CLOPIDOGREL PENSA 75 MG FILM-COATED TABLETS

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1647/004/001
  • Authorization date:
  • 26-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClopidogrelPensa75mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains75mgofclopidogrel(asclopidogrelbesilate).

Excipientwithknowneffect:eachtabletcontains2.80mgoflactosemonohydrate

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Pink,round,biconvex,film-coatedtabletswith'75'embossedononesideandadiameterofapproximately8.3mm.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clopidogrelisindicatedinadultsforthepreventionofatherothromboticeventsin:

Patientssufferingfrommyocardialinfarction(fromafewdaysuntillessthan35days),ischaemicstroke(from7days

untillessthan6months)orestablishedperipheralarterialdisease.

Forfurtherinformationpleaserefertosection5.1.

4.2Posologyandmethodofadministration

Posology

Adultsandelderly

Clopidogrelshouldbegivenasasingledailydoseof75mg.

Ifadoseismissed:

Withinlessthan12hoursafterregularscheduledtime:patientsshouldtakethedoseimmediatelyandthentakethenextdoseat

theregularscheduledtime.

Formorethan12hours:patientsshouldtakethenextdoseattheregularscheduledtimeandshouldnotdoublethedose.

Paediatricpopulation

Thesafetyandefficacyofclopidogrelinchildrenandadolescentsunder18yearsoldhavenotyetbeenestablished.

Renalimpairment

Therapeuticexperienceislimitedinpatientswithrenalimpairment(seesection4.4).

Hepaticimpairment

Therapeuticexperienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses(seesection4.4).

Methodofadministration

Fororaluse

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4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1.

Severehepaticimpairment.

Activepathologicalbleedingsuchaspepticulcerorintracranialhaemorrhage.

4.4Specialwarningsandprecautionsforuse

Bleedingandhaematologicaldisorders

Duetotheriskofbleedingandhaematologicaladversereactions,bloodcellcountdeterminationand/orotherappropriatetesting

shouldbepromptlyconsideredwheneverclinicalsymptomssuggestiveofbleedingariseduringthecourseoftreatment(see

section4.8).Aswithotherantiplateletagents,clopidogrelshouldbeusedwithcautioninpatientswhomaybeatriskofincreased

bleedingfromtrauma,surgeryorotherpathologicalconditionsandinpatientsreceivingtreatmentwithASA,heparin,

glycoproteinIIb/IIIainhibitorsornon-steroidalanti-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

ClopidogrelPensacontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

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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):Omeprazole80mgoncedailyadministeredeitheratthesametimeasclopidogrelorwith12hours

betweentheadministrationsofthetwodrugsdecreasedtheexposureoftheactivemetaboliteby45%(loadingdose)and40%

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

ofplateletaggregation.Esomeprazoleisexpectedtogiveasimilarinteractionwithclopidogrel.

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

CYP2C19inhibitor)orantacidsinterferewithantiplateletactivityofclopidogrel.

Othermedicinalproducts:Anumberofotherclinicalstudieshavebeenconductedwithclopidogrelandotherconcomitant

medicinalproductstoinvestigatethepotentialforpharmacodynamicandpharmacokineticinteractions.Noclinicallysignificant

pharmacodynamicinteractionswereobservedwhenclopidogrelwasco-administeredwithatenolol,nifedipine,orbothatenolol

andnifedipine.Furthermore,thepharmacodynamicactivityofclopidogrelwasnotsignificantlyinfluencedbytheco-

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Thepharmacokineticsofdigoxinortheophyllinewerenotmodifiedbytheco-administrationofclopidogrel.Antacidsdidnot

modifytheextentofclopidogrelabsorption.

DatafromtheCAPRIEstudyindicatethatphenytoinandtolbutamidewhicharemetabolisedbyCYP2C9canbesafelyco-

administeredwithclopidogrel.

