ADARTREL

Main information

  • Trade name:
  • ADARTREL Film Coated Tablet 0.25 Milligram
  • Dosage:
  • 0.25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ADARTREL Film Coated Tablet 0.25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1077/106/001
  • Authorization date:
  • 16-06-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ADARTREL0.25mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains0.25mgofropinirole(ashydrochloride).

Excipient:45.3mglactose(asmonohydrate)

Excipient(s):

ContainsLactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitepentagonal-shaped,bevellededgetabletsmarked"SB"ononesideand"4890"ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ADARTRELisindicatedforthesymptomatictreatmentofmoderatetosevereidiopathicRestlessLegsSyndrome(see

section5.1).

4.2Posologyandmethodofadministration

Oraluse.

Adults

Individualdosetitrationagainstefficacyandtolerabilityisrecommended.Ropiniroleshouldbetakenjustbefore

bedtime,howeverthedosecanbetakenupto3hoursbeforeretiring.Ropinirolemaybetakenwithfood,toimprove

gastrointestinaltolerance.

Treatmentinitiation(week1)

Therecommendedinitialdoseis0.25mgoncedaily(administeredasabove)for2days.Ifthisdoseiswelltolerated

thedoseshouldbeincreasedto0.5mgoncedailyfortheremainderofweek1.

Therapeuticregimen(week2onwards)

Followingtreatmentinitiation,thedailydoseshouldbeincreaseduntiloptimaltherapeuticresponseisachieved.The

averagedoseinclinicaltrials,inpatientswithmoderatetosevereRestlessLegsSyndrome,was2mgonceaday.

Thedosemaybeincreasedto1mgonceadayatweek2.Thedosemaythenbeincreasedby0.5mgperweekoverthe

nexttwoweekstoadoseof2mgonceaday.Insomepatients,toachieveoptimalimprovement,thedosemaybe

increasedgraduallyuptoamaximumof4mgonceaday.Inclinicaltrialsthedosewasincreasedby0.5mgeachweek

to3mgonceadayandthenby1mguptothemaximumrecommendeddoseof4mgonceadayasshownintable1.

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Table1 Dosetitration

*Toachieveoptimalimprovementinsomepatients.

Thepatient’sresponsetoropiniroleshouldbeevaluatedafter3monthstreatment(seesection5.1).Atthistimethe

doseprescribedandtheneedforcontinuedtreatmentshouldbeconsidered.Iftreatmentisinterruptedformorethana

fewdaysitshouldbere-initiatedbydosetitrationcarriedoutasabove.

Childrenandadolescents

ADARTRELisnotrecommendedforuseinchildrenbelow18yearsofageduetoalackofdataonsafetyandefficacy.

Elderly

Theclearanceofropiniroleisdecreasedbyapproximately15%inpatientsaged65yearsorabove.Althoughadose

adjustmentisnotrequired,ropiniroledoseshouldbeindividuallytitrated,withcarefulmonitoringoftolerability,tothe

optimalclinicalresponse.

Renalimpairment

Nodosageadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment(creatinineclearancebetween30

and50ml/min).

Astudyintotheuseofropiniroleinpatientswithendstagerenaldisease(patientsonhaemodialysis)hasshownthata

doseadjustmentinthesepatientsisrequiredasfollows:therecommendedinitialdoseofADARTRELis0.25mgonce

daily.Furtherdoseescalationsshouldbebasedontolerabilityandefficacy.Therecommendedmaximumdoseof

ADARTRELis3mg/dayinpatientsreceivingregularhaemodialysis.Supplementaldosesafterhaemodialysisarenot

required(seesection5.2).

Theuseofropiniroleinpatientswithsevererenalimpairment(creatinineclearancelessthan30ml/min)without

regularhaemodialysishasnotbeenstudied.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Severerenalimpairment(creatinineclearance<30ml/min)withoutregularhaemodialysis.

Severehepaticimpairment.

4.4Specialwarningsandprecautionsforuse

Ropiniroleshouldnotbeusedtotreatneurolepticakathisia,tasikinesia(neuroleptic-inducedcompulsivetendencyto

walk),orsecondaryRestlessLegsSyndrome(e.g.causedbyrenalfailure,irondeficiencyanaemiaorpregnancy).

