CARDICOR

Main information

  • Trade name:
  • CARDICOR Film Coated Tablet 1.25 Milligram
  • Dosage:
  • 1.25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARDICOR Film Coated Tablet 1.25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/013/001
  • Authorization date:
  • 06-10-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PPA1328/013/001

CaseNo:2034068

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrants

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cardicor1.25mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjectto

thegeneralconditionsasmaybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/03/2007until05/10/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cardicor1.25mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains1.25mgbisoprololfumarate(2:1)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablet.

ProductimportedfromItaly:

Off-white,round,film-coatedtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofstablechronicmoderatetosevereheartfailurewithreducedsystolicventricularfunction(ejectionfraction

≤35%,basedonechocardiography)inadditiontoACEinhibitors,anddiuretics,andoptionallycardiacglycosides(For

additionalinformationseesection5.1).

4.2Posologyandmethodofadministration

Thepatientsshouldhavestablechronicheartfailurewithoutacutefailureduringthepastsixweeks

andamainlyunchangedbasictherapyduringthepasttwoweeks.Theyshouldbetreatedatoptimal

dosewithanACEinhibitor(orothervasodilatorincaseofintolerancetoACEinhibitors)anda

diuretic,andoptionallycardiacglycosides,priortotheadministrationofbisoprolol.

Itisrecommendedthatthetreatingphysicianshouldbeexperiencedinthemanagementofchronic

heartfailure.

Warning:Thetreatmentofstablechronicheartfailurewithbisoprololhastobeinitiatedwitha

titrationphaseasgiveninthedescriptionbelow.

Thetreatmentwithbisoprololistobestartedwithagradualuptitrationaccordingtothefollowing

steps:

1.25mgoncedailyfor1week,ifwelltoleratedincreaseto

2.5mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

3.75mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

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7.5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

10mgoncedailyforthemaintenancetherapy.

Afterinitiationoftreatmentwith1.25mg,thepatientsshouldbeobservedoveraperiodof

approximately4hours(especiallyasregardsbloodpressure,heartrate,conductiondisturbances,signs

ofworseningofheartfailure).

Themaximumrecommendeddoseis10mgoncedaily.

Occurrenceofadverseeventsmaypreventallpatientsbeingtreatedwiththemaximumrecommended

dose.Ifnecessary,thedosereachedcanalsobedecreasedstepbystep.Thetreatmentmaybe

interruptedifnecessaryandreintroducedasappropriate.

Duringthetitrationphase,incaseofworseningoftheheartfailureorintolerance,itisrecommended

firsttoreducethedoseofbisoprolol,ortostopimmediatelyifnecessary(incaseofsevere

hypotension,worseningofheartfailurewithacutepulmonaryoedema,cardiogenicshock,

symptomaticbradycardiaorAVblock).

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Thetreatmentwithbisoprololisnotrecommendedtobestoppedabruptlysincethismightleadtoa

transitoryworseningofheartfailure.Ifdiscontinuationisnecessary,thedoseshouldbegradually

decreaseddividedintohalvesweekly.

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbe

swallowedwithliquidandshouldnotbechewed.

Renalorliverinsufficiency

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailure

andwithimpairedliverorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldtherefore

bemadewithadditionalcaution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnopaediatricexperiencewithbisoprolol,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontra-indicatedinchronicheartfailurepatientswith:

acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

cardiogenicshock

AVblockofsecondorthirddegree(withoutapacemaker)

sicksinussyndrome

sinoatrialblock

bradycardiawithlessthan60beats/minbeforethestartoftherapy

hypotension(systolicbloodpressurelessthan100mmHg)

severebronchialasthmaorseverechronicobstructivepulmonarydisease

latestagesofperipheralarterialocclusivediseaseandRaynaud'ssyndrome

untreatedphaeochromocytoma(see4.4)

metabolicacidosis

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4.4Specialwarningsandprecautionsforuse

Bisoprololmustbeusedwithcautionin:

bronchospasm(bronchialasthma,obstructiveairwaysdiseases)

diabetesmellituswithlargefluctuationsinbloodglucosevalues;symptomsofhypoglycaemiacan

bemasked

strictfasting

ongoingdesensitisationtherapy

AVblockoffirstdegree

Prinzmetal'sangina

peripheralarterialocclusivedisease(intensificationofcomplaintsmighthappenespeciallyduring

thestartoftherapy)

Generalanaesthesia

Inpatientsundergoinggeneralanaesthesiabeta-blockadereducestheincidenceofarrhythmiasand

myocardialischemiaduringinductionandintubation,andthepost-operativeperiod.Itiscurrently

recommendedthatmaintenancebeta-blockadebecontinuedperi-operatively.

