ASASANTIN RETARD

Main information

  • Trade name:
  • ASASANTIN RETARD
  • Dosage:
  • 200/25 Milligram
  • Pharmaceutical form:
  • Capsules Modified Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ASASANTIN RETARD
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1562/038/001
  • Authorization date:
  • 29-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AsasantinRetard200mg/25mgModifiedReleaseHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontainsdipyridamole200mgandacetylsalicylicacid(aspirin)25mg.

Excipients:

Eachcapsulecontains:

LactoseMonohydrate53mgandsucrose11.32mg.

Forthefulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Hardcapsulecontainingacetylsalicylicacidinstandardreleaseformanddipyridamoleinmodifiedreleaseform.

ProductimportedfromtheUK.

CapsulesconsistingofaredcapandanivorybodyimprintedwiththeCompanylogoandthefigure'OIA'.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Secondarypreventionofischaemicstrokeandtransientischaemicattacks.

4.2Posologyandmethodofadministration

Fororaladministration.

Therecommendeddoseisonecapsuletwicedaily,usuallyoneinthemorningandoneintheeveningpreferablywith

meals.

Thecapsulesshouldbeswallowedwholewithoutchewingtogetherwithaglassofwater.

ASASANTINRetardisnotindicatedforuseinchildrenandyoungpeoplelessthan16yearsofage(see“Special

WarningsandPrecautionsforUse”).

Alternativeregimenincaseofintolerableheadaches

Intheeventofintolerableheadachesduringtreatmentinitiation,switchtoonecapsuleatbedtimeandlow-dose

acetylsalicylicacid(ASA)inthemorning.Becausetherearenooutcomedatawiththisregimenandheadaches

becomelessofaproblemastreatmentcontinues,patientsshouldreturntotheusualregimenassoonaspossible,

usuallywithinoneweek.

4.3Contraindications

Hypersensitivitytoanycomponentoftheproductorsalicylates.

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Patientsinthelasttrimesterofpregnancy.

Incertainrarehereditaryconditionstheproductiscontraindicatedowingtothepresenceofcertainexcipientsinthe

product.(RefertoSpecialWarningsandPrecautionsfordetails).

4.4Specialwarningsandprecautionsforuse

Duetotheriskofbleeding,aswithotherantiplateletagents,ASASANTINshouldbeusedwithcautioninpatientsat

increasedbleedingriskandpatientsshouldbefollowedcarefullyforanysignsofbleeding,includingoccultbleeding.

Cautionshouldbeadvisedinpatientsreceivingconcomitantmedicationwhichmayincreasetheriskofbleeding,such

asanti-plateletagents(e.g.clopidogrel,ticlopidine)orselectiveserotoninreuptakeinhibitors(SSRIs).

Headacheormigraine-likeheadachewhichmayoccurespeciallyatthebeginningofASASANTINtherapyshouldnot

betreatedwithanalgesicdosesofacetylsalicylicacid.

Amongotherpropertiesdipyridamoleactsasavasodilator.Itshouldbeusedwithcautioninpatientswithsevere

coronaryarterydisease,includingunstableanginaand/orrecentmyocardialinfarction,leftventricularoutflow

obstruction,orhaemodynamicinstability(e.g.decompensatedheartfailure).

PatientsbeingtreatedwithregularoraldosesofASASANTINRetardshouldnotreceiveadditionalintravenous

dipyridamole.Clinicalexperiencesuggeststhatpatientsbeingtreatedwithoraldipyridamolewhoalsorequire

pharmacologicalstresstestingwithintravenousdipyridamole,shoulddiscontinuedrugscontainingoraldipyridamole

twenty-fourhourspriortostresstesting.Failuretodosomayimpairthesensitivityofthetest.

Inpatientswithmyastheniagravisreadjustmentoftherapymaybenecessaryafterchangesindipyridamoledosage(see

Interactions).

Asmallnumberofcaseshavebeenreportedinwhichunconjugateddipyridamolewasshowntobeincorporatedinto

gallstonestoavariableextent(upto70%bydryweightofstone).Thesepatientswereallelderly,hadevidenceof

ascendingcholangitisandhadbeentreatedwithoraldipyridamoleforanumberofyears.Thereisnoevidencethat

dipyridamolewastheinitiatingfactorincausinggallstonestoforminthesepatients.Itispossiblethatbacterial

deglucuronidationofconjugateddipyridamoleinbilemaybethemechanismresponsibleforthepresenceof

dipyridamoleingallstones.

