CARDICOR

Main information

  • Trade name:
  • CARDICOR Film Coated Tablet 5.0 Milligram
  • Dosage:
  • 5.0 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARDICOR Film Coated Tablet 5.0 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/204/003
  • Authorization date:
  • 25-01-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cardicor5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgbisoprololhemifumarate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromItaly,TheUnitedKingdomandGermany:

Yellowish-white,heart-shaped,scoredandfilm-coatedtablets

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofstablechronicmoderatetosevereheartfailurewithreducedsystolicventricularfunction(ejectionfraction

35%,basedonechocardiography)inadditiontoACEinhibitors,anddiuretics,andoptionallycardiacglycosides(for

additionalinformationseesection5.1).

4.2Posologyandmethodofadministration

StandardtreatmentofCHFconsistsofanACEinhibitor(oranangiotensinreceptorblockerincaseofintoleranceto

ACEinhibitors),abeta-blocker,diuretics,andwhenappropriatecardiacglycosides.Patientsshouldbestable(without

acutefailure)whenbisoprololtreatmentisinitiated.

Itisrecommendedthatthetreatingphysicianshouldbeexperiencedinthemanagementofchronicheartfailure.

Transientworseningofheartfailure,hypotension,orbradycardiamayoccurduringthetitrationperiodandthereafter.

Warning:Thetreatmentofstablechronicheartfailurewithbisoprololhastobeinitiatedwithatitrationphaseasgiven

inthedescriptionbelow.

Thetreatmentwithbisoprololistobestartedwithagradualuptitrationaccordingtothefollowingsteps:

-1.25mgoncedailyfor1week,ifwelltoleratedincreaseto

-2.5mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-3.75mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-7.5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

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Themaximumrecommendeddoseis10mgoncedaily.

Closemonitoringofvitalsigns(heartrate,bloodpressure)andsymptomsofworseningheartfailureisrecommended

duringthetitrationphase.Symptomsmayalreadyoccurwithinthefirstdayafterinitiatingthetherapy.

Treatmentmodification

Ifthemaximumrecommendeddoseisnotwelltolerated,gradualdosereductionmaybeconsidered.

Incaseoftransientworseningofheartfailure,hypotension,orbradycardiareconsiderationofthedosageofthe

concomitantmedicationisrecommended.Itmayalsobenecessarytotemporarilylowerthedoseofbisoprololorto

considerdiscontinuation.

Thereintroductionand/oruptitrationofbisoprololshouldalwaysbeconsideredwhenthepatientbecomesstableagain.

Ifdiscontinuationisconsidered,gradualdosedecreaseisrecommended,sinceabruptwithdrawalmayleadtoacute

deteriorationofthepatientscondition.

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Administration

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbeswallowedwithliquid

andshouldnotbechewed.

Specialpopulation

Renalorliverinsufficiency

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailureandwith

impairedliverorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldthereforebemadewithadditional

caution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnopaediatricexperiencewithbisoprolol,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontraindicatedinchronicheartfailurepatientswith:

-acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

-cardiogenicshock

-secondorthirddegreeAVblock(withoutapacemaker)

-sicksinussyndrome

-sinoatrialblock

-bradycardiawithlessthan60beats/minbeforethestartoftherapy

-hypotension(systolicbloodpressurelessthan100mmHg)

-severebronchialasthmaorseverechronicobstructivepulmonarydisease

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-untreatedphaeochromocytoma(see4.4)

-metabolicacidosis

-hypersensitivitytobisoprololortoanyoftheexcipients

4.4Specialwarningsandprecautionsforuse

Bisoprololmustbeusedwithcautionin:

-bronchospasm(bronchialasthma,obstructiveairwaysdiseases)

-diabetesmellituswithlargefluctuationsinbloodglucosevalues;symptomsofhypoglycaemiacanbemasked

-strictfasting

-ongoingdesensitisationtherapy

-AVblockoffirstdegree

-Prinzmetal'sangina

-peripheralarterialocclusivedisease(intensificationofcomplaintsmighthappenespeciallyduringthestartoftherapy)

