CARVEDILOL

Main information

  • Trade name:
  • CARVEDILOL Film Coated Tablet 6.25mg Milligram
  • Dosage:
  • 6.25mg Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARVEDILOL Film Coated Tablet 6.25mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/053/002
  • Authorization date:
  • 04-06-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Carvedilol6.25mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainscarvedilol6.25mg.

Excipient:lactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

6.25mgfilm-coatedtablets:white,oval,scoredonbothsidesandmarked"6.25"ononeside.

The6.25mgtabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Carvedilolmaybeusedasmonotherapy,orincombinationwithotherantihypertensivepreparations,especiallythiazide

diureticsorcalciumantagonistsofthenifedipinetype.

Supplementarytreatmentofheartfailure:

CarvedilolisgiventosupplementdiureticsandACEinhibitorsinthetreatmentofsymptomaticcardiacinsufficiency

(CHF)irrespectiveoftheaetiology.

4.2Posologyandmethodofadministration

Thetabletsmustbeswallowedwithwater.

Hypertension:

Therecommendeddoseistakenonceaday.

Adults

12.5mgisinitiallygivenonceadayforthefirsttwodays.Thereafter25mgonceadayisrecommended.Ifrequired

thedosemaybeincreasedinsuccessivestages,withanintervalofatleastfourweeks,uptotherecommended

maximumdailydoseof50mggivenasasingledoseordividedintotwoseparatedoses.

Elderly(>65years)

12.5mgonceadayisrecommendedinitially.Iftheresponseisinadequate,thedosemaybeincreasedbytitrationat

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Supplementarytreatmentofheartfailure

Thetreatmentshouldbesupervisedbyaspecialist,andthedosageofdiureticsandACEinhibitors,withorwithout

digitalis,mustbestable.

3.125mgtwiceadayfortwoweeksisrecommendedinitially.Ifthisdoseistolerated,thedosemaybeincreasedin

successivestagesatintervalsofatleasttwoweeks,upto6.25mgtwiceaday,followedby12.5mgtwiceadayand

thereafter25mgtwiceaday.Thedoseshouldbeincreasedtothemaximumtolerancelevel.Themaximum

recommendeddoseinmildtomoderateheartfailureis25mgtwiceadaytopatientswhoweighlessthan85kg,and50

mgtwiceadaytopatientswhoweighmorethan85kg.

Themaximumrecommendeddoseinsevereheartfailureis25mgtwiceaday.

Beforeeachdoseincrease,thepatientshouldbeexaminedbyadoctorforsymptomsofworseningheartfailureand/or

vasculardilatation.Occasionalworseningoftheheartfailureorincreasedwaterretentionshouldbetreatedwith

increaseddosesofdiuretics.Itmaysometimesbenecessarytoreducethecarvediloldoseortemporarilydiscontinue

treatmentwithcarvedilol.

4.3Contraindications

Hypersensitivitytocarvediloloranycomponentoftheproduct

Unstable/decompensatedheartfailure

Clinicallymanifestliverdysfunction

2ndand3rddegreeAVblock(unlessapermanentpacemakerisinplace)

Severebradycardia(<50bpm)

Sicksinussyndrome(includingsino-atrialblock)

Severehypotension(systolicbloodpressure<85mmHg)

Cardiogenicshock

Historyofbronchospasmorasthma

Chronicobstructivepulmonarydiseasewithbronchialobstruction(see4.4“Specialwarnings

andprecautionsforuse”)

4.4Specialwarningsandprecautionsforuse

ChronicCongestiveHeartFailure

Incongestiveheartfailurepatients,worseningcardiacfailureorfluidretentionmayoccurduringup-titrationof

carvedilol.Ifsuchsymptomsoccur,diureticsshouldbeincreasedandthecarvediloldoseshouldnotbeadvanceduntil

clinicalstabilityresumes.Occasionally,it

maybenecessarytolowerthecarvediloldoseor,inrarecases,temporarilydiscontinueit.Suchepisodesdonot

precludesubsequentsuccessfultitrationofcarvedilol.Carvedilolshouldbeusedwithcautionincombinationwith

digitalisglycosides,asbothdrugsslowAV

conduction.

