ENTACAPONE MYLAN

Main information

  • Trade name:
  • ENTACAPONE MYLAN
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ENTACAPONE MYLAN
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/137/001
  • Authorization date:
  • 19-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EntacaponeMylan200mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains200mgentacapone.

Excipient(s):

Eachtabletcontains:

0.136mgSucrose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Lightorange,oval-shaped,biconvex,filmcoatedtabletdebossedwith“EE200”ononesideofthetabletand“M”on

theotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Entacaponeisindicatedasanadjuncttostandardpreparationsoflevodopa/benserazideorlevodopa/carbidopaforuse

inadultpatientswithParkinson’sdiseaseandend-of-dosemotorfluctuations,whocannotbestabilisedonthose

combinations.

4.2Posologyandmethodofadministration

Entacaponeshouldonlybeusedincombinationwithlevodopa/benserazideorlevodopa/carbidopa.

Theprescribinginformationfortheselevodopapreparationsisapplicabletotheirconcomitantusewithentacapone.

Posology

One200mgtabletistakenwitheachlevodopa/dopadecarboxylaseinhibitordose.Themaximumrecommendeddose

is200mgtentimesdaily,i.e.2,000mgofentacapone.

Entacaponeenhancestheeffectsoflevodopa.Hence,toreducelevodopa-relateddopaminergicadversereactions,e.g.

dyskinesias,nausea,vomitingandhallucinations,itisoftennecessarytoadjustlevodopadosagewithinthefirstdaysto

firstweeksafterinitiatingentacaponetreatment.Thedailydoseoflevodopashouldbereducedbyabout10–30%by

extendingthedosingintervalsand/orbyreducingtheamountoflevodopaperdose,accordingtotheclinicalcondition

ofthepatient.

Ifentacaponetreatmentisdiscontinued,itisnecessarytoadjustthedosingofotherantiparkinsoniantreatments,

especiallylevodopa,toachieveasufficientlevelofcontroloftheparkinsoniansymptoms.

Entacaponeincreasesthebioavailabilityoflevodopafromstandardlevodopa/benserazidepreparationsslightly(5–

10%)morethanfromstandardlevodopa/carbidopapreparations.Hence,patientswhoaretakingstandard

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Renalimpairment:

Renalinsufficiencydoesnotaffectthepharmacokineticsofentacaponeandthereisnoneedfordoseadjustment.

However,forpatientswhoarereceivingdialysistherapy,alongerdosingintervalmaybeconsidered(seesection5.2).

Hepaticimpairment:

Seesection4.3.

Elderly:

Nodosageadjustmentofentacaponeisrequiredforelderlypatients.

Paediatricpopulation:

Thesafetyandefficacyofentacaponeinchildrenbelowage18havenotbeenestablished.Nodataareavailable.

Methodofadministration

Entacaponeisadministeredorallyandsimultaneouslywitheachlevodopa/carbidopaorlevodopa/benserazidedose.

Entacaponecanbetakenwithorwithoutfood(seesection5.2).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients

Hepaticimpairment.

Phaeochromocytoma.

Concomitantuseofentacaponeandnon-selectivemonoamineoxidase(MAO-AandMAO-B)inhibitors

(e.g.phenelzine,tranylcypromine).

ConcomitantuseofaselectiveMAO-AinhibitorplusaselectiveMAO-Binhibitorandentacapone(seesection4.5).

Aprevioushistoryofneurolepticmalignantsyndrome(NMS)and/ornon-traumaticrhabdomyolysis.

4.4Specialwarningsandprecautionsforuse

Rhabdomyolysissecondarytoseveredyskinesiasorneurolepticmalignantsyndrome(NMS)hasbeenobservedrarely

inpatientswithParkinson’sdisease.

NMS,includingrhabdomyolysisandhyperthermia,ischaracterisedbymotorsymptoms(rigidity,myoclonus,tremor),

mentalstatuschanges(e.g.agitation,confusion,coma),hyperthermia,autonomicdysfunction(tachycardia,labileblood

pressure)andelevatedserumcreatinephosphokinase.Inindividualcases,onlysomeofthesesymptomsand/orfindings

maybeevident.

NeitherNMSnorrhabdomyolysishavebeenreportedinassociationwithentacaponetreatmentfromcontrolledtrialsin

whichentacaponewasdiscontinuedabruptly.Sincetheintroductionintothemarket,isolatedcasesofNMShavebeen

reported,especiallyfollowingabruptreductionordiscontinuationofentacaponeandotherconcomitantdopaminergic

medicinalproducts.Whenconsiderednecessary,withdrawalofentacaponeandotherdopaminergictreatmentshould

proceedslowly,andifsignsand/orsymptomsoccurdespiteaslowwithdrawalofentacapone,anincreaseinlevodopa

dosagemaybenecessary.

