CLOPIDOGREL

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1473/053/001
  • Authorization date:
  • 09-09-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clopidogrel75mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains111.86mgclopidogrelbesilatecorrespondingto75mgclopidogrel.

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

(E322).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-CoatedTablet

ProductimportedfromtheUK:

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

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clopidogrelisindicatedinadultsforthepreventionofatherothromboticeventsin:

Patientssufferingfrommyocardialinfarction(fromafewdaysuntillessthan35days),ischaemicstroke(from

7daysuntillessthan6months)orestablishedperipheralarterialdisease.

Patientssufferingfromacutecoronarysyndrome:

-STsegmentelevationacutecoronarysyndrome(unstableanginaornon-Q-wavemyocardial

infarction),includingpatientsundergoingastentplacementfollowingpercutaneouscoronaryintervention,in

combinationwithacetylsalicylicacid(ASA).

STsegmentelevationacutemyocardialinfarction,incombinationwithASAinmedicallytreatedpatientseligible

forthrombolytictherapy.

Forfurtherinformationpleaserefertosection5.1.

4.2Posologyandmethodofadministration

Adultsandelderly

Clopidogrelshouldbegivenasasingledailydoseof75mgwithorwithoutfood.

Inpatientssufferingfromacutecoronarysyndrome:

-STsegmentelevationacutecoronarysyndrome(unstableanginaornon-Q-wavemyocardialinfarction):

clopidogreltreatmentshouldbeinitiatedwithasingle300-mgloadingdoseandthencontinuedat75mgoncea

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

higherbleedingriskitisrecommendedthatthedoseofASAshouldnotbehigherthan100mg.Theoptimal

durationoftreatmenthasnotbeenformallyestablished.Clinicaltrialdatasupportuseupto12months,andthe

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STsegmentelevationacutemyocardialinfarction:clopidogrelshouldbegivenasasingledailydoseof75mg

initiatedwitha300-mgloadingdoseincombinationwithASAandwithorwithoutthrombolytics.Forpatients

over75yearsofageclopidogrelshouldbeinitiatedwithoutaloadingdose.Combinedtherapyshouldbestarted

asearlyaspossibleaftersymptomsstartandcontinuedforatleastfourweeksThebenefitofthecombinationof

clopidogrelwithASAbeyondfourweekshasnotbeenstudiedinthissetting(seesection5.1).

Pharmacogenetics

CYP2C19poormetaboliserstatusisassociatedwithdiminishedresponsetoclopidogrel.Theoptimaldoseregimenfor

poormetabolisershasyettobedetermined(seesection5.2).

Paediatricpatients

Thesafetyandefficacyofclopidogrelinchildrenandadolescentshavenotyetbeenestablished.

Renalimpairment

Therapeuticexperienceislimitedinpatientswithrenalimpairment(seesection4.4).

Hepaticimpairment

Therapeuticexperienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses(see

section4.4).

4.3Contraindications

Hypersensitivitytotheactivesubstance,soyaoil,peanutoilortoanyoftheexcipients.

Severeliverimpairment.

Activepathologicalbleedingsuchaspepticulcerorintracranialhaemorrhage.

4.4Specialwarningsandprecautionsforuse

Bleedingandhaematologicaldisorders

Duetotheriskofbleedingandhaematologicaladversereactions,bloodcellcountdeterminationand/orother

appropriatetestingshouldbepromptlyconsideredwheneverclinicalsymptomssuggestiveofbleedingariseduringthe

courseoftreatment(seesection4.8).Aswithotherantiplateletagents,clopidogrelshouldbeusedwithcautionin

patientswhomaybeatriskofincreasedbleedingfromtrauma,surgeryorotherpathologicalconditionsandinpatients

receivingtreatmentwithASA,heparin,glycoproteinIIb/IIIainhibitorsornon-steroidalanti-inflammatorydrugs

(NSAIDs)includingCox -2inhibitors.Patientsshouldbefollowedcarefullyforanysignsofbleedingincludingoccult

bleeding,especiallyduringthefirstweeksoftreatmentand/orafterinvasivecardiacproceduresorsurgery.The

concomitantadministrationofclopidogrelwithoralanticoagulantsisnotrecommendedsinceitmayincreasethe

intensityofbleedings(seesection4.5).