-Generalanaesthesia

Inpatientsundergoinggeneralanaesthesiabeta-blockadereducestheincidenceofarrhythmiasandmyocardial

ischemiaduringinductionandintubation,andthepost-operativeperiod.Itiscurrentlyrecommendedthatmaintenance

beta-blockadebecontinuedperi-operatively.Theanaesthetistmustbeawareofbeta-blockadebecauseofthepotential

forinteractionswithotherdrugs,resultinginbradyarrhythmias,attenuationofthereflextachycardiaandthedecreased

reflexabilitytocompensateforbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blockertherapybeforesurgery,

thisshouldbedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Thereisnotherapeuticexperienceofbisoprololtreatmentofheartfailureinpatientswiththefollowingdiseasesand

conditions:

-insulindependentdiabetesmellitus(typeI)

-severelyimpairedrenalfunction

-severelyimpairedhepaticfunction

-restrictivecardiomyopathy

-congenitalheartdisease

-haemodynamicallysignificantorganicvalvulardisease

-myocardialinfarctionwithin3months

Combinationofbisoprololwithcalciumantagonistsoftheverapamilanddiltiazemtype,withClassIantiarrhythmic

drugsandwithcentrallyactingantihypertensivedrugsisgenerallynotrecommended,fordetailspleaserefertosection

4.5.

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shouldbegivenconcomitantly.Occasionallyanincreaseoftheairwayresistancemayoccurinpatientswithasthma,

thereforethedoseofbeta2-stimulantsmayhavetobeincreased.

Aswithotherbeta-blockers,bisoprololmayincreaseboththesensitivitytowardsallergensandtheseverityof

anaphylacticreactions.Adrenalinetreatmentdoesnotalwaysgivetheexpectedtherapeuticeffect.

Patientswithpsoriasisorwithahistoryofpsoriasisshouldonlybegivenbeta-blockers(e.g.bisoprolol)aftercarefully

balancingthebenefitsagainsttherisks.

Inpatientswithphaeochromocytomabisoprololmustnotbeadministereduntilafteralpha-receptorblockade.

Undertreatmentwithbisoprololthesymptomsofathyreotoxicosismaybemasked.

Theinitiationoftreatmentwithbisoprololnecessitatesregularmonitoring.Fortheposologyandmethodof

administrationpleaserefertosection4.2.

Thecessationoftherapywithbisoprololshouldnotbedoneabruptlyunlessclearlyindicated.Forfurtherinformation

pleaserefertosection4.2.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsnotrecommended

Calciumantagonistsoftheverapamiltypeandtoalesserextentofthediltiazemtype:Negativeinfluenceon

contractilityandatrio-ventricularconduction.Intravenousadministrationofverapamilinpatientson-blocker

treatmentmayleadtoprofoundhypotensionandatrioventricularblock.

ClassIantiarrhythmicdrugs(e.g.quinidine,disopyramide;lidocaine,phenytoin;flecainide,propafenone):Effecton

atrio-ventricularconductiontimemaybepotentiatedandnegativeinotropiceffectincreased.

Centrallyactingantihypertensivedrugssuchasclonidineandothers(e.g.methyldopa,moxonodine,rilmenidine):

Concomitantuseofcentrallyactingantihypertensivedrugsmayworsenheartfailurebyadecreaseinthecentral

sympathetictonus(reductionofheartrateandcardiacoutput,vasodilation).Abruptwithdrawal,particularlyifpriorto

beta-blockerdiscontinuation,mayincreaseriskof“reboundhypertension”.

Combinationstobeusedwithcaution

Calciumantagonistsofthedihydropyridinetypesuchasfelodipineandamlodipine:Concomitantusemayincreasethe

riskofhypotension,andanincreaseintheriskofafurtherdeteriorationoftheventricularpumpfunctioninpatients

withheartfailurecannotbeexcluded.

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

Topicalbeta-blockers(e.g.eyedropsforglaucomatreatment)mayaddtothesystemiceffectsofbisoprolol.