Entacaponetherapyshouldbeadministeredcautiouslytopatientswithischemicheartdisease.

Becauseofitsmechanismofaction,entacaponemayinterferewiththemetabolismofmedicinalproductscontaininga

catecholgroupandpotentiatetheiraction.Thus,entacaponeshouldbeadministeredcautiouslytopatientsbeingtreated

withmedicinalproductsmetabolisedbycatechol-O-methyltransferase(COMT),e.g.rimiterole,isoprenaline,

adrenaline,noradrenaline,dopamine,dobutamine,alpha-methyldopa,andapomorphine(seealsosection4.5).

Entacaponeisalwaysgivenasanadjuncttolevodopatreatment.Hence,theprecautionsvalidforlevodopatreatment

shouldalsobetakenintoaccountforentacaponetreatment.Entacaponeincreasesthebioavailabilityoflevodopafrom

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Consequently,adversedopaminergicreactionsmaybemorefrequentwhenentacaponeisaddedto

levodopa/benserazidetreatment(seealsosection4.8).Toreducelevodopa-relateddopaminergicadversereactions,itis

oftennecessarytoadjustlevodopadosagewithinthefirstdaystofirstweeksafterinitiatingentacaponetreatment,

accordingtotheclinicalconditionofthepatient(seesections4.2and4.8).

Entacaponemayaggravatelevodopa-inducedorthostatichypotension.Entacaponeshouldbegivencautiouslyto

patientswhoaretakingothermedicinalproductswhichmaycauseorthostatichypotension.

Inclinicalstudies,adversedopaminergicreactions,e.g.dyskinesia,weremorecommoninpatientswhoreceived

entacaponeanddopamineagonists(suchasbromocriptine),selegilineoramantadinecomparedtothosewhoreceived

placebowiththiscombination.Thedosesofotherantiparkinsonianmedicinalproductsmayneedtobeadjustedwhen

entacaponetreatmentisinitiated.

Entacaponeinassociationwithlevodopahasbeenassociatedwithsomnolenceandepisodesofsuddensleeponsetin

patientswithParkinson’sdiseaseandcautionshouldthereforebeexercisedwhendrivingoroperatingmachines(see

alsosection4.7).

Forpatientsexperiencingdiarrhoea,afollow-upofweightisrecommendedinordertoavoidpotentialexcessiveweight

decrease.Prolongedorpersistentdiarrhoeaappearingduringuseofentacaponemaybeasignofcolitis.Intheeventof

prolongedorpersistentdiarrhoea,thedrugshouldbediscontinuedandappropriatemedicaltherapyandinvestigations

considered.

Pathologicalgambling,increasedlibidoandhypersexualityhavebeenreportedinParkinson’sdiseasepatientstreated

withdopamineagonistsandotherdopaminergictreatmentssuchasentacaponeinassociationwithlevodopa.

Forpatientswhoexperienceprogressiveanorexia,astheniaandweightdecreasewithinarelativelyshortperiodoftime,

ageneralmedicalevaluationincludingliverfunctionshouldbeconsidered.

EntacaponeMylan200mgfilm-coatedtabletscontainsucrose:patientswithrarehereditaryproblemsoffructose

intolerance,glucose-galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nointeractionofentacaponewithcarbidopahasbeenobservedwiththerecommendedtreatmentschedule.

Pharmacokineticinteractionwithbenserazidehasnotbeenstudied.

Insingle-dosestudiesinhealthyvolunteers,nointeractionswereobservedbetweenentacaponeand

imipramineorbetweenentacaponeandmoclobemide.Similarly,nointeractionsbetweenentacaponeandselegiline

wereobservedinrepeated-dosestudiesinparkinsonianpatients.However,theexperienceoftheclinicaluseof

entacaponewithseveralmedicinalproducts,includingMAO-Ainhibitors,tricyclicantidepressants,noradrenaline

reuptakeinhibitorssuchasdesipramine,maprotilineandvenlafaxine,andmedicinalproductsthataremetabolisedby

COMT(e.g.catechol-structuredcompounds:rimiterol,isoprenaline,adrenaline,noradrenaline,dopamine,dobutamine,

alpha-methyldopa,apomorphine,andparoxetine)isstilllimited.Cautionshouldbeexercisedwhenthesemedicinal

productsareusedconcomitantlywithentacapone(seealsosections4.3and4.4).

