BISOPROLOL FUMARATE

Main information

  • Trade name:
  • BISOPROLOL FUMARATE
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BISOPROLOL FUMARATE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/044/003
  • Authorization date:
  • 16-04-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BisoprololFumarate10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgbisoprololfumarate

Excipient:131mgoflactosemonohydrate/tablet.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Beigemottled,roundandconvex,uncoated,“BI”and“10”debossedoneithersideofabreak-lineonthetopside,plain

onthebottomside.

Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofstablechronicheartfailurewithreducedsystolicleftventricularfunctioninadditiontoACEinhibitors,

anddiuretics,andoptionallycardiacglycosides(foradditionalinformationseesection5.1).

4.2Posologyandmethodofadministration

StandardtreatmentofCHFconsistsofanACEinhibitor(oranangiotensinreceptorblockerincaseofintoleranceto

ACEinhibitors,aBeta-blockingagent,diuretics,andwhenappropriatecardiacglycosides.Patientsshouldbestable

(withoutacutefailure)whenbisoprololtreatmentisinitiated.

Itisrecommendedthatthetreatingphysicianshouldbeexperiencedinthemanagementof

chronicheartfailure.

Transientworseningofheartfailurehypotensionorbradycardiamayoccurduringthetitrationperiodandthereafter.

TitrationPhase

Thetreatmentofstablechronicheartfailurewithbisoprololrequiresatitrationphase.

Thetreatmentwithbisoprololistobestartedwithagradualuptitrationaccordingtothe

followingsteps:

-1.25mgoncedailyfor1week,ifwelltoleratedincreaseto

-2.5mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-3.75mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-7.5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-10mgoncedailyforthemaintenancetherapy.

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Closemonitoringofvitalsigns(heartrate,bloodpressure)andsymptomsofworseningheartfailureisrecommended

duringthetitrationphase.Symptomsmayalreadyoccurwithinthefirstdayafterinitiatingtherapy.

TreatmentModification

Ifthemaximumrecommendeddoseisnotwelltolerated,gradualdosereductionmaybeconsidered.

Incaseoftransientworseningofheartfailure,hypotension,orbradycardiareconsiderationofthedosageofthe

concomitantmedicationisrecommended.Itmayalsobenecessarytotemporarilylowerthedoseofbisoprololorto

considerdiscontinuation.Thereintroductionand/oruptitrationofbisoprololshouldalwaysbeconsideredwhenthe

patientbecomesstableagain.Ifdiscontinuationisconsidered,gradualdosedecreaseisrecommended,sinceabrupt

withdrawalmayleadtoacutedeteriorationofthepatient’scondition.

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Administration

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbe

swallowedwithliquidandshouldnotbechewed.

SpecialPopulation

RenalorHepaticImpairment

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailureandwith

impairedhepaticorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldthereforebemadewith

additionalcaution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnopaediatricexperiencewithbisoprolol,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontraindicatedinpatientswith:

acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

cardiogenicshock

secondorthirddegreeAVblock(withoutapacemaker)

sicksinussyndrome

sinoatrialblock

symptomaticbradycardia

symptomatichypotension

severebronchialasthmaorseverechronicobstructivepulmonarydisease

severeformsofperipheralarterialocclusivediseaseorsevereformsofRaynaud'ssyndrome

untreatedphaeochromocytoma(seesection4.4)

metabolicacidosis

Bisoprololtabletsarecontraindicatedinpatientswithhypersensitivitytobisoprololortoanyoftheexcipients(see

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4.4Specialwarningsandprecautionsforuse

Warnings

Thetreatmentofstablechronicheartfailurewithbisoprololhastobeinitiatedwithaspecialtitrationphase(seesection

4.2).

Especiallyinpatientswithischaemicheartdiseasethecessationoftherapywithbisoprololmustnotbedoneabruptly

unlessclearlyindicated,becausethismayleadtotransitionalworseningofheartcondition(seesection4.2).

Precautions

Theinitiationoftreatmentofstablechronicheartfailurewithbisoprololnecessitatesregularmonitoring.Forthe

dosageandmethodofadministrationseesection4.2.