Duetotheacetylsalicylicacidcomponent,ASASANTINRetardshouldbeusedwithcautioninpatientswithasthma,

allergicrhinitis,nasalpolyps,chronicorrecurringgastricorduodenalcomplaints,impairedrenalorhepaticfunctionor

glucose-6-phosphatedehydrogenasedeficiency.

Inaddition,cautionisadvisedinpatientshypersensitivetonon-steroidalanti-inflammatorydrugs(NSAIDs).

ASASANTINRetardisnotindicatedforuseinchildrenandyoungpeoplelessthan16yearsofage.Thereisariskof

Reye’ssyndromewhenchildrentakeacetylsalicylicacid.

ThedoseofacetylsalicylicacidinASASANTINRetardhasnotbeenstudiedinsecondarypreventionofmyocardial

infarction.

Thisproductcontains106mgoflactoseand22.64mgsucrosepermaximumrecommendeddailydose.Patientswith

rarehereditaryproblemsoffructoseintoleranceand/orgalactoseintolerancee.g.galactosaemiashouldnottakethis

medicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Whendipyridamoleisusedincombinationwithacetylsalicylicacidorwithwarfarin,thestatementsregarding

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Acetylsalicylicacidhasbeenshowntoenhancetheeffectofanticoagulants(e.g.coumarinderivativesandheparin),

antiplateletdrugs(e.gclopidogrel,ticlopidine)valproicacidandphenytoinwhichmayresultinanincreasedriskof

sideeffects.Selectiveserotoninreuptakeinhibitors(SSRIs)mayincreasetheriskofbleeding.Gastrointestinalside

effectsalsoincreasewhenacetylsalicylicacidisadministeredconcomitantlywithNSAIDs,corticosteroids,orchronic

alcoholuse.Theadditionofdipyridamoletoacetylsalicylicaciddoesnotincreasetheincidenceofbleedingevents.

Whendipyridamolewasadministeredconcomitantlywithwarfarin,bleedingwasnogreaterinfrequencyorseverity

thanthatobservedwhenwarfarinwasadministeredalone.

Dipyridamoleincreasestheplasmalevelsandcardiovasculareffectsofadenosine.Adjustmentofadenosinedosage

shouldthereforebeconsideredifusewithdipyridamoleisunavoidable.

Dipyridamolemayincreasethehypotensiveeffectofbloodpressureloweringdrugsandmaycounteractthe

anticholinesteraseeffectofcholinesteraseinhibitorstherebypotentiallyaggravatingmyastheniagravis.

Theeffectofhypoglycaemicagentsandthetoxicityofmethotrexatemaybeincreasedbytheconcomitant

administrationofacetylsalicylicacid.

Acetylsalicylicacidmaydecreasethenatriureticeffectofspironolactoneandinhibittheeffectofuricosuricagents(e.g.

probenecid,sulphinpyrazone).

TheconcomitantadministrationofibuprofenbutnotcertainotherNSAIDsorparacetamol,inpatientswithincreased

cardiovascularriskmaylimitthebeneficialcardiovasculareffectsofacetylsalicylicacid.Experimentaldatasuggest

thatibuprofenmayinhibittheeffectoflowdoseaspirinonplateletaggregationwhentheyaredosedconcomitantly.

However,thelimitationsofthesedataandtheuncertaintiesregardingextrapolationofexvivodatatotheclinical

situationimplythatnofirmconclusionscanbemadeforregularibuprofenuse,andnoclinicallyrelevanteffectis

consideredtobelikelyforoccasionalibuprofenuse(seesection5.1).

4.6Fertility,pregnancyandlactation

ASASANTINRetardshouldonlybeusedwithcautioninthefirstandsecondtrimesterifconsideredessentialbythe

physicianintermsofbenefitandrisk.ASASANTINRetardshouldbeavoidedcompletelyinthethirdtrimester.

Dipyridamoleandsalicylatesareexcretedinbreastmilk.ThereforeASASANTINRetardshouldnotbeadministered.

4.7Effectsonabilitytodriveandusemachines

Nonestated.

4.8Undesirableeffects

Twolargescaletrials(ESPS-2,PRoFESS)enrollingatotalof26,934patients,thereof11,831patientstreatedwith

ASASANTIN,wereusedtodefinethesideeffectsprofileofASASANTIN.Inaddition,fromspontaneousreporting

alsothoseeventswherefactsandevidencequalifiedtheseassideeffectshavebeenincluded.