Ifapatientistoundergoelectivesurgeryandantiplateleteffectistemporarilynotdesirable,clopidogrelshouldbe

discontinued7dayspriortosurgery.Patientsshouldinformphysiciansanddentiststhattheyaretakingclopidogrel

beforeanysurgeryisscheduledandbeforeanynewmedicinalproductistaken.Clopidogrelprolongsbleedingtime

andshouldbeusedwithcautioninpatientswhohavelesionswithapropensitytobleed(particularlygastrointestinal

andintraocular).

Patientsshouldbetoldthatitmighttakelongerthanusualtostopbleedingwhentheytakeclopidogrel,andthatthey

shouldreportanyunusualbleeding(siteorduration)totheirphysician.

ThromboticThrombocytopenicPurpura(TTP)

ThromboticThrombocytopenicPurpura(TTP)hasbeenreportedveryrarelyfollowingtheuseofclopidogrel,

sometimesafterashortexposure.Itischaracterisedbythrombocytopeniaandmicroangiopathichaemolyticanaemia

associatedwitheitherneurologicalfindings,renaldysfunctionorfever.TTPisapotentiallyfatalconditionrequiring

prompttreatmentincludingplasmapheresis.

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Inviewofthelackofdata,clopidogrelcannotberecommendedduringthefirst7daysafteracuteischaemicstroke.

CytochromeP4502C19(CYP2C19)

Pharmacogenetics:Basedonliteraturedata,patientswithgeneticallyreducedCYP2C19functionhavelowersystemic

exposuretotheactivemetaboliteofclopidogrelanddiminishedantiplateletresponses,andgenerallyexhibithigher

cardiovasculareventratesfollowingmyocardialinfarctionthandopatientswithnormalCYP2C19function(seesection

5.2).

SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofmedicinalproductsthatinhibitthe

activityofthisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteofclopidogrel.The

clinicalrelevanceofthisinteractionisuncertain.Asaprecautionconcomitantuseofmedicinalproductsthatinhibit

CYP2C19shouldbediscouraged(seesection4.5foralistofCYP2C19inhibitors,seealsosection5.2).

Renalimpairment

Therapeuticexperiencewithclopidogrelislimitedinpatientswithrenalimpairment.Thereforeclopidogrelshouldbe

usedwithcautioninthesepatients(seesection4.2).

Hepaticimpairment

Experienceislimitedinpatientswithmoderatehepaticdiseasewhomayhavebleedingdiatheses.Clopidogrelshould

thereforebeusedwithcautioninthispopulation(seesection4.2).

Galactoseintolerance,Lapplactasedeficiency,glucose-galactosemalabsorbtion

ClopidogrelActaviscontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,Lapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Lecithin

Clopidogrelcontainslecithin(soyaoil).Ifapatientishypersensitivetopeanutorsoya,thismedicineshouldnotbe

used.

Thetabletcontainercontainsdesiccantthatshouldnotbeswallowed.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants:theconcomitantadministrationofclopidogrelwithoralanticoagulantsisnotrecommendedsince

itmayincreasetheintensityofbleedings(seesection4.4).

GlycoproteinIIb/IIIainhibitors:clopidogrelshouldbeusedwithcautioninpatientswhoreceiveconcomitant

glycoproteinIIb/IIIainhibitors(seesection4.4).

Acetylsalicylicacid(ASA):ASAdidnotmodifytheclopidogrel-mediatedinhibitionofADP-inducedplatelet

aggregation,butclopidogrelpotentiatedtheeffectofASAoncollagen-inducedplateletaggregation.However,

concomitantadministrationof500mgofASAtwiceadayforonedaydidnotsignificantlyincreasetheprolongation

ofbleedingtimeinducedbyclopidogrelintake.Apharmacodynamicinteractionbetweenclopidogreland

acetylsalicylicacidispossible,leadingtoincreasedriskofbleeding.Therefore,concomitantuseshouldbeundertaken

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

section5.1).

