DIFENE AMPOULES 75 MG/ 3 ML

Main information

  • Trade name:
  • DIFENE AMPOULES 75 MG/ 3 ML
  • Dosage:
  • 25
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIFENE AMPOULES 75 MG/3 ML
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1241/012/006
  • Authorization date:
  • 13-06-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1241/012/006

CaseNo:2071627

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

AstellasPharmaCo.Ltd

25TheCourtyard,KilcarberyBusinessPark,Clondalkin,Dublin22,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

DifeneAmpoules75mg/3ml

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom16/02/2010until27/08/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Difeneampoules75mg/3ml

2QUALITATIVEANDQUANTITATIVECOMPOSITION

ContainsDiclofenacsodium75mg/3ml.

Eachampoulecontains25mg/mlofdiclofenacsodium.

Forlistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforintramuscularinjectionorconcentrateforsolutionforinfusion.

Aclearcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Intramuscularuse:

Difenecanbeusedinthesymptomaticmanagementofacuteexacerbationofrheumatoidarthritisandosteoarthritis,in

acutebackpain,acutegout,postoperativepain,reliefofpaininacutetraumaticmusculo-skeletaldisordersand

fracturesandrenalcolic.

Intravenousinfusion:

Forthetreatmentorpreventionofpost-operativepaininthehospitalsetting.

4.2Posologyandmethodofadministration

Forintravenousinfusionorintramuscularuseonly.

Adults:

Intravenoususe:

Oneampouleshouldbedilutedinaminimumof300mlofnormalsalineandadministeredintravenouslyovera

minimumof30minutes.Aseconddosemaybeadministered8hoursafterthefirstinfusion.

Amaximumoftwodosesmaybegivenintravenously.

Intramuscularuse:

Oneampouleonce(orinseverecasestwice)dailyintramuscularlybydeepintraglutealinjectionintotheupperouter

quadrant.Iftwoinjectionsdailyarerequireditisadvisedthatthealternativebuttockbeusedforthesecondinjection.

Renalcolic:One75mgampouleintramuscularly.Afurtherampoulemaybeadministeredafter30minutesif

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AswithoralDifenethetotaldailydoseshouldnotexceed150mg.Difeneampoulesshouldnotbegivenformorethan

2days;ifnecessary,treatmentcanbecontinuedwithcapsulesorsuppositories.

Elderly:NSAIDsshouldbeusedwithparticularcautioninelderlypatientswhoaremorepronetoadverseevents.The

lowestdosecompatiblewithadequatesafeclinicalcontrolshouldbeemployed.Seealsosection4.4,Specialwarnings

andprecautionsforuse.

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.4,Specialwarningsandprecautionsforuse).

Treatmentshouldbereviewedatregularintervalsanddiscontinuedifnobenefitisseenorintoleranceoccurs.

Children:Notsuitableforchildren

4.3Contraindications

Historyofgastrointestinalbleedingorperforation,relatedtopreviousNSAIDstherapy.Active,orhistoryofrecurrent

pepticulcer/haemorrhage(twoormoredistinctepisodesofprovenulcerationorbleeding).

Patientswithahistoryofhypersensitivityreactions(e.g.bronchospasm,rhinitis,urticaria)inresponsetodiclofenac,

aspirin,nonsteroidalanti-inflammatorydrugsoranycomponentsofthepreparation.

Severeheartfailure

4.4Specialwarningsandprecautionsforuse

Warnings:

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.2,PosologyandmethodofadministrationandGIandcardiovascularrisksbelow).

TheuseofDifeneAmpouleswithconcomitantNSAIDsincludingcyclooxygenase-2selectiveinhibitorsshouldbe

avoided.

Elderly:TheelderlyhaveanincreasedfrequencyofadversereactionstoNSAIDsespeciallygastrointestinalbleeding

andperforationwhichmaybefatal(seesection4.2,Posologyandmethodofadministration).

Gastro-intestinal:

Gastrointestinalbleeding,ulcerationandperforation:GIbleeding,ulcerationorperforation,whichcanbefatal,has

beenreportedwithallNSAIDsatanytimeduringtreatment,withorwithoutwarningsymptomsoraprevioushistory

ofpreviousGIevents.

TheriskofGIbleeding,ulcerationorperforationishigherwithincreasingNSAIDdoses,inpatientswithahistoryof

ulcer,particularlyifcomplicatedwithhaemorrhageorperforation(seesection4.3,Contraindications),andinthe

elderly.Thesepatientsshouldcommencetreatmentonthelowestdoseavailable.Combinationtherapywithprotective

agents(e.g.misoprostolorprotonpumpinhibitors)shouldbeconsideredforthesepatients,andalsoforpatients

requiringconcomitantlowdoseaspirin,orotherdrugslikelytoincreasegastrointestinalrisk(seebelowandsection

4.5,Interactionwithothermedicinalproductsandotherformsofinteractions).