RenalfunctioninCongestiveHeartFailure

Reversibledeteriorationofrenalfunctionhasbeenobservedwithcarvediloltherapyinchronicheartfailurepatients

withlowbloodpressure(systolicBP<100mmHg),ischaemicheartdiseaseanddiffusevasculardisease,and/or

underlyingrenalinsufficiency.

Leftventriculardysfunctionfollowingacutemyocardialinfarction

BeforetreatmentwithcarvedilolisinitiatedthepatientmustbeclinicallystableandshouldhavereceivedanACE

inhibitorforatleastthepreceding48hours,andthedoseoftheACEinhibitorshouldhavebeenstableforatleastthe

preceding24hours.

Chronicobstructivepulmonarydisease

Carvedilolshouldbeusedwithcaution,inpatientswithchronicobstructivepulmonarydisease(COPD)witha

bronchospasticcomponentwhoarenotreceivingoralorinhaledmedication,andonlyifthepotentialbenefitoutweighs

thepotentialrisk.

Inpatientswithatendencytobronchospasm,respiratorydistresscanoccurasaresultofa

possibleincreaseinairwayresistance.Patientsshouldbecloselymonitoredduringinitiationandup-titrationof

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Diabetes

Careshouldbetakenintheadministrationofcarvediloltopatientswithdiabetesmellitus,astheearlysignsand

symptomsofacutehypoglycaemiamaybemaskedorattenuated.Inchronicheartfailurepatientswithdiabetes,theuse

ofcarvedilolmaybeassociatedwithworseningcontrolofbloodglucose.

Peripheralvasculardisease

Carvedilolshouldbeusedwithcautioninpatientswithperipheralvasculardiseaseas-blockerscanprecipitateor

aggravatesymptomsofarterialinsufficiency.

Raynaud'sphenomenon

Carvedilolshouldbeusedwithcautioninpatientssufferingfromperipheralcirculatorydisorders(egRaynaud's

phenomenon)astheremaybeexacerbationofsymptoms.

Thyrotoxicosis

Carvedilolmayobscurethesymptomsofthyrotoxicosis.

Anesthesiaandmajorsurgery

Cautionshouldbeexercisedinpatientsundergoinggeneralsurgery,becauseofthesynergisticnegativeinotropic

effectsofcarvedilolandanaestheticdrugs.

Bradycardia

Carvedilolmayinducebradycardia.Ifthepatient’spulseratedecreasestolessthan55beatsperminute,thedosageof

carvedilolshouldbereduced.

Labileorsecondaryhypertension

Carvedilolmustbegivenwithcautiontopatientswithlabileorsecondaryhypertensionuntilfurtherclinicalexperience

isavailable.

Hypersensitivity

Careshouldbetakeninadministeringcarvediloltopatientswithahistoryofserioushypersensitivityreactions,andin

thoseundergoingdesensitisationtherapy,as-blockersmayincreaseboththesensitivitytowardsallergensandthe

seriousnessofanaphylacticreactions.

Psoriasis

Patientswithahistoryofpsoriasisassociatedwith-blockertherapyshouldtakecarvedilolonlyafterconsiderationof

therisk-benefitratio.

Concomitantuseofcalciumchannelblockers

CarefulmonitoringofECGandbloodpressureisnecessaryinpatientsreceivingconcomitanttherapywithcalcium

channelblockersoftheverapamilordiltiazemtypeorotherantiarrhythmicdrugs.

Pheochromocytoma

Inpatientswithpheochromocytoma,ana-blockingagentshouldbeinitiatedpriortotheuseofany-blockingagent.

Althoughcarvedilolhasboth-and-blockingpharmacologicalactivities,thereisnoexperiencewithitsuseinthis

condition.Cautionshouldthereforebetakenintheadministrationofcarvediloltopatientssuspectedofhaving

pheochromocytoma.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacokineticinteractions

Digoxin:Digoxinconcentrationsareincreasedbyabout15%whendigoxinandcarvedilolareadministered

concomitantly.BothdigoxinandcarvedilolslowAVconduction.Increasedmonitoringofdigoxinlevelsis

recommendedwheninitiating,adjustingordiscontinuing

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Insulinororalhypoglycemics:Agentswith-blockingpropertiesmayenhancethebloodsugar-reducingeffectof

insulinandoralhypoglycemics.Thesignsofhypoglycaemiamaybemaskedorattenuated(especiallytachycardia).In

patientstakinginsulinororalhypoglycemics,regularmonitoringofbloodglucoseisthereforerecommended.

