BISPROLOL PFIZER

Main information

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

Documents

Localization

  • Available in:
  • BISPROLOL PFIZER
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/062/001
  • Authorization date:
  • 05-12-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BisoprololPfizer1.25mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1.25mgbisoprololfumarateequivalentto1.06mgbisoprolol.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

White,circular,biconvex,film-coatedtablets,5.2mmindiameter,debossedwith‘P’ononesideand‘1’ontheother

side.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofstablechronicheartfailurewithreducedsystolicleftventricularfunctioninadditiontoACEinhibitors,

anddiuretics,andoptionallycardiacglycosides(Foradditionalinformationseesection5.1).

4.2Posologyandmethodofadministration

Methodofadministration

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbeswallowedwithliquid

andshouldnotbechewed.

Treatmentofstablechronicheartfailure

StandardtreatmentofCHFconsistsofanACEinhibitor(oranangiotensinreceptorblockerincaseofintoleranceto

ACEinhibitors),abeta-blockingagent,diuretics,andwhenappropriatecardiacglycosides.Patientsshouldbestable

(withoutacutefailure)whenbisoprololtreatmentisinitiated.

Itisrecommendedthatthetreatingphysicianshouldbeexperiencedinthemanagementofchronicheartfailure.

Transientworseningofheartfailure,hypotension,orbradycardiamayoccurduringthetitrationperiodandthereafter.

Titrationphase

Thetreatmentofstablechronicheartfailurewithbisoprololrequiresatitrationphase.

Thetreatmentwithbisoprololistobestartedwithagradualuptitrationaccordingtothefollowingsteps:

1.25mgoncedailyfor1week,ifwelltoleratedincreaseto

2.5mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

3.75mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

7.5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

10mgoncedailyforthemaintenancetherapy.

Themaximumrecommendeddoseis10mgoncedaily.

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duringthetitrationphase.Symptomsmayalreadyoccurwithinthefirstdayafterinitiatingthetherapy.

Treatmentmodification

Ifthemaximumrecommendeddoseisnotwelltolerated,gradualdosereductionmaybeconsidered.

Incaseoftransientworseningofheartfailure,hypotension,orbradycardiareconsiderationofthedosageofthe

concomitantmedicationisrecommended.Itmayalsobenecessarytotemporarilylowerthedoseofbisoprololorto

considerdiscontinuation.

Thereintroductionand/oruptitrationofbisoprololshouldalwaysbeconsideredwhenthepatientbecomesstableagain.

Ifdiscontinuationisconsidered,gradualdosedecreaseisrecommended,sinceabruptwithdrawalmayleadtoacute

deteriorationofthepatientscondition.

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Renalorliverinsufficiency

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailureandwith

impairedliverorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldthereforebemadewithadditional

caution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnoexperiencewithbisoprololinchildren,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontra-indicatedinpatientswith:

-hypersensitivitytobisoprololortoanyoftheexcipients

-acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

-cardiogenicshock

-SecondorthirddegreeAVblock(withoutapacemaker)

-sicksinussyndrome

-sinoatrialblock

-symptomaticbradycardia

-symptomatichypotension

-severebronchialasthmaorseverechronicobstructivepulmonarydisease

-severeformsofperipheralarterialocclusivediseaseorsevereformsofRaynaud'ssyndrome

-untreatedphaeochromocytoma(see4.4)

-metabolicacidosis

4.4Specialwarningsandprecautionsforuse

SpecialWarnings

Thetreatmentofstablechronicheartfailurewithbisoprololhastobeinitiatedwithaspecialtitrationphase(seesection

4.2).

Especiallyinpatientswithischaemicheartdiseasethecessationoftherapywithbisoprololmustnotbedoneabruptly

unlessclearlyindicated,becausethismayleadtotransitionalworseningofheartcondition(seesection4.2).

Precautions

Theinitiationoftreatmentofstablechronicheartfailurewithbisoprololnecessitatesregularmonitoring.Forthe

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Thereisnotherapeuticexperienceofbisoprololtreatmentinheartfailureinpatientswiththefollowingdiseasesand

conditions:

insulindependentdiabetesmellitus(typeI)

severelyimpairedrenalfunction

severelyimpairedliverfunction

restrictivecardiomyopathy

congenitalheartdisease

haemodynamicallysignificantorganicvalvulardisease

myocardialinfarctionwithin3months

Bisoprololmustbeusedwithcautionin:

diabetesmellitusshowinglargefluctuationsinbloodglucosevalues.Symptomsofhypoglycaemia(e.g.

tachycardia,palpitationsorsweating)canbemasked

strictfasting

ongoingdesensitisationtherapy.Aswithotherbeta-blockers,bisoprololmayincreaseboththesensitivitytowards

allergensandtheseverityofanaphylacticreactions.Epinephrinetreatmentmaynotalwaysyieldtheexpected

therapeuticeffect.

