BIOCARD 25 MG TABLETS.

Main information

  • Trade name:
  • BIOCARD 25 MG TABLETS.
  • Dosage:
  • 25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BIOCARD 25 MG TABLETS.
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/003/004
  • Authorization date:
  • 22-08-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1063/003/004

CaseNo:2067236

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NicheGenericsLimited

1,TheCamCentre,WilburyWay,Hitchin,HertfordshireSG4OTW,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Biocard25mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom19/03/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Biocard25mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains25mgcarvedilol.

Excipients:Eachtabletcontains85mglactosemonohydrateand60mgsucrose.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablets.

Appearance:

Round,slightlybiconvex,whitebeveledgedtabletscoredononeside.

Thetabletcanbedividedintotwoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomaticchronicheartfailure(CHF)

BiocardisindicatedforthetreatmentofsymptomaticCHF(NewYorkHeartAssociation(NYHA)ClassesIIandIII)

asadjuncttostandardtherapiese.g.diuretics,digoxin,ACEinhibitors.Inthesepatients,additionofBiocardhasbeen

showntodelaytheprogressionofdisease.

PatientswithNYHAClassIICHFarecharacterisedbyslightlimitationofphysicalactivity.Theyarecomfortableat

restbutordinaryphysicalactivityresultsinfatigue,palpitationordyspnoea.

PatientswithNYHAClassIIICHFarecharacterisedbymarkedlimitationofphysicalactivity.Theyarecomfortableat

restbutevenlessthanordinaryactivitycausesfatigue,palpitationordyspnoea.

Duetolackofexperience,Biocardshouldnotbeinitiatedinpatientswithsevere(NYHAClassIV)CHF(seesection

4.3,Contra-indications).

Hypertension

Biocardisindicatedforthetreatmentofhypertension.

4.2Posologyandmethodofadministration

Thetabletsshouldbetakenwithfluid.ForCHFpatientsBiocardshouldbegivenwithfood.

Symptomaticchronicheartfailure

InitiationoftherapywithBiocardinpatientswithchronicheartfailureanditstitrationtostabilisethepatienttothe

optimaldoseshouldonlybeunderthesupervisionofahospitalphysician.

Thedosagemustbetitratedtoindividualrequirementsandpatients'clinicalstatusshouldbemonitoredfor2-3hours

afterinitiationandanydoseincreaseduringup-titration.

Forthosepatientsreceivingdiureticsand/ordigoxinand/orACEinhibitors,dosingoftheseotherdrugsshouldbe

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Adults

Therecommendeddosefortheinitiationoftherapyis3.125mgtwiceadayfortwoweeks.Ifthisdoseistolerated,the

dosageshouldbeincreasedsubsequently,atintervalsofnotlessthantwoweeks,to6.25mgtwicedaily,followedby

12.5mgtwicedailyandthereafter25mgtwicedaily.Dosingshouldbeincreasedtothehighestleveltoleratedbythe

patient.

Therecommendedmaximumdailydoseis25mggiventwicedailyinpatientsweighinglessthan85kg(187lbs)and

50mgtwicedailyinpatientsweighingmorethan85kg.

Duringup-titrationofthedoseinpatientswithsystolicbloodpressure<100mmHg,deteriorationofrenaland/or

cardiacfunctionsmayoccur.Therefore,beforeeachdoseincreasethesepatientsshouldbeevaluatedbythephysician

forrenalfunctionandsymptomsofworseningheartfailureorvasodilation.Transientworseningofheartfailure,

vasodilationorfluidretentionmaybetreatedbyadjustingdosesofdiureticsorACEinhibitorsorbymodifyingor

temporarilydiscontinuingBiocardtreatment.Underthesecircumstances,thedoseofBiocardshouldnotbeincreased

untilsymptomsofworseningheartfailureorvasodilationhavebeenstabilised.

IfBiocardisdiscontinuedformorethantwoweeks,therapyshouldberecommencedat3.125mgtwicedailyandup-

titratedinlinewiththeabovedosingrecommendation.

Elderly

Asforadults.

Children

Safetyandefficacyinchildren(under18years)hasnotbeenestablished.

Hypertension

Oncedailydosingisrecommended.

