottouseclopidogrel

duringpregnancyasaprecautionarymeasure.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

development,parturitionorpostnataldevelopment(seesection5.3).

Breast-feeding

Itisunknownwhetherclopidogrelisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

clopidogrelinbreastmilk.Asaprecautionarymeasure,breast-feedingshouldnotbecontinuedduringtreatmentwith

Clopidogrel75mgfilm-coatedtablets.

Fertility

Clopidogrelwasnotshowntoalterfertilityinanimalstudies.

4.7Effectsonabilitytodriveandusemachines

Clopidogrelhasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Clopidogrelhasbeenevaluatedforsafetyinmorethan42,000patientswhohaveparticipatedinclinicalstudies,includingover

9,000patientstreatedfor1yearormore.TheclinicallyrelevantadversereactionsobservedintheCAPRIE,CURE,CLARITY

andCOMMITstudiesarediscussedbelow.Overall,clopidogrel75mg/daywascomparabletoASA325mg/dayinCAPRIE

regardlessofage,genderandrace.Inadditiontoclinicalstudiesexperience,adversereactionshavebeenspontaneouslyreported.

Bleedingisthemostcommonreactionreportedbothinclinicalstudiesaswellasinpost-marketingexperiencewhereitwas

mostlyreportedduringthefirstmonthoftreatment.

InCAPRIE,inpatientstreatedwitheitherclopidogrelorASA,theoverallincidenceofanybleedingwas9.3%.Theincidenceof

severecaseswassimilarforclopidogrelandASA.

InCURE,therewasnoexcessinmajorbleedswithclopidogrelplusASAwithin7daysaftercoronarybypassgraftsurgeryin

patientswhostoppedtherapymorethanfivedayspriortosurgery.Inpatientswhoremainedontherapywithinfivedaysofbypass

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InCLARITY,therewasanoverallincreaseinbleedingintheclopidogrelplusASAgroupvs.theplaceboplusASAgroup.The

incidenceofmajorbleedingwassimilarbetweengroups.Thiswasconsistentacrosssubgroupsofpatientsdefinedbybaseline

characteristics,andtypeoffibrinolyticorheparintherapy.

InCOMMIT,theoverallrateofnoncerebralmajorbleedingorcerebralbleedingwaslowandsimilarinbothgroups.

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.

SystemOrgan

Class Common Uncommon Rare Veryrare

Bloodandthe

lymphaticsystem

disorders Thrombocytopenia,

leucopenia,eosinophilia Neutropenia,

includingsevere

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 Intracranialbleeding

(somecaseswere

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),

bronchospasm,

interstitial

pneumonitis

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4.9Overdose

Overdosefollowingclopidogreladministrationmayleadtoprolongedbleedingtimeandsubsequentbleeding

complications.Appropriatetherapyshouldbeconsideredifbleedingsareobserved.

Noantidotetothepharmacologicalactivityofclopidogrelhasbeenfound.Ifpromptcorrectionofprolongedbleeding

timeisrequired,platelettransfusionmayreversetheeffectsofclopidogrel.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:plateletaggregationinhibitorsexcludingheparin,ATCCode:B01AC-04.

Clopidogrelisaprodrug,oneofwhosemetabolitesisaninhibitorofplateletaggregation.Clopidogrelmustbe

metabolisedbyCYP450enzymestoproducetheactivemetabolitethatinhibitsplateletaggregation.Theactive

metaboliteofclopidogrelselectivelyinhibitsthebindingofadenosinediphosphate(ADP)toitsplateletP2Y

receptor,andthesubsequentADP-mediatedactivationoftheglycoproteinGPIIb/IIIacomplex,therebyinhibiting

plateletaggregation.Duetotheirreversiblebinding,plateletsexposedareaffectedfortheremainderoftheirlifespan

(approximately7-10days)andrecoveryofnormalplateletfunctionoccursatarateconsistentwithplateletturnover.

disorders haemorrhage,

diarrhoea,

abdominalpain,

dyspepsia duodenalulcer,gastritis,

vomiting,nausea,

constipation,flatulence haemorrhage retroperitoneal

haemorrhagewith

fataloutcome,

pancreatitis,colitis

(includingulcerative

orlymphocytic

colitis),stomatitis

Hepato-biliary

disorders Acuteliverfailure,

hepatitis,abnormal

liverfunctiontest

Skinand

subcutaneous

tissuedisorders Bruising Rash,pruritus,skin

bleeding(purpura) Bullousdermatitis

(toxicepidermal

necrolysis,Stevens

JohnsonSyndrome,

erythema

multiforme),

angioedema,rash

erythematous,

urticaria,eczema,

lichenplanus

Musculoskeletal

connectivetissue

andbonedisorders Musculo-skeletal

bleeding

(haemarthrosis),

arthritis,arthralgia,

myalgia

Renalandurinary

disorders Haematuria Glomerulonephritis,

bloodcreatinine

increased

Generaldisorders

andadministration

siteconditions Bleedingat

puncturesite Fever

Investigations Bleedingtimeprolonged,

neutrophilcount

decreased,plateletcount

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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,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

clopidogrelinpatientsover75yearswaslessthanthatobservedinpatients<75years.