ParadoxicalworseningofRestlessLegsSyndromesymptomsdescribedasaugmentation(eitherearlieronset,increased

intensity,orspreadofsymptomstopreviouslyunaffectedlimbs),orearlymorningrebound(reoccurrenceofsymptoms

intheearlymorninghours),havebeenobservedduringtreatmentwithropinirole.Ifthisoccurs,theadequacyof

ropiniroletreatmentshouldbereviewedanddosageadjustmentordiscontinuationoftreatmentmaybeconsidered(see

Week 2 3 4 5* 6* 7*

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InParkinson’sdisease,ropinirolehasbeenassociateduncommonlywithsomnolenceandepisodesofsuddensleep

onset(seesection4.8)however,inRestlessLegsSyndrome,thisphenomenonisveryrare.Nevertheless,patientsmust

beinformedofthisphenomenonandadvisedtoexercisecautionwhiledrivingoroperatingmachinesduringtreatment

withropinirole.Patientswhohaveexperiencedsomnolenceand/oranepisodeofsuddensleeponsetmustrefrainfrom

drivingoroperatingmachines.Areductionofdosageorterminationoftherapymaybeconsidered.

Patientswithmajorpsychoticdisordersshouldnotbetreatedwithdopamineagonistsunlessthepotentialbenefits

outweightherisks.

Impulsecontroldisordersincludingpathologicalgamblingandhypersexuality,andincreasedlibido,havebeenreported

inpatientstreatedwithdopamineagonists,includingropinirole,principallyforParkinson’sdisease.Thosedisorders

werereportedespeciallyathighdosesandweregenerallyreversibleuponreductionofthedoseortreatment

discontinuation.Riskfactorssuchasahistoryofcompulsivebehaviourswerepresentinsomecases(seesection4.8).

Ropiniroleshouldbeadministeredwithcautiontopatientswithmoderatehepaticimpairment.Undesirableeffects

shouldbecloselymonitored.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Duetotheriskofhypotension,patientswithseverecardiovasculardisease(inparticularcoronaryinsufficiency)should

betreatedwithcaution.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

RopiniroleisprincipallymetabolisedbythecytochromeP450isoenzymeCYP1A2.Apharmacokineticstudy(witha

ropiniroledoseof2mg,threetimesaday)revealedthatciprofloxacinincreasedtheC

andAUCofropiniroleby

60%and84%respectively,withapotentialriskofadverseevents.Hence,inpatientsalreadyreceivingropinirole,the

doseofropinirolemayneedtobeadjustedwhenmedicinalproductsknowntoinhibitCYP1A2,e.g.ciprofloxacin,

enoxacinorfluvoxamine,areintroducedorwithdrawn.

Apharmacokineticinteractionstudybetweenropinirole(atadoseof2mg,threetimesaday)andtheophylline,a

substrateofCYP1A2,revealednochangeinthepharmacokineticsofeitherropiniroleortheophylline.Therefore,itis

notexpectedthatropinirolewillcompetewiththemetabolismofothermedicinalproductswhicharemetabolisedby

CYP1A2.

Basedonin-vitrodata,ropinirolehaslittlepotentialtoinhibitcytochromeP450attherapeuticdoses.Hence,ropinirole

isunlikelytoaffectthepharmacokineticsofothermedicinalproducts,viaacytochromeP450mechanism.

SmokingisknowntoinduceCYP1A2metabolism,thereforeifpatientsstoporstartsmokingduringtreatmentwith

ropinirole,doseadjustmentmayberequired.

Increasedplasmaconcentrationsofropinirolehavebeenobservedinpatientstreatedwithhormonereplacement

therapy.Inpatientsalreadyreceivinghormonereplacementtherapy,ropiniroletreatmentmaybeinitiatedintheusual

manner.However,itmaybenecessarytoadjusttheropiniroledose,inaccordancewithclinicalresponse,ifhormone

replacementtherapyisstoppedorintroducedduringtreatmentwithropinirole.

Nopharmacokineticinteractionhasbeenseenbetweenropiniroleanddomperidone(amedicinalproductusedtotreat

nauseaandvomiting)thatwouldnecessitatedosageadjustmentofeithermedicinalproduct.Domperidoneantagonises

thedopaminergicactionsofropiniroleperipherallyanddoesnotcrosstheblood-brainbarrier.Henceitsvalueasan

anti-emeticinpatientstreatedwithcentrallyactingdopamineagonists.

Neurolepticsandothercentrallyactivedopamineantagonists,suchassulpirideormetoclopramide,maydiminishthe

effectivenessofropiniroleand,therefore,concomitantuseofthesemedicinalproductswithropiniroleshouldbe

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4.6Fertility,pregnancyandlactation

Therearenoadequatedatafromtheuseofropiniroleinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Asthepotentialriskforhumansisunknown,itis

recommendedthatropiniroleisnotusedduringpregnancyunlessthepotentialbenefittothepatientoutweighsthe

potentialrisktothefoetus.