Adults

Therecommendeddoseforinitiationoftherapyis12.5mgonceadayforthefirsttwodays.Thereafterthe

recommendeddosageis25mgonceaday.Althoughthisisanadequatedoseinmostpatients,ifnecessarythedose

maybetitrateduptoarecommendeddailymaximumdoseof50mggivenonceadayorindivideddoses.

Dosetitrationshouldoccuratintervalsofatleasttwoweeks.

Elderly

Aninitialdoseof12.5mgdailyisrecommended.Thishasprovidedsatisfactorycontrolinsomecases.Iftheresponse

isinadequatethedosemaybetitrateduptotherecommendeddailymaximumdoseof50mggivenonceadayorin

divideddoses.

Children

Safetyandefficacyinchildren(under18years)hasnotbeenestablished.

Patientswithco-existinghepaticdisease

Biocardiscontra-indicatedinpatientswithhepaticdysfunction(seesections4.3Contra-indicationsand5.2

Pharmacokineticproperties).

Patientswithco-existingrenaldysfunction

Nodoseadjustmentisanticipatedaslongassystolicbloodpressureisabove100mmHg(seealsosections4.4Special

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4.3Contraindications

Duetolackofexperience,patientswithseverechronicheartfailure(NYHAClassIV)requiringintravenousinotropic

supportshouldnotbeinitiatedontreatmentwithBiocard.Thesepatientsarecharacterisedbyinabilitytocarryonany

physicalactivitywithoutdiscomfort.Symptomsofcardiacinsufficiencymaybepresent,evenatrest.Ifanyphysical

activityisundertaken,discomfortisincreased.Patientswithobstructiveairwaysdisease,liverdysfunction,

hypersensitivityto

carvediloloranyotherconstituentsofthetablets.

Aswithotherbeta-blockingagents:Historyofseverebronchospasmorasthma,

and3 rd

degreeA-Vheartblock(unlessapermanentpacemakerisinplace),severebradycardia(<50bpm),

cardiogenicshock,sicksinussyndrome(includingsino-atrialblock),severehypotension(systolicblood<85mmHg),

metabolicacidosisandphaeochromocytoma(unlessadequatelycontrolledbyalphablockade).

4.4Specialwarningsandprecautionsforuse

Inchronicheartfailurepatients,worseningcardiacfailureorfluidretentionmayoccurduringup-titrationofBiocard.If

suchsymptomsoccur,thedoseofdiureticshouldbeadjustedandtheBiocarddoseshouldnotbeadvanceduntil

clinicalstabilityresumes.

OccasionallyitmaybenecessarytolowertheBiocarddoseortemporarilydiscontinueit.Suchepisodesdonot

precludesubsequentsuccessfultitrationofBiocard.

Patientswhoprogresstosevere(NYHAClassIV)heartfailurewhilstontherapyshould,aswithalltherapies,have

theirtherapeuticregimereassessedatregularintervalsaccordingtothediscretionofthephysician.

Specialcareshouldbetakeninpatientswhosecardiacreserveispoor.Heartfailureshouldbesatisfactorilycontrolled

withappropriatetherapybeforecarvedilolisstarted.

Inhypertensivepatientswhohavechronicheartfailurecontrolledwithdigoxin,diureticsand/oranACEinhibitor,

BiocardshouldbeusedwithcautionsincebothdigoxinandBiocardmayslowA-Vconduction.

Aswithotherdrugswithbeta-blockingactivity,Biocardmaymaskthesignsofhyperthyroidismandearlysignsof

acutehypoglycaemiainpatientswithdiabetesmellitus.Alternativestobeta-blockingagentsaregenerallypreferredin

insulin-dependentpatients.Inpatientswithdiabetes,theuseofBiocardmaybeassociatedwithworseningcontrolof

bloodglucose.Therefore,regularmonitoringofbloodglucoseisrequiredindiabeticswhenBiocardisinitiatedorup-

titratedandhypoglycaemictherapyadjustedaccordingly.

ReversibledeteriorationofrenalfunctionhasbeenobservedwithBiocardtherapyinchronicheartfailurepatientswith

lowbloodpressure(systolicBP<100mmHg),ischaemicheartdiseaseanddiffusevasculardisease,and/orunderlying

renalinsufficiency.InCHFpatientswiththeseriskfactors,renalfunctionshouldbemonitoredduringup-titrationof

Biocardandthedrugdiscontinuedordosagereducedifworseningofrenalfailureoccurs.