Entacaponemaybeusedwithselegiline(aselectiveMAO-Binhibitor),butthedailydoseofselegilineshouldnot

exceed10mg.

Entacaponemayformchelateswithironinthegastrointestinaltract.Entacaponeandironpreparationsshouldbetaken

atleast2–3hoursapart(seesection4.8).

EntacaponebindstohumanalbuminbindingsiteIIwhichalsobindsseveralothermedicinalproducts,including

diazepamandibuprofen.Clinicalinteractionstudieswithdiazepamandnonsteroidalanti-inflammatorymedicinal

productshavenotbeencarriedout.Accordingtoinvitrostudies,significantdisplacementisnotanticipatedat

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DuetoitsaffinitytocytochromeP4502C9invitro(seesection5.2),entacaponemaypotentiallyinterferewith

medicinalproductswithmetabolismdependentonthisisoenzyme,suchasS-warfarin.However,inaninteractionstudy

inhealthyvolunteers,entacaponedidnotchangetheplasmalevelsofS-warfarin,whiletheAUCforR-warfarin

increasedonaverageby18%[CI9011–26%].TheINRvaluesincreasedonaverageby13%[CI906–19%].Thus,

controlofINRisrecommendedwhenentacaponetreatmentisinitiatedforpatientsreceivingwarfarin.

4.6Fertility,pregnancyandlactation

Nooverteratogenicorprimaryfoetotoxiceffectswereobservedinanimalstudiesinwhichtheexposurelevelsof

entacaponeweremarkedlyhigherthanthetherapeuticexposurelevels.Asthereisnoexperienceinpregnantwomen,

entacaponeshouldnotbeusedduringpregnancy.

Inanimalstudiesentacaponewasexcretedinmilk.Thesafetyofentacaponeininfantsisunknown.

Womenshouldnotbreast-feedduringtreatmentwithentacapone.

4.7Effectsonabilitytodriveandusemachines

EntacaponeMylaninassociationwithlevodopamayhavemajorinfluenceontheabilitytodriveandusemachines.

Entacaponemay,togetherwithlevodopa,causedizzinessandsymptomaticorthostatism.Therefore,cautionshouldbe

exercisedwhendrivingorusingmachines.

Patientsbeingtreatedwithentacaponeinassociationwithlevodopaandpresentingwithsomnolenceand/orsudden

sleeponsetepisodesmustbeinstructedtorefrainfromdrivingorengaginginactivitieswhereimpairedalertnessmay

putthemselvesorothersatriskofseriousinjuryordeath(e.g.operatingmachines)untilsuchrecurrentepisodeshave

resolved(seealsosection4.4).

4.8Undesirableeffects

Themostfrequentadversereactionscausedbyentacaponerelatetotheincreaseddopaminergicactivityandoccurmost

commonlyatthebeginningoftreatment.Reductionoflevodopadosagedecreasestheseverityandfrequencyofthese

reactions.Theothermajorclassofadversereactionsaregastrointestinalsymptoms,includingnausea,vomiting,

abdominalpain,constipationanddiarrhoea.Urinemaybediscolouredreddish-brownbyentacapone,butthisisa

harmlessphenomenon.

Usuallytheadversereactionscausedbyentacaponearemildtomoderate.Inclinicalstudiesthemostcommonadverse

reactionsleadingtodiscontinuationofentacaponetreatmenthavebeengastrointestinalsymptoms(e.g.diarrhoea,

2.5%)andincreaseddopaminergicadversereactionsoflevodopa(e.g.dyskinesias,1.7%).

Dyskinesias(27%),nausea(11%),diarrhoea(8%),abdominalpain(7%)anddrymouth(4.2%)werereported

significantlymoreoftenwithentacaponethanwithplaceboinpooleddatafromclinicalstudiesinvolving406patients

takingthemedicinalproductand296patientstakingplacebo.

Someoftheadversereactions,suchasdyskinesia,nausea,andabdominalpain,maybemorecommonwiththehigher

doses(1,400to2,000mgperday)thanwiththelowerdosesofentacapone.

Adversereactionsarerankedunderheadingsoffrequency,themostfrequentfirst,usingthefollowingconvention:

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,sincenovalidestimatecanbederivedfrom

clinicaltrialsorepidemiologicalstudies).

