ARTHROTEC

Main information

  • Trade name:
  • ARTHROTEC Modified-release Tablets 50/0.2 Milligram
  • Dosage:
  • 50/0.2 Milligram
  • Pharmaceutical form:
  • Modified-release Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARTHROTEC Modified-release Tablets 50/0.2 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/040/001
  • Authorization date:
  • 12-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arthrotec50mgModified-releaseTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletconsistsofagastro-resistantcorecontaining50mgdiclofenacsodiumsurroundedbyanoutermantle

containing200microgrammisoprostol.

Excipient:containslactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Modified-releaseTablet

ProductimportedfromtheUK:

White,round,biconvextabletsmarked ononesideand'Searle1411'ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Arthrotec50isindicatedforpatientswhorequirethenon-steroidalanti-inflammatorydrugdiclofenactogetherwith

misoprostol.

ThediclofenaccomponentofArthrotec50isindicatedforthesymptomatictreatmentofosteoarthritisandrheumatoid

arthritis.ThemisoprostolcomponentofArthrotec50isindicatedforpatientswithaspecialneedfortheprophylaxisof

NSAID-inducedgastricandduodenalulceration.

4.2Posologyandmethodofadministration

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.4).

Adults

Onetablettobetakenwithfood,twoorthreetimesdaily.Tabletsshouldbeswallowedwhole,notchewed.

Elderly/Renal,CardiacandHepaticImpairment

Noadjustmentofdosageisnecessaryintheelderlyorinpatientswithhepaticimpairmentormildtomoderaterenal

impairmentaspharmacokineticsarenotalteredtoanyclinicallyrelevantextent.Nevertheless,elderlypatientsand

patientswithrenal,cardiacorhepaticimpairmentshouldbecloselymonitored(seesection4.4andsection4.8).

Children(under18years)

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4.3Contraindications

Arthrotec50iscontraindicatedin:

Patientswithactivepepticulcer/haemorrhageorperforationorwhohaveactiveGIbleedingorotheractive

bleedingse.g.cerebrovascularbleedings

Pregnantwomenandinwomenplanningapregnancy.

Patientswithaknownhypersensitivitytodiclofenac,aspirin,otherNSAIDs,misoprostol,otherprostaglandins,

oranyotheringredientoftheproduct.

Patientsinwhom,attacksofasthma,urticariaoracuterhinitisareprecipitatedbyaspirinorothernon-steroidal

anti-inflammatoryagents.

Treatmentofperi-operativepaininthesettingofcoronaryarterybypassgraft(CABG)surgery.

Patientswithsevererenalandhepaticfailure

Patientswithsevereheartfailure

4.4Specialwarningsandprecautionsforuse

Warnings

Theuseofdiclofenac/misoprostolwithconcomitantNSAIDsincludingCOX-2inhibitorsshouldbeavoided.

Useinpre-menopausalwomen(seealsosection4.3)

Arthrotec50shouldnotbeusedinpre-menopausalwomenunlesstheyuseeffectivecontraceptionandhavebeen

advisedoftherisksoftakingtheproductifpregnant(seesection4.6).Thelabelwillstate:‘Notforuseinpre-

menopausalwomenunlessusingeffectivecontraception’.

Precautions

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.2,andGIandcardiovascularrisksbelow).

Renal/Cardiac/Hepatic

Inpatientswithrenal,cardiacorhepaticimpairmentandintheelderly,cautionisrequiredsincetheuseofNSAIDs

mayresultindeteriorationofrenalfunction.InthefollowingconditionsArthrotec50shouldbeusedonlyin

exceptionalcircumstancesandwithcloseclinicalmonitoring:advancedcardiacfailure,advancedkidneyfailure,

advancedliverdisease,severedehydration.

Diclofenacmetabolitesareeliminatedprimarilybythekidneys(seesection5.2).Theextenttowhichthemetabolites

mayaccumulateinpatientswithrenalfailurehasnotbeenstudied.AswithotherNSAIDs,metabolitesofwhichare

excretedbythekidney,patientswithsignificantlyimpairedrenalfunctionshouldbemorecloselymonitored

Inrarecases,NSAIDs,includingdiclofenac/misoprostol,maycauseinterstitialnephritis,glomerulitis,papillary

necrosisandthenephroticsyndrome.NSAIDsinhibitthesynthesisofrenalprostaglandinwhichplaysasupportiverole

inthemaintenanceofrenalperfusioninpatientswhoserenalbloodflowandbloodvolumearedecreased.Inthese

patients,administrationofanNSAIDmayprecipitateovertrenaldecompensation,whichistypicallyfollowedby

recoverytopretreatmentstateupondiscontinuationofNSAIDtherapy.Patientsatgreatestriskofsuchareactionare

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SuchpatientsshouldbecarefullymonitoredwhilereceivingNSAIDtherapy.

Appropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildtomoderate

congestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

AswithallNSAIDS,diclofenac/misoprostolcanleadtotheonsetofnewhypertensionorworseningofpre-existing

hypertension,eitherofwhichmaycontributetotheincreasedincidenceofcardiovascularevents.NSAIDs,including

diclofenac/misoprostol,shouldbeusedwithcautioninpatientswithhypertension.Bloodpressureshouldbemonitored

closelyduringtheinitiationoftherapywithdiclofenac/misoprostolandthroughoutthecourseoftherapy.

Patientswithuncontrolledhypertension,congestiveheartfailure,establishedischaemicheartdisease,peripheral

arterialdisease,and/orcerebrovasculardiseaseshouldonlybetreatedwithdiclofenacaftercarefulconsideration.

Similarconsiderationshouldbemadebeforeinitiatinglonger-termtreatmentofpatientswithriskfactorsfor

cardiovascularevents(e.g.hypertension,hyperlipidaemia,diabetesmellitus,smoking).

Clinicaltrialandepidemiologicaldatasuggestthatuseofdiclofenac,particularlyathighdose(150mgdaily)andin

longtermtreatmentmaybeassociatedwithasmallincreasedriskofseriousarterialthromboticevents(forexample

myocardialinfarctionorstroke).

Physiciansandpatientsshouldremainalertforthedevelopmentofsuchevents,evenintheabsenceofprevious

cardiovascularsymptoms.Patientsshouldbeinformedaboutthesignsand/orsymptomsofseriouscardiovascular

toxicityandthestepstotakeiftheyoccur(seesection4.3).

Bloodsystem/Gastrointestinal

NSAIDs,includingdiclofenac/misoprostol,cancauseseriousgastrointestinal(GI)adverseeventsincluding

inflammation,bleeding,ulceration,andperforationofthestomach,smallintestine,orlargeintestine,whichcanbe

fatal.WhenGIbleedingorulcerationoccursinpatientsreceivingdiclofenac/misoprostol,thetreatmentshouldbe

withdrawn.Theseeventscanoccuratanytimeduringtreatment,withorwithoutwarningsymptomsorinpatientswith

aprevioushistoryofseriousGIevents.

PatientsmostatriskofdevelopingthesetypesofGIcomplicationswithNSAIDsarethosetreatedathigherdoses,the

elderly,patientswithcardiovasculardisease,patientsusingconcomitantaspirin,orpatientswithapriorhistoryof,or

active,gastrointestinaldisease,suchasulceration,GIbleedingorinflammatoryconditions.Therefore,

diclofenac/misoprostolshouldbeusedwithcautioninthesepatientsandcommenceontreatmentatthelowestdose

available(seesection4.3).

PatientswithahistoryofGItoxicity,particularlywhenelderly,shouldreportanyunusualabdominalsymptoms

(especiallyGIbleeding)particularlyintheinitialstagesoftreatment.Cautionshouldbeadvisedinpatientsreceiving

concomitantmedicineswhichcouldincreasetheriskofulcerationorbleeding,suchasoralcorticosteroids,

anticoagulantssuchaswarfarin,selectiveserotonin-reuptakeinhibitorsoranti-plateletagentssuchasaspirin(see

section4.5).

Arthrotec50incommonwithotherNSAIDs,maydecreaseplateletaggregationandprolongbleedingtime.Extra

supervisionisrecommendedinhaematopoieticdisordersorinconditionswithdefectivecoagulationorinpatientswith

ahistoryofcerebrovascularbleeding.

CautionisrequiredinpatientssufferingfromulcerativecolitisorCrohn'sDiseaseastheseconditionsmaybe

exacerbated(seesection4.8).

Careshouldbetakeninelderlypatientsandinpatientstreatedwithcorticosteroids,otherNSAIDs,oranti-coagulants

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SkinReactions

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedveryrarelyinassociationwiththeuseofNSAIDs,including

diclofenac/misoprostol(seesection4.8).Patientsappeartobeathighestriskfortheseeventsearlyinthecourseof

therapy,theonsetoftheeventoccurringinthemajorityofcaseswithinthefirstmonthoftreatment.

