ASASANTIN RETARD 200 MG /25 MG MODIFIED-RELEASE HA

Main information

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

Documents

Localization

  • Available in:
  • ASASANTIN RETARD 200 MG /25 MG MODIFIED-RELEASE HA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/069/001
  • Authorization date:
  • 23-02-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1328/069/001

CaseNo:2066357

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

ASASANTINRetard200mg/25mgModified-releaseHardCapsules

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom12/06/2009until22/02/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ASASANTINRetard200mg/25mgModified-releaseHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmodifiedreleasehardcapsulecontainsdipyridamole200mgandacetysalicylicacid25mg.

Excipients:Lactoseandsucrose.

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Modified-releasehardcapsule

ProductimportedfromFrance:

Capsulesconsistingofaredcapandanivorybody

ProductimportedfromtheUnitedKingdom:

Capsulesconsistingofaredcapandanivorybodyimprintedwiththecompanylogoandthefigures‘01A’.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Secondarypreventionofischaemicstrokeandtransientischaemicattacks.

4.2Posologyandmethodofadministration

Fororaladministration.

Therecommendeddoseisonecapsuletwicedaily,usuallyoneinthemorningandoneintheeveningpreferablywith

meals.

Thecapsulesshouldbeswallowedwholewithoutchewingtogetherwithaglassofwater.

ASASANTINRetardisnotindicatedforuseinchildrenandyoungpeoplelessthan16yearsofage(see“Special

WarningsandSpecialPrecautionsforUse”).

Alternativeregimenincaseofintolerableheadaches

Intheeventofintolerableheadachesduringtreatmentinitiation,switchtoonecapsuleatbedtimeandlow-dose

acetylsalicylicacid(ASA)inthemorning.Becausetherearenooutcomedatawiththisregimenandheadachesbecome

lessofaproblemastreatmentcontinues,patientsshouldreturntotheusualregimenassoonaspossible,usuallywithin

oneweek.

4.3Contraindications

Hypersensitivitytoanycomponentoftheproductorsalicylates.

Patientswithactivegastricorduodenalulcersorbleedingdisorders.

Patientsinthelasttrimesterofpregnancy.

Incertainrarehereditaryconditionstheproductiscontraindicatedowingtothepresenceofcertainexcipientsinthe

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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

Whendipyridamoleisusedincombinationwithaspirinorwithwarfarin,thestatementsregardingprecautions,

warningsandtoleranceforthesepreparationsmustbeobserved.

Acetylsalicylicacidhasbeenshowntoenhancetheeffectofanticoagulants(e.g.coumarinderivativesandheparin),

antiplateletdrugs(e.gclopidogrel,ticlopidine)valproicacidandphenytoinwhichmayresultinanincreasedriskof

sideeffects.Selectiveserotoninreuptakeinhibitors(SSRIs)mayincreasetheriskofbleeding.Gastrointestinalside

effectsalsoincreasewhenacetylsalicylicacidisadministeredconcomitantlywithNSAIDs,corticosteroids,orchronic

alcoholuse.Theadditionofdipyridamoletoacetylsalicylicaciddoesnotincreasetheincidenceofbleedingevents.

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thanthatobservedwhenwarfarinwasadministeredalone.

Dipyridamoleincreasestheplasmalevelsandcardiovasculareffectsofadenosine.Adjustmentofadenosinedosage

shouldthereforebeconsideredifusewithdipyridamoleisunavoidable.

Dipyridamolemayincreasethehypotensiveeffectofbloodpressureloweringdrugsandmaycounteractthe

anticholinesteraseeffectofcholinesteraseinhibitorstherebypotentiallyaggravatingmyastheniagravis.

Theeffectofhypoglycaemicagentsandthetoxicityofmethotrexatemaybeincreasedbytheconcomitant

administrationofacetylsalicylicacid.

Acetylsalicylicacidmaydecreasethenatriureticeffectofspironolactoneandinhibittheeffectofuricosuricagents(e.g.

probenecid,sulphinpyrazone).

TheconcomitantadministrationofibuprofenbutnotcertainotherNSAIDsorparacetamol,inpatientswithincreased

cardiovascularriskmaylimitthebeneficialcardiovasculareffectsofacetylsalicylicacid.

