CARVEDILOL

Main information

  • Trade name:
  • CARVEDILOL Tablets 6.25 Milligram
  • Dosage:
  • 6.25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARVEDILOL Tablets 6.25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/010/002
  • Authorization date:
  • 21-10-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Carvedilol6.25mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains6.25mgofcarvedilol.

Forafulllistofexcipients,seesection6.1.

Eachtabletalsocontains86.25mgoflactosemonohydrate.

3PHARMACEUTICALFORM

Tablet.

Lightyellowtoyellow,roundflattablet.Scoredononeside,debossedontheothersidewith“CVL”ontopand“T2”

onbottom.Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension

Chronicstableanginapectoris

Adjunctivetreatmentofmoderatetoseverestablechronicheartfailure

4.2Posologyandmethodofadministration

Oraluse.

Essentialhypertension:

Carvedilolmaybeusedforthetreatmentofhypertensionaloneorincombinationwithotherantihypertensives,

especiallythiazidediuretics.Oncedailydosingisrecommended,howevertherecommendedmaximumsingledoseis

25mgandtherecommendedmaximumdailydoseis50mg.

Adults

Therecommendedinitialdoseis12.5mgonceadayforthefirsttwodays.

Thereafter,thetreatmentiscontinuedatthedose25mg/day.Ifnecessary,thedosemaybefurtherincreasedgradually

atintervalsoftwoweeksormorerarely.

Elderly

Therecommendedinitialdoseinhypertensionis12.5mgonceadaywhichmayalsobesufficientforcontinued

treatment.

However,ifthetherapeuticresponseisinadequateatthisdose,thedosemaybefurtherincreasedgraduallyatintervals

oftwoweeksormorerarely.

Chronicstableanginapectoris:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 1

Adults

Theinitialdosageis12.5mgtwiceadayforthefirsttwodays.Thereafter,thetreatmentiscontinuedatthedose25mg

twiceaday.Ifnecessary,thedosemaybefurtherincreasedgraduallyatintervalsoftwoweeksormorerarelytothe

recommendedmaximumdoseof100mgadaydividedintotwodoses(twicedaily).

Elderly

Therecommendedinitialdoseis12.5mgtwicedailyfortwodays.Thereafter,thetreatmentiscontinuedatthedose25

mgtwicedaily,whichistherecommendedmaximumdailydose.

Heartfailure:

Carvedilolisgiveninmoderatetosevereheartfailureinadditiontoconventionalbasictherapywithdiuretics,ACE

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

hospitalisationduetoheartfailure)andthebasictherapymustbestabilisedforatleast4weekspriortotreatment.

Additionallythepatientshouldhaveareducedleftventricularejectionfractionandheartrateshouldbe>50bpmand

systolicbloodpressure>85mmHg(see4.3Contraindications).

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

patientisstabilised.IfbradycardiaappearsorincaseoflengtheningofAVconduction,thelevelofdigoxinshouldfirst

bemonitored.Occasionallyitmaybenecessarytoreducethecarvediloldoseortemporarilydiscontinuetreatment

altogether.Eveninthesecases,carvediloldosetitrationcanoftenbesuccessfullycontinued.

Renalfunction,thrombocytesandglucose(incaseofNIDDMand/orIDDM)shouldbemonitoredregularlyduring

dosetitration.However,afterdosetitrationthefrequencyofmonitoringcanbereduced.

Ifcarvedilolhasbeenwithdrawnformorethantwoweeks,thetherapyshouldbereinitiatedwith3.125mgtwiceaday

andincreasedgraduallyaccordingtotheaboverecommendations.

Renalinsufficiency

Dosagemustbedeterminedforeachpatientindividually,butaccordingtopharmacokineticparametersthereisno

evidencethatdoseadjustmentofcarvedilolinpatientswithrenalinsufficiencyisnecessary.

Moderatehepaticdysfunction

Doseadjustmentmayberequired.

Childrenandadolescents(<18years)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 2

Elderly

Elderlypatientsmaybemoresusceptibletotheeffectsofcarvedilolandshouldbemonitoredmorecarefully.

Aswithotherbetablockersandespeciallyinpatientswithcoronarydisease,thewithdrawalofcarvedilolshouldbe

donegradually(see4.4Specialwarningandspecialprecautionsforuse).

