CARDICOR

Main information

  • Trade name:
  • CARDICOR Film Coated Tablet 1.25 Milligram
  • Dosage:
  • 1.25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARDICOR Film Coated Tablet 1.25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/036/001
  • Authorization date:
  • 07-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cardicor1.25mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains1.25mgbisoprololhemifumarate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromItalyandGermany:

White,roundfilm-coatedtablets

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofstablechronicheartfailurewithreducedsystolicleftventricularfunctioninadditiontoACEinhibitors,

anddiuretics,andoptionallycardiacglycosides(foradditionalinformationseesection5.1).

4.2Posologyandmethodofadministration

StandardtreatmentofCHFconsistsofanACEinhibitor(oranangiotensinreceptorblockerincaseofintoleranceto

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

acutefailure)whenbisoprololtreatmentisinitiated.

Itisrecommendedthatthetreatingphysicianshouldbeexperiencedinthemanagementofchronicheartfailure.

Transientworseningofheartfailure,hypotension,orbradycardiamayoccurduringthetitrationperiodandthereafter.

Titrationphase

Thetreatmentofstablechronicheartfailurewithbisoprololrequiresatitrationphase

Thetreatmentwithbisoprololistobestartedwithagradualuptitrationaccordingtothefollowingsteps:

-1.25mgoncedailyfor1week,ifwelltoleratedincreaseto

-2.5mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-3.75mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-7.5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-10mgoncedailyforthemaintenancetherapy.

Themaximumrecommendeddoseis10mgoncedaily.

Closemonitoringofvitalsigns(heartrate,bloodpressure)andsymptomsofworseningheartfailureisrecommended

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Treatmentmodification

Ifthemaximumrecommendeddoseisnotwelltolerated,gradualdosereductionmaybeconsidered.

Incaseoftransientworseningofheartfailure,hypotension,orbradycardiareconsiderationofthedosageofthe

concomitantmedicationisrecommended.Itmayalsobenecessarytotemporarilylowerthedoseofbisoprololorto

considerdiscontinuation.

Thereintroductionand/oruptitrationofbisoprololshouldalwaysbeconsideredwhenthepatientbecomesstableagain.

Ifdiscontinuationisconsidered,gradualdosedecreaseisrecommended,sinceabruptwithdrawalmayleadtoacute

deteriorationofthepatientscondition.

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Administration

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbeswallowedwithliquid

andshouldnotbechewed.

Specialpopulation

Renalorhepaticimpairment

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailureandwith

impairedhepaticorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldthereforebemadewith

additionalcaution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnopaediatricexperiencewithbisoprolol,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontraindicatedinchronicheartfailurepatientswith:

-acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

-cardiogenicshock

-secondorthirddegreeAVblock(withoutapacemaker)

-sicksinussyndrome

-sinoatrialblock

-bradycardiawithlessthan60beats/minbeforethestartoftherapy

-hypotension(systolicbloodpressurelessthan100mmHg)

-severebronchialasthmaorseverechronicobstructivepulmonarydisease

-latestagesofperipheralarterialocclusivediseaseandRaynaud'ssyndrome

-untreatedphaeochromocytoma(see4.4)

-metabolicacidosis

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4.4Specialwarningsandprecautionsforuse

Bisoprololmustbeusedwithcautionin:

-bronchospasm(bronchialasthma,obstructiveairwaysdiseases)

-diabetesmellituswithlargefluctuationsinbloodglucosevalues;symptomsofhypoglycaemiacanbemasked

-strictfasting

-ongoingdesensitisationtherapy

-firstdegreeAVblock

-Prinzmetal’sangina

-peripheralarterialocclusivedisease(intensificationofcomplaintsmighthappenespeciallyduringthestartoftherapy)

-generalanaesthesia

Inpatientsundergoinggeneralanaesthesiabeta-blockadereducestheincidenceofarrhythmiasandmyocardial

ischemiaduringinductionandintubation,andthepost-operativeperiod.Itiscurrentlyrecommendedthat

maintenancebeta-blockadebecontinuedperi-operatively.Theanaesthesistmustbeawareofbeta-blockadebecause

ofthepotentialforinteractionswithotherdrugs,resultinginbradyarrhythmias,attenuationofthereflextachycardia

andthedecreasedreflexabilitytocompensateforbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blocker

therapybeforesurgery,thisshouldbedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Thereisnotherapeuticexperienceofbisoprololtreatmentofheartfailureinpatientswiththefollowingdiseasesand

conditions:

-insulindependentdiabetesmellitus(typeI)

-severelyimpairedrenalfunction

-severelyimpairedhepaticfunction

-restrictivecardiomyopathy

-congenitalheartdisease

-haemodynamicallysignificantorganicvalvulardisease

-myocardialinfarctionwithin3months

Combinationofbisoprololwithcalciumantagonistsoftheverapamilordiltiazemtype,withClassIantiarrhytmic

drugsandwithcentrallyactingantihypertensivedrugsisgenerallynotrecommended,fordetailspleaserefertosection

4.5.

Inbronchialasthmaorotherchronicobstructivelungdiseases,whichmaycausesymptoms,bronchodilatingtherapy

shouldbegivenconcomitantly.Occasionallyanincreaseoftheairwayresistancemayoccurinpatientswithasthma,

thereforethedoseofbeta

-stimulantsmayhavetobeincreased.

Aswithotherbeta-blockers,bisoprololmayincreaseboththesensitivitytowardsallergensandtheseverityof

anaphylacticreactions.Adrenalinetreatmentdoesnotalwaysgivetheexpectedtherapeuticeffect.

Patientswithpsoriasisorwithahistoryofpsoriasisshouldonlybegivenbeta-blockers(e.g.bisoprolol)aftercarefully

balancingthebenefitsagainsttherisks.

Inpatientswithphaeochromocytomabisoprololmustnotbeadministereduntilafteralpha-receptorblockade.

Undertreatmentwithbisoprololthesymptomsofathyreotoxicosismaybemasked.

Theinitiationoftreatmentwithbisoprololnecessitatesregularmonitoring.Fortheposologyandmethodof

administrationpleaserefertosection4.2.

Thecessationoftherapywithbisoprololshouldnotbedoneabruptlyunlessclearlyindicated.Forfurtherinformation

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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

informationongeneralanaesthesiaseealsosection4.4.).

Digitalisglycosides:Reductionofheartrate,increaseofatrio-ventricularconductiontime.

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,beta

-selectiveadrenoceptor

blockersarepreferable.

Bisoprololshouldnotbeusedduringpregnancyunlessclearlynecessary.Iftreatmentwithbisoprololisconsidered

necessary,theuteroplacentalbloodflowandthefetalgrowthshouldbemonitored.Incaseofharmfuleffectson

pregnancyorthefetusalternativetreatmentshouldbeconsidered.Thenewborninfantmustbecloselymonitored.

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Lactation:

Itisnotknownwhetherthisdrugisexcretedinhumanmilk.Therefore,breastfeedingisnotrecommendedduring

administrationofbisoprolol.

4.7Effectsonabilitytodriveandusemachines

Inastudywithcoronaryheartdiseasepatientsbisoprololdidnotimpairdrivingperformance.However,dueto

individualvariationsinreactionstothedrug,theabilitytodriveavehicleortooperatemachinerymaybeimpaired.

Thisshouldbeconsideredparticularlyatstartoftreatmentanduponchangeofmedicationaswellasinconjunction

withalcohol.

4.8Undesirableeffects

Thefollowingdefinitionsapplytothefrequencyterminologyusedhereafter:

Verycommon(1/10)

Common(1/100,<1/10)

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

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

Veryrare(<1/10,000)

Cardiacdisorders:

Verycommon:bradycardia.

Common:worseningofheartfailure.

Uncommon:AV-conductiondisturbances.

Investigations:

Rare:increasedtriglycerides,increasedliverenzymes(ALAT,ASAT).

Nervoussystemdisorders:

Common:dizziness,headache.

Rare:syncope

Eyedisorders:

Rare:reducedtearflow(tobeconsideredifthepatientuseslenses).

Veryrare:conjunctivitis.

Earandlabyrinthdisorders:

Rare:hearingimpairment.

Respiratory,thoracicandmediastinaldisorders:

Uncommon:bronchospasminpatientswithbronchialasthmaorahistoryofobstructiveairwaysdisease.

Rare:allergicrhinitis.

Gastrointestinaldisorders:

Common:gastrointestinalcomplaintssuchasnausea,vomiting,diarrhoea,constipation.

