CARVEDILOL PFIZER

Main information

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

Documents

Localization

  • Available in:
  • CARVEDILOL PFIZER
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/044/002
  • Authorization date:
  • 25-02-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CarvedilolPfizer6.25mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains6.25mgcarvedilol.

Excipients:Eachtabletcontains57.25mglactosemonohydrateand1.250mgsucrose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet

Whitetooff-white,ovalshaped,film-coatedtabletdebossedwith“F57”ononesideanddeepbreaklineontheother

side.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension

Chronicstableanginapectoris

Adjunctivetreatmentofmoderatetoseverestablechronicheartfailure

4.2Posologyandmethodofadministration

Oraluse.

Essentialhypertension:

Carvedilolmaybeusedforthetreatmentofhypertensionaloneorincombinationwithotherantihypertensives,

especiallythiazidediuretics.Oncedailydosingisrecommended,howevertherecommendedmaximumsingledoseis

25mgandtherecommendedmaximumdailydoseis50mg.

Adults

Therecommendedinitialdoseis12.5mgonceadayforthefirsttwodays.Thereafter,thetreatmentiscontinuedatthe

dose25mg/day.Ifnecessary,thedosemaybefurtherincreasedgraduallyatintervalsoftwoweeksormorerarely.

Elderly

Therecommendedinitialdoseinhypertensionis12.5mgonceadaywhichmayalsobesufficientforcontinued

treatment.

However,ifthetherapeuticresponseisinadequateatthisdose,thedosemaybefurtherincreasedgraduallyatintervals

oftwoweeksormorerarely.

Chronicstableanginapectoris:

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Adults

Therecommendedinitialdosageis12.5mgtwiceadayforthefirsttwodays.Thereafter,thetreatmentiscontinuedat

thedose25mgtwiceaday.Ifnecessary,thedosemaybefurtherincreasedgraduallyatintervalsoftwoweeksormore

rarelytotherecommendedmaximumdoseof100mgadaydividedintotwodoses(twicedaily).

Elderly

Therecommendedinitialdoseis12.5mgtwicedailyfortwodays.Thereafter,thetreatmentiscontinuedatthedose25

mgtwicedaily,whichistherecommendedmaximumdailydose.

Heartfailure:

Carvedilolisgiveninmoderatetosevereheartfailureinadditiontoconventionalbasictherapywithdiuretics,ACE

inhibitors,digitalis,and/orvasodilators.Thepatientshouldbeclinicallystable(nochangeinNYHA-class,no

hospitalisationduetoheartfailure)andthebasictherapymustbestabilizedforatleast4weekspriortotreatment.

Additionallythepatientshouldhaveareducedleftventricularejectionfractionandheartrateshouldbe>50bpmand

systolicbloodpressure>85mmHg(seesection4.3).

Theinitialdoseis3.125mgtwiceadayfortwoweeks.Ifthisdoseistolerated,thedosemaybeincreasedslowlywith

intervalsofnotlessthantwoweeksupto6.25mgtwiceaday,thenupto12.5mgtwiceadayandfinallyupto25mg

twiceaday.Thedosageshouldbeincreasedtothehighesttolerablelevel.

Therecommendedmaximumdosageis25mgtwiceadayforpatientswithabodyweightoflessthan85kg,and50

mgtwiceadayforpatientswithabodyweightabove85kg,providedthattheheartfailureisnotsevere.Adose

increaseto50mgtwicedailyshouldbeperformedcarefullyunderclosemedicalsupervisionofthepatient.