Duetothegranularityofthecodingsystem,bleedingeventsaredistributedoverseveralSystemOrganClasses(SOC);

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Table1 Bleedingeventsbrokendowntoanybleeding,majorbleeding,haemorrhageintracranialandgastrointestinal

haemorrhage

SideeffectsofASASANTINbrokendowntoSystemOrganClasses:

Frequency:Verycommon>1in10;Common>1in100,<1in10;Uncommon>1in1,000,<1in100;Rare>1in

ESPS-2 PRoFESS

ASASANTIN Placebo ASASANTIN CLOPIDOGREL

PatientstreatedN(%) 1,650(100) 1,649(100) 10,055(100) 10,040(100)

Meanexposure(years) 1.4 1.9 2.1

AnyBleeding(%) 8.7 4.5 5.3 4.9

Majorbleeding(%) 1.6 0.4 3.3 3.0

Haemorrhageintracranial(%) 0.6 0.4 1.2* 0.8*

Gastrointestinal

haemorrhage

*PRoFESS:

DP/ASA intracranialhaemorrhage(1.0%)andintraocularhaemorrhage(0.2%)

Clopidogrel intracranialhaemorrhage(0.6%)andintraocularhaemorrhage(0.2%)

SystemOrganClass:

MedDRATerm Frequency

Bloodandlymphaticsystemdisorders:

Anaemia Common

Thrombocytopenia(reductionofplateletcount) Rare

Irondeficiencyanaemiaduetooccultgastrointestinalbleeding Rare

Immunesystemdisorders:

Hypersensitivityreactions Common

rash

urticaria

severebronchospasm

angioedema

Nervoussystemdisorders:

Haemorrhageintracranial Common

Headache VeryCommon

Migraine-likeheadache Common

Dizziness VeryCommon

Eyedisorders:

Eyehaemorrhage(intraocularhaemorrhage) Uncommon

Cardiacdisorders:

Tachycardia Uncommon

Worseningofsymptomsofcoronaryheartdisease

(coronaryarterydisease) Common

Syncope Common

Vasculardisorders:

Hypotension Uncommon

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*TheseADRswerenotreportedinclinicaltrials,thereforeafrequencycouldnotbecalculated.

InadditiontothosesideeffectslistedforASASANTIN,fortherelevantmonocompoundsalsothebelowlistedside

effectsareestablished;however,havenotbeenreportedforASASANTINyet.

Dipyridamole:

Additionalsideeffectsreportedwithdipyridamolemonotherapywereasfollows:

Dipyridamolehasbeenshowntobeincorporatedintogallstones.

Acetylsalicylicacid:

Additionalsideeffectsreportedwithacetylsalicylicacidmonotherapywereasfollows;

Bloodandlymphaticsystemdisorders

Disseminatedintravascularcoagulation,coagulopathy

Immunesystemdisorders

Anaphylacticreactions(especiallyinpatientswithasthma)

Metabolismandnutritiondisorders

Hypoglycaemia(children),hyperglycaemia,thirst,dehydration,hyperkaleamia,metabolicacidosis,respiratory

alkalosis

Psychiatricdisorders

Confusionalstate

Nervoussystemdisorders

Respiratory,thoracicandmediastinaldisorders:

Epistaxis Common

Gastrointestinaldisorders:

Dyspepsia(epigastricdistress) VeryCommon

Vomiting Common

Diarrhoea VeryCommon

Nausea VeryCommon

Gastritiserosive Rare

Gastriculcer,Duodenalulcer Uncommon

(severe)Gastrointestinalhaemorrhage Common

Abdominalpain VeryCommon

Skinandsubcutaneoustissuedisorders:

Skinhaemorrhage Notknown*

contusion

ecchymosis

haematoma

Musculoskeletal,connectivetissueandbonedisorders:

Myalgia Common

Investigations:

Bleedingtimeprolonged Notknown*

Injury,poisoningandproceduralcomplications:

Postproceduralhaemorrhage Notknown*

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Earandlabyrinthdisorders

Tinnitus,deafness

Cardiacdisorders

Arrhythmia

Respiratory,thoracicandmediastinaldisorders

Dyspnoea,gingivalbleeding,laryngealoedema,hyperventilation,pulmonaryoedema,tachypnoea