Heparin:inaclinicalstudyconductedinhealthysubjects,clopidogreldidnotnecessitatemodificationoftheheparin

doseoraltertheeffectofheparinoncoagulation.Co-administrationofheparinhadnoeffectontheinhibitionof

plateletaggregationinducedbyclopidogrel.Apharmacodynamicinteractionbetweenclopidogrelandheparinis

possible,leadingtoincreasedriskofbleeding.Therefore,concomitantuseshouldbeundertakenwithcaution(see

section4.4).

Thrombolytics:thesafetyoftheconcomitantadministrationofclopidogrel,fibrinornon-fibrinspecificthrombolytic

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Theincidenceofclinicallysignificantbleedingwassimilartothatobservedwhenthrombolyticagentsandheparinare

co-administeredwithASA(seesection4.8)

NSAIDs:inaclinicalstudyconductedinhealthyvolunteers,theconcomitantadministrationofclopidogreland

naproxenincreasedoccultgastrointestinalbloodloss.However,duetothelackofinteractionstudieswithother

NSAIDsitispresentlyunclearwhetherthereisanincreasedriskofgastrointestinalbleedingwithallNSAIDs.

Consequently,NSAIDsincludingCox -2inhibitorsandclopidogrelshouldbeco-administeredwithcaution(see

section4.4).

Otherconcomitanttherapy:

SinceclopidogrelismetabolisedtoitsactivemetabolitepartlybyCYP2C19,useofmedicinalproductsthatinhibitthe

activityofthisenzymewouldbeexpectedtoresultinreduceddruglevelsoftheactivemetaboliteofclopidogrel.The

clinicalrelevanceofthisinteractionisuncertain.Asaprecautionconcomitantuseofmedicinalproductsthatinhibit

CYP2C19shouldbediscouraged(seesections4.4and5.2).

MedicinalproductsthatinhibitCYP2C19includeomeprazoleandesomeprazole,fluvoxamine,fluoxetine,

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

chloramphenicol.

ProtonPumpInhibitors(PPI):

Inacrossoverclinicalstudy,clopidogrel(300-mgloadingdosefollowedby75mg/day)aloneandwithomeprazole(80

mgatthesametimeasclopidogrel)wereadministeredfor5days.Theexposuretotheactivemetaboliteofclopidogrel

wasdecreasedby45%(Day1)and40%(Day5)whenclopidogrelandomeprazolewereadministeredtogether.Mean

inhibitionofplateletaggregation(IPA)with5µMADPwasdiminishedby39%(24hours)and21%(Day5)when

clopidogrelandomeprazolewereadministeredtogether.Inanotherstudyitwasshownthatadministeringclopidogrel

andomeprazole12hoursapartdidnotpreventtheirinteractionthatislikelytobedrivenbytheinhibitoryeffectof

omeprazoleonCYP2C19.Esomeprazoleisexpectedtogiveasimilarinteractionwithclopidogrel.

Inconsistentdataontheclinicalimplicationsofthispharmacokinetic(PK)/pharmacodynamic(PD)interactioninterms

ofmajorcardiovasculareventshavebeenreportedfrombothobservationalandclinicalstudies.Asaprecaution,

concomitantuseofomeprazoleoresomeprozoleshouldbediscouraged(seesection4.4).Noconclusivedataonthe

pharmacodynamicinteractionofclopidogrelandotherPPIsareavailable.

ThereisnoevidencethatothermedicinalproductsthatreducestomachacidsuchasH2blockers(exceptcimetidine

whichisaCYP2C19inhibitor)orantacidsinterferewithantiplateletactivityofclopidogrel.

Othermedicinalproducts:

Anumberofotherclinicalstudieshavebeenconductedwithclopidogrelandotherconcomitantmedicinalproductsto

investigatethepotentialforpharmacodynamicandpharmacokineticinteractions.Noclinicallysignificant

pharmacodynamicinteractionswereobservedwhenclopidogrelwasco-administeredwithatenolol,nifedipine,orboth

atenololandnifedipine.Furthermore,thepharmacodynamicactivityofclopidogrelwasnotsignificantlyinfluencedby

thecoadministrationofphenobarbital,oroestrogen.