Transientworseningofsymptomsofheartfailuremayoccuratthebeginningoftreatmentorduetoadoseincrease,

especiallyinpatientswithsevereheartfailureand/orunderhighdosediuretictreatment.Thisdoesusuallynotcallfor

discontinuationoftreatment,butdoseshouldnotbeincreased.Thepatientshouldbemonitoredbya

physician/cardiologistfortwohoursafterstartingtreatmentorincreasingthedose.Beforeeachdoseincrease,an

examinationshouldbeperformedforpotentialsymptomsofworseningheartfailureorforsymptomsofexcessive

vasodilatation(e.g.renalfunction,bodyweight,bloodpressure,heartrateandrhythm).Worseningofheartfailureor

fluidretentionistreatedbyincreasingthedoseofdiuretic,andthedoseofcarvedilolshouldnotbeincreaseduntilthe

patientisstabilized.IfbradycardiaappearsorincaseoflengtheningofAVconduction,thelevelofdigoxinshouldfirst

bemonitored.Occasionallyitmaybenecessarytoreducethecarvediloldoseortemporarilydiscontinuetreatment

altogether.Eveninthesecases,carvediloldosetitrationcanoftenbesuccessfullycontinued.

Renalfunction,thrombocytesandglucose(incaseofNIDDMand/orIDDM)shouldbemonitoredregularlyduring

dosetitration.However,afterdosetitrationthefrequencyofmonitoringcanbereduced.

Ifcarvedilolhasbeenwithdrawnformorethantwoweeks,thetherapyshouldbereinitiatedwith3.125mgtwiceaday

andincreasedgraduallyaccordingtotheaboverecommendations.

Renalinsufficiency

Dosagemustbedeterminedforeachpatientindividually,butaccordingtopharmacokineticparametersthereisno

evidencethatdoseadjustmentofcarvedilolinpatientswithrenalimpairmentisnecessary.

Moderatehepaticdysfunction

Doseadjustmentmayberequired.

Childrenandadolescents(<18years)

Carvedilolisnotrecommendedfortheuseinchildrenbelow18yearsofageduetoinsufficientdataontheefficacyand

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Elderly

Elderlypatientsmaybemoresusceptibletotheeffectsofcarvedilolandshouldbemonitoredmorecarefully.

Aswithotherbeta-blockersandespeciallyinpatientswithcoronarydisease,thewithdrawalofcarvedilolshouldbe

donegradually(seesection4.4).

Methodsofadministration

Thetabletsshouldbetakenwiththeadequatesupplyoffluid.Itisrecommendedthatheartfailurepatientstaketheir

carvedilolmedicationwithfoodtoallowtheabsorptiontobeslowerandtheriskoforthostatichypotensiontobe

reduced.

4.3Contraindications

HypersensitivitytothecarvedilolortoanyoftheexcipientsofCarvedilol.

HeartfailurebelongingtoNYHAClassIVoftheheartfailureclassificationwithmarkedfluidretentionor

overloadrequiringintravenousinotropictreatment.

Chronicobstructivepulmonarydiseasewithbronchialobstruction(seesection4.4).

Clinicallysignificanthepaticdysfunction.

Bronchialasthma.

AVblock,degreeIIorIII(unlessapermanentpacemakerisinplace).

Severebradycardia(<50bpm).

Sicksinussyndrome(incl.sino-atrialblock).

Cardiogenicshock.

Severehypotension(systolicbloodpressurebelow85mmHg).

Prinzmetal'sangina.

Untreatedphaeochromocytoma.

Metabolicacidosis.

Severeperipheralarterialcirculatorydisturbances.

Concomitantintravenoustreatmentwithverapamilordiltiazem(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Warningstobeconsideredparticularlyinheartfailurepatients

Inchronicheartfailurepatientscarvedilolshouldbeadministeredprincipallyinadditiontodiuretics,ACEinhibitors,

digitalisand/orvasodilators.Initiationoftherapyshouldbeunderthesupervisionofahospitalphysician.Therapy

shouldonlybeinitiated,ifthepatientisstabilizedonconventionalbasictherapyforatleast4weeks.Patientswith

severeheartfailure,saltandvolumedepletion,elderlyorpatientswithlowbasicbloodpressureshouldbemonitored

forapproximately2hoursafterthefirstdoseorafterdoseincreaseashypotensionmayoccur.Hypotensiondueto

excessivevasodilatationisinitiallytreatedbyreducingthedoseofthediuretic.Ifsymptomsstillpersist,thedoseof

anyACEinhibitormaybereduced.Atthestartoftherapyorduringup-titrationofCarvedilolworseningofheart

failureorfluidretentionmayoccur.Inthesecases,thedoseofdiureticshouldbeincreased.However,sometimesitwill

benecessarytoreduceorwithdrawCarvedilolmedication.Thecarvediloldoseshouldnotbeincreasedbefore

symptomsduetotheworseningofheartfailureorhypotensionduetovasodilatationareundercontrol.