Gastrointestinaldisorders

Gastriculcerperforation,duodenalulcerperforation,melaena,haematemesis,pancreatitis

Hepatobiliarydisorders

Hepatitis,Reye'ssyndrome

Skinandsubcutaneoustissuedisorders

Erythemaexsudativummultiforme

Musculoskeletal,connectivetissueandbonedisorders

Rhabdomyolysis

Renalandurinarydisorders

Renalfailure,nephritisinterstitial,renalpapillarynecrosis,proteinuria

Pregnancy,puerperiumandperinatalconditions

Prolongedpregnancy,prolongedlabour,smallfordatesbaby,stillbirth,antepartum,haemorrhage,postpartum

haemorrhage

Generaldisordersandadministrationsiteconditions

Pyrexia,hypothermia

Investigations

Liverfunctiontestabnormal,blooduricacidincreased(mayleadtogoutattacks),prothrombintimeprolonged

4.9Overdose

Symptoms

Becauseofthedoseratioofdipyridamoletoacetylsalicylicacid,overdosageislikelytobedominatedbysignsand

symptomsofdipyridamoleoverdose.

Duetothelownumberofobservations,experiencewithdipyridamoleoverdoseislimited.

Symptomssuchasawarmfeeling,flushes,sweating,acceleratedpulse,restlessness,feelingofweakness,dizziness,

dropinbloodpressureandanginalcomplaintscanbeexpected.

Salicylatepoisoningisusuallyassociatedwithplasmaconcentrations>350mg/L(2.5mmol/L).Mostadultdeaths

occurinpatientswhoseconcentrationsexceed700mg/L(5.1mmol/L).Singledoseslessthan100mg/kgareunlikely

tocauseseriouspoisoning.

Symptomsofsalicylateoverdosecommonlyincludevomiting,dehydration,tinnitus,vertigo,deafness,sweating,warm

extremitieswithboundingpulses,increasedrespiratoryrateandhyperventilation.Somedegreeofacid-base

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AmixedrespiratoryalkalosisandmetabolicacidosiswithnormalorhigharterialpH(normalorreducedhydrogenion

concentration)isusualinadultsandchildrenovertheageoffouryears.Inchildrenagedfouryearsorless,adominant

metabolicacidosiswithlowarterialpH(raisedhydrogenionconcentration)iscommon.Acidosismayincrease

salicylatetransferacrossthebloodbrainbarrier.

Uncommonfeaturesofsalicylatepoisoningincludehaematemesis,hyperpyrexia,hypogycaemia,hypokalaemia,

thrombocytopaenia,increasedINR/PTR,intravascularcoagulation,renalfailureandnon-cardiacpulmonaryoedema.

Centralnervoussystemfeaturesincludingconfusion,disorientation,comaandconvulsionsarelesscommoninadults

thaninchildren.

Therapy

Administrationofxanthinederivatives(e.g.aminophylline)mayreversethehaemodynamiceffectsofdipyridamole

overdose.Duetoitswidedistributiontotissuesanditspredominantlyhepaticelimination,diypridamoleisnotlikelyto

beaccessibletoenhancedremovalprocedures.Inthecaseofsalicylatepoisoningactivatedcharcoalshouldbegivento

adultswhopresentwithinonehourofingestionofmorethan250mg/kg.Theplasmasalicylateconcentrationshould

bemeasured,althoughtheseverityofpoisoningcannotbedeterminedfromthisaloneandtheclinicalandbiochemical

featuresmustbetakenintoaccount.Eliminationisincreasedbyurinaryalkalinisation,whichisachievedbythe

administrationof1.26%sodiumbicarbonate.TheurinepHshouldbemonitored.Correctmetabolicacidosiswith

intravenous8.4%sodiumbicarbonate(firstcheckserumpotassium).Forceddiuresisshouldnotbeusedsinceitdoes

notenhancesalicylateexcretionandmaycausepulmonaryoedema.

Haemodialysisisthetreatmentofchoiceforseverepoisoningandshouldbeconsideredinpatientswithplasma

salicylateconcentrations>700mg/L(5.1mmol/L),orlowerconcentrationsassociatedwithsevereclinicalormetabolic

features.Patientsundertenyearsorover70haveincreasedriskofsalicylatetoxicityandmayrequiredialysisatan

earlierstage.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

TheantithromboticactionoftheAcetylsalicylicacid(aspirin)/dipyridamolecombinationisbasedonthedifferent

biochemicalmechanismsinvolved.Acetylsalicylicacid(aspirin)inactivatesirreversiblytheenzymecyclo-oxygenase

inplateletsthuspreventingtheproductionofthromboxaneA2,apowerfulinducerofplateletaggregationand

vasoconstriction.