Ropiniroleshouldnotbeusedinnursingmothersasitmayinhibitlactation.

4.7Effectsonabilitytodriveandusemachines

Patientsbeingtreatedwithropiniroleandpresentingwithsomnolenceand/orsuddensleepepisodesmustbeinformed

torefrainfromdrivingorengaginginactivitieswhereimpairedalertnessmayputthemselvesorothersatriskof

seriousinjuryordeath(e.g.operatingmachines)untilsucheffectshaveresolved(seesection4.4).

4.8Undesirableeffects

Adversedrugreactionsarelistedbelowbysystemorganclassandfrequency.Frequenciesfromclinicaltrialsare

determinedasexcessincidenceoverplaceboandareclassedasverycommon( ≥1/10);common(≥1/100to<1/10);

uncommon( ≥1/1,000to<1/100);rare(≥1/10,000to<1/1,000);veryrare(<1/10,000);notknown(cannotbeestimated

fromtheavailabledata).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

UseofropiniroleinRestlessLegsSyndrome

InRestlessLegsSyndromeclinicaltrialsthemostcommonadversedrugreactionwasnausea(approximately30%of

patients).Undesirableeffectswerenormallymildtomoderateandexperiencedatthestartoftherapyoronincreaseof

doseandfewpatientswithdrewfromtheclinicalstudiesduetoundesirableeffects.

Table2liststheadversedrugreactionsreportedforropiniroleinthe12-weekclinicaltrialsat1.0%abovetheplacebo

rateorthosereporteduncommonlybutknowntobeassociatedwithropinirole.

Table2 Adversedrugreactionsreportedin12-weekRestlessLegsSyndromeclinicaltrials(ropinirole

n=309,placebon=307)

Psychiatricdisorders

Common Nervousness

Uncommon Confusion

Nervoussystemdisorders

Common Syncope,somnolence,dizziness(including

vertigo)

Vasculardisorders

Uncommon Posturalhypotension,hypotension

Gastrointestinaldisorders

Verycommon Vomiting,nausea

Common Abdominalpain

Generaldisordersandadministrationsiteconditions

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Table3 OtherRestlessLegsSyndromeclinicaltrials

Managementofundesirableeffects

Dosereductionshouldbeconsideredifpatientsexperiencesignificantundesirableeffects.Iftheundesirableeffect

abates,gradualup-titrationcanbere-instituted.Anti-nauseamedicinalproductsthatarenotcentrallyactivedopamine

antagonists,suchasdomperidone,maybeused,ifrequired.

Otherexperiencewithropinirole

RopiniroleisalsoindicatedforthetreatmentofParkinson'sdisease.Theadversedrugreactionsreportedinpatients

withParkinson'sdiseaseonropinirolemonotherapyandadjuncttherapyatdosesupto24mg/dayatanexcess

incidenceoverplaceboaredescribedbelow.

Table4 AdversedrugreactionsreportedinParkinson'sdiseaseclinicaltrialsatdosesupto24mg/day

Postmarketingreports

Hypersensitivityreactions(includingurticaria,angioedema,rash,pruritus).

Psychoticreactions(otherthanhallucinations)includingdelirium,delusion,paranoiahavebeenreported.

Impulsecontroldisordersincludingpathologicalgamblingandhypersexuality,andincreasedlibido,havebeenreported

(seesection4.4).

InParkinson’sdisease,ropiniroleisassociatedwithsomnolenceandhasbeenassociateduncommonly( ≥1/1,000to

<1/100)withexcessivedaytimesomnolenceandsuddensleeponsetepisodes,however,inRestlessLegsSyndrome,

thisphenomenonisveryrare(<1/10,000).

Followingropiniroletherapy,posturalhypotensionorhypotensionhasbeenreporteduncommonly( ≥1/1,000to

<1/100),rarelysevere.

Psychiatricdisorders

Uncommon Hallucinations

Nervoussystemdisorders

Common Augmentation,Earlymorningrebound(see

section4.4)

Psychiatricdisorders

Common Hallucinations,confusion

Uncommon Increasedlibido

Nervoussystemdisorders

Verycommon Syncope,dyskinesia,somnolence

Gastrointestinaldisorders

Verycommon Nausea

Common Vomiting,abdominalpain,heartburn

Generaldisordersandadministrationsiteconditions

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4.9Overdose

Thesymptomsofropiniroleoverdosearerelatedtoitsdopaminergicactivity.Thesesymptomsmaybealleviatedby

appropriatetreatmentwithdopamineantagonistssuchasneurolepticsormetoclopramide.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Dopamineagonist,ATCcode:N04BC04.