Reversibledeteriorationofrenalfunctionhasbeenobservedduringcarvediloltherapyinheartfailurepatientswithlow

bloodpressure(systolic<100mmHg),ischaemicheartdiseaseandgeneralizedatherosclerosis,and/orunderlying

renalinsufficiency.Inheartfailurepatientswiththeseriskfactors,renalfunctionshouldbemonitoredduringdose

titrationofcarvedilol.Ifsignificantworseningofrenalfunctionoccurs,thecarvediloldosemustbereducedortherapy

mustbediscontinued.

Inpatientswithchronicheartfailuretreatedwithdigitalis,carvedilolshouldbegivenwithcaution,asdigitalisand

carvedilolbothlengthentheAVconductiontime(seesection4.5).

Otherwarningsasregardscarvedilolandbeta-blockersingeneral

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Thereisnoclinicalexperiencewithcarvedilolinthesepatients,althoughthealpha-blockingactivityofcarvedilolmay

preventsuchsymptoms.However,cautionshouldbetakenintheadministrationofcarvediloltopatientssuspectedof

havingPrinzmetal’svariantangina.

Patientswithachronicobstructivepulmonarydiseasewithatendencytowardsbronchospasmswhoarenottreatedwith

oralorinhalationmedicineshouldonlybegivencarvediloliftheexpectedimprovementoutweighsthepossiblerisk.

Patientsshouldbemonitoredcloselyintheinitialphase,andtitrationofcarvedilolandcarvediloldoseshouldbe

reducedincaseofbronchospasms.

Carvedilolmaymasksymptomsandsignsofacutehypoglycaemia.Impairedbloodglucosecontrolmayoccasionally

occurinpatientswithdiabetesmellitusandheartfailureinconnectionwiththeuseofcarvedilol.Therefore,close

monitoringofdiabeticpatientsreceivingcarvedilolisrequiredbymeansofregularbloodglucosemeasurements,

especiallyduringdosetitration,andadjustmentofantidiabeticmedicationasnecessary(seesection4.5).Bloodglucose

levelsshouldalsobecloselymonitoredafteralongerperiodoffasting.

Carvedilolmaymaskfeatures(symptomsandsigns)ofthyrotoxicosis.

Carvedilolmaycausebradycardia.Ifthereisadecreaseinpulseratetolessthan55beatsperminute,andsymptoms

associatedwithbradycardiaoccur,thecarvediloldoseshouldbereduced.

Whencarvedilolisusedconcomitantlywithcalciumchannelblockingagentssuchasverapamilanddiltiazemorwith

otherantiarrhythmics,specificallyamiodarone,thepatient’sbloodpressureandECGhavetobemonitored.

Intravenousco-administrationshouldbeavoided(seesection4.5).

Cimetidineshouldbeadministeredonlywithcautionconcomitantlyaseffectsofcarvedilolmaybeincreased(see

section4.5).

Personswearingcontactlensesshouldbeadvisedofapossiblereductionofthesecretionoflacrimalfluid.

Careshouldbetakeninadministratingcarvediloltopatientswithahistoryofserioushypersensitivityreactionsandin

thoseundergoingdesensitisationtherapyasbeta-blockersmayincreaseboththesensitivitytowardsallergensandthe

seriousnessofanaphylacticreactions.Cautionsshouldbeexercisedwhenprescribingbeta-blockerstopatientswith

psoriasissinceskinreactionsmaybeaggravated.

Carvedilolshouldbeusedwithcautioninpatientswithperipheralvasculardiseases,asbeta-blockersmayaggravate

symptomsofthedisease.ThesamealsoappliestothosewithRaynaud’ssyndrome,astheremaybeexacerbationor

aggravationofsymptoms.