Dipyridamoleinhibitstheuptakeofadenosineintoerythrocytes,plateletsandendothelialcellsinvitroandinvivo;the

inhibitionamountstoapproximately80%atmaximumandoccursdose-dependentlyattherapeuticconcentrations(0.5

–2mcg/ml).Consequently,thereisanincreasedconcentrationofadenosinelocallytoactontheplateletA-receptor,

stimulatingplateletadenylatecyclase,therebyincreasingplateletcAMPlevels.

Reducedplateletaggregationreducesplateletconsumptiontowardsnormallevels.Inaddition,adenosinehasa

vasodilatoreffectandthisisoneofthemechanismsbywhichdipyridamoleproducesvasodilation.

Dipyridamolehasalsobeenshowninstrokepatientstoreducethedensityofprothromboticsurfaceproteins(PAR-1:

Thrombinreceptor)onplateletsaswellastoreducelevelsofc-reactiveprotein(CRP)andvonWillebrandFactor

(vWF).In-vitroinvestigationshaveshownthatdipyridamoleselectivelyinhibitsinflammatorycytokines(MCP-1and

MMP-9)arisingfromplatelet-monocyteinteraction.Dipyridamoleinhibitsphosphodiesterase(PDE)invarioustissues.

WhilsttheinhibitionofcAMP-PDEisweak,therapeuticlevelsofdipyridamoleinhibitcGMP-PDE,therebyaugmenting

theincreaseincGMPproducedbyEDRF(endothelium-derivedrelaxingfactor,identifiedasnitricoxide(NO)).

Dipyridamoleincreasesthereleaseoft-PAfrommicrovascularendothelialcellsandwasshowntoamplifythe

antithromboticpropertiesofendothelialcellsonthrombusformationonadjacentsubendothelialmatrixinadose

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Dipyridamolealsostimulatesthebiosynthesisandreleaseofprostacyclinbytheendotheliumandreducesthe

thrombogenicityofsubendothelialstructuresbyincreasingtheconcentrationoftheprotectivemediator13-HODE(13-

hydroxyoctadecadienicacid).

Whereasacetylsalicylicacid(aspirin)inhibitsonlyplateletaggregation,dipyridamoleinadditioninhibitsplatelet

activationandadhesion.Thereforeanadditionalbenefitfromcombiningbothdrugscanbeexpected.

Experimentaldatasuggestthatibuprofenmayinhibittheeffectoflowdoseaspirinonplateletaggregationwhenthey

aredosedconcomitantly.Inonestudy,whenasingledoseofibuprofen400mgwastakenwithin8hbeforeorwithin

30minafterimmediatereleaseaspirindosing(81mg),adecreasedeffectofASAontheformationofthromboxaneor

plateletaggregationoccurred.

However,thelimitationsofthesedataandtheuncertaintiesregardingextrapolationofexvivodatatotheclinical

situationimplythatnofirmconclusionscanbemadeforregularibuprofenuse,andnoclinicallyrelevanteffectis

consideredtobelikelyforoccasionalibuprofenuse.

ClinicalTrials:

ASASANTINRetard wasstudiedinadouble-blind,placebo-controlled,24-monthstudy(EuropeanStroke

PreventionStudy2,ESPS2)inwhich6602patientshadanischemicstrokeortransientischemicattack(TIA)within

threemonthspriortoentry.Patientswererandomizedtooneoffourtreatmentgroups:ASASANTINRetard

(ASA/extended-releasedipyridamole)25mg/200mg;extended-releasedipyridamole(ER-DP)200mgalone;ASA25

mgalone;orplacebo.Patientsreceivedonecapsuletwicedaily(morningandevening).Efficacyassessmentsincluded

analysesofstroke(fatalornonfatal)anddeath(fromallcauses)asconfirmedbyablindedmorbidityandmortality

assessmentgroup.InESPS-2ASASANTINRetardreducedtheriskofstrokeby22.1%comparedtoASA.

50mg/dayalone(p=0.008)andreducedtheriskofstrokeby24.4%comparedtoextended-releasedipyridamole400

mg/dayalone(p=0.002).ASASANTINRetardreducedtheriskofstrokeby36.8%comparedtoplacebo(p<0.001).