Mechanismofaction

RopiniroleisanonergolineD2/D3dopamineagonistwhichstimulatesstriataldopaminereceptors.

Clinicalefficacy

ADARTRELshouldonlybeprescribedtopatientswithmoderatetosevereidiopathicRestlessLegsSyndrome.

ModeratetosevereidiopathicRestlessLegsSyndromeistypicallyrepresentedbypatientswhosufferwithinsomniaor

severediscomfortinthelimbs.

Inthefour12-weekefficacystudies,patientswithRestlessLegsSyndromewererandomisedtoropiniroleorplacebo,

andtheeffectsontheIRLSscalescoresatweek12werecomparedtobaseline.Themeandoseofropiniroleforthe

moderatetoseverepatientswas2.0mg/day.InacombinedanalysisofmoderatetosevereRestlessLegsSyndrome

patientsfromthefour12-weekstudies,theadjustedtreatmentdifferenceforthechangefrombaselineinIRLSscale

totalscoreatweek12LastObservationCarriedForward(LOCF)IntentionToTreatpopulationwas-4.0points(95%

CI-5.6,-2.4,p<0.0001;baselineandweek12LOCFmeanIRLSpoints:ropinirole28.4and13.5;placebo28.2and

17.4).

A12-weekplacebo-controlledpolysomnographystudyinRestlessLegsSyndromepatientsexaminedtheeffectof

treatmentwithropiniroleonperiodiclegmovementsofsleep.Astatisticallysignificantdifferenceintheperiodicleg

movementsofsleepwasseenbetweenropiniroleandplacebofrombaselinetoweek12.

AlthoughsufficientdataarenotavailabletoadequatelydemonstratethelongtermefficacyofropiniroleinRestless

LegsSyndrome(seesection4.2),ina36-weekstudy,patientswhocontinuedonropiniroledemonstratedasignificantly

lowerrelapseratecomparedwithpatientsrandomisedtoplacebo(33%versus58%,p=0.0156).

AcombinedanalysisofdatafrommoderatetosevereRestlessLegsSyndromepatients,inthefour12-week

placebo-controlledstudies,indicatedthatropinirole-treatedpatientsreportedsignificantimprovementsoverplaceboon

theparametersoftheMedicalOutcomeStudySleepScale(scoreson0-100rangeexceptsleepquantity).Theadjusted

treatmentdifferencesbetweenropiniroleandplacebowere:sleepdisturbance(-15.2,95%CI-19.37,-10.94;

p<0.0001),sleepquantity(0.7hours,95%CI0.49,0.94);p<0.0001),sleepadequacy(18.6,95%CI13.77,23.45;

p<0.0001)anddaytimesomnolence(-7.5,95%CI-10.86,-4.23;p<0.0001).

Areboundphenomenonfollowingdiscontinuationofropiniroletreatment(endoftreatmentrebound)cannotbe

excluded.Inclinicaltrials,althoughtheaverageIRLStotalscores7-10daysafterwithdrawaloftherapywerehigher

inropinirole-treatedpatientsthaninplacebo-treatedpatients,theseverityofsymptomsfollowingwithdrawaloftherapy

generallydidnotexceedthebaselineassessmentinropinirole-treatedpatients.

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Studyoftheeffectofropiniroleoncardiacrepolarisation

AthoroughQTstudyconductedinmaleandfemalehealthyvolunteerswhoreceiveddosesof0.5,1,2and4mgof

ropinirolefilm-coated(immediaterelease)tabletsoncedailyshowedamaximumincreaseoftheQTintervalduration

atthe1mgdoseof3.46milliseconds(pointestimate)ascomparedtoplacebo.Theupperboundoftheonesided95%

confidenceintervalforthelargestmeaneffectwaslessthan7.5milliseconds.Theeffectofropiniroleathigherdoses

hasnotbeensystematicallyevaluated.

TheavailableclinicaldatafromathoroughQTstudydonotindicateariskofQTprolongationatdosesofropiniroleup

to4mg/day.

5.2Pharmacokineticproperties

Absorption

Thebioavailabilityofropiniroleisabout50%(36%to57%),withC

reachedonaverage1.5hoursafterthedose.A

highfatmealdecreasestherateofabsorptionofropinirole,asshownbyadelayinmedianT

by2.6hoursandan

average25%decreaseinC

Distribution

Plasmaproteinbindingofropiniroleislow(10–40%).Consistentwithitshighlipophilicity,ropiniroleexhibitsalarge

volumeofdistribution(approx.7l/kg).