Patientswhoareknownaspoormetabolizersofdebrisoquine,shouldbecloselymonitoredduringinitiationoftherapy

(seesection5.2).

Sincethereislimitedclinicalexperience,carvedilolshouldnotbeadministeredinpatientswithlabileorsecondary

hypertension,orthostasis,acuteinflammatoryheartdisease,haemodynamicrelevantobstructionofheartvalvesor

outflowtract,end-stageperipheralarterialdisease,concomitanttreatmentwith1-receptorantagonistor2-receptor

agonist.

Inpatientswithphaeochromocytoma,aninitialtreatmentwithalpha-blockersshouldbestartedbeforeusinganybeta-

blocker.Althoughcarvedilolexercisesalphaandbetablockadethereisnotsufficientexperienceinthisdisease,

thereforecautionshouldbeadvisedinthesepatients.

Becauseofitsnegativedromotropicaction,carvedilolshouldbegivenwithcautiontopatientswithfirstdegreeheart

block.

Beta-blockersreducetheriskofarrhythmiasatanasthesia,howevertheriskofhypotensionmaybeincreasedaswell.

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Newerstudiessuggesthowever,abenefitofbeta-blockersinpreventingperioperativecardiacmorbidityandreduction

oftheincidenceofcardiovascularcomplications.

Aswithotherbeta-blockers,carvedilolshouldnotbediscontinuedabruptly.Thisappliesinparticulartopatientswith

ischaemicheartdisease.Carvediloltherapymustbediscontinuedgraduallywithintwoweeks,e.g.byreducingthe

dailydosetohalfeverythreedays.Ifnecessary,atthesametimereplacementtherapyshouldbeinitiatedtoprevent

exacerbationofanginapectoris.

Carvedilolcontainslactosemonohydrateandsucrose.Patientswithrarehereditaryproblemsofgalactoseintolerance,

fructoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption,sucrase-isomaltaseinsufficiency

shouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Antiarrhythmics.

Isolatedcasesofconductiondisturbance(rarelycompromisedhaemodynamics)havebeenreported,iforalcarvedilol

andoraldiltiazemverapamiland/oramiodaronearegivenconcomitantly.Aswithotherbeta-blockers,ECGandblood

pressureshouldbemonitoredcloselywhenconcomitantlyadministeringcalcium-channel-blockersoftheverapamil

anddiltiazemtypeduetotheriskofAVconductiondisorderorriskofcardiacfailure(synergeticeffect).Close

monitoringshouldbedoneincaseofco-administrationofcarvedilol,andamiodaronetherapy(oral)orclassI

antiarrhythmics.Bradycardia,cardiacarrest,andventricularfibrillationhavebeenreportedshortlyafterinitiationof

beta-blockertreatmentinpatientsreceivingamiodarone.ThereisariskofcardiacfailureincaseofclassIaorIc

antiarrhythmicsconcomitantintravenoustherapy.

Concomitanttreatmentwithreserpine,guanethidine,methyldopa,guanfacineandmonoamineoxidaseinhibitors

(exceptionMAO-Binhibitors)canleadtoadditionaldecreaseinheartrate.AndhypotensionMonitoringofvitalsigns

isrecommended.

Dihydropyridines.

Theadministrationofdihydropyridinesandcarvedilolshouldbedoneunderclosesupervisionasheartfailureand

severehypotensionhavebeenreported.

Nitrates.

Increasedhypotensiveeffects.

Cardiacglycosides.

Anincreaseofsteadystatedigoxinlevelsbyapproximately16%andofdigitoxinbyapproximately13%hasbeenseen

inhypertensivepatientsinconnectionwiththeconcomitantuseofcarvedilolanddigoxin.Monitoringofplasma

digoxinconcentrationsisrecommendedwheninitiating,discontinuingoradjustingtreatmentwithcarvedilol.

Otherantihypertensivemedicines.