SincetheCAPRIEtrialwasnotpoweredtoevaluateefficacyofindividualsubgroups,itisnotclearwhetherthe

differencesinrelativeriskreductionacrossqualifyingconditionsarereal,oraresultofchance.

5.2Pharmacokineticproperties

Absorption

Aftersingleandrepeatedoraldosesof75mgperday,clopidogrelisrapidlyabsorbed.Meanpeakplasmalevelsofunchanged

clopidogrel(approximately2.2-2.5ng/mlafterasingle75mgoraldose)occurredapproximately45minutesafterdosing.

Absorptionisatleast50%,basedonurinaryexcretionofclopidogrelmetabolites.

Distribution

Clopidogrelandthemaincirculating(inactive)metabolitebindreversiblyinvitrotohumanplasmaproteins(98%and94%

respectively).Thebindingisnon-saturableinvitrooverawideconcentrationrange.

Metabolism

Clopidogrelisextensivelymetabolisedbytheliver.Invitroandinvivo,clopidogrelismetabolisedaccordingtotwomain

metabolicpathways:onemediatedbyesterasesandleadingtohydrolysisintoitsinactivecarboxylicacidderivative(85%of

circulatingmetabolites),andonemediatedbymultiplecytochromesP450.Clopidogrelisfirstmetabolisedtoa2-oxo-clopidogrel

intermediatemetabolite.Subsequentmetabolismofthe2-oxo-clopidogrelintermediatemetaboliteresultsintheformationofthe

activemetabolite,athiolderivativeofclopidogrel.Invitro,themetabolicpathwayismediatedbyCYP3A4,CYP2C19,CYP1A2

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inhibitingplateletaggregation.

TheC

oftheactivemetaboliteistwiceashighfollowingasingle300 -mgclopidogrelloadingdoseasitisafterfourdaysof

75-mgmaintenancedose.C

occursapproximately30to60minutesafterdosing.

Elimination

Followinganoraldoseof 14

C-labelledclopidogrelinman,approximately50%wasexcretedintheurineandapproximately46%

inthefaecesinthe120-hourintervalafterdosing.Afterasingleoraldoseof75mg,clopidogrelhasahalf-lifeofapproximately6

hours.Theeliminationhalf-lifeofthemaincirculatingmetabolitewas8hoursaftersingleandrepeatedadministration.

Pharmacogenetics

CYP2C19isinvolvedintheformationofboththeactivemetaboliteandthe2-oxo-clopidogrelintermediatemetabolite.

Clopidogrelactivemetabolitepharmacokineticsandantiplateleteffects,asmeasuredbyexvivoplateletaggregationassays,differ

accordingtoCYP2C19genotype.

TheCYP2C19*1allelecorrespondstofullyfunctionalmetabolismwhiletheCYP2C19*2andCYP2C19*3allelesarenon-

functional.TheCYP2C19*2andCYP2C19*3allelesaccountforthemajorityofreducedfunctionallelesinCaucasian(85%)and

Asians(99%)poormetabolisers.Otherallelesassociatedwithabsentorreducedmetabolismarelessfrequentandinclude

CYP2C19*4,*5,*6,*7,and*8.Apatientwithpoormetaboliserstatuswillpossesstwoloss-of-functionallelesasdefinedabove.

PublishedfrequenciesforthepoorCYP2C19metabolisergenotypesareapproximately2%forCaucasians,4%forBlacksand

14%forChinese.Testsareavailabletodetermineapatient’sCYP2C19gentoype.