Thefollowingadversedrugreactionshavebeenaccumulatedbothfromclinicalstudieswithentacaponeandsincethe

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Psychiatricdisorders

Common: Insomnia,hallucinations,confusion,paroniria

Veryrare: Agitation

Nervoussystemdisorders

Verycommon: Dyskinesia

Common: Parkinsonismaggravated,dizziness,dystonia,hyperkinesia

Cardiacdisorders*

Common: Ischemicheartdiseaseeventsotherthanmyocardialinfarction

(e.g.anginapectoris)

Uncommon: Myocardialinfarction

Gastrointestinaldisorders

Verycommon: Nausea

Common: Diarrhoea,abdominalpain,drymouth,constipation,vomiting

Veryrare: Anorexia

Notknown: Colitis

Hepatobiliarydisorders

Rare: Hepaticfunctiontestsabnormal

Notknown: Hepatitiswithmainlycholestaticfeatures(seesection4.4)

Skinandsubcutaneoustissuedisorders

Rare: Erythematousormaculopapularrash

Veryrare: Urticaria

Notknown: Skin,hair,beardandnaildiscolorations

Renalandurinarydisorders

Verycommon: Urinediscoloration

Generaldisordersandadministrationsiteconditions

Common: Fatigue,sweatingincreased,fall

Veryrare: Weightdecrease

Theincidenceratesofmyocardialinfarctionandotherischemicheartdiseaseevents(0.43%and1.54%,

respectively)arederivedfromananalysisof13double-blindstudiesinvolving2082patientswithend-of-dosemotor

fluctuationsreceivingentacapone.

Entacaponeinassociationwithlevodopahasbeenassociatedwithisolatedcasesofexcessivedaytimesomnolenceand

suddensleeponsetepisodes.

Parkinson’sdiseasepatientstreatedwithdopamineagonistsandotherdopaminergictreatmentssuchasentacaponein

associationwithlevodopa,especiallyathighdoses,havebeenreportedasexhibitingsignsofpathologicalgambling,

increasedlibidoandhypersexuality,whichweregenerallyreversibleuponreductionofthedoseortreatment

discontinuation.

IsolatedcasesofNMShavebeenreportedfollowingabruptreductionordiscontinuationofentacaponeandother

dopaminergictreatments.

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4.9Overdose

Thepost-marketingdataincludeisolatedcasesofoverdoseinwhichthereportedhighestdailydoseofentacaponehas

been16,000mg.Theacutesymptomsandsignsinthesecasesofoverdoseincludedconfusion,decreasedactivity,

somnolence,hypotonia,skindiscolourationandurticaria.Managementofacuteoverdoseissymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:otherdopaminergicagents,ATCcode:NO4BX02.

Entacaponebelongstoanewtherapeuticclass,catechol-O-methyltransferase(COMT)inhibitors.Itisareversible,

specific,andmainlyperipherallyactingCOMTinhibitordesignedforconcomitantadministrationwithlevodopa

preparations.Entacaponedecreasesthemetaboliclossoflevodopato3-O-methyldopa(3-OMD)byinhibitingthe

COMTenzyme.ThisleadstoahigherlevodopaAUC.Theamountoflevodopaavailabletothebrainisincreased.

Entacaponethusprolongstheclinicalresponsetolevodopa.

EntacaponeinhibitstheCOMTenzymemainlyinperipheraltissues.COMTinhibitioninredbloodcellsclosely

followstheplasmaconcentrationsofentacapone,thusclearlyindicatingthereversiblenatureofCOMTinhibition.

Clinicalstudies

IntwophaseIIIdouble-blindstudiesinatotalof376patientswithParkinson’sdiseaseandend-of-dosemotor

fluctuations,entacaponeorplacebowasgivenwitheachlevodopa/dopadecarboxylaseinhibitordose.Theresultsare

giveninTable1.InstudyI,dailyONtime(hours)wasmeasuredfromhomediariesandinstudyII,theproportionof

dailyONtime.

Table1:DailyONtime(Mean±SD)

TherewerecorrespondingdecreasesinOFFtime.

The%changefrombaselineinOFFtimewas–24%intheentacaponegroupand0%intheplacebogroupinstudyI.

ThecorrespondingfiguresinstudyIIwere–18%and–5%.

5.2Pharmacokineticproperties

Generalcharacteristicsoftheactivesubstance

Absorption

Therearelargeintra-andinterindividualvariationsintheabsorptionofentacapone.

Thepeakconcentration(C

)inplasmaisusuallyreachedaboutonehourafteringestionofa200mgentacapone

StudyI:DailyOntime(h)

Entacapone(n=85) Placebo(n=86) Difference

Baseline 9.3±2.2 9.2±2.5

Week8-24 10.7±2.2 9.4±2.6 1h20min

(8.3%)

45min,1h56

StudyII:ProportionofdailyOntime(%)

Entacapone(n=103) Placebo(n=102) Difference

Baseline 60.0±15.2 60.8±14.0

Week8-24 66.8±14.5 62.8±16.80 4.5%(0h35min)

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Thebioavailabilityofentacaponeisabout35%afteranoraldose.Fooddoesnotaffecttheabsorptionofentacaponeto

anysignificantextent.