Carvedilolmaypotentiatetheeffectsofotherconcomitantlyadministeredantihypertensives(e.g.1-receptor

antagonists)andmedicineswithantihypertensiveadversereactionssuchasbarbiturates,phenothiazines,tricyclic

antidepressants,vasodilatingagentsandalcohol.

Cyclosporin.

Theplasmalevelofcyclosporinisincreasedwhencarvedilolisco-administered.Itisrecommendedthatcyclosporin

concentrationsarecarefullymonitored.

Antidiabeticsincludinginsulin.

Thebloodsugar-loweringeffectofinsulinandoraldiabeticmedicinesmaybeintensified.Symptomsof

hypoglycaemiamaybemasked.Indiabeticpatientsregularmonitoringofbloodglucoselevelsisnecessary.

Clonidine.

Incaseofwithdrawalofbothcarvedilolandclonidine,carvedilolshouldbewithdrawnseveraldaysbeforethestepwise

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Inhalationalanaesthetics.

Cautionisadvisedincaseofanaesthesiaduetosynergistic,negativeinotropeandhypotensiveeffectofcarvediloland

certainanaesthetics.

NSAIDs,estrogensandcorticosteroids.

Theantihypertensiveeffectofcarvedilolisdecreasedduetowaterandsodiumretention.

MedicinesinducingorinhibitingcytochromeP450enzymes.

Patientsreceivingmedicinesthatinduce(e.g.rifampicinandbarbiturates)orinhibit(e.g.cimetidine,ketoconazole,

fluoxetine,haloperidol,verapamil,erythromycine)cytochromeP450enzymeshavetobemonitoredcloselyduring

concomitanttreatmentwithcarvedilolasserumcarvedilolconcentrationsmaybereducedbythefirstagentsand

increasedbytheenzymeinhibitors.

Sympathomimeticswithalpha-mimeticandbeta-mimeticeffects.

Riskofhypertensionandexcessivebradycardia.

Ergotamine.

Vasoconstrictionincreased.

Neuromuscularblockingagents.

Increasedneuromuscularblock.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofcarvedilolinpregnantwomen.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Beta-blockersreduceplacentalperfusionwhichmayresultinintrauterinefetaldeathandimmatureandpremature

deliveries.Inaddition,adversereactions(especiallyhypoglycaemia,hypotension,bradycardia,respiratorydepression

andhypothermia)mayoccurinthefetusandneonate.Thereisanincreasedriskofcardiacandpulmonary

complicationsintheneonateinthepostnatalperiod.Carvedilolshouldnotbeusedduringpregnancyunlessclearly

necessary(thatisifthepotentialbenefitforthemotheroutweighsthepotentialriskforthefetus/neonate).The

treatmentshouldbestopped2-3daysbeforeexpectedbirth.Ifthisisnotpossiblethenew-bornhastobemonitoredfor

thefirst2-3daysoflife.

Lactation

Carvedilolislipophilicandaccordingtoresultsfromstudieswithlactatinganimals,carvedilolanditsmetabolitesare

excretedinbreastmilkand,therefore,mothersreceivingcarvedilolshouldnotbreast-feed.

4.7Effectsonabilitytodriveandusemachines

Thismedicinalproducthasminorinfluenceontheabilitytodriveandusemachines.Someindividualsmayhave

reducedalertnessespeciallyoninitiationandadjustmentofmedication.

4.8Undesirableeffects

Thefollowingterminologieshavebeenusedinordertoclassifytheoccurrenceofundesirableeffects.

Verycommon(1/10)

Common(1/100to<1/10)

Uncommon(1/1,000to<1/100)

Rare(1/10,000to<1/1,000)

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Adversereactionsoccurmainlyatthebeginningoftreatment.

Adversereactionsinheartfailurepatientsreportedfromclinicalstudies.

Adversereactionsthatoccurredinheartfailurepatients,inclinicalstudies,andnotseenascommonlyinsubjectswho

receivedplaceboarelistedbelow.

