CLOPIDOGREL NUCLEUS

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1369/005/001
  • Authorization date:
  • 23-04-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1369/005/001

CaseNo:2054999

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Nucleusehf.

Borgartuni30,105Reykjavik,Iceland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

ClopidogrelNucleus75mgfilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom23/04/2010until22/04/2015.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClopidogrelNucleus75mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains111.86mgclopidogrelbesylatecorrespondingto75mgclopidogrel.

Excipients:Eachfilm-coatedtabletcontains73.61mglactoseanhydrousand0.29mglecithin(containssoyaoil)

(E322).

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

Pink9mmround,biconvex,film-coatedtablet,engravedwith“II”ononeface.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clopidogrelisindicatedinadultsforthepreventionofatherothromboticeventsin:

Patientssufferingfrommyocardialinfarction(fromafewdaysuntillessthan35days),ischaemicstroke(from7

daysuntillessthan6months)orestablishedperipheralarterialdisease.

Forfurtherinformationpleaserefertosection5.1.

4.2Posologyandmethodofadministration

Adultsandelderly

Clopidogrelshouldbegivenasasingledailydoseof75mgwithorwithoutfood.

Pharmacogenetics

CYP2C19poormetaboliserstatusisassociatedwithdiminishedresponsetoclopidogrel.Theoptimaldoseregimenfor

poormetabolisershasyettobedetermined(seesection5.2).

Paediatricpatients

Thesafetyandefficacyofclopidogrelinchildrenandadolescentshavenotyetbeenestablished.

Renalimpairment

Therapeuticexperienceislimitedinpatientswithrenalimpairment(seesection4.4).

Hepaticimpairment

Therapeuticexperienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses(see

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4.3Contraindications

Hypersensitivitytotheactivesubstance,soyaoil,peanutoilortoanyoftheexcipients.

Severeliverimpairment.

Activepathologicalbleedingsuchaspepticulcerorintracranialhaemorrhage.

4.4Specialwarningsandprecautionsforuse

Duetotheriskofbleedingandhaematologicalundesirableeffects,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)hasbeenreportedveryrarelyfollowingtheuseofclopidogrel,

sometimesafterashortexposure.Itischaracterisedbythrombocytopeniaandmicroangiopathichaemolyticanemia

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,concomitantuseof

ProtonPumpInhibitorsshouldbeavoidedunlessabsolutelynecessary.Thereisnoevidencethatotherdrugsthat

reducestomachacidsuchasH2blockersorantacidsinterferewithantiplateletactivityofclopidogrel.

Therapeuticexperiencewithclopidogrelislimitedinpatientswithrenalimpairment.Thereforeclopidogrelshouldbe

usedwithcautioninthesepatients(seesection4.2).

Experienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses.Clopidogrelshould

thereforebeusedwithcautioninthispopulation(seesection4.2).

Lactose

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Patientswithrarehereditaryproblemsofgalactoseintolerance,Lapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicinalproduct.

Lecithin

ClopidogrelNucleus75mgfilm-coatedtabletscontainlecithin(soyaoil).Ifapatientishypersensitivetopeanutor

soya,thismedicineshouldnotbeused.

Thetabletcontainercontainsdesiccantthatshouldnotbeswallowed.

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)

NSAIDs:inaclinicalstudyconductedinhealthyvolunteers,theconcomitantadministrationofclopidogreland

naproxenincreasedoccultgastrointestinalbloodloss.However,duetothelackofinteractionstudieswithother

NSAIDsitispresentlyunclearwhetherthereisanincreasedriskofgastrointestinalbleedingwithallNSAIDs.

Consequently,NSAIDsincludingCox-2inhibitorsandclopidogrelshouldbeco-administeredwithcaution(seesection

4.4).

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,concomitantuseof

ProtonPumpInhibitorsshouldbeavoidedunlessabsolutelynecessary.Thereisnoevidencethatotherdrugsthat

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Anumberofotherclinicalstudieshavebeenconductedwithclopidogrelandotherconcomitantmedicinalproductsto

investigatethepotentialforpharmacodynamicandpharmacokineticinteractions.