Inducersandinhibitorsofhepaticmetabolism:Rifampicinreducedplasmaconcentrationsofcarvedilolbyabout70%

CimetidineincreasedAUCbyabout30%butcausednochangeinCmax.Caremayberequiredinthosepatients

receivinginducersofmixedfunctionoxidases

egrifampicin,asserumlevelsofcarvedilolmaybereduced,orinhibitorsofmixedfunctionoxidasesegcimetidine,as

serumlevelsofcarvedilolmaybeincreased.However,basedontherelativelysmalleffectofcimetidineoncarvedilol

druglevels,thelikelihoodofanyclinicallyimportantinteractionisminimal.

Catecholamine-depletingagents:Patientstakingbothagentswith-blockingpropertiesandadrugthatcandeplete

catecholamines(egreserpineandmonoamineoxidaseinhibitors)shouldbeobservedcloselyforsignsofhypotension

and/orseverebradycardia.

Cyclosporin:Modestincreasesinmeantroughcyclosporinconcentrationswereobservedfollowinginitiationof

carvediloltreatmentin21renaltransplantpatientssufferingfromchronicvascularrejection.Inabout30%ofpatients,

thedoseofcyclosporinhadtobereduced

inordertomaintaincyclosporinconcentrationswithinthetherapeuticrange,whileintheremaindernoadjustmentwas

needed.Onaverage,thedoseofcyclosporinwasreducedabout20%inthesepatients.Duetowideinterindividual

variabilityinthedoseadjustmentrequired,itisrecommendedthatcyclosporinconcentrationsbemonitoredclosely

afterinitiationofcarvediloltherapyandthatthedoseofcyclosporinbeadjustedasappropriate.

Verapamil,diltiazem,orotherantiarrhythmics:IncombinationwithcarvedilolcanincreasetheriskofAVconduction

disturbances(seesection4.4Specialwarningsandprecautionsforuse).

Pharmacodynamicinteractions

Clonidine:Concomitantadministrationofclonidinewithagentswith-blockingpropertiesmaypotentiateblood-

pressure-andheart-rate-loweringeffects.Whenconcomitanttreatmentwithagentswith-blockingpropertiesand

clonidineistobeterminated,the-blockingagentshouldbediscontinuedfirst.Clonidinetherapycanthenbe

discontinuedseveraldayslaterbygraduallydecreasingthedosage.Calciumchannelblockers(seesection4.4Special

warningsandprecautionsforuse).Isolatedcasesofconductiondisturbance(rarelywithhaemodynamiccompromise)

havebeenobservedwhencarvedilolisco-administeredwithdiltiazem.

Aswithotheragentswith-blockingproperties,ifcarvedilolistobeadministeredorallywithcalciumchannel

blockersoftheverapamilordiltiazemtype,itisrecommendedthatECGandbloodpressurebemonitored.

Aswithotheragentswith-blockingactivity,carvedilolmaypotentiatetheeffectofotherconcomitantlyadministered

drugsthatareanti-hypertensiveinaction(eg1-receptorantagonists)orhavehypotensionaspartoftheiradverse

effectprofile.

Carefulattentionmustbepaidduringanaesthesiatothesynergisticnegativeinotropicandhypotensiveeffectsof

carvedilolandanaestheticdrugs.

Additionally,thefollowingclassinteractionsgenerallyapplytobeta-blockers:

Epinephrine:Sometenreportsareavailableofpronouncedhypertensionandbradycardiainpatientstreatedwithnon-

selectivebeta-receptorblockers(e.g.pindololandpropranolol)towhomepinephrine(adrenaline)wasadministered.

Theseclinicalfindingshavebeenconfirmedinstudiesinhealthyvolunteers.Ithasalsobeenproposedthatepinephrine

asasupplementtolocalanaestheticscantriggerthesereactionsduringintravascular

administration.Theriskisprobablyconsiderablylowerwithcardioselectivebeta-receptorblockers.