Diclofenac/misoprostolshouldbediscontinuedatthefirstappearanceofskinrash,mucosallesions,oranyothersign

ofhypersensitivity.

Hypersensitivity

NSAIDsmayprecipitatebronchospasminpatientssufferingfrom,orwithahistoryofbronchialasthmaorallergic

disease.

Long-termtreatment

Allpatientswhoarereceivinglong-termtreatmentwithNSAIDsshouldbemonitoredasaprecautionarymeasure(e.g.

renal,hepaticfunctionandbloodcounts).Duringlong-term,highdosetreatmentwithanalgesic/anti-inflammatory

drugs,headachescanoccurwhichmustnotbetreatedwithhigherdosesofthemedicinalproduct.

Arthrotecmaymaskfeverandthusanunderlyinginfection.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

NSAIDsmayattenuatethenatriureticefficacyofdiureticsduetoinhibitionofintrarenalsynthesisofprostaglandins.

Concomitanttreatmentwithpotassium-sparingdiureticsmaybeassociatedwithincreasedserumpotassiumlevels;

henceserumpotassiumshouldbemonitored.

Becauseoftheireffectonrenalprostaglandins,cyclo-oxygenaseinhibitorssuchasdiclofenaccanincreasethe

nephrotoxicityofciclosporin.ThereisapossibleincreasedriskofnephrotoxicitywhenNSAIDsaregivenwith

tacrolimus.

Steadystateplasmalithiumanddigoxinlevelsmaybeincreasedandketoconazolelevelsmaybedecreased.

Pharmacodynamicstudieswithdiclofenachaveshownnopotentiationoforalhypoglycaemicandanticoagulantdrugs.

HoweverasinteractionshavebeenreportedwithotherNSAIDs,cautionandadequatemonitoringare,nevertheless

advised(seestatementonplateletaggregationinPrecautions).

BecauseofdecreasedplateletaggregationcautionisadvisedwhenusingArthrotec50withanti-coagulants.NSAIDs

mayenhancetheeffectsofanti-coagulants,suchaswarfarin,antiplateletagents,suchasaspirin,andserotoninre-

uptakeinhibitors(SSRIs)therebyincreasingtheriskofgastrointestinalbleeding(seesection4.4).

Casesofhypoandhyperglycaemiahavebeenreportedwhendiclofenacwasassociatedwithantidiabeticagents.

CautionisadvisedwhenmethotrexateisadministeredconcurrentlywithNSAIDsbecauseofpossibleenhancementof

itstoxicitybytheNSAIDasaresultofincreaseinmethotrexateplasmalevels.

ConcomitantusewithotherNSAIDsorwithcorticosteroidsmayincreasethefrequencyofgastrointestinalulceration

orbleedingandofsideeffectsgenerally.

Anti-hypertensivesincludingdiuretics,angiotensin-convertingenzyme(ACE)inhibitorsandangiotensinIIantagonists

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Inpatientswithimpairedrenalfunction(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenalfunction),

theco-administrationofanACEinhibitororanAIIAwithacyclo-oxygenaseinhibitorcanincreasethedeteriorationof

therenalfunction,includingthepossibilityofacuterenalfailure,whichisusuallyreversible.Theoccurrenceofthese

interactionsshouldbeconsideredinpatientstakingdiclofenac/misoprostolwithanACEinhibitororanAIIA.

Antacidsmaydelaytheabsorptionofdiclofenac.Magnesium-containingantacidshavebeenshowntoexacerbate

misoprostol-associateddiarrhoea.

AnimaldataindicatethatNSAIDscanincreasetheriskofconvulsionsassociatedwithquinoloneantibiotics.Patients

takingNSAIDsandquinolonesmayhaveanincreasedriskofdevelopingconvulsions.

NSAIDsshouldnotbeusedfor8-12daysaftermifepristoneadministrationasNSAIDscanreducetheeffectof

mifepristone.

4.6Fertility,pregnancyandlactation

Pregnancy

Arthrotec50iscontraindicatedinpregnantwomenandinwomenplanningapregnancybecausemisoprostolinduces

uterinecontractionsandisassociatedwithabortion,prematurebirth,andfetaldeath.Useofmisoprostolhasbeen

associatedwithbirthdefects.Alsodiclofenacmaycauseprematureclosureoftheductusarteriosus.