PatientswithahistoryofGItoxicityespeciallywhenelderly,shouldreportanyunusualabdominalsymptoms

(especiallyGIbleeding)particularlyintheinitialstagesoftreatment.

WhenGIbleedingorulcerationoccursinpatientsreceivingDifeneAmpoules,thetreatmentshouldbewithdrawn.

NSAIDsshouldbegivenwithcaretopatientswithahistoryofgastrointestinaldisease(ulcerativecolitis,Crohn’s

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Cardiovascularandcerebrovasculareffects

Cautionandappropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildto

moderatecongestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

Clinicaltrialandepidemiologicaldatasuggestthatuseofdiclofenac,particularlyathighdose(150mginitiatingdaily)

andinlongtermtreatmentmaybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexample

myocardialinfarctionorstroke).

Patientswithuncontrolledhypertension,congestiveheartfailure,establishedischaemicheartdisease,peripheral

arterialdisease,and/orcerebrovasculardiseaseshouldonlybetreatedwithdiclofenacaftercarefulconsideration.

Similarconsiderationshouldbemadebeforelonger-termtreatmentofpatientwithriskfactorsforcardiovascular

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

Hepatic:

Closemedicalsurveillanceisalsoimperativeinpatientssufferingfromsevereimpairmentofhepaticfunction.

Hypersensitivityreactions:

Aswithothernonsteroidalanti-inflammatorydrugs,allergicreactions,includinganaphylactic/anaphylactoidreactions,

canalsooccurwithoutearlierexposuretothedrug.

Seriousskinreaction,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedveryrarelyinassociationwiththeuseofNSAIDs(seesection4.8,

Undesirableeffects).Patientsappeartobeatthehighestriskofthesereactionsearlyinthecourseoftherapy,theonset

ofthereactionoccurringinthemajorityofcaseswithinthefirstmonthoftreatment.DifeneAmpoulesshouldbe

discontinuedatthefirstappearanceofskinrash,mucosallesions,oranyothersignofhypersensitivity.

TheuseofDifeneAmpoulesmayimpairthefemalefertilityandisnotrecommendedinwomenattemptingto

conceive.Inwomanwhohavedifficultiesconceivingorwhoareundergoinginvestigationofinfertility,withdrawalof

DifeneAmpoulesshouldbeconsidered.

LikeotherNSAIDs,Difenemaymaskthesignsandsymptomsofinfectionduetoitspharmacodynamicproperties.

Precautions:

Renal:

Patientswithrenal,cardiacorhepaticimpairmentandtheelderlyshouldbekeptundersurveillance,sincetheuseof

NSAIDSmayresultindeteriorationofrenalfunction.Thelowesteffectivedoseshouldbeusedandrenalfunction

monitoredpriortotheinitiationoftherapyandregularlythereafter.

Theimportanceofprostaglandinsinmaintainingrenalbloodflowshouldbetakenintoaccountinpatientswith

impairedcardiacorrenalfunction,thosebeingtreatedwithdiureticsorrecoveringfrommajorsurgery.Effectsonrenal

functionareusuallyreversibleonwithdrawalofDifene.

Hepatic:

Ifabnormalliverfunctiontestspersistorworsen,clinicalsignsorsymptomsconsistentwithliverdiseasedeveloporif

othermanifestationsoccur(eosinophilia,rash),Difeneshouldbediscontinued.Hepatitismayoccurwithoutprodromal

symptoms.UseofDifeneinpatientswithhepaticporphyriamaytriggeranattack.

Haematological:

AswithotherNSAIDs,Difenemayreversiblyinhibitplateletaggregation(seeanticoagulantsinsection4.5,

Interactionswithothermedicinalproductsandotherformsofinteraction).Patientswithdefectsofhaemostasis,

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Long-termtreatment:

Allpatientswhoarereceivingnon-steroidalanti-inflammatoryagentsshouldbemonitoredasaprecautionarymeasure

e.g.hepaticfunction(elevationofliverenzymesmayoccur)andbloodcounts.Thisisparticularlyimportantinthe

elderly.

Maycausetoxicreactionsandanaphylactoidreactionsininfantsandchildrenupto3yearsold.