Noclinicallysignificantpharmacodynamicinteractionswereobservedwhenclopidogrelwasco-administeredwith

atenolol,nifedipine,orbothatenololandnifedipine.Furthermore,thepharmacodynamicactivityofclopidogrelwasnot

significantlyinfluencedbythecoadministrationofphenobarbital,cimetidine,oroestrogen.

Thepharmacokineticsofdigoxinortheophyllinewerenotmodifiedbytheco-administrationofclopidogrel.Antacids

didnotmodifytheextentofclopidogrelabsorption.

Datafromstudieswithhumanlivermicrosomesindicatedthatthecarboxylicacidmetaboliteofclopidogrelcould

inhibittheactivityofCytochromeP4502C9.Thiscouldpotentiallyleadtoincreasedplasmalevelsofmedicinal

productssuchasphenytoinandtolbutamideandtheNSAIDs,whicharemetabolisedbyCytochromeP4502C9.Data

fromtheCAPRIEstudyindicatethatphenytoinandtolbutamidecanbesafelyco-administeredwithclopidogrel.

Apartfromthespecificmedicinalproductinteractioninformationdescribedabove,interactionstudieswithclopidogrel

andsomemedicinalproductscommonlyadministeredinpatientswithatherothromboticdiseasehavenotbeen

performed.However,patientsenteredintoclinicaltrialswithclopidogrelreceivedavarietyofconcomitantmedicinal

productsincludingdiuretics,betablockers,ACEI,calciumantagonists,cholesterolloweringagents,coronary

vasodilators,antidiabeticagents(includinginsulin),antiepilepticagentsandGPIIb/IIIaantagonistswithoutevidenceof

clinicallysignificantadverseinteractions.

4.6Pregnancyandlactation

Asnoclinicaldataonexposuretoclopidogrelduringpregnancyareavailable,itispreferablenottouseclopidogrel

duringpregnancyasaprecautionarymeasure.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

development,parturitionorpostnataldevelopment(seesection5.3).

Itisunknownwhetherclopidogrelisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

clopidogrelinbreastmilk.Asaprecautionarymeasure,breast-feedingshouldnotbecontinuedduringtreatmentwith

ClopidogrelNucleus75mgfilm-coatedtablets.

4.7Effectsonabilitytodriveandusemachines

Clopidogrelhasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Clopidogrelhasbeenevaluatedforsafetyinmorethan42,000patientswhohaveparticipatedinclinicalstudies,

includingover9,000patientstreatedfor1yearormore.Theclinicallyrelevantadversereactionsobservedinthe

CAPRIE,CURE,CLARITYandCOMMITstudiesarediscussedbelow.

Overall,clopidogrel75mg/daywascomparabletoASA325mg/dayinCAPRIE,regardlessofage,genderandrace.In

additiontoclinicalstudiesexperience,adversereactionshavebeenspontaneouslyreported.

Bleedingisthemostcommonreactionreportedbothinclinicalstudiesaswellasinpost-marketingexperiencewhereit

wasmostlyreportedduringthefirstmonthoftreatment.

InCAPRIE,inpatientstreatedwitheitherclopidogrelorASA,theoverallincidenceofanybleedingwas9.3%.The

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InCURE,themajorbleedingeventrateforclopidogrel+ASAwasdose-dependentonASA(<100mg:2.6%;100-200

mg: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+ASAwithin7daysaftercoronarybypassgraftsurgeryin

patientswhostoppedtherapymorethanfivedayspriortosurgery(4.4%clopidogrel+ASAvs.5.3%placebo+ASA).In

patientswhoremainedontherapywithinfivedaysofbypassgraftsurgery,theeventratewas9.6%for

clopidogrel+ASA,and6.3%forplacebo+ASA.

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,adversedrugreactionsarepresentedinorderofdecreasingseriousness.