Parasympathomimeticdrugs:Concomitantusemayincreaseatrio-ventricularconductiontimeandtheriskof

bradycardia.

Insulinandoralantidiabeticdrugs:Intensificationofbloodsugarloweringeffect.Blockadeofbeta-adrenoreceptors

maymasksymptomsofhypoglycaemia.

Anaestheticagents:Attenuationofthereflextachycardiaandincreaseoftheriskofhypotension(forfurther

informationongeneralanaesthesiaseealsosection4.4Specialwarningsandprecautionsforuse.).

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Non-steroidalanti-inflammatorydrugs(NSAIDs):NSAIDsmayreducethehypotensiveeffectofbisoprolol.

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

agents.

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

bisoprololmayunmaskthe-adrenoceptor-mediatedvasoconstrictoreffectsoftheseagentsleadingtobloodpressure

increaseandexacerbatedintermittentclaudication.Suchinteractionsareconsideredtobemorelikelywithnonselective

-blockers.

Concomitantusewithantihypertensiveagentsaswellaswithotherdrugswithbloodpressureloweringpotential(e.g.

tricyclicantidepressants,barbiturates,phenothiazines)mayincreasetheriskofhypotension.

Combinationstobeconsidered

Mefloquine:increasedriskofbradycardia

Monoamineoxidaseinhibitors(exceptMAO-Binhibitors):Enhancedhypotensiveeffectofthebeta-blockersbutalso

riskforhypertensivecrisis.

4.6Fertility,pregnancyandlactation

Pregnancy:

Bisoprololhaspharmacologicaleffectsthatmaycauseharmfuleffectsonpregnancyand/orthefetus/newborn.In

general,beta-adrenoceptorblockersreduceplacentalperfusion,whichhasbeenassociatedwithgrowthretardation,

intrauterinedeath,abortionorearlylabour.Adverseeffects(e.g.hypoglycaemiaandbradycardia)mayoccurinthe

fetusandnewborninfant.Iftreatmentwithbeta-adrenoceptorblockersisnecessary,beta1-selectiveadrenoceptor

blockersarepreferable.

Bisoprololshouldnotbeusedduringpregnancyunlessclearlynecessary.Iftreatmentwithbisoprololisconsidered

necessary,theuteroplacentalbloodflowandthefetalgrowthshouldbemonitored.Incaseofharmfuleffectson

pregnancyorthefetusalternativetreatmentshouldbeconsidered.Thenewborninfantmustbecloselymonitored.

Symptomsofhypoglycaemiaandbradycardiaaregenerallytobeexpectedwithinthefirst3days.

Lactation:

Itisnotknownwhetherthisdrugisexcretedinhumanmilk.Therefore,breastfeedingisnotrecommendedduring

administrationofbisoprolol.

4.7Effectsonabilitytodriveandusemachines

Inastudywithcoronaryheartdiseasepatientsbisoprololdidnotimpairdrivingperformance.However,dueto

individualvariationsinreactionstothedrug,theabilitytodriveavehicleortooperatemachinerymaybeimpaired.

Thisshouldbeconsideredparticularlyatstartoftreatmentanduponchangeofmedicationaswellasinconjunction

withalcohol.

4.8Undesirableeffects

Thefollowingdefinitionsapplytothefrequencyterminologyusedhereafter:

Common(>1%and<10%),

uncommon(>0.1%and<1%),

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veryrare(<0.01%),

singlecases.

Cardiacdisorders:

Verycommon:bradycardia.

Common:worseningofheartfailure.

Uncommon:AV-conductiondisturbances .

Earandlabyrinthdisorders:

Rare:hearingimpairment.

Eyedisorders:

Rare:reducedtearflow(tobeconsideredifthepatientuseslenses).

Veryrare:conjunctivitis.

Gastrointestinaldisorders:

Common:gastrointestinalcomplaintssuchasnausea,vomiting,diarrhoea,constipation.

Generaldisorders:

Common:asthenia,fatigue.

Hepatobiliarydisorders:

Rare:hepatitis.

