COSMEGEN LYOVAC POWDER FOR SOLUTION FOR INJECTION

Main information

  • Trade name:
  • COSMEGEN LYOVAC POWDER FOR SOLUTION FOR INJECTION
  • Dosage:
  • 0.5 Milligram
  • Pharmaceutical form:
  • Pdr for Soln for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COSMEGEN LYOVAC POWDER FOR SOLUTION FOR INJECTION
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1301/003/001
  • Authorization date:
  • 01-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cosmegen ®

Lyovac*500microgramsPowderforSolutionforInjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialprovides500microgramsDactinomycin.

Whenreconstitutedasdirected,theresultingsolutionwillcontain500microgramsDactinomycinpermL.

Forafulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinjection.

Ayellow/orangelyophilisedpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

‘Cosmegen’isacytotoxic,antineoplasticantibioticwithimmunosuppressantproperties.

‘Cosmegen’,aspartofacombinationchemotherapyand/ormulti-modalitytreatmentregimen,isindicatedforthe

treatmentofWilms’tumor,childhoodrhabdomyosarcoma,Ewing’ssarcoma,andmetastaticnonseminomatous

testicularcancer.

‘Cosmegen’isindicatedasasingleagent,oraspartofacombinationchemotherapyregimen,forthetreatmentof

gestationaltrophoblasticneoplasia.

‘Cosmegen’,asacomponentofregionalperfusionincombinationwithmelphalan,isindicatedforthetreatmentof

locallyrecurrentorlocoregionallymetastaticmelanoma.

4.2Posologyandmethodofadministration

Toxicreactionsdueto‘Cosmegen’arefrequentandmaybesevere(see4.8‘Undesirableeffects’),thuslimitingthe

amountthatmaybegiveninmanycases.However,theseverityoftoxicityvariesmarkedlyandisonlypartly

dependentonthedosageused.

Thedosageof‘Cosmegen’willvarywiththetoleranceofthepatient,thesizeandlocationoftheneoplasm,andtheuse

ofotherformsoftherapy.Itmaybenecessarytoreducetheusualdosagesuggestedbelowwhenadditional

chemotherapyorradiationtherapyisusedconcurrently,orhasbeenemployedpreviously.

Thedosageof‘Cosmegen’iscalculatedinmicrograms.Thedoseintensityper-two-weekcycleforadultsorchildren

shouldnotexceed15microgramsperkgperdayor400to600microgramspersquaremetreofbodysurfacedaily

intravenouslyforfivedays.Calculationofthedosageforobeseoroedematouspatientsshouldbeonthebasisof

surfaceareainanefforttorelatedosagetoleanbodymass.

Useininfantslessthanoneyear

Asthereisagreaterfrequencyoftoxiceffectsof‘Cosmegen’ininfants‘Cosmegen’shouldonlybegiventoinfants

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Useintheelderly:

Clinicalstudiesof‘Cosmegen’didnotincludesufficientnumbersofsubjectsaged65andovertodeterminewhether

theyresponddifferentlyfromyoungersubjects.Otherreportedclinicalexperiencehasnotidentifieddifferencesin

responsesbetweentheelderlyandyoungerpatients.However,apublishedmeta-analysisofallstudiesperformedby

theEasternCooperativeOncologyGroup(ECOG)overa13 -yearperiodsuggeststhatadministrationof‘Cosmegen’to

elderlypatientsmaybeassociatedwithanincreasedriskofmyelosuppressioncomparedtoyoungerpatients.

Awidevarietyofsingleagentandcombinationchemotherapyregimenswith‘Cosmegen’maybeemployed.Because

chemotherapeuticregimensareconstantlychanging,dosingandadministrationshouldbeperformedunderthedirect

supervisionofphysiciansfamiliarwithcurrentoncologicpracticesandnewadvancesintherapy.Thefollowing

suggestedregimensarebaseduponareviewofcurrentliteratureconcerningtherapywith‘Cosmegen’andareonaper-

cyclebasis.

Wilms’tumor

Variousregimensusing‘Cosmegen’havebeenusedinthetreatmentofWilm’sTumour.Theseinclude‘Cosmegen’at

aStandardDividedDose(STD)of15micrograms/kgIVdailyfor5days.‘Cosmegen’asasinglepulseintensivedose

(PI)of45micrograms/kghasalsobeenutilized.Dosingregimensshouldbeprescribedbyphysiciansfamiliarwith

currentoncologicpracticesandnewadvancesintherapy.