NSAIDs:Anti-inflammatoriesoftheNSAIDtypecounteractstheantihypertensiveactivityofbeta-receptorblocking

substances.Thesubstancestudiedisprimarilyindomethacin.Thisinteractionisnotthoughttooccurwithsulindac.In

onediclofenacstudy,nosuchinteractionhasbeendemonstrated.Noexperienceofthecombinationofcarvediloland

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Barbituricacidpreparations:Combinationwithbarbituricacidpreparationsshouldbeavoided.

Phenylpropranolamine:Phenylpropranolamine(norephedrine)insingledosesof50mgcanraisethediastolicblood

pressuretopathologicallevelsinhealthyvolunteers.Propranololgenerallycounteractstheincreaseinbloodpressure

triggeredbyphenylpropranololamine.However,beta-receptorblockerscantriggerparadoxicalhypertensivereactions

inpatientstakinglargedosesofphenylpropranolamine.Hypertensivecrisesduringtreatmentwith

phenylpropranolaminealonehavebeendescribedinafewcases.

4.6Fertility,pregnancyandlactation

Thereisnoadequateclinicalexperiencewithcarvedilolinpregnantwomen.

Animalstudiesareinsufficientwithrespecttoeffectsonpregnancy,embryonal/foetaldevelopment,parturitionand

postnataldevelopment(seesection5.3).Thepotentialriskforhumansisunknown.

Carvedilolshouldnotbeusedduringpregnancyunlessthepotentialbenefitoutweighsthepotentialrisk.Thetreatment

shouldbestopped2-3daysbeforeexpectedbirth.Ifthisisnotpossiblethenew-bornhastobemonitoredforthefirst

2-3daysoflife.

Betablockersreduceplacentalperfusion,whichmayresultinintrauterinefoetaldeath,andimmatureandpremature

deliveries.Inaddition,adverseeffects(especiallyhypoglycaemiaandbradycardia)mayoccurinthefoetusand

neonate.Theremaybeanincreasedriskofcardiacandpulmonarycomplicationsintheneonateinthepostnatalperiod.

Animalstudieshavenotshownsubstantiveevidenceofteratogenicitywithcarvedilol(seealsosection5.3).

Animalstudiesdemonstratedthatcarvediloloritsmetabolitesareexcretedinbreastmilk.Itisnotknownwhether

carvedilolisexcretedinhumanmilk.Breastfeedingisthereforenotrecommendedduringadministrationofcarvedilol.

4.7Effectsonabilitytodriveandusemachines

Nostudieshavebeenperformedontheeffectsofcarvedilolonpatients’fitnesstodriveortooperatemachinery.

Becauseofindividuallyvariablereactions(e.g.dizziness,tiredness),theabilitytodrive,operatemachinery,orwork

withoutfirmsupportmaybeimpaired.Thisappliesparticularlyat

thestartoftreatment,afterdoseincreases,onchangingproducts,andincombinationwithalcohol..

4.8Undesirableeffects

(a)Summaryofthesafetyprofile

Thefrequencyofadversereactionsisnotdose-dependent,withtheexceptionofdizziness,abnormalvisionand

bradycardia.

(b)Tabulatedlistofadversereactions

Theriskofmostadversereactionsassociatedwithcarvedilolissimilaracrossallindications.Exceptionsaredescribed

insubsection(c).

Frequencycategoriesareasfollows:

Verycommon 1/10

Common 1/100and<1/10

Uncommon 1/1,000and<1/100

Rare 1/10,000and<1/1,000

Veryrare<1/10,000

Infectionsandinfestations

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Bloodandlymphaticsystemdisorders

Common:Anaemia

Rare:Thrombocytopaenia

Veryrare:Leukopenia

Immunesystemdisorders

Veryrare:Hypersensitivity(allergicreaction)