Cautionshouldbeadvisedinpatientsreceivingconcomitantmedicationswhichcouldincreasetheriskofulcerationor

bleeding,suchasoralcorticosteroids,anticoagulantssuchaswarfarin,selectiveserotonin-reuptakeinhibitorsoranti-

plateletagentssuchasaspirin(seesection4.5,Interactionwithothermedicinalproductsandotherformsof

interactions).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Lithiumanddigoxin:

Difenemayincreaseplasmaconcentrationsoflithiumanddigoxin.

Anti-coagulants:

NSAIDSsmayenhancetheeffectsofanti-coagulants,suchaswarfarin(seesection4.4,Specialwarningsand

precautionsforuse).

ItisconsideredunsafetotakeNSAIDsincombinationwithwarfarinorheparinunlessunderdirectmedical

supervision.

Anti-plateletagentsandselectiveserotonin-reuptakeinhibitors(SSRIs):

Increasedriskofgastrointestinalbleeding(seesection4.4,Specialwarningsandprecautionsforuse).

Antidiabeticagents:

ClinicalstudieshaveshownthatDifenecanbegiventogetherwithoralantidiabeticagentswithoutinfluencingtheir

clinicaleffect.Howevertherehavebeenisolatedreportsofhypoglycaemicandhyperglycaemiceffectswhichhave

requiredadjustmenttothedosageofhypoglycaemicagents.

Ciclosporin:

CasesofnephrotoxicityhavebeenreportedinpatientsreceivingconcomitantciclosporinandNSAIDS,including

Difene.ThismightbemediatedthroughcombinedrenalantiprostaglandineffectsofboththeNSAIDandciclosporin.

Methotrexate:

CasesofserioustoxicityhavebeenreportedwhenmethotrexateandNSAIDSaregivenwithin24hoursofeachother.

Thisinteractionismediatedthroughaccumulationofmethotrexateresultingfromimpairmentofrenalexcretioninthe

presenceoftheNSAID.

Quinoloneantimicrobials:

ConvulsionsmayoccurduetoaninteractionbetweenquinolonesandNSAIDS.Thismayoccurinpatientswithor

withoutaprevioushistoryofepilepsyorconvulsions.Therefore,cautionshouldbeexercisedwhenconsideringtheuse

ofaquinoloneinpatientswhoarealreadyreceivinganNSAID.

OtherNSAIDSandsteroids:

Co-administrationofDifenewithothersystemicNSAIDSandsteroidsmayincreasethefrequencyofunwantedeffects.

Concomitanttherapywithaspirinlowerstheplasmalevelsofeach,althoughnoclinicalsignificanceisknown.

Corticosteroids:

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Diuretics:

VariousNSAIDSareliabletoinhibittheactivityofdiuretics.Concomitanttreatmentwithpotassium-sparingdiuretics

maybeassociatedwithincreasedserumpotassiumlevels,henceserumpotassiumshouldbemonitored.Diureticscan

increasetheriskofnephrotoxicityofNSAIDs

Cardiacglycosides:

NSAIDsmayexacerbatecardiacfailure,reduceGFRandincreaseplasmacardiacglycosidelevels.

Anti-hypertensives:

Reducedanti-hypertensiveeffect.

Aminoglycosides:

Reductioninrenalfunctioninsusceptibleindividuals,decreasedeliminationofaminoglycosideandincreasedplasma

concentrations.

Probenecid:

ReductioninmetabolismandeliminationofNSAIDandmetabolites.

NSAIDsmayreducetheeffectofdiureticsandotherantihypertensivedrugs.Insomepatientswithcompromisedrenal

function(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenalfunction)theco-administrationofan

ACEinhibitororAngiotensinIIantagonistandagentsthatinhibitcyclo-oxygenasemayresultinfurtherdeterioration

ofrenalfunction,includingpossibleacuterenalfailure,whichisusuallyreversible.Theseinteractionsshouldbe

consideredinpatientstakingDifeneconcomitantlywithACEinhibitorsorangiotensinIIantagonists.Therefore,the

combinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbeadequatelyhydratedand

considerationshouldbegiventomonitoringofrenalfunctionafterinitiationofconcomitanttherapy,andperiodically

thereafter.

4.6Pregnancyandlactation

Althoughanimalstudieshavenotdemonstratedteratogeniceffects,Difeneshouldnotbeusedinpregnancyorlactation

unlessconsideredessentialbythephysicianandifsothelowesteffectivedoseshouldbeused.Useofprostaglandin

synthetaseinhibitorsinthethirdtrimestermayresultinprematureclosureoftheductusarteriosus.Tracesofdrugare

detectableinbreastmilkbutarenotclinicallysignificant.