Methodsofadministration

Thetabletsshouldbetakenwiththeadequatesupplyoffluid.Thetabletsdonotneedtobetakenwithameal.

However,itisrecommendedthatheartfailurepatientstaketheircarvedilolmedicationwithfoodtoallowthe

absorptiontobeslowerandtheriskoforthostatichypotensiontobereduced.

4.3Contraindications

HeartfailurebelongingtoNYHAClassIVoftheheartfailureclassificationrequiringintravenousinotropic

treatment.

Chronicobstructivepulmonarydiseasewithbronchialobstruction(see4.4Specialwarningandspecial

precautionsforuse).

Clinicallysignificanthepaticdysfunction.

Bronchialasthma.

AVblock,degreeIIorIII.

Severebradycardia(<50bpm).

Sicksinussyndrome(incl.sino-atrialblock).

Cardiogenicshock.

Severehypotension(systolicbloodpressurebelow85mmHg).

Prinzmetal'sangina.

Untreatedphaeochromocytoma.

Hypersensitivitytocarvedilolortoanyoftheexcipients.

Metabolicacidosis.

Severeperipheralarterialcirculatorydisturbances.

Concomitantintravenoustreatmentwithverapamilordiltiazem(see4.5Interactionwithothermedicinal

productsandotherformsofinteraction).

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),ischaemicheartdiseaseandgeneralisedatherosclerosis,and/orunderlying

renalinsufficiency.Inheartfailurepatientswiththeseriskfactors,renalfunctionshouldbemonitoredduringdose

titrationofcarvedilol.Ifsignificantworseningofrenalfunctionoccurs,thecarvediloldosemustbereducedortherapy

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 3

Inpatientswithchronicheartfailuretreatedwithdigitalis,carvedilolshouldbegivenwithcaution,asdigitalisand

carvedilolbothlenghtentheAVconductiontime(see4.5Interactionwithothermedicinalproductsandotherformsof

interaction).

Otherwarningsasregardscarvedilolandbeta-blockersingeneral

Patientswithachronicobstructivepulmonarydiseasewithatendencytowardsbronchospasmwhoarenottreatedwith

oralorinhalationmedicineshouldonlybegivencarvediloliftheexpectedimprovementoutweighsthepossiblerisk.

Patientsshouldbemonitoredcloselyintheinitialphase,andtitrationofcarvedilolandcarvediloldoseshouldbe

reducedincaseofbronchospasms.

Carvedilolmaymasksymptomsandsignsofacutehypoglycaemia.Impairedbloodglucosecontrolmayoccasionally

occurinpatientswithdiabetesmellitusandheartfailureinconnectionwiththeuseofcarvedilol.Therefore,close

monitoringofdiabeticpatientsreceivingcarvedilolisrequiredbymeansofregularbloodglucosemeasurements,

especiallyduringdosetitration,andadjustmentofantidiabeticmedicationasnecessary(see4.5Interactionwithother

medicinalproductsandotherformsofinteraction).Bloodglucoselevelsshouldalsobecloselymonitoredaftera

longerperiodoffasting.

Carvedilolmaymaskfeatures(symptomsandsigns)ofthyrotoxicosis.

Carvedilolmaycausebradycardia.Ifthereisadecreaseinpulseratetolessthan55beatsperminute,andsymptoms

associatedwithbradycardiaoccur,thecarvediloldoseshouldbereduced.

Whencarvedilolisusedconcomitantlywithcalciumchannelblockingagentssuchasverapamilanddiltiazemorwith

otherantiarrhythmics,specificallyamiodarone,thepatient’sbloodpressureandECGhavetobemonitored.

Intravenousco-administrationshouldbeavoided(see4.5Interactionwithothermedicinalproductsandotherformsof

interaction).

Cimetidineshouldbeadministeredonlywithcautionconcomitantlyaseffectsofcarvedilolmaybeincreased(see4.5

Interactionwithothermedicinalproductsandotherformsofinteraction).

Personswearingcontactlensesshouldbeadvisedofapossiblereductionofthesecretionoflacrimalfluid.