Thereisnotherapeuticexperienceofbisoprololtreatmentinheartfailureinpatientswiththefollowingdiseasesand

conditions:

insulin-dependentdiabetesmellitus(typeI)

severelyimpairedrenalfunction

severelyimpairedliverfunction

restrictivecardiomyopathy

congenitalheartdisease

haemodynamicallysignificantorganicvalvulardisease

myocardialinfarctionwithin3months

Bisoprololmustbeusedwithcautionin:

diabetesmellituswithlargefluctuationsinbloodglucosevalues;symptomsofhypoglycaemia(e.g.

tachycardia,palpitationsorsweating)canbemasked,

strictfasting

ongoingdesensitisationtherapy.Aswithotherbeta-blockers,bisoprololmayincreaseboththesensitivity

towardsallergensandtheseverityofanaphylacticreactions.Epinephrinetreatmentmaynotalwaysyieldthe

expectedtherapeuticeffect,

FirstdegreeAVblock,

Prinzmetal’sangina,

peripheralarterialocclusivedisease.Aggravationofsymptomsmayoccurespeciallywhenstartingtherapy.

Patientswithpsoriasisorwithahistoryofpsoriasisshouldonlybegivenbeta-blockers(e.g.bisoprolol)afteracareful

balancingofbenefitsagainstrisks.

Thesymptomsofthyrotoxicosismaybemaskedundertreatmentwithbisoprolol.

Inpatientswithphaeochromocytomabisoprololmustnotbeadministereduntilafteralpha-receptorblockade.

Inpatientsundergoinggeneralanaesthesiabeta-blockadereducestheincidenceofarrhythmiasandmyocardial

ischemiaduringinductionandintubation,andthepost-operativeperiod.Itiscurrentlyrecommendedthatmaintenance

ofbeta-blockadebecontinuedperi-operatively.Theanaesthesistmustbeawareofbeta-blockadebecauseofthe

potentialforinteractionswithotherdrugs,resultinginbradyarrhythmias,attenuationofthereflextachycardia,and

decreasedreflexabilitytocompensateforbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blockertherapy

beforesurgery,thisshouldbedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Inbronchialasthmaorotherchronicobstructivepulmonarydiseases,whichmaycausesymptoms,concomitant

bronchodilatingtherapyisrecommended.Occasionallyanincreaseoftheairwayresistancemayoccurinpatientswith

asthma,thereforethedoseofbeta

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Lactose:thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,the

Lapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsnotrecommended

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

Effectonatrio-ventricularconductiontimemaybepotentiatedandnegativeinotropiceffectincreased.

Calciumantagonistsoftheverapamiltypeandtoalesserextentofthediltiazemtype::Negativeeffectoncontractility

andatrio-ventricularconduction.Intravenousadministrationofverapamilinpatientsonbeta-blockertreatmentmay

leadtoprofoundhypoensionandatrio-ventricularblock.

Centrally-actingantihypertensivedrugs(e.g.clonidinemethyldopa,moxonidine,rilmenidine):

Concomitantuseofcentrally-actingantihypertensivedrugsmayfurtherdecreasethecentralsympathetictonusandmay

thusleadtoreductionofheartrateandcardiacoutputandtovasodilation.Abruptwithdrawal,particularlyifpriorto

beta-blockerdiscontinuation,mayincreasetheriskof"reboundhypertension".

Combinationstobeusedwithcaution

Calciumantagonistsofthedihydropyridinetype(e.g.felodipineandamlodipine):Concomitantusemayincreasethe

riskofhypotension,andanincreaseintheriskoffurtherdeteriorationoftheventricularpumpfunctioninpatientswith

heartfailurecannotbeexcluded.

Class-IIIantiarrhythmicdrugs(e.g.amiodarone):

Effectonatrio-ventricularconductiontimemaybepotentiated.

Parasympathomimeticdrugs:

Concomitantusemayincreaseatrio-ventricularconductiontimeandtheriskofbradycardia.

Topicalbeta-blockers(e.g.eye-dropsforglaucomatreatment)mayaddtothesystemiceffectsofbisoprolol.

Insulinandoralantidiabeticdrugs:

Increaseofbloodsugarloweringeffect.Blockadeofbetaadrenoreceptorsmaymasksymptomsofhypoglycaemia.