4.7Effectsonabilitytodriveandusemachines

Isolatedcasesofdisorientationandblurredvisionhavebeenreportedwithdiclofenacsodium.Ifaffectedrefrainfrom

drivingoroperatingmachinery.

4.8Undesirableeffects

Ifseriousside-effectsoccur,Difeneshouldbewithdrawn.

Gastrointestinaltract:

Occasional:epigastricpain,othergastrointestinaldisorders(egnausea,vomiting,diarrhoea,abdominalcramps/pain,

dyspepsia,flatulence,anorexia,gastritis).

Rare:gastro-intestinalbleeding,pepticulcer(withorwithoutbleedingorperforation),bloodydiarrhoea.

Isolatedcases:lowergutdisorders(egnon-specifichaemorrhagiccolitisandexacerbationsofulcerativecolitisor

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CentralNervousSystem:

Occasional:headache,dizzinessorvertigo.

Rare:drowsiness,tiredness.

Isolatedcases:disturbancesofsensation(paraesthesiae,memorydisturbance,disorientation,disturbanceofvision,

blurredvision,diplopia),impairedhearing,tinnitus,insomnia,irritability,convulsions,depression,anxiety,nightmares,

tremor,psychoticreactions.Tastealterationdisorders.

Skin:

Occasional:injectionsitedisorderse.g.localpainandinduration,rashesorskineruptions.

Rare:urticaria

Isolatedcases:injectionsiteabscessesandlocalnecrosishavebeenreportedwithintramuscularuse,bullouseruptions,

eczema,erythemamultiforme,Steven-Johnsonsyndrome,lyell’ssyndrome,(acutetoxicepidermolysis),erythroderma

(exfoliativedermatitis),lossofhair,photosensitivityreactions,purpuraincludingallergicpurpura.

Kidney:

Isolatedcases:acuterenalinsufficiency,urinaryabnormalities(eghaematuria,proteinuria),interstitialnephritis,

nephroticsyndrome,papillarynecrosis.

Liver:

Occasional:elevationofserumaminotransferaseenzymes(SGOT,SGPT).

Rare:liverfunctiondisordersincludinghepatitis(inisolatedcasesfulminant)withorwithoutjaundice.

Blood:

Isolatedcases:thrombocytopenia,leucopenia,agranulocytosis,haemolyticanaemia,aplasticanaemia.

Cardiovascularsystem:

Isolatedcases:Oedema,palpitations,chestpain,hypertension,congestiveheartfailure.

Clinicalandepidemiologicaldatasuggestthatuseofdiclofenac,particularilyathighdose(150mgdaily)andinlong

termtreatmentmaybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexamplemyocardial

infarctionorstroke).

Otherorgansystems:

Rare:oedema,hypersensitivityreactions(egbronchospasm,anaphylactic/anaphylactoidsystemicreactionsincluding

hypotension).

Isolatedcases:impotence(associationwithDiclofenacsodiumintakeisdoubtful),palpitation,chestpain,hypertension.

4.9Overdose

Managementofacutepoisoningwithdiclofenacandothernon-steroidalanti-inflammatorydrugsconsistsofsupportive

andsymptomaticmeasures.

Therapeuticmeasuresthatcanbetakeninclude;supportiveandsymptomatictreatmentforthecomplicationsof

overdosagesuchashypotension,renalfailure,convulsions,gastro-intestinalirritationandrespiratorydepression;

Forceddiuresisordialysisareprobablyofnohelpineliminatingdiclofenacandothernon-steroidalanti-inflammatory

medicinesduetotheirhighrateofproteinbinding.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Diclofenacsodiumisaphenylaceticacidderivativeandanon-steroidalanti-inflammatoryagentwithanalgesic,anti-

inflammatoryandanti-pyreticproperties.Diclofenacisaninhibitorofcyclo-oxygenaseandthereforereduces

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5.2Pharmacokineticproperties

Absorption:

Absorptioniscompletebutonsetisdelayeduntilpassagethroughthestomach,whichmaybeaffectedbyfoodwhich

delaysstomachemptying.Themeanpeakplasmadiclofenacconcentrationsreachedatabout2hours(50mgdose

produces1.48±0.65g/ml(1.5g/ml5mol/l)).

Bioavailability:

Abouthalfoftheadministereddiclofenacismetabolisedduringitsfirstpassagethroughtheliver("first-pass"effect),

theareaundertheconcentrationscurve(AUC)followingoraladministrationisabouthalfthatfollowinganequivalent

parenteraldose.

Distribution:

Theactivesubstanceis99.7%proteinbound,mainlytoalbumin(99.4%).