Careshouldbetakeninadministratingcarvediloltopatientswithahistoryofserioushypersensitivityreactionsandin

thoseundergoingdesensitisationtherapyasbeta-blockersmayincreaseboththesensitivitytowardsallergensandthe

seriousnessofanaphylacticreactions.Cautionsshouldbeexercisedwhenprescribingbeta-blockerstopatientswith

psoriasissinceskinreactionsmaybeaggravated.

Carvedilolshouldbeusedwithcautioninpatientswithperipheralvasculardiseases,asbeta-blockersmayaggravate

symptomsofthedisease.ThesamealsoappliestothosewithRaynaud’ssyndrome,astheremaybeexacerbationor

aggravationofsymptoms.

Patientswhoareknownaspoormetabolizersofdebrisoquine,shouldbecloselymonitoredduringinitiationoftherapy

(see5.2Pharmacokineticproperties).

Sincethereislimitedclinicalexperience,carvedilolshouldnotbeadministeredinpatientswithlabileorsecondary

hypertension,orthostasis,acuteinflammatoryheartdisease,haemodynamicrelevantobstructionofheartvalvesor

outflowtract,end-stageperipheralarterialdisease,concomitanttreatmentwith

-receptorantagonistor

-receptor

agonist.

Inpatientswithphaeochromocytoma,aninitialtreatmentwithalphablockersshouldbestartedbeforeusinganybeta

blocker.Althoughcarvedilolexercisesalphaandbetablockadethereisnotsufficientexperienceinthisdisease,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 4

Becauseofitsnegativedromotropicaction,carvedilolshouldbegivenwithcautiontopatientswithfirstdegreeheart

block.

Betablockersreducetheriskofarrhythmiasatanasthesia,howevertheriskofhypotensionmaybeincreasedaswell.

Cautionshouldthereforebeobservedwiththeuseofcertainanaestheticdrugs.Newerstudiessuggesthowever,a

benefitofbetablockersinpreventingperioperativecardiacmorbidityandreductionoftheincidenceofcardiovascular

complications.

Aswithotherbeta-blockers,carvedilolshouldnotbediscontinuedabruptly.Thisappliesinparticulartopatientswith

ischaemicheartdisease.Carvediloltherapymustbediscontinuedgraduallywithintwoweeks,e.g.byreducingthe

dailydosetohalfeverythreedays.Ifnecessary,atthesametimereplacementtherapyshouldbeinitiatedtoprevent

exacerbationofanginapectoris.

Thismedicinalproductcontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,

theLapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Antiarrhythmics.Isolatedcasesofconductiondisturbance(rarelycompromisedhaemodynamics)havebeenreported,if

oralcarvedilolandoraldiltiazemverapamiland/oramiodaronearegivenconcomitantly.Aswithotherbeta-blockers,

ECGandbloodpressureshouldbemonitoredcloselywhenconcomitantlyadministeringcalcium-channel-blockersof

theverapamilanddiltiazemtypeduetotheriskofAVconductiondisorderorriskofcardiacfailure(synergeticeffect).

Closemonitoringshouldbedoneincaseofco-administrationofcarvedilol,andamiodaronetherapy(oral)orclassI

antiarrhythmics.Bradycardia,cardiacarrest,andventricularfibrillationhavebeenreportedshortlyafterinitiationof

beta-blockertreatmentinpatientsreceivingamiodarone.ThereisariskofcardiacfailureincaseofclassIaorIc

antiarrhythmicsconcomitantintravenoustherapy.

Concomitanttreatmentwithreserpine,guanethidine,methyldopa,guanfacineandmonoamineoxidaseinhibitors

(exceptionMAO-Binhibitors)canleadtoadditionaldecreaseinheartrate.Monitoringofvitalsignsisrecommended.

Dihydropyridines.Theadministrationofdihydropyridinesandcarvedilolshouldbedoneunderclosesupervisionas

heartfailureandseverehypotensionhavebeenreported.

Nitrates.Increasedhypotensiveeffects.

Cardiacglycosides.Anincreaseofsteadystatedigoxinlevelsbyapproximately16%andofdigitoxinby

approximately13%hasbeenseeninhypertensivepatientsinconnectionwiththeconcomitantuseofcarvediloland

digoxin.Monitoringofplasmadigoxinconcentrationsisrecommendedwheninitiating,discontinuingoradjusting

treatmentwithcarvedilol.