Metabolism

RopiniroleisprimarilyclearedbythecytochromeP450enzyme,CYP1A2,anditsmetabolitesaremainlyexcretedin

theurine.Themajormetaboliteisatleast100timeslesspotentthanropiniroleinanimalmodelsofdopaminergic

function.

Elimination

Ropiniroleisclearedfromthesystemiccirculationwithanaverageeliminationhalf-lifeofapproximately6hours.No

changeintheoralclearanceofropiniroleisobservedfollowingsingleandrepeatedoraladministration.Wideinter-

individualvariabilityinthepharmacokineticparametershasbeenobserved.

Linearity

Thepharmacokineticsofropinirolearelinearoverall(C

andAUC)inthetherapeuticrangebetween0.25mgand

4mg,afterasingledoseandafterrepeateddosing.

Population-relatedcharacteristics

Oralclearanceofropiniroleisreducedbyapproximately15%inelderlypatients(65yearsorabove)comparedto

youngerpatients.Dosingadjustmentisnotnecessaryintheelderly.

RenalImpairment

Inpatientswithmildtomoderaterenalimpairment(creatinineclearancebetween30and50ml/min),nochangeinthe

pharmacokineticsofropiniroleisobserved.

Inpatientswithendstagerenaldiseasereceivingregularhaemodialysis,oralclearanceofropiniroleisreducedby

approximately30%.OralclearanceofthemetabolitesSKF-104557andSKF-89124werealsoreducedby

approximately80%and60%,respectively.Therefore,therecommendedmaximumdoseislimitedto3mg/dayinthese

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Paediatricpopulation

Limitedpharmacokineticdataobtainedinadolescents(12-17years,n=9)showedthatthesystemicexposurefollowing

singledoesesof0.125mgand0.25mgwassimilartothatobservedinadults(seealsosection4.2:subparagraphy

"Childrenandadolescents").

5.3Preclinicalsafetydata

Toxicology

Thetoxicologyprofileisprincipallydeterminedbythepharmacologicalactivityofropinirole:behaviouralchanges,

hypoprolactinaemia,decreaseinbloodpressureandheartrate,ptosisandsalivation.Inthealbinoratonly,retinal

degenerationwasobservedinalongtermstudyatthehighestdose(50mg/kg/day),andwasprobablyassociatedwith

anincreasedexposuretolight.

Genotoxicity

Genotoxicitywasnotobservedintheusualbatteryofinvitroandinvivotests.

Carcinogenicity

Fromtwo-yearstudiesconductedinthemouseandratatdosagesupto50mg/kg/daytherewasnoevidenceofany

carcinogeniceffectinthemouse.Intherat,theonlyropinirole-relatedlesionswereLeydigcellhyperplasiaand

testicularadenomaresultingfromthehypoprolactinaemiceffectofropinirole.Theselesionsareconsideredtobea

speciesspecificphenomenonanddonotconstituteahazardwithregardtotheclinicaluseofropinirole.

ReproductiveToxicity

Administrationofropiniroletopregnantratsatmaternallytoxicdosesresultedindecreasedfoetalbodyweightat

60mg/kg/day(approximately15timestheAUCatthemaximumdoseinhumans),increasedfoetaldeathat

90mg/kg/day(approximately25timestheAUCatthemaximumdoseinhumans)anddigitmalformationsat

150mg/kg/day(approximately40timestheAUCatthemaximumdoseinhumans).Therewerenoteratogeniceffects

intheratat120mg/kg/day(approximately30timestheAUCatthemaximumdoseinhumans)andnoindicationofan

effectondevelopmentintherabbit.

SafetyPharmacology

InvitrostudieshaveshownthatropiniroleinhibitshERG-mediatedcurrents.TheIC

isatleast30-foldhigherthan

theexpectedmaximumplasmaconcentrationinpatientstreatedatthehighestrecommendeddose(4mg/day),see

section5.1.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcores:

Lactosemonohydrate

Microcrystallinecellulose

Croscarmellosesodium

Magnesiumstearate.

Filmcoating:

Hypromellose

Macrogol400

Titaniumdioxide(E171)

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

PVC/PCTFE/AluminiumorPVC/PCTFE/PVC/Aluminiumblister.

Packsof2or12tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

GlaxoSmithKline(Ireland)Limited

StonemasonsWay

Rathfarnham

Dublin16

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1077/106/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16June2006

Dateoflastrenewal:30June2009

10DATEOFREVISIONOFTHETEXT

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