CARDICOR

Main information

  • Trade name:
  • CARDICOR Tablets 5 Milligram
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARDICOR Tablets 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/013/003
  • Authorization date:
  • 08-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PPA1328/013/003

CaseNo:2034068

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrants

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cardicor5mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjectto

thegeneralconditionsasmaybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/03/2007until07/09/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cardicor5mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgbisoprololfumarate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromItalyandtheUK:

Lightyellow,heartshaped,film-coatedtablet,scoredonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofstablechronicmoderatetosevereheartfailurewithreducedsystolicventricularfunction(ejectionfraction

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

additionalinformationseesection5.1).

4.2Posologyandmethodofadministration

Thepatientsshouldhavestablechronicheartfailurewithoutacutefailureduringthepastsixweeks

andamainlyunchangedbasictherapyduringthepasttwoweeks.Theyshouldbetreatedatoptimal

dosewithanACEinhibitor(orothervasodilatorincaseofintolerancetoACEinhibitors)anda

diuretic,andoptionallycardiacglycosides,priortotheadministrationofbisoprolol.

Itisrecommendedthatthetreatingphysicianshouldbeexperiencedinthemanagementofchronic

heartfailure.

Warning:Thetreatmentofstablechronicheartfailurewithbisoprololhastobeinitiatedwitha

titrationphaseasgiveninthedescriptionbelow.

Thetreatmentwithbisoprololistobestartedwithagradualuptitrationaccordingtothefollowing

steps:

-1.25mgoncedailyfor1week,ifwelltoleratedincreaseto

-2.5mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-3.75mgoncedailyforafurtherweek,ifwelltoleratedincreaseto

-5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-7.5mgoncedailyforthe4followingweeks,ifwelltoleratedincreaseto

-10mgoncedailyforthemaintenancetherapy.

Afterinitiationoftreatmentwith1.25mg,thepatientsshouldbeobservedoveraperiodof

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ofworseningofheartfailure).

Themaximumrecommendeddoseis10mgoncedaily.

Occurrenceofadverseeventsmaypreventallpatientsbeingtreatedwiththemaximumrecommended

dose.Ifnecessary,thedosereachedcanalsobedecreasedstepbystep.Thetreatmentmaybe

interruptedifnecessaryandreintroducedasappropriate.Duringthetitrationphase,incaseof

worseningoftheheartfailureorintolerance,itisrecommendedfirsttoreducethedoseofbisoprolol,

ortostopimmediatelyifnecessary(incaseofseverehypotension,worseningofheartfailurewith

acutepulmonaryoedema,cardiogenicshock,symptomaticbradycardiaorAVblock).

Treatmentofstablechronicheartfailurewithbisoprololisgenerallyalong-termtreatment.

Thetreatmentwithbisoprololisnotrecommendedtobestoppedabruptlysincethismightleadtoa

transitoryworseningofheartfailure.Ifdiscontinuationisnecessary,thedoseshouldbegradually

decreaseddividedintohalvesweekly.

Bisoprololtabletsshouldbetakeninthemorningandcanbetakenwithfood.Theyshouldbe

swallowedwithliquidandshouldnotbechewed.

Renalorliverinsufficiency

Thereisnoinformationregardingpharmacokineticsofbisoprololinpatientswithchronicheartfailure

andwithimpairedliverorrenalfunction.Uptitrationofthedoseinthesepopulationsshouldtherefore

bemadewithadditionalcaution.

Elderly

Nodosageadjustmentisrequired.

Children

Thereisnopaediatricexperiencewithbisoprolol,thereforeitsusecannotberecommendedforchildren.