FirstdegreeAVblock

Prinzmetal’sangina

peripheralarterialocclusivedisease.Aggravationofsymptomsmayoccurespeciallywhenstartingtherapy.

Patientswithpsoriasisorwithahistoryofpsoriasisshouldonlybegivenbeta-blockers(e.g.bisoprolol)afteracareful

balancingofbenefitsagainstrisks.

Thesymptomsofathyrotoxicosismaybemaskedundertreatmentwithbisoprolol

Inpatientswithphaeochromocytomabisoprololmustnotbeadministereduntilafteralpha-receptorblockade.

Inpatientsundergoinggeneralanaesthesiabeta-blockadereducestheincidenceofarrhythmiasandmyocardial

ischemiaduringinductionandintubationandthepost-operativeperiod.Itiscurrentlyrecommendedthatmaintenance

beta-blockadebecontinuedperi-operatively.Theanaesthetistmustbeawareofbeta-blockadebecauseofthepotential

forinteractionswithothermedicinalproducts,resultinginbradyarrhythmias,attenuationofreflextachycardiaand

decreasedreflexabilitytocompensateforbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blockertherapybefore

surgery,thisshouldbedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Inbronchialasthmaorotherchronicobstructivelungdiseases,whichmaycausesymptoms,concomitant

bronchodilatingtherapyisrecommended.Occasionallyanincreaseoftheairwayresistancemayoccurinpatientswith

asthma,thereforethedoseofbeta2-stimulantsmayhavetobeincreased.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsnotrecommended

Class-Iantiarrhythmicdrugs(e.g.quinidine,disopyramide,lidocaine,phenytoin,flecainide,propafenone):effecton

atrio-ventricularconductiontimemaybepotentiatedandnegativeinotropiceffectincreased.

Calciumantagonistsoftheverapamiltypeandtoalesserextentofthediltiazemtype:negativeeffectoncontractility

andatrio-ventricularconduction.Intravenousadministrationofverapamilinpatientsonbeta-blockertreatmentmay

leadtoprofoundhypotensionandatrio-ventricularblock.

Centrally-actingantihypertensivedrugs(e.g.clonidine,methyldopa,moxonidine,rilmenidine):concomitantuseof

centrally-actingantihypertensivedrugsmayfurtherdecreasethecentralsympathetictonusandmaythusleadto

reductionofheartrateandcardiacoutputandtovasodilatation.Abruptwithdrawal,particularlyifpriortobeta-blocker

discontinuation,mayincreasetheriskof“reboundhypertension”.

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Combinationstobeusedwithcaution

Calciumantagonistsofthedihydropyridinetypesuchasfelodipineandamlodipine:Concomitantusemayincreasethe

riskofhypotension,andanincreaseintheriskofafurtherdeteriorationoftheventricularpumpfunctioninpatients

withheartfailurecannotbeexcluded.

Class-IIIantiarrhythmicmedicinalproduct(e.g.amiodarone):Effectonatrio-ventricularconductiontimemaybe

potentiated.

Parasympathomimeticmedicinalproducts:Concomitantusemayincreaseatrio-ventricularconductiontimeandtherisk

ofbradycardia.

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

Insulinandoralantidiabeticmedicinalproducts:Increaseofbloodsugarloweringeffect.Blockadeofbeta-

adrenoreceptorsmaymasksymptomsofhypoglycaemia.

Anaestheticagents:Attenuationofthereflextachycardiaandincreaseoftheriskofhypotension(forfurther

informationongeneralanaesthesiaseealsosection4.4.).

Digitalisglycosides:increaseofatrio-ventricularconductiontime,reductioninheartrate

Non-steroidalanti-inflammatorymedicinalproducts(NSAIDs):NSAIDsmayreducethehypotensiveeffectof

bisoprolol.

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

agents.