Otherantihypertensivedrugs.Carvedilolmaypotentiatetheeffectsofotherconcomitantlyadministered

antihypertensives(e.g.

-receptorantagonists)anddrugswithantihypertensivesideeffectssuchasbarbiturates,

phenothiazines,tricyclicantidepressants,vasodilatingagentsandalcohol.

Cyclosporin.Theplasmalevelofcyclosporinisincreasedwhencarvedilolisco-administered.Itisrecommendedthat

cyclosporinconcentrationsarecarefullymonitored.

Antidiabeticsincludinginsulin.Thebloodsugar-loweringeffectofinsulinandoraldiabeticdrugsmaybeintensified.

Symptomsofhypoglycaemiamaybemasked.Indiabeticpatientsregularmonitoringofbloodglucoselevelsis

necessary.

Clonidine.Incaseofwithdrawalofbothcarvedilolandclonidine,carvedilolshouldbewithdrawnseveraldaysbefore

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 5

Inhalationalanaesthetics.Cautionisadvisedincaseofanaesthesiaduetosynergistic,negativeinotropeand

hypotensiveeffectofcarvedilolandcertainanaesthetics.

NSAIDs,estrogensandcorticosteroids.Theantihypertensiveeffectofcarvedilolisdecreasedduetowaterandsodium

retention.

MedicinesinducingorinhibitingcytochromeP450enzymes.Patientsreceivingmedicinesthatinduce(e.g.rifampicin

andbarbiturates)orinhibit(e.g.cimetidine,ketoconazole,fluoxetine,haloperidol,verapamil,erythromycine)

cytochromeP450enzymeshavetobemonitoredcloselyduringconcomitanttreatmentwithcarvedilolasserum

carvedilolconcentrationsmaybereducedbythefirstagentsandincreasedbytheenzymeinhibitors.

Sympathomimeticswithalpha-mimeticandbeta-mimeticeffects.Riskofhypertensionandexcessivebradycardia.

Ergotamine.Vasoconstrictionincreased.

Neuromuscularblockingagents.Increasedneuromuscularblock.

4.6Fertility,pregnancyandlactation

Useofcarvedilolisnotrecommendedduringpregnancyandlactation.Carvediloldidnotdemonstrateanyteratogenic

effectsinanimalreproductionstudies,butthereisinsufficientclinicalevidenceofitssafetyinpregnantwomen(see

5.3Preclinicalsafetydata).

Beta-blockersreduceplacentalperfusionwhichmayresultinintrauterinefetaldeathandimmatureandpremature

deliveries.Inaddition,adversereactions(especiallyhypoglycaemiabradycardia,respiratorydepressionand

hypothermia)mayoccurinthefetalandneonate).Thereisanincreasedriskofcardiacandpulmonarycomplicationsin

theneonateinthepostnatalperiod.Carvedilolshouldonlybeusedforpregnantwomen,ifthepotentialbenefitforthe

motheroutweighsthepotentialriskforthefetal/neonate.Thetreatmentshouldbestopped2-3daysbeforeexpected

birth.Ifthisisnotpossiblethenew-bornhastobemonitoredforthefirst2-3daysoflife.

Carvedilolislipophilicandaccordingtoresultsfromstudieswithlactatinganimals,carvedilolanditsmetabolitesare

excretedinbreastmilkand,therefore,mothersreceivingcarvedilolshouldnotbreast-feed.

4.7Effectsonabilitytodriveandusemachines

Someindividualsmayhavereducedalertnessespeciallyoninitiationandadjustmentofmedication.Undergood

therapeuticcontrol,carvedilolisnotknowntoreducetheabilitytodriveorusemachines.

4.8Undesirableeffects

Adversereactionsoccurmainlyatthebeginningoftreatment.

Theadversereactionprofileinpatientswithhypertensionandanginaissimilartothatobservedinpatientswithheart

failure.However,thefrequencyofadversereactionsislowerinpatientswithhypertensionandanginapectoris.

Adversereactionsinheartfailurepatientsreportedfromclinicalstudies.

Adversereactionsthatoccurredinheartfailurepatientsinclinicalstudiesandnotseenascommonlyinsubjectswho

receivedplaceboarelistedinthetablebelow.