Metabolismandnutritiondisorders

Common:Weightincrease,hypercholesterolaemia,impairedbloodglucosecontrol(hyperglycaemia,hypoglycaemia)

inpatientswithpre-existingdiabetes

Psychiatricdisorders

Common:Depression,depressedmood

Uncommon:Sleepdisorders

Nervoussystemdisorders

Verycommon:Dizziness,headache

Uncommon:Presyncope,syncope,paraesthesia

Eyedisorders

Common:Visualimpairment,lacrimationdecreased(dryeye),eyeirritation

Cardiacdisorders

Verycommon:Cardiacfailure

Common:Bradycardia,oedema,hypervolaemia,fluidoverload

Uncommon:Atrioventricularblock,anginapectoris

Vasculardisorders

Verycommon:Hypotension

Common:Orthostatichypotension,disturbancesofperipheralcirculation(coldextremities,peripheralvasculardisease,

exacerbationofintermittentclaudicationandReynaud’s

phenomenon)

Respiratory,thoracicandmediastinaldisorders

Common:Dyspnoea,pulmonaryoedema,asthmainpredisposedpatients

Rare:Nasalcongestion

Gastrointestinaldisorders

Common:Nausea,diarrhoea,vomiting,dyspepsia,abdominalpain

Rare:Constipation

Hepatobiliarydisorders

Veryrare:Alanineaminotransferase(ALT),aspartateaminotransferase(AST)andgammaglutamyltransferase(GGT)

increased

Skinandsubcutaneoustissuedisorders

Uncommon:Skinreactions(e.g.allergicexanthema,dermatitis,urticaria,pruritus,psoriaticandlichenplanuslikeskin

lesions),alopecia

Musculoskeletalandconnectivetissuedisorders

Common:Paininextremities

Renalandurinarydisorders

Common:Renalfailureandrenalfunctionabnormalitiesinpatientswithdiffusevasculardiseaseand/orunderlying

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Veryrare:Urinaryincontinenceinwomen

Reproductivesystemandbreastdisorders

Uncommon:Erectiledysfunction

Generaldisordersandadministrationsiteconditions

Verycommon:Asthenia(fatigue)

Common:Pain

(c)Descriptionofselectedadversereactions

Dizziness,syncope,headacheandastheniaareusuallymildandaremorelikelytooccuratthebeginningoftreatment.

Inpatientswithcongestiveheartfailure,worseningcardiacfailureandfluidretentionmayoccurduringup-titrationof

carvediloldose(seesection4.4).

Cardiacfailureisacommonlyreportedadverseeventinbothplaceboandcarvedilol-treatedpatients(14.5%and15.4%

respectively,inpatientswithleftventriculardysfunctionfollowingacutemyocardialinfarction).

Reversibledeteriorationofrenalfunctionhasbeenobservedwithcarvediloltherapyinchronicheartfailurepatients

withlowbloodpressure,ischaemicheartdiseaseanddiffusevasculardiseaseand/orunderlyingrenalinsufficiency(see

section4.4).

Asaclass,beta-adrenergicreceptorblockersmaycauselatentdiabetestobecomemanifest,manifestdiabetestobe

aggravated,andbloodglucosecounter-regulationtobeinhibited.

Carvedilolmaycauseurinaryincontinenceinwomenwhichresolvesupondiscontinuationofthemedication.

4.9Overdose

Symptomsandsigns

Intheeventofoverdose,theremaybeseverehypotension,bradycardia,heartfailure,cardiogenicshockandcardiac

arrest.Theremayalsoberespiratoryproblems,bronchospasm,vomiting,disturbedconsciousnessandgeneralised

seizures.

Treatment

Inadditiontogeneralsupportivetreatment,thevitalparametersmustbemonitoredandcorrected,ifnecessary,under

intensivecareconditions.

Atropinecanbeusedforexcessivebradycardia,whiletosupportventricularfunctionintravenousglucagonor

sympathomimetics(dobutamine,isoprenaline)arerecommended.Ifpositiveinotropiceffectisrequired,

phosphodiesteraseinhibitors(PDE)shouldbeconsidered.

Ifperipheralvasodilationdominatestheintoxicationprofilethennorfenephrineornoradrenalineshouldbe

administeredwithcontinuousmonitoringofthecirculation.Inthecaseofdrug-resistantbradycardia,pacemaker

therapyshouldbeinitiated.

Forbronchospasm,-sympathomimetics(asaerosolorintravenous)shouldbegiven,oraminophyllinemaybe

administeredintravenouslybyslowinjectionorinfusion.Intheeventofseizures,slowintravenousinjectionof

diazepamorclonazepamisrecommended.