Thepharmacokineticsofdigoxinortheophyllinewerenotmodifiedbytheco-administrationofclopidogrel.Antacids

didnotmodifytheextentofclopidogrelabsorption.

Datafromstudieswithhumanlivermicrosomesindicatedthatthecarboxylicacidmetaboliteofclopidogrelcould

inhibittheactivityofCytochromeP

2C9.Thiscouldpotentiallyleadtoincreasedplasmalevelsofmedicinal

productssuchasphenytoinandtolbutamideandtheNSAIDs,whicharemetabolisedbyCytochromeP

2C9.Data

fromtheCAPRIEstudyindicatethatphenytoinandtolbutamidecanbesafelyco-administeredwithclopidogrel.

Apartfromthespecificmedicinalproductinteractioninformationdescribedabove,interactionstudieswithclopidogrel

andsomemedicinalproductscommonlyadministeredinpatientswithatherothromboticdiseasehavenotbeen

performed.However,patientsenteredintoclinicaltrialswithclopidogrelreceivedavarietyofconcomitantmedicinal

productsincludingdiuretics,betablockers,ACEI,calciumantagonists,cholesterolloweringagents,coronary

vasodilators,antidiabeticagents(includinginsulin),antiepilepticagentsandGPIIb/IIIaantagonistswithoutevidenceof

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4.6Fertility,pregnancyandlactation

Asnoclinicaldataonexposuretoclopidogrelduringpregnancyareavailable,itispreferablenottouseclopidogrel

duringpregnancyasaprecautionarymeasure.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

development,parturitionorpostnataldevelopment(seesection5.3).

Itisunknownwhetherclopidogrelisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

clopidogrelinbreastmilk.Asaprecautionarymeasure,breast-feedingshouldnotbecontinuedduringtreatmentwith

ClopidogrelActavis.

4.7Effectsonabilitytodriveandusemachines

Clopidogrelhasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Clopidogrelhasbeenevaluatedforsafetyinmorethan42,000patientswhohaveparticipatedinclinicalstudies,

includingover9,000patientstreatedfor1yearormore.Theclinicallyrelevantadversereactionsobservedinthe

CAPRIE,CURE,CLARITYandCOMMITstudiesarediscussedbelow.Overall,clopidogrel75mg/daywas

comparabletoASA325mg/dayinCAPRIE,regardlessofage,genderandrace.Inadditiontoclinicalstudies

experience,adversereactionshavebeenspontaneouslyreported.

Bleedingisthemostcommonreactionreportedbothinclinicalstudiesaswellasinpost-marketingexperiencewhereit

wasmostlyreportedduringthefirstmonthoftreatment.

InCAPRIE,inpatientstreatedwitheitherclopidogrelorASA,theoverallincidenceofanybleedingwas9.3%.The

incidenceofseverecaseswas1.4%forclopidogreland1.6%forASA.

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

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

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Adversereactionsthatoccurredeitherduringclinicalstudiesorthatwerespontaneouslyreportedarepresentedinthe

tablebelow.Theirfrequencyisdefinedusingthefollowingconventions:

common(1/100to<1/10);

uncommon(1/1,000to<1/100);

rare(1/10,000to<1/1,000);

veryrare(<1/10,000).

Withineachsystemorganclass,adversedrugreactionsarepresentedinorderofdecreasingseriousness.

SystemOrgan

Class Common Uncommon Rare VeryRare

Bloodandthe

lymphatic

systemdisorders Thrombocytopenia,

leucopenia,

eosinophilia Neutropenia,

including

severe

neutropenia Thrombotic

thrombocytopenic

purpura(TTP)(see

section4.4),

aplasticanaemia,

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)

Earand

labyrinth

disorders Vertigo

Vascular

disorders Haematoma Serious

haemorrhage,

haemorrhageof

operativewound,

vasculitis,

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Respiratory,

thoracicand

mediastinal

disorders Epistaxis Respiratorytract

bleeding

(haemoptysis,

pulmonary

haemorrhage),

bronchospasm,

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(including

ulcerativeor

lymphocytic

colitis),

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,

connective

tissueandbone

disorders Musculo-skeletal

bleeding

(haemarthrosis),

arthritis,arthralgia,

myalgia

Renaland

urinarydisorders Haematuria Glomerulonephritis,

bloodcreatinine

increased

General

disordersand

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)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

(<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.