Apartfromthespecificmedicinalproductinteractioninformationdescribedabove,interactionstudieswithclopidogrelandsome

medicinalproductscommonlyadministeredinpatientswithatherothromboticdiseasehavenotbeenperformed.However,patients

enteredintoclinicaltrialswithclopidogrelreceivedavarietyofconcomitantmedicinalproductsincludingdiuretics,betablockers,

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

antiepilepticagentsandGPIIb/IIIaantagonistswithoutevidenceofclinicallysignificantadverseinteractions.

4.6Fertility,pregnancyandlactation

Pregnancy

Asnoclinicaldataonexposuretoclopidogrelduringpregnancyareavailable,itispreferablenottouseclopidogrelduring

pregnancyasaprecautionarymeasure.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetaldevelopment,

parturitionorpostnataldevelopment(seesection5.3).

Breastfeeding

Itisunknownwhetherclopidogrelisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionofclopidogrelinbreast

milk.Asaprecautionarymeasure,breast-feedingshouldnotbecontinuedduringtreatmentwithclopidogrel.

Fertility

Clopidogrelwasnotshowntoalterfertilityinanimalstudies.

4.7Effectsonabilitytodriveandusemachines

Clopidogrelhasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Clopidogrelhasbeenevaluatedforsafetyinmorethan44,000patientswhohaveparticipatedinclinicalstudies,includingover

12,000patientstreatedfor1yearormore.Overall,clopidogrel75mg/daywascomparabletoASA325mg/dayinCAPRIE

regardlessofage,genderandrace.TheclinicallyrelevantadversereactionsobservedintheCAPRIE,CURE,CLARITY,

COMMITandACTIVE-Astudiesarediscussedbelow.Inadditiontoclinicalstudiesexperience,adversereactionshavebeen

spontaneouslyreported.

Bleedingisthemostcommonreactionreportedbothinclinicalstudiesaswellasinpost-marketingexperiencewhereitwas

mostlyreportedduringthefirstmonthoftreatment.

InCAPRIE,inpatientstreatedwitheitherclopidogrelorASA,theoverallincidenceofanybleedingwas9.3%.Theincidenceof

severecaseswassimilarforclopidogrelandASA.

InCURE,therewasnoexcessinmajorbleedswithclopidogrelplusASAwithin7daysaftercoronarybypassgraftsurgeryin

patientswhostoppedtherapymorethanfivedayspriortosurgery.Inpatientswhoremainedontherapywithinfivedaysof

bypassgraftsurgery,theeventratewas9.6%forclopidogrelplusASA,and6.3%forplaceboplusASA.

InCLARITY,therewasanoverallincreaseinbleedingintheclopidogrelplusASAgroupvs.theplaceboplusASAgroup.The

incidenceofmajorbleedingwassimilarbetweengroups.Thiswasconsistentacrosssubgroupsofpatientsdefinedbybaseline

characteristics,andtypeoffibrinolyticorheparintherapy.

InCOMMIT,theoverallrateofnoncerebralmajorbleedingorcerebralbleedingwaslowandsimilarinbothgroups.

InACTIVE-A,therateofmajorbleedingwasgreaterintheclopidogrel+ASAgroupthanintheplacebo+ASAgroup(6.7%

versus4.3%).Majorbleedingwasmostlyofextracranialorigininbothgroups(5.3%intheclopidogrel+ASAgroup;3.5%inthe

placebo+ASAgroup),mainlyfromthegastrointestinaltract(3.5%vs.1.8%).Therewasanexcessofintracranialbleedinginthe

clopidogrel+ASAtreatmentgroupcomparedtotheplacebo+ASAgroup(1.4%versus0.8%,respectively).Therewasno

statisticallysignificantdifferenceintheratesoffatalbleeding(1.1%intheclopidogrel+ASAgroupand0.7%intheplacebo

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Fortheavoidanceofanydoubt,acutecoronarysyndromeandcombinationtreatmentwithaspirinarenottherapeuticindications

ofClopidogrelPensa75mgfilm-coatedtablets.

Adversereactionsthatoccurredeitherduringclinicalstudiesorthatwerespontaneouslyreportedarepresentedinthetablebelow.

Theirfrequencyisdefinedusingthefollowingconventions:common(1/100to<1/10);uncommon(1/1,000to<1/100);rare

(1/10,000to<1/1,000);veryrare(<1/10,000).Withineachsystemorganclass,adversereactionsarepresentedinorderof

decreasingseriousness.