Experimentaldatasuggestthatibuprofenmayinhibittheeffectoflowdoseaspirinonplateletaggregationwhenthey

aredosedconcomitantly.

However,thelimitationsofthesedataandtheuncertaintiesregardingextrapolationof

exvivodatatotheclinicalsituationimplythatnofirmconclusionscanbemadeforregularibuprofenuse,andno

clinicallyrelevanteffectisconsideredtobelikelyforoccasionalibuprofenuse(seesection5.1)

4.6Pregnancyandlactation

ASASANTINRetardshouldbeusedwithcautioninthefirstandsecondtrimesterifconsideredessentialbythe

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);

therefore,asummarydescriptionofbleedingisgiveninTable1below.

Table1Bleedingeventsbrokendowntoanybleeding,majorbleeding,haemorrhageintracranialandgastrointestinal

haemorrhage

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

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SideeffectsofASASANTINbrokendowntoSystemOrganClasses:

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

10,000,<1in1,000.

Haemorrhageintracranial(%) 0.6 0.4 1.2* 0.8*

Gastrointestinalhaemorrhage

*PRoFESS:

DP/ASAintracranialhaemorrhage(1.0%)andintraocularhaemorrhage(0.2%)

Clopidogrelintracranialhaemorrhage(0.6%)andintraocularhaemorrhage(0.2%)

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 Common

(coronaryarterydisease)

Syncope Common

Vasculardisorders:

Hypotension Uncommon

Hotflush Uncommon

Respiratory,thoracicandmediastinaldisorders:

Epistaxis Common

Gastrointestinaldisorders:

Dyspepsia(epigastricdistress) VeryCommon

Vomiting Common

Diarrhoea VeryCommon

Nausea VeryCommon

Gastritiserosive Rare

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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

Agitation,brainoedema,lethargy,convulsion

Earandlabyrinthdisorders

Tinnitus,deafness

Cardiacdisorders

Arrhythmia

Respiratory,thoracicandmediastinaldisorders

(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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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,antepartumhaemorrhage,postpartum

haemorrhage

Generaldisordersandadministrationsiteconditions

Pyrexia,hypothermia

Investigations

Liverfunctiontestabnormal,blooduricacidincreased(mayleadtogoutattacks),prothrombintimeprolonged

4.9Overdose

Symptoms

Becauseofthedoseratioofdipyridamoletoaspirin,overdosageislikelytobedominatedbysignsandsymptomsof

dipyridamoleoverdose.

Duetothelownumberofobservations,experiencewithdipyridamoleoverdoseislimited.

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

dropinbloodpressureandanginalcomplaintscanbeexpected.

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

inpatientswhoseconcentrationsexceed700mg/L(5.1mmol/L).Singledoseslessthan100mg/kgareunlikelyto

causeseriouspoisoning.

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

extremitieswithboundingpulses,increasedrespiratoryrateandhyperventilation.Somedegreeofacid-base

disturbanceispresentinmostcases.

AmixedrespiratoryalkalosisandmetabolicacidosiswithnormalorhigharterialpH(normalorreducedhydrogenion

concentration)isusualinadultsandchildrenovertheageoffouryears.Inchildrenagedfouryearsorless,adominant

metabolicacidosiswithlowarterialpH(raisedhydrogenionconcentration)iscommon.Acidosismayincrease

salicylatetransferacrossthebloodbrainbarrier.

Uncommonfeaturesofsalicylatepoisoningincludehaematemesis,hyperpyrexia,hypogycaemia,hypokalaemia,

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

Centralnervoussystemfeaturesincludingconfusion,disorientation,comaandconvulsionsarelesscommoninadults

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Therapy

Administrationofxanthinederivatives(e.g.aminophylline)mayreversethehaemodynamiceffectsofdipyridamole

overdose.Duetoitswidedistributiontotissuesanditspredominantlyhepaticelimination,dipyridamoleisnotlikelyto

beaccessibletoenhancedremovalprocedures.

Inthecaseofsalicylatepoisoningactivatedcharcoalshouldbegiventoadultswhopresentwithinonehourof

ingestionofmorethan250mg/kg.Theplasmasalicylateconcentrationshouldbemeasured,althoughtheseverityof

poisoningcannotbedeterminedfromthisaloneandtheclinicalandbiochemicalfeaturesmustbetakenintoaccount.