Incasesofsevereoverdosewithsymptomsofshock,supportivetreatmentmustbecontinuedforasufficientlylong

period,i.e.untilthepatient’sconditionhasstabilised,asaprolongationofeliminationhalf-lifeandredistributionof

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:beta-andalpha

1 -receptorblockersATCcode:C07AG02

Carvedilolisanon-selectivebeta-receptorblockerwhichalsoselectivelyblocksalpha

-receptors.Theperipheral

vascularresistancediminishesduringalpha

-receptorblockade,whiletheactivityintherenin-angiotensin-aldosterone

systemdecreasesduetoblockadeofbeta-receptors.Antioxidantpropertiesofcarvedilolanditsmetaboliteshavebeen

demonstratedinanimalstudiesinvitroandinvivo,andinanumberofhumancelltypesinvitro.

Inhypertensivepatientsaloweringofthebloodpressureisnotassociatedwithasimultaneousincreaseinthetotal

peripheralvascularresistancewhichisseeninthecaseofpurebeta-blockingsubstances.Theheartrateisreducedless

withcarvedilolthanwithbeta-blockersalone.Therenalbloodflowandkidneyfunctionremainsunchanged.Peri-

pheralbloodflowremainsunchangedandcoldextremitiesthereforerarelyoccur.Cardiacoutputisunchanged.

AnormalHDL/LDLratioismaintainedandnoincreaseinserumcholesterolisobserved.

Inpatientswithcoronaryheartdisease,carvedilolhasshownanti-ischaemicandanti-anginalpropertieswhichpersisted

duringlong-termtreatment.Acutehaemodynamicstudieshaveshownthatcarvedilolreducesleft-ventricularpreload

andafter-load.

Inpatientswithleft-ventriculardysfunctionorcardiacinsufficiency,carvedilolhasshownbeneficialhaemodynamic

effectsandimprovementsoftheleft-ventricularfunctioninrespectoftheejectionfractionanddimensionsoftheleft

ventricle.

Beneficialhaemodynamiceffectsandimprovedleft-ventricularfunctionareobservedinclinicalstudiesinpatientswith

heartfailureofischaemicandnon-ischaemicoriginwhoarebeingtreatedwithACEinhibitors,diuretics,digitalisand

withsupplementarycarvedilol.

Adouble-blind,placebo-controlledstudyincluding1094patientswithchronic,stablemild-to-severeheartfailurewith

reducedleft-ventricularfunction(ejectionfraction 35%)randomisedtofourdifferenttreatmentprotocolsonthebasis

ofwalkingdistanceshowsthatcarvedilolasasupplementtoconventionaltreatment(diuretics,ACEinhibitorsand

whenindicateddigitalisandnitrates)reducesmortality(3.2%inthecarvedilolgroupversus7.8%intheplacebogroup,

relativereduction65%;p<0.001)andtherequirementforhospitalisationonaccountofcardiovasculardisease.

Carvediloltreatmentwasassociatedwithincreasedwell-beingandproducedadelayintheprogressionofthedisease.

Thestudyincludedpatientswhotoleratedcarvedilol6.25mg,andthefollow-upperiodwasbarelysevenmonths

(median).Afewpatientswithsevereheartfailure(NYHAclassIV)andpatientsrequiringhospitalisationwith

inotropicsupportwereincluded.

IntheCopernicusstudy,2289patientswithstable,chronicsevereheartfailure(NYHAclassIV,ejectionfraction<

25%)wererandomisedtotreatmentwithcarvedilolorplaceboasasupplementtoconventionaltreatment.Patients

whorequiredi.v.inotropicsupportorthosewithsymptomatichypotensionorseverelyimpairedkidneyfunctionwere

notincludedinthestudy.Theprimaryeffectvariable,totalmortality,wasreducedfrom19.7%to12.8%(relative

reduction35%,p=0.00013).Treatmentof1000patientswithcarvedilolforoneyearpreventsonaverage70deaths,

whichgivesanNNT(NumberNeededToTreat)of14.

A24%relativereductioninthesecondaryeffectvariable,totalmortalityorhospitalisationirrespectiveofcause,was

observed.Therewasasignificantreductioninsuddendeathfrom7.8%to4.2%.