Theanaesthetistmustbeawareofbeta-blockadebecauseofthepotentialforinteractionswithother

drugs,resultinginbradyarrhythmias,attenuationofthereflextachycardiaandthedecreasedreflex

abilitytocompensateforbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blockertherapybefore

surgery,thisshouldbedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Thereisnotherapeuticexperienceofbisoprololtreatmentofheartfailureinpatientswiththe

followingdiseasesandconditions:

-NYHAclassIIheartfailure

-insulindependentdiabetesmellitus(typeI)

-impairedrenalfunction(serumcreatinine>300micromol/l)

-impairedliverfunction

-patientsolderthan80years

-restrictivecardiomyopathy

-congenitalheartdisease

-haemodynamicallysignificantorganicvalvulardisease

-myocardialinfarctionwithin3months

Combinationofbisoprololwithcalciumantagonistsoftheverapamilanddiltiazemtype,withClassI

antiarrhythmicdrugsandwithcentrallyactingantihypertensivedrugsisgenerallynotrecommended,

fordetailspleaserefertosection4.5.

Inbronchialasthmaorotherchronicobstructivelungdiseases,whichmaycausesymptoms,

bronchodilatingtherapyshouldbegivenconcomitantly.Occasionallyanincreaseoftheairway

resistancemayoccurinpatientswithasthma,thereforethedoseofbeta2-stimulantsmayhavetobe

increased.

Aswithotherbeta-blockers,bisoprololmayincreaseboththesensitivitytowardsallergensandthe

severityofanaphylacticreactions.Adrenalinetreatmentdoesnotalwaysgivetheexpectedtherapeutic

effect.

Patientswithpsoriasisorwithahistoryofpsoriasisshouldonlybegivenbeta-blockers(e.g.

bisoprolol)aftercarefullybalancingthebenefitsagainsttherisks.

Inpatientswithphaeochromocytomabisoprololmustnotbeadministereduntilafteralpha-receptor

blockade.

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Theinitiationoftreatmentwithbisoprololnecessitatesregularmonitoring.Fortheposologyand

methodofadministrationpleaserefertosection4.2.

Thecessationoftherapywithbisoprololshouldnotbedoneabruptlyunlessclearlyindicated.Forfurtherinformation

pleaserefertosection4.2.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsnotrecommended

Calciumantagonistsoftheverapamiltypeandtoalesserextentofthediltiazemtype:Negative

influenceoncontractilityandatrio-ventricularconduction.Intravenousadministrationofverapamilin

patientson-blockertreatmentmayleadtoprofoundhypotensionandatrioventricularblock.

ClassIantiarrhythmicdrugs(e.g.quinidine,disopyramide;lidocaine,phenytoin;flecainide,

propafenone):Effectonatrio-ventricularconductiontimemaybepotentiatedandnegativeinotropic

effectincreased.

Centrallyactingantihypertensivedrugssuchasclonidineandothers(e.g.methyldopa,moxonodine,

rilmenidine):Concomitantuseofcentrallyactingantihypertensivedrugsmayworsenheartfailureby

adecreaseinthecentralsympathetictonus(reductionofheartrateandcardiacoutput,vasodilation).

Abruptwithdrawal,particularlyifpriortobeta-blockerdiscontinuation,mayincreaseriskof“rebound

hypertension”.

Combinationstobeusedwithcaution

Calciumantagonistsofthedihydropyridinetypesuchasfelodipineandamlodipine:Concomitantuse

mayincreasetheriskofhypotension,andanincreaseintheriskofafurtherdeteriorationofthe

ventricularpumpfunctioninpatientswithheartfailurecannotbeexcluded.