Distribution

Afterabsorptionfromthegastrointestinaltract,entacaponeisrapidlydistributedtotheperipheraltissueswitha

distributionvolumeof20litresatsteadystate(Vd

).Approximately92%ofthedoseiseliminatedduringß-phase

withashorteliminationhalf-lifeof30minutes.Thetotalclearanceofentacaponeisabout800ml/min.

Entacaponeisextensivelyboundtoplasmaproteins,mainlytoalbumin.Inhumanplasmatheunboundfractionisabout

2.0%inthetherapeuticconcentrationrange.Attherapeuticconcentrations,entacaponedoesnotdisplaceother

extensivelyboundsubstances(e.g.warfarin,salicylicacid,phenylbutazone,ordiazepam),norisitdisplacedtoany

significantextentbyanyofthesesubstancesattherapeuticorhigherconcentrations.

Metabolism

Asmallamountofentacapone,the(E)-isomer,isconvertedtoits(Z)-isomer.The(E)-isomeraccountsfor95%ofthe

AUCofentacapone.The(Z)-isomerandtracesofothermetabolitesaccountfortheremaining5%.

Datafrominvitrostudiesusinghumanlivermicrosomalpreparationsindicatethatentacaponeinhibitscytochrome

P4502C9(IC50~4µM).EntacaponeshowedlittleornoinhibitionofothertypesofP450isoenzymes(CYP1A2,

CYP2A6,CYP2D6,CYP2E1,CYP3AandCYP2C19)(seesection4.5).

Elimination

Theeliminationofentacaponeoccursmainlybynon-renalmetabolicroutes.Itisestimatedthat80–90%ofthedoseis

excretedinfaeces,althoughthishasnotbeenconfirmedinman.Approximately10–20%isexcretedinurine.Only

tracesofentacaponearefoundunchangedinurine.Themajorpart(95%)oftheproductexcretedinurineisconjugated

withglucuronicacid.Ofthemetabolitesfoundinurineonlyabout1%havebeenformedthroughoxidation.

Characteristicsinpatients

Thepharmacokineticpropertiesofentacaponearesimilarinbothyoungandelderlyadults.Themetabolismofthe

medicinalproductisslowedinpatientswithmildtomoderateliverinsufficiency(Child-PughClassAandB),which

leadstoanincreasedplasmaconcentrationofentacaponeinboththeabsorptionandeliminationphases(seesection

4.3).Renalimpairmentdoesnotaffectthepharmacokineticsofentacapone.However,alongerdosingintervalmaybe

consideredforpatientswhoarereceivingdialysistherapy.

5.3Preclinicalsafetydata

Non-clinicaldatarevealednospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,

repeateddosetoxicity,genotoxicity,andcarcinogenicpotential.Inrepeateddosetoxicitystudies,anaemiamostlikely

duetoironchelatingpropertiesofentacaponewasobserved.Regardingreproductiontoxicity,decreasedfoetalweight

andaslightlydelayedbonedevelopmentwerenoticedinrabbitsatsystemicexposurelevelsinthetherapeuticrange.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Mannitol

Low-substitutedhydroxypropylcellulose

Magnesiumstearate

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Film-coating:

Hypromellose

Titaniumdioxide(E171)

Glycerin

Magnesiumstearate

Ironoxideyellow(E172)

Sucrose

Polysorbate80

Ironoxidered(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Blisterpack:Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Bottlepack:Thismedicinalproductdoesnotrequireanyspecialstorageconditions.Onceopenusewithin30days.

6.5Natureandcontentsofcontainer

BlisterpackscomprisingofcleartransparentPVC/PE/PVdCfilmononesideandhardtemperedaluminiumfoilcoated

withheatseallacquerontheothersidecontaining30,60,100,200,300or400tablets.

Whitecolouredhigh-densitypolyethylene(HDPE)bottlewithwhiteopaquepolypropylene(PP)screwcapcontaining

30,50,60,100or500tablets.

Cartonscontaining200,300,or400tabletsas4,6or8bottlesof50tablets.Bottlescompriseofwhitecolouredhigh-

densitypolyethylene(HDPE)bottlewithwhiteopaquepolypropylene(PP)screwcap.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd.

t/aGerardLaboratories

35/36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

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8MARKETINGAUTHORISATIONNUMBER

PA577/137/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19thAugust2011

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