Skinandsubcutaneoustissuedisorders:

Rare:hypersensitivityreactions(itching,flush,rash).

Veryrare:beta-blockersmayprovokeorworsenpsoriasisorinducepsoriasis-likerash,alopecia.

Musculoskeletalandconnectivetissuedisorders:

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Vasculardisorders:

Common:feelingofcoldnessornumbnessintheextremities,hypotension.

Uncommon:orthostatichypotension.

Generaldisorders:

Common:asthenia,fatigue.

Hepatobiliarydisorders:

Rare:hepatitis.

Reproductivesystemandbreastdisorders:

Rare:potencydisorders.

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

(maximum:2000mg)withbisoprololhavebeenreportedinpatientssufferingfromhypertensionand/orcoronaryheart

diseaseshowingbradycardiaand/orhypotension;allpatientsrecovered.Thereisawideinterindividualvariationin

sensitivitytoonesinglehighdoseofbisoprololandpatientswithheartfailureareprobablyverysensitive.Thereforeit

ismandatorytoinitiatethetreatmentofthesepatientswithagradualuptitrationaccordingtotheschemegivenin

section4.2.

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,beta

-sympathomimeticdrugsand/or

aminophylline.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Betablockingagents,selective

ATCCode:C07AB07

Bisoprololisahighlybeta

-selective-adrenoceptorblockingagent,lackingintrinsicstimulatingandrelevantmembrane

stabilisingactivity.Itonlyshowslowaffinitytothebeta

-receptorofthesmoothmusclesofbronchiandvesselsas

wellastothebeta

-receptorsconcernedwithmetabolicregulation.Therefore,bisoprololisgenerallynottobeexpected

toinfluencetheairwayresistanceandbeta

-mediatedmetaboliceffects.Itsbeta

-selectivityextendsbeyondthe

therapeuticdoserange.

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.

TheCIBISIIItrialinvestigated1010patientsaged65yearswithmildtomoderatechronicheartfailure(CHF;NYHA

classIIorIII)andleftventricularejectionfraction35%,whohadnotbeentreatedpreviouslywithACEinhibitors,

beta-blockers,orangiotensinreceptorblockers.Patientsweretreatedwithacombinationofbisoprololandenalaprilfor

6to24monthsafteraninitial6monthstreatmentwitheitherbisoprololorenalapril.

Therewasatrendtowardhigherfrequencyofchronicheartfailureworseningwhenbisoprololwasusedastheinitial6

monthstreatment.Noninferiorityofbisoprolol-firstversusenalapril-firsttreatmentwasnotprovenintheper-protocol

analysis,althoughthetwostrategiesforinitiationofCHFtreatmentshowedasimilarrateoftheprimarycombined

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

group,per-protocolpopulation).Thestudyshowsthatbisoprololcanalsobeusedinelderlychronicheartfailure

patientswithmildtomoderatedisease.

Bisoprololisalsousedforthetreatmentofhypertensionandangina.

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.Sincethe

eliminationtakesplaceinthekidneysandthelivertothesameextentadosageadjustmentisnotrequiredforpatients

withimpairedliverfunctionorrenalinsufficiency.Thepharmacokineticsinpatientswithstablechronicheartfailure

andwithimpairedliverorrenalfunctionhasnotbeenstudied.

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Inpatientswithchronicheartfailure(NYHAstageIII)theplasmalevelsofbisoprololarehigherandthehalf-lifeis

prolongedcomparedtohealthyvolunteers.Maximumplasmaconcentrationatsteadystateis64+21ng/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

Pregelatinisedmaizestarch

MaizeStarch

Microcrystallinecellulose

Calciumhydrogenphosphate,anhydrous

Filmcoating:

Dimeticone

Talc

Macrogol400

Titaniumdioxide(E171)

Hypromellose

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 º C

6.5Natureandcontentsofcontainer

ProductimportedfromItaly:

Anover-labelledoutercartoncontainingtwoPVC/PE/PVDC/aluminiumfoilblisterstripsof14tablets.

Packsize:28tablets.

ProductimportedfromGermany:

Anover-labelledoutercartoncontainingtwoPVC/PE/PVDC/aluminiumfoilblisterstripsof10tablets(tenblistersper

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Packsize:100tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

NoSpecialRequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/36/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:7 th

August2009

10DATEOFREVISIONOFTHETEXT

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