Sympathomimeticsthatactivateboth-and-adrenoceptors(e.g.norepinephrine,epinephrine):Combinationwith

bisoprololmayunmaskthe-adrenoceptor-mediatedvasoconstrictoreffectsoftheseagentsleadingtobloodpressure

increaseandexacerbatedintermittentclaudication.Suchinteractionsareconsideredtobemorelikelywithnonselective

-blockers.

Concomitantusewithantihypertensiveagentsaswellaswithothermedicinalproductswithbloodpressurelowering

potential(e.g.tricyclicantidepressants,barbiturates,phenothiazines)mayincreasetheriskofhypotension.

Combinationstobeconsidered

Mefloquine:increasedriskofbradycardia

Monoamineoxidaseinhibitors(exceptMAO-Binhibitors):Enhancedhypotensiveeffectofthebeta-blockingagents

butalsoriskforhypertensivecrisis.

Rifampicin:Slightreductionofthehalf-lifeofbisoprololpossibleduetotheinductionofhepaticdrugmetabolising

enzymes.Normallynodosageadjustmentisnecessary.

Ergotaminederivatives:Exacerbationofperipheralcirculatorydisturbances.

4.6Fertility,pregnancyandlactation

Pregnancy:

Bisoprololhaspharmacologicaleffectsthatmaycauseharmfuleffectsonpregnancyand/orthefetus/newborn.In

general,beta-adrenoceptorblockingagentsreduceplacentalperfusion,whichhasbeenassociatedwithgrowth

retardation,intrauterinedeath,abortionorearlylabour.Adverseeffects(e.g.hypoglycaemiaandbradycardia)may

occurinthefetusandnewborninfant.Iftreatmentwithbeta-adrenoceptorblockingagentsisnecessary,beta

-selective

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Bisoprololisnotrecommendedduringpregnancyunlessclearlynecessary.Iftreatmentwithbisoprololisconsidered

necessary,theuteroplacentalbloodflowandfetalgrowthshouldbemonitored.Incaseofharmfuleffectsonpregnancy

orthefetusalternativetreatmentshouldbeconsidered.Thenewborninfantmustbecloselymonitored.Symptomsof

hypoglycaemiaandbradycardiaaregenerallytobeexpectedwithinthefirst3days.

Lactation:

Therearenodataontheexcretionofbisoprololinhumanbreastmilkorthesafetyofbisoprololexposureininfants.

Therefore,breastfeedingisnotrecommendedduringadministrationofbisoprolol.

4.7Effectsonabilitytodriveandusemachines

Inastudywithcoronaryheartdiseasepatients,bisoprololdidnotimpairdrivingperformance.However,dependingon

theindividualpatientsresponsetotreatmentaneffectontheabilitytodriveavehicleortousemachinescannotbe

excluded.Thisneedstobeconsideredparticularlyatstartoftreatment,uponchangeofmedication,orinconjunction

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)

Notknown(cannotbeestimatedfromtheavailabledata)

Cardiacdisorders:

Verycommon:bradycardia.

Common:worseningofheartfailure

Uncommon:AV-conductiondisturbances.

Investigations:

Rare:increasedtriglycerides,increasedliverenzymes(ALT,AST).

Nervoussystemdisorders:

Common:dizziness,headache.

Rare:syncope.

Eyedisorders:

Rare:reducedtearflow(tobeconsideredifthepatientuseslenses).

Veryrare:conjunctivitis.

Earandlabyrinthdisorders:

Rare:hearingdisorders.

Respiratory,thoracicandmediastinaldisorders:

Uncommon:bronchospasminpatientswithbronchialasthmaorahistoryofobstructiveairwaysdisease.

Rare:allergicrhinitis.

Gastrointestinaldisorders:

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Skinandsubcutaneoustissuedisorders:

Rare:hypersensitivityreactionssuchasitching,flush,rash

Veryrare:beta-blockingagentsmayprovokeorworsenpsoriasisorinducepsoriasis-likerash,alopecia.

Musculoskeletalandconnectivetissuedisorders:

Uncommon:muscleweakness,musclecramps.

Vasculardisorders:

Common:feelingofcoldnessornumbnessintheextremities,hypotension.

Generaldisorders:

Common:asthenia,fatigue

Hepatobiliarydisorders:

Rare:hepatitis.

Reproductivesystemandbreastdisorders:

Rare:potencydisorders.

Psychiatricdisorders:

Uncommon:sleepdisorders,depression.

Rare:nightmares,hallucinations.