Cardiacdisorders

Common:bradycardia,posturalhypotension,hypotension,oedema(includinggeneralised,peripheral,dependentand

genitaloedema,oedemaofthelegs,hypervolaemiaandfluidoverload).

Uncommon:syncope(includingpresyncope),AV-blockandaggravationofheartinsufficiencyduringup-titration.

Bloodandlymphaticsystemdisorder

Rare:thrombocytopenia.

Veryrare:leucopenia.

Nervoussystemdisorders

Verycommon:dizziness*,headache*(usuallymild),asthenia(includingfatigue).

Eyedisorders

Common:visionabnormalities.

Gastrointestinaldisorders

Common:nausea,diarrhoea,andvomiting.

RenalandUrinarydisorders

Rare:acuterenalfailureandrenalfunctionabnormalitiesinpatientswithdiffusevasculardiseaseand/orimpairedrenal

function(seesection4.4).

Metabolismandnutritiondisorders

Common:weightincrease,hypercholesterolemia,hyperglycaemia,hypoglycaemiaandworseningcontrolofblood

glucose(inpatientswithpre-existingdiabetesmellitus)(seesection4.4).

*Occuringparticularlyatthestartoftreatment.

Thefrequencyofadversereactionsisnotdosedependent,withtheexceptionofdizziness,visualdisturbance,

bradycardiaandaggravationofheartinsufficiency.

Cardiaccontractilitymaybedecreasedduringdosetitration,butthisisrare.

Adversereactionsinpatientswithhypertensionandanginapectorisreportedfromclinicalstudies

Theadversereactionprofileinpatientswithhypertensionandanginaissimilartothatobservedinpatientswithheart

failure.However,thefrequencyofadversereactionsislowerinpatientswithhypertensionandanginapectoris.

Cardiacdisorders

Common:bradycardia*,posturalhypotension*

Uncommon:syncope*,disturbancesofperipheralcirculation(coldextremities,PVD,exacerbationofintermittent

claudicationandRaynaudsphenomenon).AV-block,anginapectoris(includingchestpain),symptomsofheartfailure

andperipheraloedema.

Bloodandlymphaticsystemdisorders

Veryrare:IncreaseofALAT,ASATandgamma-GT,thrombocytopenia,leucopenia.

Nervoussystemdisorder

Common:dizziness*,headaches*andfatigue*

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Eyedisorder

Common:reducedlacrimation(inparticularinpatientswearingcontactlenses),eyeirritation

Uncommon:disturbedvision.

Respiratorydisorders:

Common:asthmaanddyspnoeainpredisposedpatients.

Rare:stuffynose.

Gastrointestinaldisorders

Common:nausea,abdominalpain,diarrhoea

Uncommon:constipationandvomiting.

Rare:drynessofthemouth

Renalandurinarydisorders

Rare:disturbancesofmicturition

Skinandsubcutaneousdisorders

Uncommon:skinreactions(e.g.allergicexanthema,dermatitis,urticaria,pruritus,lichenplanus-likereactions,and

increasedsweating).Psoriaticskinlessionsmayoccurorexistinglesionsexacerbated.

Musculoskeletalandconnectivetissuedisorders

Common:painintheextremeties

Generaldisordersandadministrationsiteconditions

Isolatedcasesofallergicreactions

Reproductivesystemandbreastdisorders

Uncommon:impotence

Psychiatricdisorder

Uncommon:sleepdisturbance,depression,hallucination,confusion

Veryrare:psychosis

*Occuringparticularlyatthestartoftreatment.

Non-selectivebeta-blockersinparticularmayalsoresultinlatentdiabetesmellitusbecomingmanifest,manifest

diabetesbeingaggravatedandbloodglucosecontrolbeingdisturbed.Milddisturbancesofglucosebalanceare

possible,howevernotcommon,alsoduringtreatmentwithcarvedilol.

Thefrequencyofadversereactionsisnotdosedependent,withtheexceptionofdizziness,visualdisturbance,

bradycardiaandaggravationofheartinsufficiency.