4.3Contraindications

Bisoprololiscontraindicatedinchronicheartfailurepatientswith:

-acuteheartfailureorduringepisodesofheartfailuredecompensationrequiringi.v.inotropictherapy

-cardiogenicshock

-AVblockofsecondorthirddegree(withoutapacemaker)

-sicksinussyndrome

-sinoatrialblock

-bradycardiawithlessthan60beats/minbeforethestartoftherapy

-hypotension(systolicbloodpressurelessthan100mmHg)

-severebronchialasthmaorseverechronicobstructivepulmonarydisease

-latestagesofperipheralarterialocclusivediseaseandRaynaud'ssyndrome

-untreatedphaeochromocytoma(see4.4)

-metabolicacidosis

-hypersensitivitytobisoprololortoanyoftheexcipients

4.4Specialwarningsandprecautionsforuse

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-bronchospasm(bronchialasthma,obstructiveairwaysdiseases)

-diabetesmellituswithlargefluctuationsinbloodglucosevalues;symptomsofhypoglycaemiacan

bemasked

-strictfasting

-ongoingdesensitisationtherapy

-AVblockoffirstdegree

-Prinzmetal'sangina

-peripheralarterialocclusivedisease(intensificationofcomplaintsmighthappenespeciallyduring

thestartoftherapy)

-Generalanaesthesia

Inpatientsundergoinggeneralanaesthesiabeta-blockadereducestheincidenceofarrhythmiasand

myocardialischemiaduringinductionandintubation,andthepost-operativeperiod.Itiscurrently

recommendedthatmaintenancebeta-blockadebecontinuedperi-operatively.Theanaesthetistmustbe

awareofbeta-blockadebecauseofthepotentialforinteractionswithotherdrugs,resultingin

bradyarrhythmias,attenuationofthereflextachycardiaandthedecreasedreflexabilitytocompensate

forbloodloss.Ifitisthoughtnecessarytowithdrawbeta-blockertherapybeforesurgery,thisshould

bedonegraduallyandcompletedabout48hoursbeforeanaesthesia.

Thereisnotherapeuticexperienceofbisoprololtreatmentofheartfailureinpatientswiththe

followingdiseasesandconditions:

-NYHAclassIIheartfailure

-insulindependentdiabetesmellitus(typeI)

-impairedrenalfunction(serumcreatinine>300micromol/l)

-impairedliverfunction

-patientsolderthan80years

-restrictivecardiomyopathy

-congenitalheartdisease

-haemodynamicallysignificantorganicvalvulardisease

-myocardialinfarctionwithin3months

Combinationofbisoprololwithcalciumantagonistsoftheverapamilanddiltiazemtype,withClassI

antiarrhythmicdrugsandwithcentrallyactingantihypertensivedrugsisgenerallynotrecommended,

fordetailspleaserefertosection4.5.

Inbronchialasthmaorotherchronicobstructivelungdiseases,whichmaycausesymptoms,

bronchodilatingtherapyshouldbegivenconcomitantly.Occasionallyanincreaseoftheairway

resistancemayoccurinpatientswithasthma,thereforethedoseofbeta2-stimulantsmayhavetobe

increased.

Aswithotherbeta-blockers,bisoprololmayincreaseboththesensitivitytowardsallergensandthe

severityofanaphylacticreactions.Adrenalinetreatmentdoesnotalwaysgivetheexpectedtherapeutic

effect.

Patientswithpsoriasisorwithahistoryofpsoriasisshouldonlybegivenbeta-blockers(e.g.

bisoprolol)aftercarefullybalancingthebenefitsagainsttherisks.

Inpatientswithphaeochromocytomabisoprololmustnotbeadministereduntilafteralpha-receptor

blockade.

Undertreatmentwithbisoprololthesymptomsofathyreotoxicosismaybemasked.

Theinitiationoftreatmentwithbisoprololnecessitatesregularmonitoring.Fortheposologyand

methodofadministrationpleaserefertosection4.2.

Thecessationoftherapywithbisoprololshouldnotbedoneabruptlyunlessclearlyindicated.Forfurtherinformation

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsnotrecommended

Calciumantagonistsoftheverapamiltypeandtoalesserextentofthediltiazemtype:Negative

influenceoncontractilityandatrio-ventricularconduction.Intravenousadministrationofverapamilin

patientson-blockertreatmentmayleadtoprofoundhypotensionandatrioventricularblock.

ClassIantiarrhythmicdrugs(e.g.quinidine,disopyramide;lidocaine,phenytoin;flecainide,

propafenone):Effectonatrio-ventricularconductiontimemaybepotentiatedandnegativeinotropic

effectincreased.