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

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ocular,retinal)

Earandlabyrinth

disorders Vertigo

Vascular

disorders Haematoma Serioushaemorrhage,

haemorrhageof

operativewound,

vasculitis,

hypotension

Respiratory,

thoracicand

mediastinal

disorders Epistaxis Respiratorytract

bleeding

(haemoptysis,

pulmonary

haemorrhage),

bronchospasm,

interstitial

pneumonitis

Gastrointestinal

disorders Gastrointestinal

haemorrhage,

diarrhoea,

abdominalpain,

dyspepsia Gastriculcerand

duodenalulcer,

gastritis,vomiting,

nausea,

constipation,

flatulence Retroperitoneal

haemorrhage Gastrointestinaland

retroperitoneal

haemorrhagewith

fataloutcome,

pancreatitis,

colitis(including

ulcerativeor

lymphocyticcolitis),

stomatitis

Hepatobiliary

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

andbone

disorders Musculo-skeletal

bleeding

(haemarthrosis),

arthritis,arthralgia,

myalgia

Renalandurinary

disorders Haematuria Glomerulonephritis,

bloodcreatinine

increased

Generaldisorders

administration

siteconditions Bleedingat

puncturesite Fever

Investigations Bleedingtime

prolonged,

neutrophilcount

decreased,platelet

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4.9Overdose

Overdosefollowingclopidogreladministrationmayleadtoprolongedbleedingtimeandsubsequentbleeding

complications.Appropriatetherapyshouldbeconsideredifbleedingsareobserved.Noantidotetothepharmacological

activityofclopidogrelhasbeenfound.Ifpromptcorrectionofprolongedbleedingtimeisrequired,platelettransfusion

mayreversetheeffectsofclopidogrel

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:plateletaggregationinhibitorsexcl.heparin,ATCCode:B01AC04.

Clopidogrelisaprodrug,oneofwhosemetabolitesisaninhibitorofplateletaggregation.Clopidogrelmustbe

metabolisedbyCYP450enzymestoproducetheactivemetabolitethatinhibitsplateletaggregation.Theactive

metaboliteofclopidogrelselectivelyinhibitsthebindingofadenosinediphosphate(ADP)toitsplateletP2Y12receptor

andthesubsequentADP-mediatedactivationoftheglycoproteinGPIIb/IIIacomplex,therebyinhibitingplatelet

aggregation.Duetotheirreversiblebinding,plateletsexposedareaffectedfortheremainderoftheirlifespan

(approximately7-10days)andrecoveryofnormalplateletfunctionoccursatarateconsistentwithplateletturnover.

PlateletaggregationinducedbyagonistsotherthanADPisalsoinhibitedbyblockingtheamplificationofplatelet

activationbyreleasedADP.BecausetheactivemetaboliteisformedbyCYP450enzymes,someofwhichare

polymorphicorsubjecttoinhibitionbyotherdrugs,notallpatientswillhaveadequateplateletinhibition.

Repeateddosesof75mgperdayproducedsubstantialinhibitionofADP-inducedplateletaggregationfromthefirst

day;thisincreasedprogressivelyandreachedsteadystatebetweenDay3andDay7.Atsteadystate,theaverage

inhibitionlevelobservedwithadoseof75mgperdaywasbetween40%and60%.Plateletaggregationandbleeding

timegraduallyreturnedtobaselinevalues,generallywithin5daysaftertreatmentwasdiscontinued.

Thesafetyandefficacyofclopidogrelhavebeenevaluatedin4double-blindstudiesinvolvingover80,000patients:

theCAPRIEstudy,acomparisonofclopidogreltoASA,andtheCURE,CLARITYandCOMMITstudiescomparing

clopidogreltoplacebo,bothmedicinalproductsgivenincombinationwithASAandotherstandardtherapy.

Recentmyocardialinfarction(MI),recentstrokeorestablishedperipheralarterialdisease

TheCAPRIEstudyincluded19,185patientswithatherothrombosisasmanifestedbyrecentmyocardialinfarction(<

35days),recentischaemicstroke(between7daysand6months)orestablishedperipheralarterialdisease(PAD).