Eliminationisincreasedbyurinaryalkalinisation,whichisachievedbytheadministrationof1.26%sodium

bicarbonate.TheurinepHshouldbemonitored.Correctmetabolicacidosiswithintravenous8.4%sodiumbicarbonate

(firstcheckserumpotassium).Forceddiuresisshouldnotbeusedsinceitdoesnotenhancesalicylateexcretionand

maycausepulmonaryoedema.

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,thereisanincreasedconcentrationofadenosinelocallytoactontheplateletA2-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,thereby

augmentingtheincreaseincGMPproducedbyEDRF(endothelium-derivedrelaxingfactor,identifiedasnitricoxide

(NO)).

Dipyridamoleincreasesthereleaseoft-PAfrommicrovascularendothelialcellsandwasshowntoamplifythe

antithromboticpropertiesofendothelialcellsonthrombusformationonadjacentsubendothelialmatrixinadose

dependentmanner.Dipyridamoleisapotentradicalscavengerforoxy-andperoxy-radicals.

Dipyridamolealsostimulatesthebiosynthesisandreleaseofprostacyclinbytheendotheliumandreducesthe

thrombogenicityofsubendothelialstructuresbyincreasingtheconcentrationoftheprotectivemediator13-HODE(13-

hydroxyoctadecadienicacid).

Whereasacetylsalicylicacid(aspirin)inhibitsonlyplateletaggregation,dipyridamoleinadditioninhibitsplatelet

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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/day

alone(p=0.008)andreducedtheriskofstrokeby24.4%comparedtoextended-releasereduceddipyridamole400

mg/dayalone(p=0.002).ASASANTINRetardtheriskofstrokeby36.8%comparedtoplacebo(p<0.001).The

resultsoftheESPS-2studyaresupportedbytheEuropean/AustralasianStrokePreventioninReversibleIschaemia

Trial(ESPRIT)studywhichstudiedacombinationtreatmentofdiypridamole400mgdaily(83%ofpatientstreated

withtheextended-releasedipyridamoleformulation)andASA30-325mgdaily.Atotalof2739patientsafter

ischaemicstrokeofarterialoriginwereenrolledintheASA-alone(n=1376)andcombinationASAplusdipyridamole

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

fatalmyocardialinfarction(MI),ormajorbleedingcomplications.PatientsintheASAplusdipyridamolegroup

showeda20%riskreduction(p<0.05)fortheprimarycompositeendpointcomparedwiththoseintheASAalone

group(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

acetylsalicylicacid(aspirin).ThereforepharmacokineticsofASASANTINRetardisreflectedbythepharmacokinetics

oftheindividualcomponents.

Dipyridamole

(Mostpharmacokineticdatarefertohealthyvolunteers.)

Withdipyridamole,thereisdoselinearityforalldosesusedintherapy.

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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

pharmacokineticsofdipyridamoleinacetylsalicylicacid(aspirin)modifiedreleasecapsules.

Distribution

Theapparentvolumeofdistributionofthecentralcompartment(Vc)isabout5l(similartoplasmavolume).The

apparentvolumeofdistributionatsteadystateisabout100l,reflectingdistributiontovariouscompartments.

Thedrugdoesnotcrosstheblood-brainbarriertoasignificantextent.TheproteinbindingofDipyridamoleisabout

97-99%,primarilyitisboundtoalpha1-acidglycoproteinandalbumin.

Metabolism

Metabolismofdipyridamoleoccursintheliver.Dipyridamoleismetabolizedprimarilybyconjugationwithglucuronic

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

MRTofabout6.4handameantimeofabsorptionof4.6h).Aswithi.v.administrationaprolongedterminal

eliminationhalf-lifeofapproximately13hoursisobserved.

Thisterminaleliminationphaseisofrelativelyminorimportanceinthatitrepresentsasmallproportionofthetotal

AUC,asevidencedbythefactthatsteadystateisachievedwithin2dayswithb.i.d.regimensofmodifiedrelease

capsules.Thereisnosignificantaccumulationofthedrugwithrepeateddosing.