TheresultsoftheESPS-2studyaresupportedbytheEuropean/AustralasianStrokePreventioninReversible

IschaemiaTrial(ESPRIT)studywhichstudiedacombinationtreatmentofdiypridamole400mgdaily(83%of

patientstreatedwiththeextended-releasedipyridamoleformulation)andASA30-325mgdaily.Atotalof2739

patientsafterischaemicstrokeofarterialoriginwereenrolledintheASA-alone(n=1376)andcombinationASAplus

dipyridamole(n=1363)arm.Theprimaryoutcomeeventwasthecompositeofdeathfromallvascularcauses,non-

fatalstroke,non-fatalmyocardialinfarction(MI),ormajorbleedingcomplications.PatientsintheASAplus

dipyridamolegroupshoweda20%riskreduction(p<0.05)fortheprimarycompositeendpointcomparedwiththosein

theASAalonegroup(12.7%vs.15.7%;hazardratio[HR]0.80,95%CI0.66–0.98).

ThePRoFESS(PReventionRegimenForEffectivelyavoidingSecondStrokes)studywasarandomized,parallel

group,international,double-blind,double-dummy,activeandplacebocontrolled,2x2factorialstudytocompare

ASASANTINwithclopidogrel,andtelmisartanwithmatchingplacebointhepreventionofstrokeinpatientswhohad

alreadyexperiencedanischaemicstrokeofnoncardioembolicorigin.Individualswhowere>55yearsofageandwho

hadhadanischemicstrokewithin90daysofentrytothestudywereincluded.Atotalof20,332patientswere

randomizedtoASASANTIN(n=10,181)orclopidogrel(n=10,151),bothgivenonabackgroundofstandard

treatment.Theprimaryendpointwasthetimetofirstrecurrentstrokeofanytype.

Theincidenceoftheprimaryendpointwassimilarinbothtreatmentgroups(9.0%forASASANTINvs.8.8%for

clopidogrel;HR1.01,95%CI0.92-1.11).NosignificantdifferencebetweentheASASANTINandclopidogrel

treatmentgroupsweredetectedforseveralotherimportantpre-specifiedendpoints,includingthecompositeof

recurrentstroke,myocardialinfarction,ordeathduetovascularcauses(13.1%inbothtreatmentgroups;HR0.99,95

%CI0.92-1.07)andthecompositeofrecurrentstrokeormajorhaemorrhagicevent(11.7%forASASANTINvs.

11.4%forclopidogrel;HR1.03,95%CI0.95-1.11).Thefunctionalneurologicaloutcome3monthspostrecurrent

strokewasassessedbytheModifiedRankinScale(MRS)andnosignificantdifferenceinthedistributionoftheMRS

betweenASASANTINandclopidogrelwasobserved(p=0.3073byCochran-Armitagetestforlineartrend).

5.2Pharmacokineticproperties

Thereisnonoteworthypharmacokineticinteractionbetweentheextendedreleasepelletsofdipyridamoleand

aetylsalicylicacid(aspirin).ThereforepharmacokineticsofASASANTINRetardisreflectedbythepharmacokinetics

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Dipyridamole

(Mostpharmacokineticdatarefertohealthyvolunteers.)

Withdipyridamole,thereisdoselinearityforalldosesusedintherapy.

Forlong-termtreatmentdipyridamolemodifiedreleasecapsules,formulatedaspelletsweredeveloped.ThepH

dependentsolubilityofdipyridamolewhichpreventsdissolutioninthelowerpartsofthegastro-intestinaltract(where

sustainedreleasepreparationsmuststillreleasetheactiveprinciple)wasovercomebycombinationwithtartaricacid.

Retardationisachievedbyadiffusionmembrane,whichissprayedontothepellets.

Variouskineticstudiesatsteadystateshowed,thatallpharmacokineticparameterswhichareappropriateto

characterisethepharmacokineticpropertiesofmodifiedreleasepreparationsareeitherequivalentorsomewhat

improvedwithdipyridamolemodifiedreleasecapsulesgivenb.i.d.comparedtodipyridamoletabletsadministered

t.d.s./q.d.s.:Bioavailabilityisslightlygreater,peakconcentrationsaresimilar,troughconcentrationsareconsiderably

higherandpeaktroughfluctuationisreduced.