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.Patientsweretreatedforuptoone

year.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 -1,1-3,3-6,6-9and

-12monthstudyintervals,respectively.Thus,beyond3monthsoftreatment,thebenefitobservedintheclopidogrel

+ASAgroupwasnotfurtherincreased,whereastheriskofhaemorrhagepersisted(seesection4.4).

TheuseofclopidogrelinCUREwasassociatedwithadecreaseintheneedofthrombolytictherapy(RRR=43.3%;CI:

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

Thenumberofpatientsexperiencingtheco-primaryendpoint(CVdeath,MI,strokeorrefractoryischaemia)was1035

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

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

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

treatedgroup].Therewasnoobservedeffectontherateofrehospitalisationforunstableangina.

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

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

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

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TheCLARITYtrialincluded3,491patientspresentingwithin12hoursoftheonsetofaSTelevationMIandplanned

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

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

fibrinolyticagentand,whenappropriate,heparin.Thepatientswerefollowedfor30days.

Theprimaryendpointwastheoccurrenceofthecompositeofanoccludedinfarct-relatedarteryonthepredischarge

angiogram,ordeathorrecurrentMIbeforecoronaryangiography.Forpatientswhodidnotundergoangiography,the

primaryendpointwasdeathorrecurrentmyocardialinfarctionbyDay8orbyhospitaldischarge.Thepatient

populationincluded19.7%womenand29.2%patients 65years.Atotalof99.7%ofpatientsreceivedfibrinolytics

(fibrinspecific:68.7%,non-fibrinspecific:31.1%),89.5%heparin,78.7%betablockers,54.7%ACEinhibitorsand

63%statins.

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

(162mg/day),for28daysoruntilhospitaldischarge.Theco -primaryendpointsweredeathfromanycauseandthe

firstoccurrenceofre -infarction,strokeordeath.Thepopulationincluded27.8%women,58.4%patients60years

(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)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

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Pharmacogenetics

SeveralpolymorphicCYP450enzymesactivateclopidogrel.CYP2C19isinvolvedintheformationofboththeactive

metaboliteandthe2-oxo-clopidogrelintermediatemetabolite.Clopidogrelactivemetabolitepharmacokineticsand

antiplateleteffects,asmeasuredbyexvivoplateletaggregationassays,differaccordingtoCYP2C19genotype.

TheCYP2C19*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.Loweractivemetaboliteexposureresultsinlessplateletinhibitionorhigher

residualplateletreactivity.Todate,diminishedantiplateletresponsestoclopidogrelhavebeendescribedfor

intermediateandpoormetabolisersin21reportedstudiesinvolving4,520subjects.Therelativedifferencein

antiplateletresponsebetweengenotypegroupsvariesacrossstudiesdependingonthemethodusedtoevaluate

response,butistypicallygreaterthan30%.

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

White

(n=1356) Black

(n=966) Chinese

(n=573)

Extensivemetabolism:CYP2C19*1/*1 74 66 38

Intermediatemetabolism:CYP2C19*1/*2or*1/*3 26 29 50

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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

palatability)cannotbeexcluded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactoseanhydrous

Microcrystallinecellulose

CrospovidoneTypeA

Glyceroldibehenate

Talc

Coating:

Polyvinylalcohol

Talc

Macrogol3350

Lecithin(soyaoil)(E322)

Titaniumdioxide(E171)

Ironoxidered(E172)

6.2Incompatibilities

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6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecartonandblisterfoil,afterEXP,oftheproduct

onthemarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Aluminium/aluminiumblisterpacks

Packsizes:

Blisters:28or30tablets.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

McDowellPharmaceuticals

4AltonaRoad

Lisburn

N.Ireland

BT275QB

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1473/053/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9 th

September2011

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