Class-IIIantiarrhythmicdrugs(e.g.amiodarone):Effectonatrio-ventricularconductiontimemaybe

potentiated.

Topicalbeta-blockers(e.g.eyedropsforglaucomatreatment)mayaddtothesystemiceffectsof

bisoprolol.

Parasympathomimeticdrugs:Concomitantusemayincreaseatrio-ventricularconductiontimeandthe

riskofbradycardia.

Insulinandoralantidiabeticdrugs:Intensificationofbloodsugarloweringeffect.Blockadeofbeta-

adrenoreceptorsmaymasksymptomsofhypoglycaemia.

Anaestheticagents:Attenuationofthereflextachycardiaandincreaseoftheriskofhypotension(for

furtherinformationongeneralanaesthesiaseealsosection4.4.).

Digitalisglycosides:Reductionofheartrate,increaseofatrio-ventricularconductiontime.

Non-steroidalanti-inflammatorydrugs(NSAIDs):NSAIDsmayreducethehypotensiveeffectof

bisoprolol.

-Sympathomimeticagents(e.g.isoprenaline,dobutamine):Combinationwithbisoprololmayreduce

theeffectofbothagents.

Sympathomimeticsthatactivateboth-and-adrenoceptors(e.g.noradrenaline,adrenaline):

Combinationwithbisoprololmayunmaskthe-adrenoceptor-mediatedvasoconstrictoreffectsof

theseagentsleadingtobloodpressureincreaseandexacerbatedintermittentclaudication.Such

interactionsareconsideredtobemorelikelywithnonselective-blockers.

Concomitantusewithantihypertensiveagentsaswellaswithotherdrugswithbloodpressure

loweringpotential(e.g.tricyclicantidepressants,barbiturates,phenothiazines)mayincreasetheriskof

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Combinationstobeconsidered

Mefloquine:increasedriskofbradycardia

Monoamineoxidaseinhibitors(exceptMAO-Binhibitors):Enhancedhypotensiveeffectofthebeta-blockersbutalso

riskforhypertensivecrisis.

4.6Pregnancyandlactation

Pregnancy

Bisoprololhaspharmacologicaleffectsthatmaycauseharmfuleffectsonpregnancyand/orthe

fetus/newborn.Ingeneral,-blockersreduceplacentalperfusion,whichhasbeenassociatedwith

growthretardation,intrauterinedeath,abortionorearlylabour.Adverseeffects(e.g.hypoglycaemia

andbradycardia)mayoccurinthefetusandnewborninfant.Iftreatmentwith-adrenoceptorblockers

isnecessary,

-selectiveadrenoceptorblockersarepreferable.

Bisoprololshouldnotbeusedduringpregnancyunlessclearlynecessary.Iftreatmentwithbisoprolol

isconsiderednecessary,theuteroplacentalbloodflowandthefetalgrowthshouldbemonitored.In

caseofharmfuleffectsonpregnancyorthefetusalternativetreatmentshouldbeconsidered.The

newborninfantmustbecloselymonitored.Symptomsofhypoglycaemiaandbradycardiaare

generallytobeexpectedwithinthefirst3days.

Lactation

Itisnotknownwhetherthisdrugisexcretedinhumanmilk.Therefore,breastfeedingisnotrecommendedduring

administrationofbisoprolol.

4.7Effectsonabilitytodriveandusemachines

Inastudywithcoronaryheartdiseasepatientsbisoprololdidnotimpairdrivingperformance.However,dueto

individualvariationsinreactionstothedrug,theabilitytodriveavehicleortooperatemachinerymaybeimpaired.

Thisshouldbeconsideredparticularlyatstartoftreatmentanduponchangeofmedicationaswellasinconjunction

withalcohol.

4.8Undesirableeffects

Clinicaltrialdata

Thetablebelowshowsincidencesofadverseeventsreportedfromboththeplaceboandthebisoprololcohortofthe

CIBISIItrial.Regardlessofcausalrelationshipalladverseeventsareincluded.Eachpatientisonlycountedoncefor

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AE=AdverseEvents

Post-marketingdata

Therearenopost-marketingdataavailableforbisoprololintheindicationstablechronicheartfailure.