Verycommon(>1/10):

Metabolismandnutritiondisorders:

Hyperglycaemia*,peripheraloedema,hypervolaemia,fluidretention

Eyedisorders:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 6

Cardiacdisorders:

Peripheraloedema,bradycardia

Vasculardisorders:

Orthostatichypotension

Gastrointestinaldisorders:

Nausea,diarrhoea,vomiting

Reproductivesystemandbreastdisorders:

Genitaloedema

Generaldisordersandadministrationsiteconditions:

Oedema

Common(>1/100):

Bloodandlymphaticsystemdisorders:

Mildthrombocytopenia

Nervoussystemdisorders:

Dizziness

Uncommon(>1/1000,<1/100)

Gastrointestinaldisorders:

Constipation

Rare(<1/1000)

Nervoussystemdisorders:

Syncope

Cardiacdisorders:

Totalatrio-ventricularblock,aggravationofheartfailure

Renalandurinarydisorders:

Aggravationofrenalfunction

*Hyperglycaemia(inpatientswithdiabetesmellitus)(see4.4Specialwarningandspecialprecautionsforuse).

Acuterenalinsufficiencyanddisturbanceofrenalfunctioninpatientswithgeneralisedatherosclerosisand/orimpaired

renalfunctionhavebeenrareadversereactions.Thefrequencyofadversereactionsisnotdosedependent,withthe

exceptionofdizziness,visualdisturbance,bradycardiaandaggravationofheartinsufficiency.

Cardiaccontractilitymaybedecreasedduringdosetitrationbutthisisrare.

Adversereactionsinpatientswithhypertensionandanginareportedfromclinicalstudies.

Verycommon(>1/10)

Nervoussystemdisorders:

Dizziness*,headache*

Eyedisorders:

Lacrimationdecreased

Cardiacdisorders:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 7

Vasculardisorders:

Orthostatichypotension

Musculoskeletal,connectivetissueandbonedisorders:

Paininlimb

Generaldisordersandadministrationsiteconditions:

Fatigue*

Common(>1/100)

Metabolismandnutritiondisorders:

Hypercholesterolaemia

Gastrointestinaldisorders:

Nausea,abdominalpain,diarrhoea

Rare(<1/1000)

Bloodandlymphaticsystemdisorders:

Mildthrombocytopenia,leukopenia

Metabolismandnutritiondisorders:

Peripheraloedema

Psychiatricdisorders:

Sleepdisorders,depression

Nervoussystemdisorders:

Paraesthesia,syncope*

Vasculardisorders:

Peripheralcirculatoryfailure

Respiratory,thoracicandmediastinaldisorders:

Nasalcongestion

Gastrointestinaldisorders:

Constipation,vomiting

Renalandurinarydisorders:

Aggravationofrenalfunction

Investigations:

Serumtransaminaseincreased

Veryrare(<1/10000)

Eyedisorders:

Visualdisturbance,eyeirritation

Gastrointestinaldisorders:

Drymouth

Renalandurinarydisorders:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 8

Reproductivesystemandbreastdisorders:

Impotence

*Thesereactionsoccurinparticularatthebeginningoftreatment.

Veryrareadversereactionsincludeangina,AVblockandexacerbationofsymptomsinpatientssufferingfrom

intermittentclaudicationorRaynaud'sphenomenon.

Respiratory,thoracicandmediastinaldisorders.Asthmaticdyspnoeahasbeenobservedcommonlyinpredisposed

patients.

Skinandsubcutaneoustissuedisorders.Variousskinreactionshavebeenreportedrarely(e.g.allergicexanthema,

urticaria,pruritusandlichenplanus-likereaction).Psoriaticskinlesionsmayoccurorexistinglesionsmaybe

aggravated.

Non-selectivebeta-blockersinparticularmayalsoresultinlatentdiabetesmellitusbecomingmanifestandaggravated,

andbloodglucosecontrolbeingdisturbed.Milddisturbancesofglucosebalancearepossible,howevernotcommon,

alsoduringtreatmentwithcarvedilol.

4.9Overdose

Symptoms.Overdosemaycauseserioushypotension,bradycardia,heartfailure,cardiogenicshockandcardiacarrest.