Absorption

Theabsolutebioavailabilityisabout70%.Asfirstpassremovesapprox.1/3ofthedoseadministered,neartocomplete

absorptionofdipyridamolefollowingadministrationofacetylsalicylicacid(aspirin)modifiedreleasecapsulescanbe

assumed.

Peakplasmaconcentrationsofdipyridamolefollowingadailydoseof400mgacetylsalicylicacid(aspirin)(givenas

200mgb.i.d)arereachedabout2-3hoursafteradministration.Thereisnorelevanteffectoffoodonthe

pharmaconkineticsofdipyridamoleinacetylsalicylicacid(aspirin)modifiedreleasecapsules.

Distribution

Theapparentvolumeofdistributionofthecentralcompartment(Vc)isabout5l(similartoplasmavolume).The

apparentvolumeofdistributionatsteadystateisabout100l,reflectingdistributiontovariouscompartments.

Thedrugdoesnotcrosstheblood-brainbarriertoasignificantextent.TheproteinbindingofDipyridamoleisabout

97-99%,primarilyitisboundtoalpha1-acidglycoproteinandalbumin.

Metabolism

Metabolismofdipyridamoleoccursintheliver.Dipyridamoleismetabolisedprimarilybyconjugationwithglucuronic

acidtoformmainlyamonoglucuronideandonlysmallamountsofdiglucuronide.Inplasmaabout80%ofthetotal

amountispresentasparentcompound,and20%ofthetotalamountasmonoglucuronide.Thepharmacodynamic

activityofdipyridamoleglucuronidesisconsiderablylowerthanofdipyridamole.

Elimination

Thedominanthalf-lifewithoraladministrationisabout40minutesasitisthecasewithi.v.administration.

Renalexcretionofparentcompoundisnegligible(<0.5%).Urinaryexcretionoftheglucuronidemetaboliteislow

(5%),themetabolitesaremostly(about95%)excretedviathebileintothefaeces,withsomeevidenceofentero-

hepaticrecirculation.

Totalclearanceisapproximately250ml/minandmeanresidencetimeisabout11hours(resultingfromanintrinsic

MRTofabout6.4hrandameantimeofabsorptionof4.6h).

Aswithi.v.administrationaprolongedterminaleliminationhalf-lifeofapproximately13hoursisobserved.

Thisterminaleliminationphaseisofrelativelyminorimportanceinthatitrepresentsasmallproportionofthetotal

AUC,asevidencedbythefactthatsteadystateisachievedwithin2dayswithb.i.d.regimensofmodifiedrelease

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Kineticsinelderly

Dipyridamoleplasmaconcentrations(determinedasAUC)inelderlysubjects(>65years)wereabout50%higherfor

tablettreatmentandabout30%higherwithintakeofASASANTINRetardmodifiedreleasecapsulesthaninyoung(<

55years)subjects.Thedifferenceiscausedmainlybyreducedclearance;absorptionappearstobesimilar.

SimilarincreasesinplasmaconcentrationsinelderlypatientswereobservedintheESPS2studyforPERSANTIN®

modifiedreleasecapsulesaswellasforASASANTINRetard.

Kineticsinpatientswithrenalimpairment

Sincerenalexcretionisverylow(5%),nochangeinpharmaconkineticsistobeexpectedincasesofrenal

insufficiency.IntheESPS2trial,inpatientswithcreatinineclearancesrangingfromabout15mL/minto>100mL/min,

nochangeswereobservedinthepharmacokineticsofdipyridamoleoritsglucuronidemetaboliteifdatawerecorrected

fordifferencesinage.

Kineticsinpatientswithhepaticimpairment

Patientswithhepaticinsufficiencyshownochangeinplasmaconcentrationsofdipyridamole,butanincreaseof

(pharmacodynamicallylowactive)glucuronides.Itissuggestedtodosedipyridamolewithoutrestrictionaslongas

thereisnoclinicalevidenceofliverfailure.

Acetylsalicylicacid(aspirin)

Absorption

Afteroraladministrationacetylsalicylicacid(aspirin)israpidlyandcompletelyabsorbedinthestomachandintestine.

Approximately30%ofthedoseofacetylsalicylicacid(aspirin)ishydrolyzedpresystemicallytosalicylicacid.

