CARDICOR

Main information

  • Trade name:
  • CARDICOR Film Coated Tablet 3.75 Milligram
  • Dosage:
  • 3.75 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARDICOR Film Coated Tablet 3.75 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/204/005
  • Authorization date:
  • 05-06-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cardicor3.75mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains3.75mgbisoprololhemifumarate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromtheUKandGermany:

Off-white,heart-shaped,scoredandfilm-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

duringthetitrationphase.Symptomsmayalreadyoccurwithinthefirstdayafterinitiatingthetherapy.

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Ifthemaximumrecommendeddoseisnotwelltolerated,gradualdosereductionmaybeconsidered.

Incaseoftransientworseningofheartfailure,hypotension,orbradycardiareconsiderationofthedosageofthe

concomitantmedicationisrecommended.Itmayalsobenecessarytotemporarilylowerthedoseofbisoprololorto

considerdiscontinuation.

Thereintroductionand/oruptitrationofbisoprololshouldalwaysbeconsideredwhenthepatientbecomesstableagain.

Ifthediscontinuationisconsidered,gradualdosedecreaseisrecommended,sinceabruptwithdrawalmayleadtoacute

deteriorationofthepatientscondition.

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Administration

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbeswallowedwithliquid

andshouldnotbechewed.

Specialpopulation

Renalorhepaticimpairment

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailureandwith

impairedhepaticorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldthereforebemadewithadditional

caution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnopaediatricexperiencewithbisoprolol,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontraindicatedinchronicheartfailurepatientswith:

-acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

-cardiogenicshock

-secondofthirddegreeAVblock(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,andpost-operativeperiod.Itiscurrentlyrecommendedthatmaintenance

beta-blockedbecontinuedperi-operatively.Theanaesthetistmustbeawareofbeta-blockadebecauseofthepotential

forinteractionswithotherdrugs,resultinginbradyarrhythmias,attenuationofthereflextachycardiaandthedecreased

reflexabilitytocompensateforbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blockertherapybeforesurgery,

thisshouldbedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Thereisnotherapeuticexperienceofbisoprololtreatmentofheartfailureinpatientswiththefollowingdiseasesand

conditions:

-insulindependentdiabetesmellitus(typeI)

-severelyimpairedrenalfunction

-severelyimpairedhepaticfunction

-restrictivecardiomyopathy

-congenitalheartdisease

-haemodynamicallysignificantorganicvalvulardisease

-myocardialinfarctionwithin3months

Combinationofbisoprololwithcalciumantagonistsoftheverapamilordiltiazemtype,withClassIantiarrhythmic

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

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4.6Fertility,pregnancyandlactation

Pregnancy:

Bisoprololhaspharmacologicaleffectsthatmaycauseharmfuleffectsonpregnancyand/orthefetus/newborn.In

general,beta-adrenoceptorblockersreduceplacentalperfusion,whichhasbeenassociatedwithgrowthretardation,

intrauterinedeath,abortionorearlylabour.

Adverseeffects(e.g.hypoglycaemiaandbradycardia)mayoccurinthefetusandnewborninfant.Iftreatmentwith

beta-adrenoceptorblockersisnecessary,beta

-selectiveadrenoceptorblockersarepreferable.

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:

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).

Earandlabyrinthdisorders:

Rare:hearingimpairment.

Eyedisorders:

Rare:reducedtearflow(tobeconsideredifthepatientuseslenses).

Veryrare:conjunctivitis.

Gastrointestinaldisorders:

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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,hypotension.

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

(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.

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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.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.

TheCIBISIIItrialinvestigated1010patientsaged ≥65yearswithmildtomoderatechronicheartfailure(CHF;NYHA

classIIorIII)andleftventricularejectionfraction ≤35%,whohadnotbeentreatedpreviouslywithACEinhibitors,

beta-blockers,orangiotensinreceptorblockers.Patientsweretreatedwithacombinationofbisoprololandenalaprilfor

6to24monthsafteraninitial6monthstreatmentwitheitherbisoprololorenalapril.

Therewasatrendtowardhigherfrequencyofchronicheartfailureworseningwhenbisoprololwasusedastheinitial6

monthstreatment.Noninferiorityofbisoprolol-firstversusenalapril-firsttreatmentwasnotprovenintheper-protocol

analysis,althoughthetwostrategiesforinitiationofCHFtreatmentshowedasimilarrateoftheprimarycombined

endpointdeathandhospitalizationatstudyend(32.4%inthebisoprolol-firstgroupversus33.1%intheenalapril-first

group,per-protocolpopulation).Thestudyshowsthatbisoprololcanalsobeusedinelderlychronicheartfailure

patientswithmildtomoderatedisease.

Bisoprololisalsousedforthetreatmentofhypertensionandangina.

Inacuteadministrationinpatientswithcoronaryheartdiseasewithoutchronicheartfailurebisoprololreducestheheart

rateandstrokevolumeandthusthecardiacoutputandoxygenconsumption.Inchronicadministrationtheinitially

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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.

Thekineticsofbisoprololarelinearandindependentofage.

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

maizestarch

microcrystallinecellulose

anhydrouscalciumhydrogenphosphate.

Filmcoating:

Dimeticone;

macrogol400;

titaniumdioxide(E171);

hypromellose,

ironoxideyellow(E172).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

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6.4Specialprecautionsforstorage

Donotstoreabove25 o

6.5Natureandcontentsofcontainer

Theimmediatecontainerisablister,whichispackagedinanoutercarton.

Packsize:28or100tablets

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturingLtd

Unit10,AshbourneBusinessPark

Rath,Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/204/5

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:5thJune2009

10DATEOFREVISIONOFTHETEXT

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