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,

anaphylactoidreactions

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,

haemorrhageofoperative

wound,vasculitis,

hypotension

Respiratory,

thoracicand

mediastinal

disorders Epistaxis Respiratorytractbleeding

(haemoptysis,pulmonary

haemorrhage),

bronchospasm,interstitial

pneumonitis

Gastrointestinal

disorders Gastrointestinal

haemorrhage,

diarrhoea,

abdominalpain,

dyspepsia Gastriculcerand

duodenalulcer,

gastritis,vomiting,

nausea,

constipation,

flatulence Retroperitoneal

haemorrhage Gastrointestinaland

retroperitoneal

haemorrhagewithfatal

outcome,pancreatitis,

colitis(includingulcerative

orlymphocyticcolitis),

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4.9Overdose

Overdosefollowingclopidogreladministrationmayleadtoprolongedbleedingtimeandsubsequentbleeding

complications.Appropriatetherapyshouldbeconsideredifbleedingsareobserved.Noantidotetothe

pharmacologicalactivityofclopidogrelhasbeenfound.Ifpromptcorrectionofprolongedbleedingtimeisrequired,

platelettransfusionmayreversetheeffectsofclopidogrel.

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

byothermedicinalproducts,notallpatientswillhaveadequateplateletinhibition.

Repeateddosesof75mgperdayproducedsubstantialinhibitionofADP-inducedplateletaggregationfromthefirst

day;thisincreasedprogressivelyandreachedsteadystatebetweenDay3andDay7.Atsteadystate,theaverage

inhibitionlevelobservedwithadoseof75mgperdaywasbetween40%and60%.Plateletaggregationandbleeding

Hepato-biliary

disorders Acuteliverfailure,

hepatitis,abnormalliver

functiontest

Skinand

subcutaneoustissue

disorders Bruising Rash,pruritus,

skinbleeding

(purpura) Bullousdermatitis(toxic

epidermalnecrolysis,

StevensJohnsonSyndrome,

erythemamultiforme),

angioedema,rash

erythematous,urticaria,

eczema,lichenplanus

Musculoskeletal,

connectivetissue

andbonedisorders Musculo-skeletalbleeding

(haemarthrosis),arthritis,

arthralgia,myalgia

Renalandurinary

disorders Haematuria Glomerulonephritis,blood

creatinineincreased

Generaldisorders

andadministration

siteconditions Bleedingat

puncturesite Fever

Investigations Bleedingtime

prolonged,

neutrophilcount

decreased,platelet

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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,mostofthepatientsreceivedASAforthefirstfewdaysfollowingtheacutemyocardial

infarction.

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(especiallythosewho

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

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

solebasisofarecentmyocardialinfarction,clopidogrelwasnumericallyinferior,butnotstatisticallydifferentfrom

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

clopidogrelinpatientsover75yearswaslessthanthatobservedinpatients75years.

SincetheCAPRIEtrialwasnotpoweredtoevaluateefficacyofindividualsubgroups,itisnotclearwhetherthe

differencesinrelativeriskreductionacrossqualifyingconditionsarereal,oraresultofchance.

Paediatricpopulation

Inadoseescalationstudyof86neonatesorinfantsupto24monthsofageatriskfor

thrombosis(PICOLO),clopidogrelwasevaluatedatconsecutivedosesof0.01,0.1and0.2mg/kginneonatesand

infantsand0.15mg/kgonlyinneonates.Thedoseof0.2mg/kgachievedthemeanpercentinhibitionof49.3%(5µM

ADP-inducedplateletaggregation)whichwascomparabletothatofadultstakingclopidogrel75mg/day.