Centrallyactingantihypertensivedrugssuchasclonidineandothers(e.g.methyldopa,moxonodine,

rilmenidine):Concomitantuseofcentrallyactingantihypertensivedrugsmayworsenheartfailureby

adecreaseinthecentralsympathetictonus(reductionofheartrateandcardiacoutput,vasodilation).

Abruptwithdrawal,particularlyifpriortobeta-blockerdiscontinuation,mayincreaseriskof“rebound

hypertension”.

Combinationstobeusedwithcaution

Calciumantagonistsofthedihydropyridinetypesuchasfelodipineandamlodipine:Concomitantuse

mayincreasetheriskofhypotension,andanincreaseintheriskofafurtherdeteriorationofthe

ventricularpumpfunctioninpatientswithheartfailurecannotbeexcluded.

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

potentiated.

Topicalbeta-blockers(e.g.eyedropsforglaucomatreatment)mayaddtothesystemiceffectsof

bisoprolol.

Parasympathomimeticdrugs:Concomitantusemayincreaseatrio-ventricularconductiontimeandthe

riskofbradycardia.

Insulinandoralantidiabeticdrugs:Intensificationofbloodsugarloweringeffect.Blockadeofbeta-

adrenoreceptorsmaymasksymptomsofhypoglycaemia.

Anaestheticagents:Attenuationofthereflextachycardiaandincreaseoftheriskofhypotension(for

furtherinformationongeneralanaesthesiaseealsosection4.4.).

Digitalisglycosides:Reductionofheartrate,increaseofatrio-ventricularconductiontime.

Non-steroidalanti-inflammatorydrugs(NSAIDs):NSAIDsmayreducethehypotensiveeffectof

bisoprolol.

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

Combinationwithbisoprololmayreducetheeffectofbothagents.

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

Combinationwithbisoprololmayunmaskthe-adrenoceptor-mediatedvasoconstrictoreffectsof

theseagentsleadingtobloodpressureincreaseandexacerbatedintermittentclaudication.Such

interactionsareconsideredtobemorelikelywithnonselective-blockers.

Concomitantusewithantihypertensiveagentsaswellaswithotherdrugswithbloodpressure

loweringpotential(e.g.tricyclicantidepressants,barbiturates,phenothiazines)mayincreasetheriskof

hypotension.

Combinationstobeconsidered

Mefloquine:increasedriskofbradycardia

Monoamineoxidaseinhibitors(exceptMAO-Binhibitors):Enhancedhypotensiveeffectofthebeta-blockersbutalso

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4.6Pregnancyandlactation

Pregnancy:

Bisoprololhaspharmacologicaleffectsthatmaycauseharmfuleffectsonpregnancyand/orthe

fetus/newborn.Ingeneral,beta-adrenoceptorblockersreduceplacentalperfusion,whichhasbeen

associatedwithgrowthretardation,intrauterinedeath,abortionorearlylabour.Adverseeffects(e.g.

hypoglycaemiaandbradycardia)mayoccurinthefetusandnewborninfant.Iftreatmentwithbeta-

adrenoceptorblockersisnecessary,beta1-selectiveadrenoceptorblockersarepreferable.

Bisoprololshouldnotbeusedduringpregnancyunlessclearlynecessary.Iftreatmentwithbisoprolol

isconsiderednecessary,theuteroplacentalbloodflowandthefetalgrowthshouldbemonitored.In

caseofharmfuleffectsonpregnancyorthefetusalternativetreatmentshouldbeconsidered.The

newborninfantmustbecloselymonitored.Symptomsofhypoglycaemiaandbradycardiaare

generallytobeexpectedwithinthefirst3days.

Lactation:

Itisnotknownwhetherthisdrugisexcretedinhumanmilk.Therefore,breastfeedingisnotrecommendedduring

administrationofbisoprolol.

4.7Effectsonabilitytodriveandusemachines

Inastudywithcoronaryheartdiseasepatientsbisoprololdidnotimpairdrivingperformance.However,dueto

individualvariationsinreactionstothedrug,theabilitytodriveavehicleortooperatemachinerymaybeimpaired.