Anaestheticagents:

Attenuationofthereflextachycardiaandincreaseoftheriskofhypotension(forfurtherinformationongeneral

anaesthesiaseesection4.4).

Digitalisglycosides:

Increaseofatrio-ventricularconductiontime,reductioninheartrate.

Non-steriodalanti-inflammatorydrugs(NSAIDs):

NSAIDsmayreducethehypotensiveeffectofbisoprolol.

Beta-sympathomimetics(eg.isoprenaline,dobutamine):

Combinationwithbisoprololmayreducetheeffectofbothagents.

Sympathomimeticsthatactivatebothbeta-andalpha-adrenoceptors(e.g.norepinephrine,epinephrine):

Combinationwithbisoprololmayunmaskthealpha-adrenoceptor-mediatedvasoconstrictoreffectsoftheseagents

leadingtobloodpressureincreaseandexacerbatedintermittentclaudication.Suchinteractionsareconsideredtobe

morelikelywithnonselectivebeta-blockers.

Concomitantusewithantihypertensiveagentsaswellaswithotherdrugswithbloodpressureloweringpotential(e.g.

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Combinationstobeconsidered

Mefloquine:increasedriskofbradycardia.

Monoamineoxidaseinhibitors(exceptMAO-Binhibitors):Enhancedhypotensiveeffectofthebetablockersbutalso

riskofhypertensivecrisis.

Rifampicin:Slightreductionofthehalf-lifeofbisoprololpossibleduetotheinductionofthehepaticdrugmetabolising

enzymes.Normallynodosageadjustmentisnecessary.

Ergotaminederivatives:Exacerbationofperipheralcirculatorydisturbances.

4.6Fertility,pregnancyandlactation

Pregnancy

Bisoprololhaspharmacologicaleffectsthatmaycauseharmfuleffectsonpregnancyand/orthefoetus/newborn.In

general,beta-adrenoceptorblockersreduceplacentalperfusion,whichhasbeenassociatedwithgrowthretardation,

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

foetusandnewborninfant.Iftreatmentwithbeta-adrenoceptorblockersisnecessary,beta

-selectiveadrenoceptor

blockersarepreferable.

Bisoprololisnotrecommendedduringpregnancyunlessclearlynecessary.Iftreatmentisconsiderednecessary,

monitoringoftheuteroplacentalbloodflowandthefoetalgrowthisrecommended.Incaseofharmfuleffectson

pregnancyorthefoetusconsiderationofalternativetreatmentisrecommended.Thenewborninfantmustbeclosely

monitored.Symptomsofhypoglycaemiaandbradycardiaaregenerallytobeexpectedwithinthefirst3days.

Lactation

Thereisnodataontheexcretionofbisoprololinhumanbreastmilkorthesafetyofbisoprololexposureininfants.

Therefore,breastfeedingisnot

recommendedduringadministrationofbisoprolol.

4.7Effectsonabilitytodriveandusemachines

Inastudywithcoronaryheartdiseasepatients,bisoprololdidnotimpairdrivingperformance.

However,dependingontheindividualpatientsresponsetotreatmentaneffectontheabilitytodriveavehicleortouse

machinescannotbeexcluded.Thisneedstobeconsideredparticularlyatstartoftreatment,uponchangeofmedication,

orinconjunctionwithalcohol.

4.8Undesirableeffects

Verycommon(10%),

common(1%and<10%),

uncommon(0.1%and<1%),

rare(0.01%and<0.1%),

veryrare(<0.01%).

Investigations

Rare: increasedtriglycerides,increasedliverenzymes(ALAT,ASAT)

Cardiacdisorders

Verycommon: bradycardia

Common: worseningofpre-existingheartfailure

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Nervoussystemdisorders

Common: dizziness,headache

Rare: syncope

Eyedisorders

Rare: reducedtearflow(tobeconsideredifthepatientusescontactlenses)

Veryrare: conjunctivitis

Earandlabyrinthdisorders

Rare: hearingdisorders

Respiratory,thoracicandmediastinaldisorders

Uncommon: bronchospasminpatientswithbronchialasthmaora

historyofobstructiveairwaydisease

Rare: allergicrhinitis

Gastrointestinaldisorders

Common: gastrointestinalcomplaintssuchasnausea,vomiting,diarrhoea,

Constipation

Skinandsubcutaneoustissuedisorders

Rare: hypersensitivityreactionssuchasitching,flush,rash

Veryrare: alopecia.Beta-blockersmayprovokeorworsenpsoriasisorinduce

psoriasis-likerash.