Maximumplasmaconcentrationsafteradailydoseof50mgacetylsalicylicacidfromASASANTINRetard(givenas

25mgtwicedaily)areattainedafter30minutesofeachdose,andpeakplasmaconcentrationatsteadystateamounted

toapproximately360ng/mLforacetylsalicylicacid(aspirin);maximumplasmaconcentrationsofsalicylicacidare

achievedafter60-90minutesandamounttoapproximately1100ng/ml.Thereisnorelevanteffectoffoodonthe

pharmacodynamicsofacetylsalicylicacidinASASANTINRetard.

Distribution

Acetylsalicylicacid(aspirin)israpidlyconvertedtosalicylatebutisthepredominantformofthedrugintheplasma

duringthefirst20minutesfollowingoraladministration.Plasmaacetylsalicylicacid(aspirin)concentrationsdecline

rapidlywithahalf-lifeofapprox.15minutes.Itsmajormetabolite,salicylicacid,ishighlyboundtoplasmaproteins,

anditsbindingisconcentration-dependent(nonlinear).Atlowconcentrations(<100µg/mL),approximately90%of

salicylicacidisboundtoalbumin.Salicylateswhicharewidelydistributedtoalltissuesandfluidsinthebody,

includingthecentralnervoussystem,breastmilk,andfetaltissues.

Metabolism

Acetylsalicylicacid(aspirin)ismetabolisedrapidlybynon-specificesterasestosalicylicacid.Salicylicacidis

metabolisedtosalicyluricacid,salicylphenolicglucuronide,salicylicacylglucuronide,andtoaminorextentto

gentisicacidandgentisuricacid.Theformationofthemajormetabolitessalicyluricacidandsalicylicphenolic

glucuronideiseasilysaturatedandfollowsMichaelis-Mentenkinetics;theothermetabolicroutesarefirst-order

processes.

Elimination

Acetylsalicylicacid(aspirin)hasaneliminationhalf-lifeofeliminationof15-20minutesinplasma;themajor

metabolitesalicylicacidhasahalf-lifeofeliminationof2-3hoursatlowdoses(e.g.325mg),whichmayriseto30

hoursathigherdosesbecauseofnon-linearityinmetabolismandplasmaproteinbinding.

Morethan90%ofacetylsalicylicacid(aspirin)isexcretedasmetabolitesviathekidneys.Thefractionofsalicylicacid

excretedunchangedintheurineincreaseswithincreasingdoseandtherenalclearanceoftotalsalicylatealsoincreases

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Kineticsinpatientswithrenalimpairment

Renaldysfunction:acetylsalicylicacid(aspirin)istobeavoidedinpatientswithsevererenalfailure(glomerular

filtrationratelessthan10mL/min).Anincreaseintotalplasmaconcentrationsandintheunboundfractionofsalicylic

acidhasbeenreported.

Kineticsinpatientswithhepaticimpairment

Hepaticdysfunction:acetylsalicylicacidistobeavoidedinpatientswithseverehepaticinsufficiency.Anincreasein

theunboundfractionofsalicylicacidhasbeenreported.

5.3Preclinicalsafetydata

Dipyridamoleandacetylsalicylicacidhavebeenextensivelyinvestigatedinanimalmodelsandnoclinicallysignificant

findingshavebeenobservedatdosesequivalenttotherapeuticdosesinhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tartaricacid

Acacia

Povidone

Methacrylicacid-methacrylatecopolymer(1:2)

Hypromellosephthalate

Hypromellose

Dimethicone350

Triacetin

Talc

Stearicacid

Lactosemonohydrate

Aluminiumstearate

Colloidalsilica

Maizestarch

Microcrystallinecellulose

Sucrose

Titaniumdioxide(E171)

Capsuleshells

Gelatin

Titaniumdioxide(E17l)

Redandyellowironoxides(EI72)

PrintingInk

Shellac

Ethylalcohol

Isopropylalcohol

Propyleneglycol

N-butylalcohol

Ammoniumhydroxide

Potassiumhydroxide

Purifiedwater

Redironoxide(E172)

6.2Incompatibilities

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6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthebottleandouterpackageoftheproductonthemarket

inthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Discardanycapsulesremaining6weeksafteropening.

6.5Natureandcontentsofcontainer

Whitepolypropylenebottleswithchildresistantmultipartpolypropylene/polyethylenescrewcapcontaininga

desiccantmadefromsilicagel/molecularsieves.Packsizeof60capsules

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharmaLimited

Unit18OxleasowRoad

EastMoonMoat

Redditch

WorcestershireB980RE

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1562/38/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thofOctober2010

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Date Printed 29/10/2010 CRN 2089907 page number: 12