Wearersofcontactlensesshouldbeadvisedofthepossibilityofreducedlacrimation.

Althoughanginahasnotbeenreportedonstoppingtreatment,discontinuationshouldbegradual(1-2weeks),

particularlyinpatientswithischaemicheartdisease,asBiocardhasbeta-blockingactivity.

Biocardmaybeusedinpatientswithperipheralvasculardisease.Purebeta-blockerscanprecipitateoraggravate

symptomsofarterialinsufficiency.However,asBiocardalsohasalpha-blockingproperties,thiseffectislargely

counterbalanced.

Biocard,aswithotheragentswithbeta-blockingactivity,maymaskthesymptomsofthyrotoxicosis.

IfBiocardinducesbradycardia,withadecreaseinpulseratetolessthan55beatsperminute,thedosageofBiocard

shouldbereduced.

CareshouldbetakeninadministeringBiocardtopatientswithahistoryofserioushypersensitivityreactionsandin

thoseundergoingdesensitisationtherapyasbeta-blockersmayincreaseboththesensitivitytowardsallergensandthe

seriousnessofanaphylacticreactions.

InpatientssufferingfromtheperipheralcirculatorydisorderRaynaud’sphenomenon,theremaybeexacerbationof

symptoms.

Patientswithahistoryofpsoriasisassociatedwithbeta-blockertherapyshouldbegivenBiocardonlyafter

considerationoftherisk-benefitratio.

Inpatientswithphaeochromocytoma,analpha-blockingagentshouldbeinitiatedpriortotheuseofanybeta-blocking

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Thereisnoexperienceoftheuseofcarvedilolinthiscondition.Therefore,cautionshouldbetakeninthe

administrationofBiocardtopatientssuspectedofhavingphaeochromocytoma.

Agentswithnon-selectivebeta-blockingactivitymayprovokechestpaininpatientswithPrinzmetal’svariantangina.

ThereisnoclinicalexperiencewithBiocardinthesepatients,althoughthealpha-blockingactivityofBiocardmay

preventsuchsymptoms.However,cautionshouldbetakenintheadministrationofBiocardtopatientssuspectedof

havingPrinzmetal’svariantangina.

Inpatientswithatendencytobronchospasticreactions,respiratorydistresscanoccurasaresultofapossibleincrease

inairwayresistance.

BioCardcontainslactoseandsucroseandshouldthereforenotbetakenbypatientswithrarehereditaryproblemsof

fructoseintolerance,galactoseintolerance,theLapplactasedeficiency,glucose-galactosemalabsorptionorsucrase-

isomaltaseinsufficiency.

Usageofcarvedilolinpatientswithsymptomaticcongestiveheartfailurehasnotbeenshowntoreducemortality.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Duringgeneralanaesthesia,attentionshouldbepaidtothepotentialsynergisticnegativeinotropiceffectsofcarvedilol

andanaestheticdrugs.

Aswithotherantihypertensives,thereisapotentialforpronouncedhypotensionduringgeneralanaesthesia.BioCard

maypotentiatetheeffectofotherconcomitantlyadministereddrugsthatareanti-hypertensiveinaction(e.g.alpha

receptorantagonists)orhavehypotensionaspartoftheiradverseeffectprofile.

Patientstakingbothagentswithbeta-blockingpropertiesandadrugthatcandepletecatecholamines(e.g.reserpineand

monoamineoxidaseinhibitors)shouldbeobservedcloselyforsignsofhypotensionand/orseverebradycardia.

Aswithotherdrugswithbeta-blockingactivity,cautionshouldbeexercisedwhenadministeringClassIantiarrhythmic

drugsorcalciumantagonistssuchasverapamil.Thesedrugsshouldnotbeadministeredintravenously.

Troughplasmadigoxinlevelsmaybeincreasedbyapproximately16%inhypertensivepatientsco-administered

BioCardanddigoxin.Increasedmonitoringofdigoxinlevelsisrecommendedwheninitiating,adjustingor

discontinuingBioCard.