Rhabdomyosarcoma

Regimensof15micrograms/kgintravenouslydailyforfivedaysadministeredinvariouscombinationsandschedules

withotherchemotherapeuticagents.

Ewing’ssarcoma

Regimens of 1.25mg/mintravenously administered in various combinations and schedules with other

chemotherapeuticagents.

Testicularcarcinoma

1,000micrograms/m 2

intravenouslyonDay1aspartofacombinationregimenwithcyclophosphamide,bleomycin,

vinblastine,andcisplatin.

Gestationaltrophoblasticneoplasia

12micrograms/kgintravenouslydailyforfivedaysasasingleagent.

500microgramsintravenouslyonDays1and2aspartofacombinationregimenwithetoposide,methotrexate,folinic

acid,vincristine,cyclophosphamideandcisplatin.

Regionalperfusioninlocallyrecurrentandlocoregionallymetastaticmelanoma

Thedosageschedulesandthetechniqueitselfvaryfromoneinvestigatortoanother;thepublishedliteratureshould,

therefore,beconsultedfordetails.Ingeneral,thefollowingdosesaresuggested:

Foralowerextremityorpelvis-50microgramsperkgbodyweight.

Foranupperextremity-35microgramsperkgbodyweight.

Itmaybeadvisabletouselowerdosesinobesepatients,orwhenpreviouschemotherapyorradiationtherapyhasbeen

employed.

Whenreconstituted,thesolutionofdactinomycincanbeaddedtoaninfusionsolutionof5%dextroseinjectionor

sodiumchlorideinjection,eitherdirectlyorintothetubingofarunningintravenousinfusion.

Althoughreconstituted‘Cosmegen’ischemicallystable,theproductdoesnotcontainapreservativeandaccidental

microbialcontaminationmightresult.Anyunusedportionofthesolutionshouldbediscarded(Seesection6.6).

Partialremovalofdactinomycinfromintravenoussolutionsbycelluloseestermembranefiltersusedinsome

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If‘Cosmegen’istobeinjecteddirectlyintotheveinwithouttheuseofaninfusion,the‘two-needle’techniqueshould

beused.Thecalculateddoseshouldbereconstitutedandwithdrawnfromthevialwithonesterileneedle;direct

injectionintotheveinshouldthenbeperformedwithanotherneedle.

4.3Contraindications

Hypersensitivitytoanycomponentofthisproduct.

Useinpatientswithvaricellaorherpeszoster.‘Cosmegen’shouldnotbegivenatoraboutthetimeofinfectionwith

chickenpoxorherpeszosterbecauseoftheriskofseveregeneraliseddisease,whichmayresultindeath.

4.4Specialwarningsandprecautionsforuse

‘Cosmegen’shouldbeadministeredonlyunderthesupervisionofaphysicianwhoisexperiencedintheuseofacancer

chemotherapeuticagent.Duetothetoxicpropertiesofdactinomycin(e.g.corrosivity,carcinogenicity,mutagenicity,

teratogenicity),specialhandlingproceduresshouldbereviewedpriortohandlingandfolloweddiligently.

‘Cosmegen’isHIGHLYTOXICandbothpowderandsolutionmustbehandledandadministeredwithcare.Since

‘Cosmegen’isextremelycorrosivetosofttissues,itisintendedforintravenoususe.Inhalationofdustorvapoursand

contactwithskinormucousmembranes,especiallythoseoftheeyes,mustbeavoided.Appropriateprotective

equipmentshouldbewornwhenhandling‘Cosmegen’.Shouldaccidentaleyecontactoccur,copiousirrigationforat

least15minuteswithwater,normalsalineorabalancedsaltophthalmicirrigatingsolutionshouldbeinstituted

immediately,followedbypromptophthalmicconsultation.Shouldaccidentalskincontactoccur,theaffectedpartmust

beirrigatedimmediatelywithcopiousamountsofwaterforatleast15minuteswhileremovingcontaminatedclothing

andshoes.Medicalattentionshouldbesoughtimmediately.Contaminatedclothingshouldbedestroyedandshoes

cleanedthoroughlybeforereuse(see6.6‘Instructionsforuse/handling’).

Ifextravasationoccursduringintravenoususe,severedamagetosofttissuesmayoccur(see6.6‘Instructionsfor

use/handling’).

‘Cosmegen’likeallantineoplasticagents,isatoxicdrug,andverycarefulandfrequentobservationofthepatientfor

adversereactionsisnecessary. Thesereactionsmayinvolveanytissueofthebody,mostcommonlythe

haematopoieticsystemresultinginmyelosuppression.Thepossibilityofananaphylactoidreactionshouldbebornein

mind.