Diclofenacentersthesynovialfluid,wheremaximumconcentrationsaremeasured2-4hoursafterthepeakplasma

valueshavebeenattained.Theapparenthalf-lifeforeliminationfromthesynovialfluidis3-6hours.Twohoursafter

reachingthepeakplasmavalues,concentrationsoftheactivesubstancearealreadyhigherinthesynovialfluidthan

theyareintheplasma,andremainhigherforupto12hours.

Metabolism:

Biotransformationofdiclofenactakesplacepartlybyglucuronidationoftheintactmolecule,butmainlybysingleand

multiplehydroxylationandmethoxylation,resultinginseveralphenolicmetabolites,mostofwhichareconvertedto

glucuronideconjugates.Twophenolicmetabolitesarebiologicallyactive,buttoamuchlesserextentthandiclofenac.

Elimination:

Totalsystemicclearanceofdiclofenacinplasmais263+/-56mL/min(meanvalue+/-SD).Theterminalhalf-lifein

plasmais1-2hours.

Fourofthemetabolites,includingthetwoactiveones,alsohaveshortplasmahalf-livesof1-3hours.

About60%oftheadministereddoseisexcretedintheurineastheglucuronideconjugateoftheintactmoleculeandas

metabolites,mostofwhicharealsoconvertedtoglucuronideconjugates.Lessthan1%isexcretedasunchanged

substance.Therestofthedoseiseliminatedasmetabolitesthroughthebileinthefaeces.

Characteristicsinpatients

Elderly:Norelevantage-dependentdifferencesinthedrug'sabsorption,metabolism,orexcretionhavebeenobserved,

otherthanthefindingthatinfiveelderlypatients,a15minuteivinfusionresultedin50%higherplasmaconcentrations

thanexpectedwithyounghealthysubjects.

Patientswithrenalimpairment:Inpatientssufferingfromrenalimpairment,noaccumulationoftheunchangedactive

substancecanbeinferredfromthesingle-dosekineticswhenapplyingtheusualdosageschedule.Atacreatinine

clearanceof<10mL/min,thecalculatedsteady-stateplasmalevelsofthehydroxymetabolitesareabout4timeshigher

thaninnormalsubjects.However,themetabolitesareultimatelyclearedthroughthebile.

Patientswithhepaticdisease:Inpatientswithchronichepatitisornon-decompensatedcirrhosis,thekineticsand

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5.3Preclinicalsafetydata

Animalstudieshavebeencarriedoutinanumberofspeciestodeterminethetoxicityofdiclofenacsodium.Acute

toxicitystudieshavebeencarriedoutintheratandwhenadministeredorallyanLD50of53mg/kgproduced

behaviouraleffectsandrespiratorystimulation.Acuteoraltoxicitystudiesintherabbitshowednotoxiceffectatadose

of157mg/kg.

Toxicitybytheintravenousroutehasbeenmeasuredintherat,anadministereddoseof117mg/kghasbeenshownto

havenoadverseeffect.Intraperitonealstudieshaveshownannoadverseeffectlevelof25mg/kgintherat,and

subcutaneoustoxicityintheratshowsanotoxiceffectlevelof83mg/kg.

Reproductivetoxicityhasbeenstudiedinboththeratandtherabbit,adoseof1mg/kg/dayfor21daysinratshasbeen

showntoproducedevelopmentalabnormalitiesofthecardiovascularsystem.Intherabbitadoseof10mg/kghasbeen

showntoreducefertility.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzylalcohol

Propyleneglycol

Acetylcysteine

Mannitol

Sodiumhydroxide

6.2Incompatibilities

DifeneAmpoulesforintramuscularuseshouldnotbemixedwithotherinjectionsolutions.

6.3ShelfLife

Shelflifeofthemedicinalproductaspackagedforsale.

3years.

ShelflifeafterdilutionforIVinfusion

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessreconstitution/dilution(etc.)hastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Fivecolourless,Type1Ph.Eur.glassampoulesinanampouletray,oneortwotraysperbox.

Packsize:5or10ampoules.

Notallpacksizesmaybemarketed.

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suchmedicinalproductandotherhandlingoftheproduct

Standardprecautionsfordisposalofglassampoulesshouldbefollowed.

Forsingleuseonly.Discardanyunusedinjection.

7MARKETINGAUTHORISATIONHOLDER

AstellasPharmaCo.Ltd

25TheCourtyard

KilcarberyBusinessPark

Clondalkin

Dublin22

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1241/012/006

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 28August1990

Dateoflastrenewal: 28August2005

10DATEOFREVISIONOFTHETEXT

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