Thisshouldbeconsideredparticularlyatstartoftreatmentanduponchangeofmedicationaswellasinconjunction

withalcohol.

4.8Undesirableeffects

Clinicaltrialdata

Thetablebelowshowsincidencesofadverseeventsreportedfromboththeplaceboandthebisoprolol

cohortoftheCIBISIItrial.Regardlessofcausalrelationshipalladverseeventsareincluded.Each

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AE=AdverseEvents

Post-marketingdata

Thefollowingdataresultsfrompost-marketingexperiencewithbisoprolol:

Common(>1%and<10%),uncommon(>0.1%and<1%),rare(>0.01%and<0.1%),veryrare

(<0.01%),singlecases.

Cardiacdisorders:

Uncommon:bradycardia,AV-stimulusdisturbances,worseningofheartfailure.

Earandlabyrinthdisorders:

Rare:hearingimpairment.

Eyedisorders:

Rare:reducedtearflow(tobeconsideredifthepatientuseslenses).

Veryrare:conjunctivitis.

Gastrointestinaldisorders:

Common:Nausea,vomiting,diarrhoea,constipation.

PreferredTerm

Placebo

(n=1321) Bisoprolol

(n=1328)

Pat.

with

%Pat.

with

Pat.

with

%Pat.

with

Cardiacfailure 301 22.8 244 18.4

Dyspnoea 224 17.0 183 13.8

Dizziness 126 9.5 177 13.3

Cardiomyopathy 132 10.0 141 10.6

Bradycardia 60 4.5 202 15.2

Hypotension 96 7.3 152 11.4

Tachycardia 144 10.9 79 5.9

Fatigue 94 7.1 123 9.3

Viralinfection 75 5.7 86 6.5

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Uncommon:Muscularweaknessandcramps.

Hepatobiliarydisorders:

Rare:increasedliverenzymes(ALAT,ASAT),hepatitis.

Metabolismandnutritiondisorders:

Rare:Increasedtriglycerides.

Nervoussystemdisorders:

Common:Tiredness*,exhaustion*,dizziness*,headache*.

Uncommon:Sleepdisturbances,depression.

Rare:Nightmares,hallucinations.

Reproductivesystemandbreastdisorders:

Rare:Potencydisorders.

Respiratory,thoracicandmediastinaldisorders:

Uncommon:Bronchospasminpatientswithbronchialasthmaorahistoryofobstructiveairways

disease.

Rare:allergicrhinitis.

Skinandsubcutaneoustissuedisorders:

Rare:hypersensitivityreactions(itching,flush,rash).

Veryrare:beta-blockersmayprovokeorworsenpsoriasisorinducepsoriasis-likerash,alopecia.

Vasculardisorders:

Common:Feelingofcoldnessornumbnessintheextremities.

Uncommon:orthostatichypotension.

*Thesesymptomsespeciallyoccuratthebeginningofthetherapy.Theyaregenerallymildandusuallydisappear

within1-2weeks.

4.9Overdose

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

dizzinesshavebeenreported.Ingeneralthemostcommonsignsexpectedwithoverdosageofabeta-

blockerarebradycardia,hypotension,bronchospasm,acutecardiacinsufficiencyandhypoglycaemia.

Todateafewcasesofoverdose(maximum:2000mg)withbisoprololhavebeenreportedinpatients

sufferingfromhypertensionand/orcoronaryheartdiseaseshowingbradycardiaand/orhypotension;

allpatientsrecovered.Thereisawideinterindividualvariationinsensitivitytoonesinglehighdoseof

bisoprololandpatientswithheartfailureareprobablyverysensitive.Thereforeitismandatoryto

initiatethetreatmentofthesepatientswithagradualuptitrationaccordingtotheschemegivenin

section4.2.

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shouldbeprovided.Limiteddatasuggestthatbisoprololishardlydialysable.Basedontheexpected

pharmacologicactionsandrecommendationsforotherbeta-blockers,thefollowinggeneralmeasures

shouldbeconsideredwhenclinicallywarranted.

Bradycardia:Administerintravenousatropine.Iftheresponseisinadequate,isoprenalineoranother

agentwithpositivechronotropicpropertiesmaybegivencautiously.Undersomecircumstances,

transvenouspacemakerinsertionmaybenecessary.