Womenofchildbearingpotentialshouldnotbestartedondiclofenac/misoprostoluntilpregnancyisexcluded,and

shouldbefullycounseledontheimportanceofadequatecontraceptionwhileundergoingtreatment.Ifpregnancyis

suspected,useoftheproductshouldbediscontinued.

Lactation

Misoprostolisrapidlymetabolisedinthemothertomisoprostolacid,whichisbiologicallyactiveandisexcretedin

breastmilk.Diclofenacisexcretedinbreastmilkinverysmallquantities.Ingeneral,thepotentialeffectsontheinfant

fromanyexposuretomisoprostolanditsmetabolitesviabreastfeedingareunknown.However,diarrhoeaisa

recognisedsideeffectofmisoprostolandcouldoccurininfantsofnursingmothers.Arthrotec50shouldthereforenot

beadministeredtonursingmothers.

4.7Effectsonabilitytodriveandusemachines

PatientswhoexperiencedizzinessorothercentralnervoussystemdisturbanceswhiletakingNSAIDsshouldrefrain

fromdrivingoroperatingmachinery.

4.8Undesirableeffects

InthetablebelowtheincidenceofadversedrugreactionsreportedincontrolledclinicalstudieswhereArthrotecwas

administeredtomorethan2000patientsarelisted.Additionally,adversedrugreactionsreportedduringpost-

marketingsurviellancearewhosefrequencycannotbeestimatedfromtheavailabledata,suchasspontaneousreports,

havebeenlistedatfrequency‘unknown’.Themostcommonlyobservedadverseeventsaregastrointestinalinnature.

OrganSystem Very

Common

(1/10) Common

(1/100

and<1/10) Uncommon

(1/1,000

and<1/100) Rare

(1/10,000,

<1/1,000) Frequency:

Unknown

(Post-marketing

experience)

Infectionsand

infestations Aseptic

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Bloodand

lymphatic

system

disorders Thrombo-

cytopenia Aplastic

anaemia,

agranulocytosis,

haemolytic

anaemia,

leucopenia

Immunesystem

disorders Anaphylactic

reaction Hypersensitivity

Metabolismand

nutrition

disorders Anorexia

Psychiatric

disorders Insomnia Psychotic

reaction,

disorientation,

depression,

anxiety,

nightmares,

moodchange,

irritability

Nervoussystem

disorders Headache,

dizziness Convulsions,

memory

disturbance,

drowsiness,

tremor,taste

disturbance,

paraesthesia

Eyesdisorders Visual

disturbances,

blurredvision

Earand

labyrinth

disorders Tinnitus

Cardiac

disorders Cardiacfailure,

palpitations

Vascular

disorders Shock,

hypertension,

hypotension,

vasculitis

Respiratory,

thoracicand

mediastinal

disorders Asthma,

pneumonitis,

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Gastrointestinal

disorders Abdominal

pain,

diarrhoea 2

nausea,

dyspepsia Gastritis,

vomiting,

flatulence,

eructation,

constipation,

pepticulcer Stomatitis GIperforation 3

gastrointestinal

bleeding 3

melaena,

haematemesis,

colitis,Crohn's

disease,

oesophageal

disorder,mouth

ulceration,

glossitis,tongue

odema,dry

mouth

Hepato-biliary

disorders Alanine

amino-

transferase

increased Hepatitis,

jaundice Hepatitis

fulminant,

aspartate

aminotransferase

increased,blood

bilirubin

increased

Skinand

subcutaneous

tissuedisorders Erythema

multiforme,

rash,

pruritus Purpura,

urticaria Angioedema Toxicepidermal

necrolysis 4

Stevens-Johnson

syndrome 4

dermatitis

exfoliative 4

dermatitis

bullous,Henoch

Schonlein

purpura,

mucocutaneous

rash,rash

vesicular,

photosensitivity

reaction,

alopecia,

urticaria

Renaland

urinary

disorders Renalfailure,

acuterenal

failure,renal

papillary

necrosis,

nephritis

interstitial,

nephrotic

syndrome,

proteinuria,

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Symptomsofasepticmeningitis(stiffneck,headache,nausea,vomiting,feverorimpairedconsciousness)have

beenreportedduringtreatmentwithNSAIDs.Patientssufferingfromautoimmunedisease(e.g.lupus

erythematosus,mixedconnectivetissuedisorders)seemtobemoresusceptible.