Thefollowingdataresultfrompost-marketingexperiencewithbisoprololintheindications

PreferredTerm

Placebo

(n=1321) Bisoprolol

(n=1328)

Pat.

with

%Pat.

with

Pat.

with

%Pat.

with

Cardiacfailure 301 22.8 244 18.4

Dyspnoea 224 17.0 183 13.8

Dizziness 126 9.5 177 13.3

Cardiomyopathy 132 10.0 141 10.6

Bradycardia 60 4.5 202 15.2

Hypotension 96 7.3 152 11.4

Tachycardia 144 10.9 79 5.9

Fatigue 94 7.1 123 9.3

Viralinfection 75 5.7 86 6.5

Pneumonia 69 5.2 65 4.9

Common

1%and<10%) Circ: Feelingofcoldnessornumbnessintheextremities

CNS: Tiredness*,exhaustion*,dizziness*,headache*

GI: Nausea,vomiting,diarrhoea,constipation

Uncommon

0.1%and<1%) General: Muscularweaknessandcramps

Circ: Bradycardia,AV-stimulusdisturbances,

worseningofheartfailure,orthostatichypotension

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*Thesesymptomsespeciallyoccuratthebeginningofthetherapy.Theyaregenerallymildandoftendisappearwithin

1-2weeks.

4.9Overdose

Thereisnoexperienceyetregardingoverdosageofbisoprololinpatientswithstablechronicheart

failure.Themostcommonsignsexpectedwithoverdosageofaß-blockerarebradycardia,

hypotension,bronchospasm,acutecardiacinsufficiencyandhypoglycaemia.Todateafewcasesof

overdose(maximum:2000mg)withbisoprololhavebeenreportedinpatientssufferingfrom

hypertensionand/orcoronaryheartdiseaseshowingbradycardiaand/orhypotension;allpatients

recovered.Thereisawideinterindividualvariationinsensitivitytoonesinglehighdoseofbisoprolol

andpatientswithheartfailureareprobablyverysensitive.Thereforeitismandatorytoinitiatethe

Airways: Bronchospasminpatientswithbronchialasthma

orahistoryofobstructiveairwaysdisease.

Rare

0.01%and

<0.1%) CNS: Nightmares,hallucinations

Skin: hypersensitivityreactions(itching,flush,rash)

Liver: increasedliverenzymes(ALAT,ASAT),hepatitis

Metabolism: Increasedtriglycerides

Urogenital: Potencydisorders

Ear-nose-

throat: hearingimpairment,allergicrhinitis

Eyes: reducedtearflow(tobeconsideredifthepatient

useslenses)

Singlecases

(<0.01%) Eyes: conjunctivitis

Skin: -blockersmayprovokeorworsenpsoriasisor

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Ingeneral,ifoverdoseoccurs,bisoprololtreatmentshouldbestoppedandsupportiveand

symptomatictreatmentshouldbeprovided.Limiteddatasuggestthatbisoprololishardlydialysable.

Basedontheexpectedpharmacologicalactionsandrecommendationsforotherß-blockers,the

followinggeneralmeasuresshouldbeconsideredwhenclinicallywarranted.

Bradycardia:Administerintravenousatropine.Iftheresponseisinadequate,isoprenalineoranother

agentwithpositivechronotropicpropertiesmaybegivencautiously.Undersomecircumstances,

transvenouspacemakerinsertionmaybenecessary.

Hypotension:Intravenousfluidsandvasopressorsshouldbeadministered.Intravenousglucagonmay

beuseful.

AVblock(secondorthirddegree):Patientsshouldbecarefullymonitoredandtreatedwith

isoprenalineinfusionortransvenouscardiacpacemakerinsertion.

Acuteworseningofheartfailure:Administeri.v.diuretics,inotropicagents,vasodilatingagents.

Bronchospasm:Administerbronchodilatortherapysuchasisoprenaline,ß

-sympathomimeticdrugs

and/oraminophylline.