4.9Overdose

Symptoms

Overdosemaycauseserioushypotension,bradycardia,heartfailure,cardiogenicshockandcardiacarrest.Theremay

alsoberespiratoryproblems,bronchospasm,vomiting,reducedconsciousnessandconvulsions.

Treatment

Inadditiontonormaltreatmentprocedures,vitalsignsmustbemonitoredand,ifnecessary,correctedatanintensive

careunit.Thefollowingsupportivemeasuresmaybetaken:Atropine:0.5-2mgintravenously(fortreatmentofsevere

bradycardia).Glucagon:initially1-10mgintravenouslyfollowedifnecessarybyaslowinfusionof2–5mg/hour(in

ordertomaintaincardiovascularfunction).

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Ifperipheralvasodilatationisthedominantsymptomofoverdose,thepatienthastobegivennoradneralineor

etilefrine.Thepatient’scirculationmustbemonitoredcontinuously.

Ifthepatienthasbradycardiaunresponsivetopharmacotherapy,pacemakertherapyshouldbestarted.Forthetreatment

ofbronchospasm,thepatientmustbegivenbeta-sympathomimetics(asaerosolorintravenously,iftheaerosoldoesnot

provideadequateeffect)ortheophyllineintravenously.Ifthepatienthasconvulsions,diazepammaybeadministeredas

aslowintravenousinjection.

Carvedilolishighlyprotein-bound.Therefore,itcannotbeeliminatedbydialysis.

Important!Incasesofsevereoverdosewhenthepatientisinshock,supportivetreatmentshouldbecontinuedfora

sufficientlylongperiodoftime,sincetheeliminationandredistributionofcarvedilolarelikelytobeslowerthan

normal.Durationoftheantidotetreatmentdependsontheseriousnessoftheoverdose;supportivetreatmentmustbe

continueduntilthepatientstabilises.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Alpha-andbeta-blockingagents

ATCcode:C07AG02

Carvedilolisavasodilatorynon-selectivebeta-blocker,whichreducestheperipheralvascularresistancebyselective

alpha1-receptorblockadeandsuppressestherenin-angiotensinthroughnon-selectivebeta-blockade.Plasmarennin

activityisreducedandfluidretentionisrare.

Carvedilolhasnointrinsicsympathomimeticactivity(ISA).Likepropranolol,ithasmembranestabilisingproperties.

Carvedilolisaracemateoftwostereoisomers.Bothenantiomerswerefoundtohavealpha-adrenergicblockingactivity

inanimalmodels.Non-selectivebeta1-andbeta2-adrenoceptorblockadeisattributedmainlytotheS(-)enantiomer.

Theantioxidantpropertiesofcarvedilolanditsmetaboliteshavebeendemonstratedininvitroandinvivoanimal

studiesandinvitroinanumberofhumancelltypes.

Inhypertensivepatients,areductioninbloodpressureisnotassociatedwithaconcomitantincreaseinperipheral

resistance,asobservedwithpurebeta-blockingagents.Heartrateisslightlydecreased.Strokevolumeremains

unchanged.Renalbloodflowandrenalfunctionremainnormal,asdoesperipheralbloodflow,therefore,cold

extremities,oftenobservedwithbeta-blockers,arerarelyseen.Inhypertensivepatientscarvedilolincreasestheplasma

norepinephrineconcentration.

Inprolongedtreatmentofpatientswithangina,carvedilolhasbeenseentohaveananti-ischaemiceffectandto

alleviatepain.Haemodynamicstudiesdemonstratedthatcarvedilolreducesventricularpre-andafter-load.Inpatients

withleftventriculardysfunctionorcongestiveheartfailure,carvedilolhasafavourableeffectonhaemodynamicsand

leftventricularejectionfractionanddimensions.

Carvedilolhasnonegativeeffectontheserumlipidprofileorelectrolytes.TheratioofHDL(high-density

lipoproteins)andLDL(low-densitylipoproteins)remainsnormal.