Kineticsinelderly

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

tablettreatmentandabout30%higherwithintakeofASASANTINRetardmodifiedreleasecapsulesthaninyoung

(<55years)subjects.Thedifferenceiscausedmainlybyreducedclearance;absorptionappearstobesimilar.Similar

increasesinplasmaconcentrationsinelderlypatientswereobservedintheESPS2studyforPERSANTIN®modified

releasecapsulesaswellasforASASANTINRetard.

Kineticsinpatientswithrenalimpairment

Sincerenalexcretionisverylow(5%),nochangeinpharmacokineticsistobeexpectedincasesofrenalinsufficiency.

IntheESPS2trial,inpatientswithcreatinineclearancesrangingfromabout15mL/minto>100mL/min,nochanges

wereobservedinthepharmacokineticsofdipyridamoleoritsglucuronidemetaboliteifdatawerecorrectedfor

differencesinage.

Kineticsinpatientswithhepaticimpairment

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(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.Salicylatesarewidelydistributedtoalltissuesandfluidsinthebody,includingthe

centralnervoussystem,breastmilk,andfetaltissues.

Metabolism

Acetylsalicylicacid(aspirin)ismetabolisedrapidlybynon-specificesterasestosalicylicacid.

Salicylicacidismetabolisedtosalicyluricacid,salicylphenolicglucuronide,salicylicacylglucuronide,andtoaminor

extenttogentisicacidandgentisuricacid.Theformationofthemajormetabolitessalicyluricacidandsalicylic

phenolicglucuronideiseasilysaturatedandfollowsMichaelis-Mentenkinetics;theothermetabolicroutesarefirst-

orderprocesses.

Elimination

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

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

hoursathigherdosesbecauseofnonlinearityinmetabolismandplasmaproteinbinding.

Morethan90%ofacetylsalicylicacid(aspirin)isexcretedasmetabolitesviathekidneys.Thefractionofsalicylicacid

excretedunchangedintheurineincreaseswithincreasingdoseandtherenalclearanceoftotalsalicylatealsoincreases

withincreasingurinarypH.

Kineticsinpatientswithrenalimpairment

Renaldysfunction:acetylsalicylicacid(aspirin)istobeavoidedinpatientswithsevererenalfailure(glomerular

filtrationratelessthan10mL/min).Anincreaseintotalplasmaconcentrationsandintheunboundfractionofsalicylic

acidhasbeenreported.

Kineticsinpatientswithhepaticimpairment

Hepaticdysfunction:acetylsalicylicacidistobeavoidedinpatientswithseverehepaticinsufficiency.Anincreasein

theunboundfractionofsalicylicacidhasbeenreported.

5.3Preclinicalsafetydata

Dipyridamoleandacetylsalicylicacidhavebeenextensivelyinvestigatedinanimalmodelsandnoclinicallysignificant

findingshavebeenobservedatdosesequivalenttotherapeuticdosesinhumans.

6PHARMACEUTICALPARTICULARS

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Tartaricacid

Povidone

Methacrylicacid-methylmethacrylatecopolymer(1:2)

Talc

Acacia

Hypromellosephthalate

Hypromellose

Triacetin

Dimeticone350

Stearicacid

Lactosemonohydrate

Aluminiumstearate

Colloidalanhydroussilica

Maizestarch

Microcrystallinecellulose

Sucrose

Titaniumdioxide(E171)

CapsuleShells

Gelatin

Titaniumdioxide(E171)

Redandyellowironoxides(E172)

PrintingInk

Shellac

Ethanol

Isopropylalcohol

Propyleneglycol

N-butylalcohol

Ammoniumhydroxide

Potassiumhydroxide

Purifiedwater

Redironoxide(E172)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Discardanycapsulesremaining6weeksafterfirstopening.

6.5Natureandcontentsofcontainer

Whitepolypropylenetubeswithlow-densitypolyethyleneAir-secstoppersfilledwithdesiccatingagent(90%white

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit7,CrystalWay

ElmgroveRoad

Harrow

Middlesex

HA12HP

8ParallelProductAuthorisationNumber

PPA1328/69/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:23rdFebruary2007

10DATEOFREVISIONOFTHETEXT

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