DiarrhoeaisusuallymildtomoderateandtransientandcanbeminimisedbytakingArthrotec50withfoodandby

avoidingtheuseofpredominantlymagnesium-containingantacids.

GIperforationorbleedingcansometimesbefatal,particularlyintheelderly(seesection4.4).

Seriousskinreactions,someofthemfatal,havebeenreportedveryrarely(seesection4.4).

Pregnancy,

puerperiumand

perinatal

conditions Intra-uterine

death,uterine

rupture,

incomplete

abortion,

prematurebaby,

anaphylactoid

syndromeof

pregnancy,

retainedplacenta

ormembranes,

uterine

contractions

abnormal

Reproductive

systemand

breastdisorders Menorrhagia,

metrorrhagia,

vaginal

haemorrhage,

postmenopausal

haemorrhage Uterine

haemorrhage

Congenital,

familialand

genetic

disorders Birthdefects

General

disordersand

administration

siteconditions Oedema 5

,chest

pain,face

oedema,fatigue,

pyrexia,chills,

inflammation

Investigations Blood

alkaline

phosphatase

increased Decreased

haemoglobin

Injury,

poisoningand

procedural

complications Uterine

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Giventhelackofpreciseand/orreliabledenominatorandnumeratorfigures,thespontaneousadverseeventreporting

systemthroughwhichpostmarketingsafetydataarecollecteddoesnotallowforamedicallymeaningfulfrequencyof

occurrenceofanyundesirableeffects.

Withregardtotherelativefrequencyofreportingofadversereactionsduringpostmarketingsurveillance,the

undesirableeffectsatthegastrointestinallevelwerethosereceivedmostfrequentlybytheMAH(approximately45%

ofallcasereportsinthecompanysafetydatabase)followedbycutaneous/hypersensitivity-typereactions,whichisin

agreementwiththeknownsideeffectsprofileoftheNSAIDsdrugclass.

Clinicaltrialandepidemiologicaldatasuggestthatuseofdiclofenac,particularlyathighdoses(150mgdaily)andin

longtermtreatmentmaybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexample

myocardialinfarctionorstroke)(seesection4.4).

4.9Overdose

ThetoxicdoseofArthrotec50hasnotbeendeterminedandthereisnoexperienceofoverdosage.Intensificationofthe

pharmacologicaleffectsmayoccurwithoverdosage.ManagementofacutepoisoningwithNSAIDsessentially

consistsofsupportiveandsymptomaticmeasures.Itisreasonabletotakemeasurestoreduceabsorptionofany

recentlyconsumeddrugbyforcedemesis,gastriclavageoractivatedcharcoal.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Arthrotec50isanon-steroidal,anti-inflammatorydrug,whichiseffectiveintreatingthesignsandsymptomsof

arthriticconditions.

Thisactivityisduetothepresenceofdiclofenac,whichhasbeenshowntohaveanti-inflammatoryandanalgesic

properties.

Arthrotec50alsocontainsthegastroduodenalmucosalprotectivecomponentmisoprostol,whichisasynthetic

prostaglandinE1analoguethatenhancesseveralofthefactorsthatmaintaingastroduodenalmucosalintegrity.

5.2Pharmacokineticproperties

ThepharmacokineticprofilesofdiclofenacandmisoprostoladministeredasArthrotec50aresimilartotheprofiles

whenthetwodrugsareadministeredasseparatetabletsandtherearenopharmacokineticinteractionsbetweenthetwo

components.

5.3Preclinicalsafetydata

Inco-administrationstudiesinanimals,theadditionofmisoprostoldidnotenhancethetoxiceffectsofdiclofenac.The

combinationwasalsoshownnottobeteratogenicormutagenic.Theindividualcomponentsshownoevidenceof

carcinogenicpotential.

Misoprostolinmultiplesoftherecommendedtherapeuticdoseinanimalshasproducedgastricmucosalhyperplasia.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Microcrystallinecellulose

Maizestarch

Povidone

Magnesiumstearate

Celluloseacetatephthalate

Diethylphthalate

Hypromellose

Crospovidone

Hydrogenatedcastoroil

Colloidalsilicondioxide

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 ˚C.Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Coldformedaluminiumblisters,10tablets/blister,60tabletsinanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited,

SterlingHouse,

501MiddletonRoad,

Chadderton,

Oldham,

Lancashire,

OL99LY,

8PARALLELPRODUCTAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12thAugust2011.

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