Musculoskeletalandconnectivetissuedisorders

Uncommon: muscleweakness,musclecramps

Vasculardisorders

Common: feelingofcoldnessornumbnessintheextremities,hypotension

especiallyinpatientswithheartfailure

Generaldisorders

Common: asthenia,fatigue

Hepatobiliarydisorders

Rare: hepatitis.

Reproductivesystemandbreastdisorders

Rare: potencydisorders

Psychiatricdisorders

Uncommon: depression,sleepdisorders

Rare: nightmares,hallucinations

4.9Overdose

Themostcommonsignsexpectedwithoverdoseofabeta-blockerarebradycardia,hypotension,bronchospasm,acute

cardiacinsufficiencyandhypoglycaemia.Thereislimitedexperiencewithoverdoseofbisoprolol,onlyafewcasesof

overdosewithbisoprololhavebeenreported.Bradycardiaand/orhypotensionwerenoted.Allpatientsrecovered.

Thereisawideinter-individualvariationinsensitivitytoonesinglehighdoseofbisoprololandpatientswithheart

failureareprobablyverysensitive.

Ingeneral,ifoverdoseoccurs,discontinuationofbisoprololtreatmentandsupportiveandsymptomatictreatmentis

recommended.

Basedontheexpectedpharmacologicactionsandrecommendationsforotherbeta-blockers,thefollowinggeneral

measuresmaybeconsideredwhenclinicallywarranted.

Bradycardia:Administerintravenousatropine.Iftheresponseisinadequate,isoprenalineoranotheragentwith

positivechronotropicpropertiesmaybegivencautiously.Undersomecircumstances,transvenouspacemakerinsertion

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Hypotension:Intravenousfluidsandvasopressorsshouldbeadministered.Intravenousglucagonsmaybeuseful.

AVblock(secondorthirddegree):Patientsshouldbecarefullymonitoredandtreatedwithisoprenalineinfusionor

temporarypacing.

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

Bronchospasm:Administerbronchodilatortherapysuchasisoprenaline,beta2-sympathomimeticdrugsand/or

aminophylline.

Hypoglycaemia:Administeri.v.-glucose.

Limiteddatasuggestthatbisorololishardlydialysable.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Beta-blockingagents,selective

ATCcode:C07_AB07

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-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.

Bisoprololisalsousedforthetreatmentofhypertensionandangina.

Inacuteadministrationinpatientswithcoronaryheartdiseasewithoutchronicheartfailurebisoprololreducestheheart

rateandstrokevolumeandthusthecardiacoutputandoxygenconsumption.Inchronicadministrationtheinitially

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5.2Pharmacokineticproperties

Bisoprololisabsorbedandhasabiologicalavailabilityofabout90%afteroraladministration. Theplasmaprotein

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

Thehalf-lifeinplasmaof10-12hoursgivesa24houreffectafterdosingoncedaily.

Bisoprololisexcretedfromthebodybytworoutes,50%ismetabolisedbythelivertoinactivemetaboliteswhichare

thenexcretedbythekidneys.Theremaining50%isexcretedbythekidneysinanunmetabolisedform.Since

eliminationtakesplaceinthekidneysandthelivertothesameextentadosageadjustmentisnotrequiredforpatients

withimpairedliverfunctionorrenalinsufficiency.Thepharmacokineticsinpatientswithstablechronicheartfailure

andwithimpairedliverorrenalfunctionhasnotbeenstudied.

Thekineticsofbisoprololarelinearandindependentofage.

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

Lactosemonohydrate

Cellulose,microcrystallineE460

MagnesiumstearateE572

Crospovidone(TypeB)E1201

BeigePB27215(lactosemonohydrateandironoxidesredandyellow[E172])

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove30 °

6.5Natureandcontentsofcontainer

BlisterscomprisingofuPVC/PVdC/aluminiumfoilcontainedwithinaprintedcardboardcarton.

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6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

Hertfordshire

SG40TW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/44/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16April2010

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