Nervoussystemdisorders:

Common:dizziness,headache.

Rare:syncope.

Reproductivesystemandbreastdisorders:

Rare:Potencydisorders.

Respiratory,thoracicandmediastinaldisorders:

Uncommon:Bronchospasminpatientswithbronchialasthmaorahistoryofobstructiveairwaysdisease.

Rare:allergicrhinitis.

Skinandsubcutaneoustissuedisorders:

Rare:hypersensitivityreactions(itching,flush,rash).

Veryrare:beta-blockersmayprovokeorworsenpsoriasisorinducepsoriasis-likerash,alopecia.

Musculoskeletalandconnectivetissuedisorders:

Uncommon:muscularweaknessandcramps.

Vasculardisorders:

Common:Feelingofcoldnessornumbnessintheextremities.

Uncommon:orthostatichypotension.

Psychiatricdisorders:

Uncommon:sleepdisorders,depression.

Rare:nightmares,hallucinations.

4.9Overdose

Withoverdose(e.g.dailydoseof15mginsteadof7.5mg)thirddegreeAV-block,bradycardia,anddizzinesshave

beenreported.Ingeneralthemostcommonsignsexpectedwithoverdosageofabeta-blockerarebradycardia,

hypotension,bronchospasm,acutecardiacinsufficiencyandhypoglycaemia.Todateafewcasesofoverdose

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diseaseshowingbradycardiaand/orhypotension;allpatientsrecovered.Thereisawideinterindividualvariationin

sensitivitytoonesinglehighdoseofbisoprololandpatientswithheartfailureareprobablyverysensitive.Thereforeit

ismandatorytoinitiatethetreatmentofthesepatientswithagradualuptitrationaccordingtotheschemegivenin

section4.2Posologyandmethodofadministration.

Ifoverdoseoccurs,bisoprololtreatmentshouldbestoppedandsupportiveandsymptomatictreatmentshouldbe

provided.Limiteddatasuggestthatbisoprololishardlydialysable.Basedontheexpectedpharmacologicactionsand

recommendationsforotherbeta-blockers,thefollowinggeneralmeasuresshouldbeconsideredwhenclinically

warranted.

Bradycardia:Administerintravenousatropine.Iftheresponseisinadequate,isoprenalineoranotheragentwithpositive

chronotropicpropertiesmaybegivencautiously.Undersomecircumstances,transvenouspacemakerinsertionmaybe

necessary.

Hypotension:Intravenousfluidsandvasopressorsshouldbeadministered.Intravenousglucagonmaybeuseful.

AVblock(secondorthirddegree):Patientsshouldbecarefullymonitoredandtreatedwithisoprenalineinfusionor

transvenouscardiacpacemakerinsertion.

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

Bronchospasm:Administerbronchodilatortherapysuchasisoprenaline,beta2-sympathomimeticdrugsand/or

aminophylline.

Hypoglycaemia:Administeri.v.glucose.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Betablockingagents,selective

ATCCode:C07AB07

Bisoprololisahighlybeta1-selective-adrenoceptorblockingagent,lackingintrinsicstimulatingandrelevantmembrane

stabilisingactivity.Itonlyshowslowaffinitytothebeta2-receptorofthesmoothmusclesofbronchiandvesselsas

wellastothebeta2-receptorsconcernedwithmetabolicregulation.Therefore,bisoprololisgenerallynottobe

expectedtoinfluencetheairwayresistanceandbeta2-mediatedmetaboliceffects.Itsbeta1-selectivityextendsbeyond

thetherapeuticdoserange.

Intotal2647patientswereincludedintheCIBISIItrial.83%(n=2202)wereinNYHAclassIIIand17%(n=445)

wereinNYHAclassIV.Theyhadstablesymptomaticsystolicheartfailure(ejectionfraction<35%,basedon

echocardiography).Totalmortalitywasreducedfrom17.3%to11.8%(relativereduction34%).Adecreaseinsudden

death(3.6%vs6.3%,relativereduction44%)andareducednumberofheartfailureepisodesrequiringhospital

admission(12%vs17.6%,relativereduction36%)wasobserved.Finally,asignificantimprovementofthefunctional

statusaccordingtoNYHAclassificationhasbeenshown.Duringtheinitiationandtitrationofbisoprololhospital

admissionduetobradycardia(0.53%),hypotension(0.23%),andacutedecompensation(4.97%)wereobserved,but

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

strokesduringthetotalstudyperiodwere20inthebisoprololgroupand15intheplacebogroup.