Itisextremelyimportanttoobservethepatientdailyfortoxicsideeffectswhencombinedtherapyisemployed,sincea

fullcourseoftherapyisoccasionallynottolerated.Ifstomatitis,diarrhoea,orseverehaematopoieticdepressionappear

duringtherapy,thesedrugsshouldbediscontinueduntilthepatienthasrecovered.

Veno-occlusivedisease

Veno-occlusivedisease(primarilyhepatic)mayresultinfatality,particularlyinchildrenyoungerthan48months(see

4.8‘Undesirableeffects,GastrointestinalDisorders’).

‘Cosmegen’andradiationtherapy

Anincreasedincidenceofgastro-intestinaltoxicityandmarrowsuppressionhasbeenreportedwithcombination

therapyincorporating‘Cosmegen’andradiation.Moreover,thenormalskin,aswellasthebuccalandpharyngeal

mucosa,mayshowearlyerythema.Asmallerthanusualradiationdoseadministeredincombinationwith‘Cosmegen’

causeserythemaandvesiculation,whichprogressmorerapidlythroughthestagesoftanninganddesquamation.

Healingmayoccurinfourtosixweeksratherthantwotothreemonths.Erythemafrompreviousradiationtherapy

maybereactivatedby‘Cosmegen’alone,evenwhenradiationtherapywasadministeredmanymonthsearlier,and

especiallywhentheintervalbetweenthetwoformsoftherapyisbrief.Thispotentiationofradiationeffectrepresentsa

specialproblemwhentheradiationtherapyinvolvesthemucousmembrane.Whenirradiationisdirectedtowardthe

nasopharynx,thecombinationmayproducesevereoropharyngealmucositis.Severereactionsmayensueifhighdoses

ofboth‘Cosmegen’andradiationtherapyareusedorifthepatientisparticularlysensitivetosuchcombinedtherapy.

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right-sidedWilms’tumor,sincehepatomegalyandelevatedASTlevelshavebeennoted.

Ingeneral‘Cosmegen’shouldnotbeconcomitantlyadministeredwithradiationtherapyinthetreatmentofWilms’

tumorunlessthebenefitoutweighstherisk.

Reportsindicateanincreasedincidenceofsecondaryprimarytumours(includingleukaemia)followingtreatmentwith

radiationandantineoplasticagents,suchas‘Cosmegen’.Multi-modaltherapycreatestheneedforcareful,long-term

observationofcancersurvivors.

Appropriatecontraceptivemeasuresshouldbeemployedbybothmaleandfemalepatientsduringtreatmentand6

monthsafterwards.

Laboratorytests

Avarietyofabnormalitiesofrenal,hepaticandbone-marrowfunctionhavebeenreportedinpatientswithneoplastic

diseaseandreceiving‘Cosmegen’.Renal,hepaticandbone-marrowfunctionshouldbeassessedfrequently.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Ithasbeenreportedthatdactinomycinmayinterferewithbio-assayproceduresforthedeterminationofantibacterial

druglevels.

4.6Fertility,pregnancyandlactation

‘Cosmegen’(dactinomycin)hasbeenshowntobeteratogenicinanimalsandshouldnotnormallybegiventopregnant

women.

‘Cosmegen’(dactinomycin)shouldnotbeadministeredtomotherswhoarebreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Therearesideeffectsassociatedwiththisproductthatmayaffectsomepatients’abilitytodriveoroperatemachinery

(see4.8.‘Undesirableeffects’).

4.8Undesirableeffects

Toxiceffects(exceptnauseaandvomiting)donotusuallybecomeapparentuntiltwotofourdaysafteracourseof

therapyisstopped,andmaynotpeakuntilonetotwoweekshaveelapsed.Deathshavebeenreported.However,side

effectsareusuallyreversibleondiscontinuingtherapy.Theyincludethefollowing:

Infectionsandinfestations:Infection,pharyngitis.

Metabolismandnutritiondisorders:Anorexia,hypocalcemia.

Respiratory,thoracicandmediastinaldisorders:Pneumonitis.

Gastrointestinaldisorders:Nausea,vomiting,abdominalpain,diarrhoea,gastro-intestinalulceration,cheilitis,

dysphagia,oesphagitis,proctitis,ulcerativestomatitis.Nauseaandvomiting,whichoccurearlyduringthefirstfew

hoursafteradministration,maybealleviatedbygivinganti-emetics.