Inarandomised,double-blind,parallel-groupstudy(CLARINET),906paediatricpatients(neonatesandinfants)with

cyanoticcongenitalheartdiseasepalliatedwithasystemic-topulmonaryarterialshuntwererandomisedtoreceive

clopidogrel0.2mg/kg(n=467)orplacebo(n=439)alongwithconcomitantbackgroundtherapyuptothetimeof

secondstagesurgery.Themeantimebetweenshuntpalliationandfirstadministrationofstudymedicinalproductwas

20days.Approximately88%ofpatientsreceivedconcomitantASA(rangeof1to23mg/kg/day).Therewasno

significantdifferencebetweengroupsintheprimarycompositeendpointofdeath,shuntthrombosisorcardiac-related

interventionpriorto120daysofagefollowinganeventconsideredofthromboticnature(89[19.1%]forthe

clopidogrelgroupand90[20.5%]fortheplacebogroup)(seesection4.2).Bleedingwasthemostfrequentlyreported

adversereactioninbothclopidogrelandplacebogroups;however,therewasnosignificantdifferenceinthebleeding

ratebetweengroups.Inthelong-term

safetyfollow-upofthisstudy,26patientswiththeshuntstillinplaceatoneyearofage

receivedclopidogrelupto18monthsofage.Nonewsafetyconcernswerenotedduringthislong-termfollow-up.

TheCLARINETandthePICOLOtrialswereconductedusingaconstitutedsolutionof

clopidogrel.Inarelativebioavailabilitystudyinadults,theconstitutedsolutionofclopidogrelshowedasimilarextent

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5.2Pharmacokineticproperties

Absorption

Aftersingleandrepeatedoraldosesof75mgperday,clopidogrelisrapidlyabsorbed.Meanpeakplasmalevelsofunchanged

clopidogrel(approximately2.2 -2.5ng/mlafterasingle75mgoraldose)occurredapproximately45minutesafter

dosing.Absorptionisatleast50%,basedonurinaryexcretionofclopidogrelmetabolites.

Distribution

Clopidogrelandthemaincirculating(inactive)metabolitebindreversiblyinvitrotohumanplasmaproteins(98%and94%

respectively).Thebindingisnon-saturableinvitrooverawideconcentrationrange.

Biotransformation

Clopidogrelisextensivelymetabolisedbytheliver.Invitroandinvivo,clopidogrelismetabolisedaccordingtotwomain

metabolicpathways:onemediatedbyesterasesandleadingtohydrolysisintoitsinactivecarboxylicacidderivative(85%of

circulatingmetabolites),andonemediatedbymultiplecytochromesP450.Clopidogrelisfirstmetabolisedtoa2-oxo-clopidogrel

intermediatemetabolite.Subsequentmetabolismofthe2-oxo-clopidogrelintermediatemetaboliteresultsinformationofthe

activemetabolite,athiolderivativeofclopidogrel.Invitro,thismetabolicpathwayismediatedbyCYP3A4,CYP2C19,CYP1A2

andCYP2B6.Theactivethiolmetabolitewhichhasbeenisolatedinvitro,bindsrapidlyandirreversiblytoplateletreceptors,thus

inhibitingplateletaggregation.

TheCmaxoftheactivemetaboliteistwiceashighfollowingasingle300-mgclopidogrelloadingdoseasitisafterfourdaysof

75-mgmaintenancedose.Cmaxoccursapproximately30to60minutesafterdosing.

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*3allelesare

nonfunctional.TheCYP2C19*2andCYP2C19*3allelesaccountforthemajorityofreducedfunctionallelesinCaucasian(85%)

andAsian(99%)poormetabolisers.Otherallelesassociatedwithabsentorreducedmetabolismarelessfrequentandinclude

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

PublishedfrequenciesforthepoorCYP2C19metabolisergenotypesareapproximately2%forCaucasians,4%forBlacksand

14%forChinese.Testsareavailabletodetermineapatient’sCYP2C19genotype.

Acrossoverstudyin40healthysubjects,10eachinthefourCYP2C19metabolisergroups(ultrarapid,extensive,intermediateand

poor),evaluatedpharmacokineticandantiplateletresponsesusing300mgfollowedby75mg/dayand600mgfollowedby150

mg/day,eachforatotalof5days(steadystate).Nosubstantialdifferencesinactivemetaboliteexposureandmeaninhibitionof

plateletaggregation(IPA)wereobservedbetweenultrarapid,extensiveandintermediatemetabolisers.Inpoormetabolisers,active

metaboliteexposurewasdecreasedby63-71%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,andweresimilartotheotherCYP2C19metabolisergroupsreceivingthe300

mg/75mgregimen.Anappropriatedoseregimenforthispatientpopulationhasnotbeenestablishedinclinicaloutcometrials.