4.9Overdose

Themostcommonsignsexpectedwithoverdoseofabeta-blockerarebradycardia,hypotension,bronchospasm,acute

cardiacinsufficiencyandhypoglycaemia.Thereislimitedexperiencewithoverdoseofbisoprolol,onlyafewcasesof

overdosewithbisoprololhavebeenreported.Bradycardiaand/orhypotensionwerenoted.Allpatientsrecovered.There

isawideinter-individualvariationinsensitivitytoonesinglehighdoseofbisoprololandpatientswithheartfailureare

probablyverysensitive.

Ingeneral,ifoverdoseoccurs,discontinuationofbisoprololtreatmentandsupportiveandsymptomatictreatmentis

recommended.

Basedontheexpectedpharmacologicactionsandrecommendationsforotherbeta-blockingagents,thefollowing

generalmeasuresshouldbeconsideredwhenclinicallywarranted.

Bradycardia:Administerintravenousatropine.Iftheresponseisinadequate,isoprenalineoranotheragentwithpositive

chronotropicpropertiesmaybegivencautiously.Undersomecircumstances,transvenouspacemakerinsertionmaybe

necessary.

Hypotension:Intravenousfluidsandvasopressorsshouldbeadministered.Intravenousglucagonmaybeuseful.

AVblock(secondorthirddegree):Patientsshouldbecarefullymonitoredandtreatedwithisoprenalineinfusionor

temporarypacing

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

Bronchospasm:Administerbronchodilatortherapysuchasisoprenaline,beta

-sympathomimeticmedicinalproducts

and/oraminophylline.

Hypoglycaemia:Administeri.v.glucose.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Betablockingagents,selective.

ATCCode:C07AB07

Bisoprololisahighlybeta

-selective-adrenoceptorblockingagent,lackingintrinsicsympathomimeticandrelevant

membranestabilisingactivity.Itonlyshowslowaffinitytothebeta

-receptorofthesmoothmusclesofbronchiand

vesselsaswellastothebeta

-receptorsconcernedwithmetabolicregulation.Therefore,bisoprololisgenerallynotto

beexpectedtoinfluencetheairwayresistanceandbeta

-mediatedmetaboliceffects.Itsbeta

-selectivityextends

beyondthetherapeuticdoserange.

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

wereinNYHAclassIV.Theyhadstablesymptomaticsystolicheartfailure(ejectionfraction35%,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-blockingagents,orangiotensinreceptorblockers.Patientsweretreatedwithacombinationofbisoprololand

enalaprilfor6to24monthsafteraninitial6monthstreatmentwitheitherbisoprololorenalapril.

Therewasatrendtowardhigherfrequencyofchronicheartfailureworseningwhenbisoprololwasusedastheinitial6

monthstreatment.Noninferiorityofbisoprolol-firstversusenalapril-firsttreatmentwasnotprovenintheper-protocol

analysis,althoughthetwostrategiesforinitiationofCHFtreatmentshowedasimilarrateoftheprimarycombined

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

group,per-protocolpopulation).Thestudyshowsthatbisoprololcanalsobeusedinelderlychronicheartfailure

patientswithmildtomoderatedisease.

Bisoprololisalsousedforthetreatmentofhypertensionandanginapectoris

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-blockingagents,bisoprololcausedmaternal(decreased

foodintakeanddecreasedbodyweight)andembryo/fetaltoxicity(increasedincidenceofresorptions,reducedbirth

weightoftheoffspring,retardedphysicaldevelopment)athighdosesbutwasnotteratogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Cellulose,Microcrystalline

CalciumHydrogenPhosphate,Anhydrous

SilicaColloidalAnhydrous

Crospovidone(TypeA)

MagnesiumStearate

Tabletcoat:

Hypromellose6cP(E464)

TitaniumDioxide(E171)

Macrogol400

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

InuseshelflifeforHDPEbottlepack[500tablets]:6months

6.4Specialprecautionsforstorage

Storebelow25ºC.

Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

BisoprololPfizerfilm-coatedtabletsareavailableincoldformAluminum-Aluminumblisterswithpeelablelidding

foilandHDPEbottlepacks.

Packsizes:

Blisterpack:1,10,20,28,30film-coatedtablets

Bottlepack:30,500film-coatedtablets

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6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirement.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk,

NationalDigitalPark,

CitywestBusinessCampus,

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0822/062/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:5thDecember2011

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