Modestincreasesinmeantroughcyclosporinconcentrationswereobservedfollowinginitiationofcarvediloltreatment

in21renaltransplantpatientssufferingfromchronicvascularrejection.Inabout30%ofpatients,thedoseof

cyclosporinhadtobereducedinordertomaintaincyclosporinconcentrationswithinthetherapeuticrange,whileinthe

remainder,noadjustmentwasneeded.Onaverage,thedoseofcyclosporinwasreducedabout20%inthesepatients.

Duetowideinterindividualvariabilityinthedoseadjustmentrequired,itisrecommendedthatcyclosporin

concentrationsbemonitoredcloselyafterinitiationofcarvediloltherapyandthatthedoseofcyclosporinbeadjustedas

appropriate.

WhentreatmentwithBioCardandclonidinetogetheristobeterminated,carvedilolshouldbewithdrawnfirst,several

daysbeforegraduallydecreasingthedosageofclonidine.

Caremayberequiredinthosereceivinginducersofmixedfunctionoxidasese.g.rifampicin,asserumlevelsof

carvedilolmaybereducedorinhibitorsofmixedfunctionoxidasese.g.cimetidine,asserumlevelsmaybeincreased.

Theeffectsofinsulinororalhypoglycaemicsmaybeintensified.Thesignsofhypoglycaemia(especiallypalpitation)

maybemaskedorattenuated.

4.6Pregnancyandlactation

ThereisnoadequateexperiencewithBiocardinpregnantwomen.

Biocardshouldnotbeusedinpregnancyorinbreastfeedingmothersunlesstheanticipatedbenefitsoutweighthe

potentialrisks.

ThereisnoevidencefromanimalstudiesthatBiocardhasanyteratogeniceffects.Embryotoxicitywasobservedonly

afterlargedosesinrabbits.Therelevanceofthesefindingsforhumansisuncertain.

Betablockersreduceplacentalperfusionwhichmayresultinintrauterinefoetaldeathandimmatureandpremature

deliveries.Inaddition,animalstudieshaveshownthatcarvedilolcrossestheplacentalbarrierandisexcretedinbreast

milkandthereforethepossibleconsequencesofalphaandbetablockadeinthehumanfoetusandneonateshouldalso

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(bradycardia,hypotension,respiratorydepression,hypoglycaemia,hypothermia).Thereisanincreasedriskofcardiac

andpulmonarycomplicationsintheneonateinthepostnatalperiod.

4.7Effectsonabilitytodriveandusemachines

Nostudiesoftheeffectsonabilitytodriveandusemachineshavebeenperformed.Asforotherdrugswhichproduce

changesinbloodpressure,patientstakingBiocardshouldbewarnednottodriveoroperatemachineryifthey

experiencedizzinessorrelatedsymptoms.Thisappliesparticularlywhenstartingorchangingtreatmentandin

conjunctionwithalcohol.

4.8Undesirableeffects

Adverseeventsarelistedseparatelyforeachindicationbecauseofdifferencesinthebackgrounddiseases.Theyare

rankedunderfrequencyusingthefollowingconvention:verycommon: ≥1/10;common:≥1/100to<1/10;

uncommon: ≥1/1000to<1/100;rare:≥1/10,000to<1/1000;veryrare:<1/10,000;notknown:cannotbeestimated

fromtheavailabledata.

INCONGESTIVEHEARTFAILURE:

Haematological

Rare:thrombocytopenia.

Leucopeniahasbeenreportedinisolatedcases.

Metabolic

Common:weightincreaseandhypercholesterolaemia.Hyperglycaemia,hypoglycaemiaandworseningcontrolofblood

glucosearealsocommoninpatientswithpre-existingdiabetesmellitus(seesection4.4).

Centralnervoussystem

Verycommon:dizziness,headachesareusuallymildandoccurparticularlyatthestartoftreatment.Asthenia

(includingfatigue).

Cardiovascularsystem

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

genitaloedema,oedemaofthelegs,hypervolaemiaandfluidoverload).

Uncommon:syncope(includingpresyncope),AV-blockandcardiacfailureduringup-titration.Anginapectorishas

beenreportedrarely.

Gastro-intestinalsystem

Common:nausea,diarrhoea,vomitingandabdominalpain.

Others

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Rare:acuterenalfailureandrenalfunctionabnormalitiesinpatientswithdiffusevasculardiseaseand/orimpairedrenal

function(seesection4.4).