Hepatobiliarydisorders:Livertoxicityincludingascites,hepaticfailurewithreportsofdeath,hepatomegaly,hepatitis

andliverfunctiontestabnormalities.Hepaticveno-occlusivedisease,whichmaybeassociatedwithintravascular

clottingdisorderandmulti-organfailure,hasbeenreportedinpatientsreceiving‘Cosmegen’aspartofamultidrug

chemotherapyregimen,particularlyinpatientsundertheageof12months(see4.4‘Specialwarningsandprecautions

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Bloodandlymphaticsystemdisorders:Anaemia(eventothepointofaplasticanaemia,agranulocytosis,leukopenia,

thrombocytopenia,pancytopenia,reticulocytopenia,neutropenia,febrileneutropenia).Plateletandwhiteblood-cell

countsshouldbeperformedfrequentlytodetectseverehaematopoieticdepression.Ifeithershowsamarkeddecrease,

dactinomycinshouldbewithheldtoallowmarrowrecovery.Thisoftentakesuptothreeweeks.

Skinandsubcutaneoustissuedisorders:Alopecia,skineruptions,acne,erythemamultiforme,flare-upoferythemaor

increasedpigmentationofpreviouslyirradiatedskin.ToxicEpidermalNecrolysis(TEN)andStevensJohnson

Syndrome(SJS)havebeenobservedfrompostmarketingexperience.

Musculoskeletalandconnectivetissuedisorders:Myalgia.

Renalandurinarydisorders:Renalabnormalities,renalfailure.

Generaldisordersandadministrationsiteconditions:Malaise,fatigue,lethargy,fever,growthretardation.

Dactinomycinisextremelycorrosivetosofttissues.Ifextravasationoccursduringintravenoususe,severedamageto

softtissueswilloccur.Inatleastoneinstance,thishasledtocontractureofthearms.Epidermolysis,erythema,and

oedema,attimessevere,havebeenreportedwithregionallimbperfusion.

‘Cosmegen’andregional-perfusiontechnique:

Complicationsoftheperfusiontechniquearerelatedmainlytotheamountofdrugthatescapesintothesystemic

circulationandmayconsistofhaematopoieticdepression,increasedsusceptibilitytoinfection,absorptionoftoxic

productsfrommassivedestructionofneoplastictissue,impairedwoundhealing,andsuperficialulcerationofthe

gastricmucosa.Othersideeffectsmayincludeoedemaoftheextremityinvolved,damagetothesofttissuesofthe

perfusedarea,andpotentiallyvenousthrombosis.

4.9Overdose

Intheeventofoverdosage,dactinomycintherapyshouldbewithdrawnimmediately.Limitedinformationisavailable

onoverdosageinhumans.Manifestationsofoverdosehaveincludednausea,vomiting,diarrhoea,mucositisincluding

stomatitis,gastro-intestinalulceration,severeskindisordersincludingskinexfoliation,exanthema,desquamationand

epidermolysis,severehaematopoieticdepression,veno-occlusivedisease,acuterenalfailure,anddeath.Treatment

shouldbesymptomaticandsupportive.Thereisnoknownantidote.Itisadvisabletocheckskinandmucous

membraneintegrityaswellasrenal,hepatic,andbone-marrowfunctionsfrequently.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Modeofaction:‘Cosmegen’inhibitstheproliferationofcellsbyformingastablecomplexwithDNAandinterfering

withDNA -dependentRNAsynthesis.

Generally,theactinomycinsinhibitGram-positiveandGram-negativebacteriaandonsomefungi.However,thetoxic

propertiesoftheactinomycins(includingdactinomycin)inrelationtoantibacterialactivityprecludetheiruseas

antibioticsinthetreatmentofinfectiousdiseases.

Becausetheactinomycinsarecytotoxic,theyhaveanantineoplasticeffectwhichhasbeendemonstratedin

experimentalanimalswithvarioustypesoftumourimplant.Thiscytotoxicactionisthebasisfortheiruseinthe

palliativetreatmentofcertaintypesofcancer.

5.2Pharmacokineticproperties

Resultsofastudyinpatientswithmalignantmelanomaindicatethatdactinomycin( 3

HactinomycinD)isminimally

metabolised,isconcentratedinnucleatedcellsanddoesnotpenetratethebloodbrainbarrier.Approximately30%of

thedosewasrecoveredinurineandfaecesinoneweek.Theterminalplasmahalf-lifeforradioactivitywas

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5.3Preclinicalsafetydata

TheinternationalAgencyonResearchonCancerhasjudgedthatdactinomycinisapositivecarcinogeninanimals.