Atthestartandduringthetitrationphase,theoccurrenceofadverseeventswashigherinthecarvedilolgroup(22.9%

versus16.0%)principallyduetonon-seriousdizzinessorhypotension.Theoccurrenceofseriouseventsdidnotdiffer

betweenthetreatmentgroups.Throughoutthestudytheoccurrenceofseriouseventswaslowerinthecarvedilolgroup

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In-vitroandanimalexperimentationhasshownthattwohydroxycarbazolemetabolitesofcarvedilolareextremely

potentantioxidantswhichare30-80timesmorepotentthancarvedilol.

5.2Pharmacokineticproperties

Theabsolutebioavailabilityofcarvedilolinhumansisonaverage25-35%,withgreatindividualvariation.Thepeak

plasmaconcentrationisreached1hourafteroraladministration.Thereisalinearrelationshipbetweendoseandserum

concentrations.Concomitantfoodintakedoesnotinfluencethebioavailabilityorthepeakplasmaconcentration,

althoughthetimetothepeakplasmaconcentrationincreasessomewhat.Carvedilolishighlylipophilic,andabout

98%-99%isboundtoplasmaproteins.Thedistributionvolumeisabout2l/kg.

Theaveragehalf-lifetimeofcarvedilolis6to10hours.Theplasmaclearanceisabout590ml/min.Inhumans

carvedilolislargelymetabolisedtoanumberofmetaboliteswhicharemainlyexcretedviathebileandinthefaeces.A

smallerproportionisexcretedviathekidneysintheformofvariousmetabolites.

Demethylationandhydroxylationatthephenolringproducesthreeactivemetaboliteswithbeta-receptorblocking

activity.Onthebasisofpre-clinicalstudies,the4’-hydroxyphenolmetaboliteisabout13timesmorepotentforbeta

blockadethancarvedilol.Comparedwithcarvedilolthethreeactivemetabolitesdemonstrateaweakvasodilative

effect.Inhumanstheirconcentrationsareabouttentimeslowerthantheparentcompound.

Specialpopulations

Thepharmacokineticpropertiesofcarvedilolareinfluencedbyage;theplasmalevelsareabout50%higherinelderly

ascomparedwithyoungerpersons.Inastudyofpatientswithcirrhosisoftheliver,thebioavailabilityofcarvedilol

wasfourtimeshigherandthepeakplasmalevelfivetimeshigherthaninhealthysubjects.Inpatientswithcirrhosisof

theliverthevolumeofdistributionisthreetimeshigher.

Inhypertensivepatientswithmoderaterenalinsufficiency(creatinineclearance20-30ml/min)tosevererenal

insufficiency(creatinineclearance<20ml/min),anapproximate40-55%increaseintheplasmaconcentrationof

carvedilol(basedontheAUC)wasseenascomparedwithhypertensivepatientswithnormalkidneyfunction.There

wasalargevariationandaconsiderableoverlapwithnormalvalues.

5.3Preclinicalsafetydata

Toxicitystudiesrevealnohazardsforhumansinrespectofgenotoxicityandcarcinogenicity.

Administrationofcarvediloltopregnantratsindosestoxictofemalesresultedinfertilitydisturbance(lowmatingrate,

fewercorporaluteaandimplementations),togetherwithretardedgrowth/developmentintheoffspring.

Embryotoxicity(increasedpost-implantationdeathbutnomalformationswereseeninratsandrabbitsatdosestoxicto

females.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Lactosemonohydrate

Crospovidone

Povidone

Anhydrouscolloidalsilicondioxide

Magnesiumstearate

Tabletcoat:

Hydroxypropylmethylcellulose

Titaniumdioxide(E171)

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Macrogol

Polydextrose

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Storeintheoriginalpackage.

Plasticbottle:Donotstoreabove25 °

Blisterpack:Donotstoreabove30 °

6.5Natureandcontentsofcontainer

Plasticbottle(HDPE)orblisterpack(PVC/Alu)

Packsizes:10,14,28,30,50,56,98,100and250(plasticbottleonly)tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd

TradingasGerardLaboratories

35/36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

8MARKETINGAUTHORISATIONNUMBER

PA577/53/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4 th

June2004

Dateoflastrenewal:30 th

June2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 17/11/2011 CRN 2095220 page number: 10