Hypotension:Intravenousfluidsandvasopressorsshouldbeadministered.Intravenousglucagonmay

beuseful.

AVblock(secondorthirddegree):Patientsshouldbecarefullymonitoredandtreatedwith

isoprenalineinfusionortransvenouscardiacpacemakerinsertion.

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

Bronchospasm:Administerbronchodilatortherapysuchasisoprenaline,beta2-sympathomimetic

drugsand/oraminophylline.

Hypoglycaemia:Administeri.v.glucose.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Betablockingagents,selective

ATCCode:C07AB07

Bisoprololisahighlybeta1-selective-adrenoceptorblockingagent,lackingintrinsicstimulatingand

relevantmembranestabilisingactivity.Itonlyshowslowaffinitytothebeta2-receptorofthesmooth

musclesofbronchiandvesselsaswellastothebeta2-receptorsconcernedwithmetabolicregulation.

Therefore,bisoprololisgenerallynottobeexpectedtoinfluencetheairwayresistanceandbeta2-

mediatedmetaboliceffects.Itsbeta1-selectivityextendsbeyondthetherapeuticdoserange.

Intotal2647patientswereincludedintheCIBISIItrial.83%(n=2202)wereinNYHAclassIIIand

17%(n=445)wereinNYHAclassIV.Theyhadstablesymptomaticsystolicheartfailure(ejection

fraction<35%,basedonechocardiography).Totalmortalitywasreducedfrom17.3%to11.8%

(relativereduction34%).Adecreaseinsuddendeath(3.6%vs6.3%,relativereduction44%)anda

reducednumberofheartfailureepisodesrequiringhospitaladmission(12%vs17.6%,relative

reduction36%)wasobserved.Finally,asignificantimprovementofthefunctionalstatusaccordingto

NYHAclassificationhasbeenshown.Duringtheinitiationandtitrationofbisoprololhospital

admissionduetobradycardia(0.53%),hypotension(0.23%),andacutedecompensation(4.97%)were

observed,buttheywerenotmorefrequentthanintheplacebo-group(0%,0.3%and6.74%).The

numbersoffatalanddisablingstrokesduringthetotalstudyperiodwere20inthebisoprololgroup

and15intheplacebogroup.

Bisoprololisalreadyusedforthetreatmentofhypertensionandangina.

Inacuteadministrationinpatientswithcoronaryheartdiseasewithoutchronicheartfailurebisoprololreducestheheart

rateandstrokevolumeandthusthecardiacoutputandoxygenconsumption.Inchronicadministrationtheinitially

elevatedperipheralresistancedecreases.

5.2Pharmacokineticproperties

Bisoprololisabsorbedandhasabiologicalavailabilityofabout90%afteroraladministration.The

plasmaproteinbindingofbisoprololisabout30%.Thedistributionvolumeis3.5l/kg.Totalclearance

isapproximately15l/h.Thehalf-lifeinplasmaof10-12hoursgivesa24houreffectafterdosingonce

daily.

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metaboliteswhicharethenexcretedbythekidneys.Theremaining50%isexcretedbythekidneysin

anunmetabolisedform.Sincetheeliminationtakesplaceinthekidneysandthelivertothesame

extentadosageadjustmentisnotrequiredforpatientswithimpairedliverfunctionorrenal

insufficiency.Thepharmacokineticsinpatientswithstablechronicheartfailureandwithimpaired

liverorrenalfunctionhasnotbeenstudied.

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

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Colloidalanhydroussilica

Magnesiumstearate

Crospovidone

Pregelatinisedmaizestarch

Maizestarch

Microcrystallinecellulose

Calciumhydrogenphosphate,anhydrous

Filmcoating:

Dimeticone

Macrogol400

Titaniumdioxide(E171)

Hypromellose

Yellowironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageof

theproductonthemarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Tabletscontainedin2x14blisterstrips

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerials

derivedfromsuchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

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Middlesex

HA40NU

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8ParallelProductAuthorisationNumber

PPA1328/13/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:8thSeptember2006

10DATEOFREVISIONOFTHETEXT

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