Consistentwiththeaboveresults,inameta-analysisincluding6studiesof335clopidogrel-treatedsubjectsatsteadystate,itwas

shownthatactivemetaboliteexposurewasdecreasedby28%forintermediatemetabolisers,and72%forpoormetaboliserswhile

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

comparedtoextensivemetabolisers.

Specialpopulations

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Renalimpairment

Afterrepeateddosesof75mgclopidogrelperdayinsubjectswithsevererenaldisease(creatinineclearancefrom5to15ml/min)

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

ofbleedingtimewassimilartothatseeninhealthysubjectsreceiving75mgofclopidogrelperday.Inaddition,clinicaltolerance

wasgoodinallpatients.

Hepaticimpairment

Afterrepeateddosesof75mgclopidogrelperdayfor10daysinpatientswithseverehepaticimpairment,inhibitionof

-inducedplateletaggregationwassimilartothatobservedinhealthysubjects.Themeanbleedingtimeprolongationwasalso

similarinthetwogroups.

Race

TheprevalenceofCYP2C19allelesthatresultinintermediateandpoorCYP2C19metabolismdiffersaccordingtorace/ethnicity

(seePharmacogenetics).Fromliterature,limiteddatainAsianpopulationsareavailabletoassesstheclinicalimplicationof

genotypingofthisCYPonclinicaloutcomeevents.

5.3Preclinicalsafetydata

Duringnonclinicalstudiesinratandbaboon,themostfrequentlyobservedeffectswereliverchanges.Theseoccurred

atdosesrepresentingatleast25timestheexposureseeninhumansreceivingtheclinicaldoseof75mg/dayandwerea

consequenceofaneffectonhepaticmetabolisingenzymes.Noeffectonhepaticmetabolisingenzymeswasobserved

inhumansreceivingclopidogrelatthetherapeuticdose.

Atveryhighdoses,apoorgastrictolerability(gastritis,gastricerosionsand/orvomiting)ofclopidogrelwasalso

reportedinratandbaboon.

Therewasnoevidenceofcarcinogeniceffectwhenclopidogrelwasadministeredfor78weekstomiceand104weeks

toratswhengivenatdosesupto77mg/kgperday(representingatleast25timestheexposureseeninhumans

receivingtheclinicaldoseof75mg/day).

Clopidogrelhasbeentestedinarangeofinvitroandinvivogenotoxicitystudies,andshowednogenotoxicactivity.

Clopidogrelwasfoundtohavenoeffectonthefertilityofmaleandfemaleratsandwasnotteratogenicineitherratsor

rabbits.Whengiventolactatingrats,clopidogrelcausedaslightdelayinthedevelopmentoftheoffspring.

Specificpharmacokineticstudiesperformedwithradiolabelledclopidogrelhaveshownthattheparentcompoundorits

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

palatability)cannotbeexcluded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

MaizeStarch,Pregelatinised

Cellulose,Microcrystalline

CrospovidoneTypeA

Silica,ColloidalAnhydrous

StearicAcidType50

Film-coating:

Carnaubawax

Lactosemonohydrate

Hypromellose(E464)

Titaniumdioxide(E171)

Triacetin(E1518)

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6.2Incompatibilities

Notapplicable

6.3Shelflife

36months

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

OPA/Aluminium/PVC/Aluminiumblistersincardboardcartonscontaining:

Packsizes:14,28,30,50,84,90,100film-coatedtablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedmedicinalproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements

7MARKETINGAUTHORISATIONHOLDER

PensaPharmaAB

BirgerJarlsgatan22

11434Stockholm

Sweden

8MARKETINGAUTHORISATIONNUMBER

PA1647/4/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26thAugust2011

10DATEOFREVISIONOFTHETEXT

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