Thefrequencyofadverseexperiencesisnotdosedependent,withtheexceptionofdizziness,abnormalvisionand

bradycardia.

INHYPERTENSION:

Theprofileissimilartothatobservedincongestiveheartfailurealthoughtheincidenceofeventsisgenerallylowerin

thehypertensivepopulationtreatedwithBioCard.

Bloodchemistryandhaematological

Isolatedcasesofchangesinserumtransaminases,thrombocytopeniaandleucopeniahavebeenreported.

Centralnervoussystem

Common:dizziness,headachesandfatigue,whichareusuallymildandoccurparticularlyatthebeginningoftreatment.

Uncommon:depressedmood,sleepdisturbance,paraesthesia,asthenia.

Cardiovascularsystem

Common:posturalhypotension,hypotension,especiallyatthebeginningoftreatmentandbradycardia.

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

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

andperipheraloedema.

Respiratorysystem

Common:asthmaanddyspnoeainpredisposedpatients.

Rare:stuffynose,flu-likesymptoms.

Gastro-intestinalsystem

Common:gastro-intestinalupset(withsymptomssuchasnausea,abdominalpain,diarrhoea).

Uncommon:constipationandvomiting.

Skinandappendages

Uncommon:skinreactions(e.g.allergicexanthema,dermatitis,urticaria,pruritusandlichenplanuslikereactions).

Psoriaticskinlesionsmayoccurorexistinglesionsexacerbated.

Others

Common:painintheextremities,reducedlacrimationandeyeirritation.

Uncommon:casesofsexualimpotenceanddisturbedvision.

Rare:drynessofthemouthanddisturbancesofmicturition.

Isolatedcasesofallergicreactionshavebeenreported.

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Isolatedcasesofurinaryincontinenceinwomen,whichresolvedupondiscontinuationofthemedication,havebeen

reported.

4.9Overdose

Symptomsandsigns

Profoundcardiovasculareffectssuchashypotensionandbradycardiawouldbeexpectedaftermassiveoverdose.Heart

failure,cardiogenicshockandcardiacarrestmayfollow.Theremayalsoberespiratoryproblems,bronchospasm,

vomiting,disturbedconsciousnessandgeneralisedseizures.

Treatment

Gastriclavageorinducedemesismaybeusefulinthefirstfewhoursafteringestion.

Inadditiontogeneralprocedures,vitalsignsmustbemonitoredandcorrected,ifnecessaryunderintensivecare

conditions.

Patientsshouldbeplacedinthesupineposition.Atropine,0.5mgto2mgi.v.and/orglucagon1to10mgi.v.(followed

byaslowi.v.infusionof2to5mg/hourifnecessary)maybegivenwhenbradycardiaispresent.Pacemakertherapy

maybenecessary.Forexcessivehypotension,intravenousfluidsmaybeadministered.

Inaddition,norepinephrinemaybegiven,either5to10microgramsi.v.,repeatedaccordingtobloodpressure

response,or5microgramsperminutebyinfusiontitratedtobloodpressure.Bronchospasmmaybetreatedusing

salbutamolorotherbeta

-agonistsgivenasaerosolor,ifnecessary,bytheintravenousroute.Intheeventofseizures,

slowi.v.injectionofdiazepamorclonazepamisrecommended.

Incasesofsevereoverdosewithsymptomsofshock,supportivetreatmentasdescribedshouldbecontinuedfora

sufficientlylongperiodoftime,i.e.untilthepatientstabilises,sinceprolongedeliminationhalflifeandredistribution

ofcarvedilolfromdeepercompartmentscanbeexpected.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:beta-andalpha

-receptorblockers,ATCcode:C07AG02

Carvedilolisavasodilatingnon-selectivebetablockingagentwithantioxidantproperties.Vasodilationis

predominantlymediatedthroughalpha

receptorantagonism.

Carvedilolreducestheperipheralvascularresistancethroughvasodilationandsuppressestherenin-angiotensin-

aldosteronesystemthroughbetablockade.Theactivityofplasmareninisreducedandfluidretentionisrare.

Carvedilolhasnointrinsicsympathomimeticactivityandlikepropranolol,ithasmembranestabilisingproperties.