5.2Pharmacokineticproperties

Generaldescription:

Theabsolutebioavailabilityoforallyadministeredcarvedilolisapproximately25%.Plasmalevelspeakat

approximately1hourafterdosing.Thereisalinearcorrelationbetweenthedoseandplasmaconcentrations.Inpatients

withslowhydroxylationofdebrisoquineplasmacarvedilolconcentrationsincreasedupto2-3-foldcomparedtorapid

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Fooddoesnotaffectbioavailabilityalthoughthetimetoreachmaximumplasmaconcentrationisdelayed.Carvedilolis

ahighlylipophiliccompound.Approximately98%to99%ofcarvedilolisboundtoplasmaproteins.Itsvolumeof

distributionisapproximately2l/kg.Thefirstpasseffectafteroraladministrationisapproximately60-75%.

Theaverageeliminationhalf-lifeofcarvedilolrangesfrom6to10hours.Plasmaclearanceisapproximately590

ml/min.Eliminationismainlybiliary.Theprimaryrouteofexcretionofcarvedilolisviathefaeces.Aminorportionis

eliminatedviathekidneysasmetabolites.

Carvedilolisfoundtobeextensivelymetabolisedintovariousmetabolites,whicharemainlyeliminatedinbile.

Carvedilolismetabolisedinthelivermainlythrougharomaticringoxidationandglucuronidation.Demethylationand

hydroxylationatthephenolringyieldthreeactivemetaboliteswithbeta-blockingactivity.Comparedtocarvedilol,

thesethreeactivemetaboliteshaveaweakvasodilatoryeffect.Onthebasisofpreclinicalstudies,the4’-

hydroxyphenolmetabolitehasabeta-blockingactivity13timesmorepotentthanthatofcarvedilol.However,the

metaboliteconcentrationsinhumansareapproximately10timeslowerthanthoseofcarvedilol.Twoofthe

hydroxycarbazolemetabolitesofcarvedilolarehighlypotentantioxidants,witha30-80-foldpotencycomparedto

carvedilol.

Propertiesinthepatient.

Thepharmacokineticsofcarvedilolareaffectedbyage;plasmalevelsofcarvedilolareapproximately50%higherin

theelderlycomparedtoyoungsubjects.Inastudyinpatientswithlivercirrhosis,thebioavailabilityofcarvedilolwas

fourtimesgreaterandthepeakplasmalevelfivetimeshigherandthevolumeofdistributionthreetimeshigherthanin

healthysubjects.Insomeofthehypertensivepatientswithmoderate(creatinineclearance20-30ml/min)orsevere

(creatinineclearance<20ml/min)renalinsufficiency,anincreaseinplasmacarvedilolconcentrationsof

approximately40-55%wasseencomparedtopatientswithnormalrenalfunction.However,therewasalargevariation

intheresults.

5.3Preclinicalsafetydata

Carvediloldemonstratednomutagenicorcarcinogenicpotential.

Highdosesofcarvedilolimpairedfertilityandaffectedpregnancyinrats(increasedresorptions).Decreasedfetal

weightanddelayedskeletaldevelopmentwerealsoseeninrats.Embryotoxicity(increasedpost-implantationloss)

occurredinratsandrabbits.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Lactosemonohydrate

SilicaColloidalanhydrous

Crospovidone(TypeA)

Crospovidone(TypeB)

Povidone30

Sucrose

Magnesiumstearate

Film-coating

Macrogol400

Polysorbate80

Titaniumdioxide(E171)

Hypromellose

6.2Incompatibilities

Irish Medicines Board

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Date Printed 21/11/2011 CRN 2095193 page number: 10

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Storebelow25°C.

6.5Natureandcontentsofcontainer

PVC/PE/PVDC–Aluminiumblisterpacks:

Packsizes:10,14,28,30,50,56,60,98(Carvedilol6.25mgand25mgonly)and100film-coatedtablets.

HDPEbottlewithwhiteopaquepolypropylenestockribbedclosure:

Packsizes:30and1000film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

8MARKETINGAUTHORISATIONNUMBER

PA822/44/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25thFebruary2011

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 21/11/2011 CRN 2095193 page number: 11