Theremayalsoberespiratoryproblems,bronchospasm,vomiting,reducedconsciousnessandconvulsions.

Treatment.Inadditiontonormaltreatmentprocedures,vitalsignsmustbemonitoredand,ifnecessary,correctedatan

intensivecareunit.Thefollowingsupportivemeasuresmaybetaken:

Atropine:0.5-2mgintravenously(fortreatmentofseverebradycardia).

Glucagon:initially1-10mgintravenouslyfollowedifnecessarybyaslowinfusionof2–5mg/hour(inorderto

maintaincardiovascularfunction).

Sympathomimeticsaccordingtotheirefficacyandthepatient’sweight:dobutamine,isoprenalineoradrenaline.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 9

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:alpha-andbeta-blockingagents

ATCcode:C07AG02

Carvedilolisavasodilatorynon-selectivebeta-blocker,whichreducestheperipheralvascularresistancebyselective

alpha

-receptorblockadeandsuppressestherenin-angiotensinthroughnon-selectivebeta-blockade.Plasmarennin

activityisreducedandfluidretentionisrare.

Carvedilolhasnointrinsicsympathomimeticactivity(ISA).Likepropranolol,ithasmembranestabilisingproperties.

Carvedilolisaracemateoftwostereoisomers.Bothenantiomerswerefoundtohavealpha-adrenergicblockingactivity

inanimalmodels.Non-selectivebeta

-andbeta

-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%.Plasma

levelspeakatapproximately1hourafterdosing.Thereisalinearcorrelationbetweenthedoseandplasma

concentrations.Inpatientswithslowhydroxylationofdebrisoquineplasmacarvedilolconcentrationsincreasedupto2-

3-foldcomparedtorapiddebrisoquinemetabolisers.Fooddoesnotaffectbioavailabilityalthoughthetimetoreach

maximumplasmaconcentrationisdelayed.Carvedilolisahighlylipophiliccompound.Approximately98%to99%of

carvedilolisboundtoplasmaproteins.Itsvolumeofdistributionisapproximately2l/kgThefirstpasseffectafteroral

administrationisapproximately60-75%.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 10

Propertiesinthepatient.Thepharmacokineticsofcarvedilolareaffectedbyage;plasmalevelsofcarvedilolare

approximately50%higherintheelderlycomparedtoyoungsubjects.Inastudyinpatientswithlivercirrhosis,the

bioavailabilityofcarvedilolwasfourtimesgreaterandthepeakplasmalevelfivetimeshigherandthevolumeof

distributionthreetimeshigherthaninhealthysubjects.Insomeofthehypertensivepatientswithmoderate(creatinine

clearance20-30ml/min)orsevere(creatinineclearance<20ml/min)renalinsufficiency,anincreaseinplasma

carvedilolconcentrationsofapproximately40-55%wasseencomparedtopatientswithnormalrenalfunction.

However,therewasalargevariationintheresults.

5.3Preclinicalsafetydata

Studiesonratsandmicerevealednocarcinogenicpotentialofcarvedilolatdosesof75mg/kgand200mg/kg(38-100

timesthehumanmaximumdailydose).

Carvediloldemonstratednomutagenicpotentialinstudiesconductedonmammalsorotheranimalsinvitroorinvivo.

Whenhighdosesofcarvedilolwereadministeredtopregnantrats(200mg/kg= 100timesthehumanmaximum

dailydose),undesirableeffectsonpregnancyandfertilitywereobserved.Physicalgrowthanddevelopmentofthe

foetusweredelayedatdosesof 60mg/kg(30timesthehumanmaximumdailydose).Embryotoxicity(increased

mortalityafterimplantationoftheembryo)occurred,buttherewerenodeformationsinratsorrabbitsatdosesof

200mg/kgand75mg/kg,respectively(38–100timesthehumanmaximumdailydose).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Povidone

Crospovidone

Colloidalsilicaanhydrous

Magnesiumstearate

YellowironoxideE172

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

WhiteopaquePVC/PVdCaluminiumblisters.

Packsizes:14,28,30,50,56&100tablets.

Hospitalpacksof50and100tablets.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 11

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DrUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/10/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21October2005

Dateoflastrenewal:25February2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/03/2011 CRN 2092893 page number: 12