Acrossoverstudyin40healthysubjects,10eachinthefourCYP2C19metabolisergroups(ultrarapid,extensive,intermediateand

poor),evaluatedpharmacokineticandantiplateletresponsesusing300mgfollowedby75mg/dayand600mgfollowedby

150mg/day,eachforatotalof5days(steadystate).Nosubstantialdifferencesinactivemetaboliteexposureandmeaninhibition

ofplateletaggregation(IPA)wereobservedbetweenultrarapid,extensiveandintermediatemetabolisers.Inpoormetabolisers,

activemetaboliteexposurewasdecreasedby63 -71%comparedtoextensivemetabolisers.Afterthe300mg/75mgdoseregimen,

antiplateletresponsesweredecreasedinthepoormetaboliserswithmeanIPA(5µMADP)of24%(24hours)and37%(Day5)as

comparedtoIPAof39%(24hours)and58%(Day5)intheextensivemetabolisersand37%(24hours)and60%(Day5)inthe

intermediatemetabolisers.Whenpoormetabolisersreceivedthe600mg/150mgregimen,activemetaboliteexposurewasgreater

thanwiththe300mg/75mgregimen.Inaddition,IPAwas32%(24hours)and61%(Day5),whichweregreaterthaninthepoor

metabolisersreceivingthe300mg/75mgregimen,andweresimilartotheotherCYP2C19metabolisergroupsreceivingthe

300mg/75mgregimen.Anappropriatedoseregimenforthispatientpopulationhasnotbeenestablishedinclinicaloutcome

trials.

Consistentwiththeaboveresults,inameta -analysisincluding6studiesof335clopidogrel-treatedsubjectsatsteadystate,itwas

shownthatactivemetaboliteexposurewasdecreasedby28%forintermediatemetabolisers,and72%forpoormetaboliserswhile

plateletaggregationinhibition(5µMADP)wasdecreasedwithdifferencesinIPAof5.9%and21.4%,respectively,when

comparedtoextensivemetabolisers.

TheinfluenceofCYP2C19genotypeonclinicaloutcomesinpatientstreatedwithclopidogrelhasnotbeenevaluatedin

prospective,randomised,controlledtrials.Therehavebeenanumberofretrospectiveanalyses,however,toevaluatethiseffectin

patientstreatedwithclopidogrelforwhomtherearegenotypingresults:CURE(n=2721),CHARISMA(n=2428),

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

studies.

InTRITON -TIMI38and3ofthecohortstudies(Collet,Sibbing,Giusti)thecombinedgroupofpatientswitheitherintermediate

orpoormetaboliserstatushadahigherrateofcardiovascularevents(death,myocardialinfarction,andstroke)orstentthrombosis

comparedtoextensivemetabolisers.

InCHARISMAandonecohortstudy(Simon),anincreasedeventratewasobservedonlyinpoormetaboliserswhencomparedto

extensivemetabolisers.

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

metaboliserstatus.

Noneoftheseanalyseswereadequatelysizedtodetectdifferencesinoutcomeinpoormetabolisers.

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Thepharmacokineticsoftheactivemetaboliteofclopidogrelisnotknowninthesespecialpopulations.

Renalimpairment

Afterrepeateddosesof75mgclopidogrelperdayinsubjectswithsevererenaldisease(creatinineclearancefrom5to15ml/ml),

inhibitionofADP-inducedplateletaggregationwaslower(25%)thanthatobservedinhealthysubjects,however,theprolongation

ofbleedingtimewassimilartothatseeninhealthysubjectsreceiving75mgofclopidogrelperday.Inaddition,clinicaltolerance

wasgoodinallpatients.

Hepaticimpairment

Afterrepeateddosesof75mgclopidogrelperdayfor10daysinpatientswithseverehepaticimpairment,inhibitionofADP-

inducedplateletaggregationwassimilartothatobservedinhealthysubjects.Themeanbleedingtimeprolongationwasalso

similarinthetwogroups.

Race

TheprevalenceofCYP2C19allelesthatresultinintermediateandpoorCYP2C19metabolismdiffersaccordingtorace/ethnicity

(seePharmacogenetics).Fromliterature,limiteddatainAsianpopulationsareavailabletoassesstheclinicalimplicationof

genotypingofthisCYPonclinicaloutcomeevents.

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:

Macrogol6000

Microcrystallinecellulose

Lowsubstitutedhydroxypropylcellulose

Glyceroldibehenate

Castoroilhydrogenated

Coat:

OpadryII,pink,containing:

Ironoxidered(E172),

Macrogol4000

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Titaniumdioxide(E171)

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Blisterstrips(PVC/Aclarbaseoraluminiumbasewithaluminiumlid)containedinacardboardbox.Packsizeof28,

30,50and84film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialinstructions.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

WockhardtUKLtd

AshRoadNorth

Wrexham

LL139UF

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1339/26/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4thFebruary2011

10DATEOFREVISIONOFTHETEXT

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