Hypoglycaemia:Administeri.v.glucose.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCode:C07AB07

Bisoprololisahighly

-selective-adrenoceptorblockingagent,lackingintrinsicstimulatingand

relevantmembranestabilisingactivity.Itonlyshowslowaffinitytothe

-receptorofthesmooth

musclesofbronchiandvesselsaswellastothe

-receptorsconcernedwithmetabolicregulation.

Therefore,bisoprololisgenerallynottobeexpectedtoinfluencetheairwayresistanceand

mediatedmetaboliceffects.Its

-selectivityextendsbeyondthetherapeuticdoserange.

Intotal2647patientswereincludedintheCIBISIItrial.83%(n=2202)wereinNYHAclassIIIand

17%(n=445)wereinNYHAclassIV.Theyhadstablesymptomaticsystolicheartfailure(ejection

fraction ≤

35%,basedonechocardiography).Totalmortalitywasreducedfrom17.3%to11.8%

(relativereduction34%).

Adecreaseinsuddendeath(3.6%vs6.3%,relativereduction44%)andareducednumberofheart

failureepisodesrequiringhospitaladmission(12%vs17.6%,relativereduction36%)wasobserved.

Finally,asignificantimprovementofthefunctionalstatusaccordingtoNYHAclassificationhasbeen

shown.Duringtheinitiationandtitrationofbisoprololhospitaladmissionsduetobradycardia

(0.53%),hypotension(0.23%),andacutedecompensation(4.97%)wereobserved,buttheywerenot

morefrequentthanintheplacebo-group(0%,0.3%and6.74%).Thenumbersoffatalanddisabling

strokesduringthetotalstudyperiodwere20inthebisoprololgroupand15intheplacebogroup.

Bisoprololisalreadyusedforthetreatmentofhypertensionandangina.

Inacuteadministrationinpatientswithcoronaryheartdiseasewithoutchronicheartfailurebisoprololreducestheheart

rateandstrokevolumeandthusthecardiacoutputandoxygenconsumption.Inchronicadministrationtheinitially

elevatedperipheralresistancedecreases.

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Bisoprololisabsorbedandhasabiologicalavailabilityofabout90%afteroraladministration.The

plasmaproteinbindingofbisoprololisabout30%.Thedistributionvolumeis3.5l/kg.Totalclearance

isapproximately15l/h.Thehalf-lifeinplasmaof10-12hoursgivesa24houreffectafterdosingonce

daily.

Bisoprololisexcretedfromthebodybytworoutes.50%ismetabolisedbythelivertoinactive

metaboliteswhicharethenexcretedbythekidneys.Theremaining50%isexcretedbythekidneysin

anunmetabolisedform.Sincetheeliminationtakesplaceinthekidneysandthelivertothesame

extentadosageadjustmentisnotrequiredforpatientswithimpairedliverfunctionorrenal

insufficiency.Thepharmacokineticsinpatientswithstablechronicheartfailureandwithimpaired

liverorrenalfunctionhasnotbeenstudied.

Thekineticsofbisoprololarelinearandindependentofage.

Inpatientswithchronicheartfailure(NYHAstageIII)theplasmalevelsofbisoprololarehigherandthehalf-lifeis

prolongedcomparedtohealthyvolunteers.Maximumplasmaconcentrationatsteadystateis64±21ng/mlatadaily

doseof10mgandthehalf-lifeis17±5hours.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityorcarcinogenicity.Likeother-blockers,bisoprololcausedmaternal(decreasedfoodintake

anddecreasedbodyweight)andembryo/fetaltoxicity(increasedincidenceofresorptions,reducedbirthweightofthe

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Colloidalanhydroussilica

Magnesiumstearate

Crospovidone

Pregelatinisedmaizestarch

Maizestarch

Microcrystallinecellulose

Calciumhydrogenphosphate,anhydrous.

Filmcoating:

Dimeticone

Talc

Macrogol400

Titaniumdioxide(E171)

Hypromellose.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageof

theproductonthemarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Tabletscontainedin2x14calendarblisterstrips

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerials

derivedfromsuchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

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Ruislip

Middlesex

HA40NU

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8ParallelProductAuthorisationNumber

PPA1328/13/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:6thOctober2006.

10DATEOFREVISIONOFTHETEXT

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