Patientswererandomisedtoclopidogrel75mg/dayorASA325mg/day,andwerefollowedfor1to3years.Inthe

myocardialinfarctionsubgroup,mostofthepatientsreceivedASAforthefirstfewdaysfollowingtheacute

myocardialinfarction.

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

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SincetheCAPRIEtrialwasnotpoweredtoevaluateefficacyofindividualsubgroups,itisnotclearwhetherthe

differencesinrelativeriskreductionacrossqualifyingconditionsarereal,oraresultofchance.

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,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

Followinganoraldoseof14C-labelledclopidogrelinman,approximately50%wasexcretedintheurineand

approximately46%inthefaecesinthe120-hourintervalafterdosing.Afterasingleoraldoseof75mg,clopidogrel

hasahalf-lifeofapproximately6hours.Theeliminationhalf-lifeofthemaincirculating(inactive)metabolitewas8

hoursaftersingleandrepeatedadministration.

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

phenotypesandgenotypesarelistedinthetablebelow.

CYP2C19PhenotypeandGenotypeFrequency

Frequency(%)

Todate,theimpactofCYP2C19genotypeonthepharmacokineticsoftheactivemetaboliteofclopidogrelhasbeen

evaluatedin227subjectsfrom7reportedstudies.ReducedCYP2C19metabolisminintermediateandpoor

metabolisersdecreasedtheCmaxandAUCoftheactivemetaboliteby30-50%following300-or600-mgloading

dosesand75-mgmaintenancedoses.Loweractivemetaboliteexposureresultsinless

plateletinhibitionorhigherresidualplateletreactivity.Todate,diminishedantiplateletresponsestoclopidogrelhave

beendescribedforintermediateandpoormetabolisersin21reportedstudiesinvolving4,520subjects.Therelative

differenceinantiplateletresponsebetweengenotypegroupsvariesacrossstudiesdependingonthemethodusedto

White(n=1356) Black(n=966) Chinese(n=573)

Extensivemetabolism:CYP2C19*1/*1 74 66 38

Intermediatemetabolism:CYP2C19*1/*2

or*1/*3 26 29 50

Poormetabolism:CYP2C19*2/*2,*2/*3or

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TheassociationbetweenCYP2C19genotypeandclopidogreltreatmentoutcomewasevaluatedin2posthocclinical

trialanalyses(substudiesofCLARITY[n=465]andTRITON-TIMI38[n=1,477])and5cohortstudies(totaln=6,489).

InCLARITYandoneofthecohortstudies(n=765;Trenk),cardiovasculareventratesdidnotdiffersignificantlyby

genotype.InTRITON-TIMI38and3ofthecohortstudies(n=3,516;Collet,Sibbing,Giusti),patientswithan

impairedmetaboliserstatus(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

ADP-inducedplateletaggregationwassimilartothatobservedinhealthysubjects.Themeanbleedingtime

prolongationwasalsosimilarinthetwogroups.

Race

TheprevalenceofCYP2C19allelesthatresultinintermediateandpoorCYP2C19metabolismdiffersaccordingto

race/ethnicity(seePharmacogenetics).Fromliterature,limiteddatainAsianpopulationsareavailabletoassessthe

clinicalimplicationofgenotypingofthisCYPonclinicaloutcomeevents.

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

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactoseanhydrous

Microcrystallinecellulose

CrospovidoneTypeA

Glyceroldibehenate

Talc

Coating:

Polyvinylalcohol

Talc

Macrogol3350

Lecithin(soyaoil)(E322)

Titaniumdioxide(E171)

Ironoxidered(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Aluminium/aluminiumblisterpacksandtabletcontainers(HDPE)closedwithsnap-oncap(LDPE)withatemper

evidentringandwithadesiccant(silicagel).

Packsizes:

Blisters:10,14,20,28,30,50,56,60,84,90and100tablets.

Tabletcontainers:100tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Nucleusehf

Borgartuni30

105Reykjavik

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8MARKETINGAUTHORISATIONNUMBER

PA1369/5/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23rdApril2010

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