TheCIBISIIItrialinvestigated1010patientsaged ≥65yearswithmildtomoderatechronicheartfailure(CHF;

NYHAclassIIorIII)andleftventricularejectionfraction ≤35%,whohadnotbeentreatedpreviouslywithACE

inhibitors,beta-blockers,orangiotensinreceptorblockers.Patientsweretreatedwithacombinationofbisoprololand

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Therewasatrendtowardhigherfrequencyofchronicheartfailureworseningwhenbisoprololwasusedastheinitial6

monthstreatment.Noninferiorityofbisoprolol-firstversusenalapril-firsttreatmentwasnotprovenintheper-protocol

analysis,althoughthetwostrategiesforinitiationofCHFtreatmentshowedasimilarrateoftheprimarycombined

endpointdeathandhospitalizationatstudyend(32.4%inthebisoprolol-firstgroupvs.33.1%intheenalapril-first

group,per-protocolpopulation).Thestudyshowsthatbisoprololcanalsobeusedinelderlychronicheartfailure

patientswithmildtomoderatedisease.

Bisoprololisalreadyusedforthetreatmentofhypertensionandangina.

Inacuteadministrationinpatientswithcoronaryheartdiseasewithoutchronicheartfailurebisoprololreducestheheart

rateandstrokevolumeandthusthecardiacoutputandoxygenconsumption.Inchronicadministrationtheinitially

elevatedperipheralresistancedecreases.

5.2Pharmacokineticproperties

Bisoprololisabsorbedandhasabiologicalavailabilityofabout90%afteroraladministration.Theplasmaprotein

bindingofbisoprololisabout30%.Thedistributionvolumeis3.5l/kg.Totalclearanceisapproximately15l/h.The

half-lifeinplasmaof10-12hoursgivesa24houreffectafterdosingoncedaily.

Bisoprololisexcretedfromthebodybytworoutes.50%ismetabolisedbythelivertoinactivemetaboliteswhichare

thenexcretedbythekidneys.

Theremaining50%isexcretedbythekidneysinanunmetabolisedform.Sincetheeliminationtakesplaceinthe

kidneysandthelivertothesameextentadosageadjustmentisnotrequiredforpatientswithimpairedliverfunctionor

renalinsufficiency.Thepharmacokineticsinpatientswithstablechronicheartfailureandwithimpairedliverorrenal

functionhasnotbeenstudied.

Thekineticsofbisoprololarelinearandindependentofage.

Inpatientswithchronicheartfailure(NYHAstageIII)theplasmalevelsofbisoprololarehigherandthehalf-lifeis

prolongedcomparedtohealthyvolunteers.Maximumplasmaconcentrationatsteadystateis64+21mg/mlatadaily

doseof10mgandthehalf-lifeis17+5hours.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityorcarcinogenicity.Likeotherbeta-blockers,bisoprololcausedmaternal(decreasedfood

intakeanddecreasedbodyweight)andembryo/fetaltoxicity(increasedincidenceofresorptions,reducedbirthweight

oftheoffspring,retardedphysicaldevelopment)athighdosesbutwasnotteratogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore:

Silica,Colloidalanhydrous

MagnesiumStearate

Crospovidone

Maizestarch

Microcrystallinecellulose

Calciumhydrogenphosphate,anhydrous.

Filmcoating:

Dimeticone

Macrogol400

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Ironoxideyellow(E172)

Hypromellose.

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Theimmediatecontainerisablister,whichispackagedinanoutercarton.

Packsize:28or100tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/204/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:25thJanuary2008

10DATEOFREVISIONOFTHETEXT

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