Carvedilolisaracemateoftwostereoisomers.Beta-blockadeisattributedtotheS(-)enantiomer;incontrast,both

enantiomersexhibitthesame

-blockingactivity.

Carvedilolisapotentantioxidant,ascavengerofreactiveoxygenradicalsandananti-proliferativeagent.The

propertiesofcarvedilolanditsmetaboliteshavebeendemonstratedininvitroandinvivoanimalstudiesandinvitroin

anumberofhumancelltypes.

Clinicalstudieshaveshownthatthebalanceofvasodilationandbeta-blockadeprovidedbycarvedilolresultsinthe

followingeffects:

Inhypertensivepatients,areductioninbloodpressureisnotassociatedwithaconcomitantincreaseintotal

peripheralresistance,asobservedwithpurebeta-blockingagents.Heartrateisslightlydecreased.Renalblood

flowandrenalfunctionaremaintained.Peripheralbloodflowismaintained,therefore,coldextremities,often

observedwithdrugspossessingbeta-blockingactivity,arerarelyseen.

Inpatientswithstableangina,Biocardhasdemonstratedanti-ischaemicandanti-anginalproperties.Acute

haemodynamicstudiesdemonstratedthatBiocardreducesventricularpre-andafter-load.

Inpatientswithleftventriculardysfunctionorchronicheartfailure,carvedilolhasdemonstratedfavourable

effectsonhaemodynamicsandimprovementsinleftventricularejectionfractionanddimensions.

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5.2Pharmacokineticproperties

Theabsolutebioavailabilityofcarvedilolisapproximately25%inhumans.Bioavailabilityisstereo-selective,30%for

theR-formand15%fortheS-form.Serumlevelspeakatapproximately1hourafteranoraldose.Thereisalinear

relationshipbetweenthedoseandserumconcentrations.Fooddoesnotaffectbioavailabilityorthemaximumserum

concentrationalthoughthetimetoreachmaximumserumconcentrationisdelayed.Carvedilolishighlylipophilic,

approximately98%to99%isboundtoplasmaproteins.

Thedistributionvolumeisapproximately2l/kgandincreasedinpatientswithlivercirrhosis.Thefirstpasseffectafter

oraladministrationisapproximately60-75%;enterohepaticcirculationoftheparentsubstancehasbeenshownin

animals.

Carvedilolexhibitsaconsiderablefirstpasseffect.Themetabolitepatternrevealsintensivemetabolismwith

glucuronidationasoneofthemajorsteps.Demethylationandhydroxylationatthephenolringproduce3metabolites

withbeta-receptorblockingactivity.

Theaverageeliminationhalf-liferangesfrom6to10hours.Plasmaclearanceisapproximately590ml/min.Elimination

ismainlybiliary.Theprimaryrouteofexcretionisviathefaeces.Aminorportioniseliminatedviathekidneysinthe

formofvariousmetabolites.

Thepharmacokineticsofcarvedilolareaffectedbyage;plasmalevelsofcarvedilolareapproximately50%higherin

theelderlycomparedtoyoungsubjects.Inastudyinpatientswithcirrhoticliverdisease,thebioavailabilityof

carvedilolwasfourtimesgreaterandthepeakplasmalevelfivetimeshigherthaninhealthysubjects.Sincecarvedilol

isprimarilyexcretedviathefaeces,significantaccumulationinpatientswithrenalimpairmentisunlikely.Inpatients

withimpairedliverfunction,bioavailabilityisraisedtoasmuchas80%duetoareducedfirstpasseffect.

5.3Preclinicalsafetydata

Animalstudiesrevealednospecialfindingsrelevanttoclinicaluse(althoughseesection4.6,Pregnancyandlactation).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sucrose

Lactosemonohydrate

PovidoneK25

Colloidalanhydroussilica

MagnesiumStearate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

HDPEcontainerandPPclosures:Storeintheoriginalcontainer.

Blister(OPA/A1/PVCfoil-aluminiumfoil):Storeintheoriginalblister.

6.5Natureandcontentsofcontainer

Blister(laminatedOPA/A1/PVCfoil–aluminiumfoil)andHDPEcontainers(PPclosureanddesiccantinsertofPE

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Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchen

HertfordshireSG4OTW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/003/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22August2003

Dateoflastrenewal:22August2008

10DATEOFREVISIONOFTHETEXT

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