Localsarcomaswereproducedinmiceandratsafterrepeatedsubcutaneousorintraperitonealinjection.Mesenchymal

tumoursoccurredinmaleF344ratsgivenintraperitonealinjectionsof0.05mg/kg,twotofivetimesperweekfor18

weeks.Thefirsttumourappearedat23weeks.

Dactinomycinhasbeenshowntobemutagenicinanumberoftestsystemsinvitroandinvivo,includinghuman

fibroblastsandleukocytes,andHeLacells.DNAdamageandcytogeneticeffectshavebeendemonstratedinthemouse

andtherat.

Impairmentoffertility

Adequatefertilitystudieshavenotbeenreported,althoughreportssuggestanincreasedincidenceofinfertility

followingtreatmentwithotherantineoplasticagents.

Teratogenicity

‘Cosmegen’hasbeenshowntocausemalformationsandembryotoxicityintherat,rabbitandhamsterwhengivenin

dosesof50-100micrograms/kgintravenously(threetoseventimesthemaximumrecommendedhumandose).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421).

6.2Incompatibilities

Useofwatercontainingpreservatives(benzylalcoholorparabens)toreconstitute‘Cosmegen’forinjectionresultsin

theformationofaprecipitate.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Lyophilisedpowderaspackagedforsale:3years.

Reconstitutedsolutiondoesnotcontainapreservativeandmustbeusedimmediately.Discardanyunusedsolution.

6.4Specialprecautionsforstorage

Storebelow25 °

C.Donotfreeze.Keepthevialintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

3mLamberglassvial(TypeIglass)witha13mmredordark-greyrubberstopper(butylrubberTypeI)andaluminum

“Flip-off”cap".

Packsize:single3mLvial.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

‘Cosmegen’shouldbeadministeredonlybyorunderthesupervisionofaphysicianwhoisexperiencedintheuseof

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Forsingleuseonly.Discardanyunusedcontents.

Reconstitutionandadministration

‘Cosmegen’isreconstitutedbyadding1.1mLofWaterforInjectionsPh.Eur.withoutpreservativetothevial.For

injection,1.0mLofthereconstitutedsolution,whichwillcontain500microgramsofdactinomycin,iswithdrawninto

thesyringe.OnlyWaterforInjectionsPh.Eur.(whichdoesnotcontainpreservatives)shouldbeused.Otherinjection

fluidsmaycauseprecipitation.‘Cosmegen’shouldbeinspectedforparticulatematteranddiscolouration,whenever

possible.Thereconstitutedsolutionisclearandgold-coloured.

Studiesconductedondactinomycinlyophilizedpowderforinjectiondemonstratethatreconstituteddrugproduct

dilutedatconcentrationsof10mcg/mLorhigherinWFI,0.9%salineand5%dextroseinglassorPVCinfusion

containersarestableforupto10hourswhenstoredatambientroomtemperature.Drugproductdilutedto

concentrationslowerthan10mcg/mLandstoredatambientroomtemperatureshowedsignificantlylowerrecoveries.

Therefore,onlydrugproductdilutedatconcentrationsgreaterthan10mcg/mLandstoredfornotmorethan10hoursat

ambientroomtemperaturearerecommendedforadministration(Seesection4.2).

Specialhandling

Animalstudieshaveshowndactinomycintobecorrosivetoskin,irritatingtotheeyesandmucousmembranesofthe

respiratorytractandhighlytoxicbytheoralroute.Ithasalsobeenshowntobecarcinogenic,mutagenic,embryotoxic

andteratogenic.Duetothedrug’stoxicproperties,appropriateprecautionsincludingtheuseofappropriatesafety

equipmentarerecommendedforthepreparationof‘Cosmegen’forparenteraladministration.Inhalationofdustor

vapoursandcontactwithskinormucousmembranes,especiallythoseoftheeyesmustbeavoided.Avoidexposure

duringpregnancy.Pregnantstaffshouldnothandle‘Cosmegen’.

ItisrecommendedthatthepreparationofinjectableantineoplasticdrugsshouldbeperformedinaClassIIlaminarflow

biologicalsafetycabinet.Personnelpreparingdrugsofthisclassshouldwearchemicalresistant,imperviousgloves,

safetygoggles,outergarments,andshoecovers.Additionalbodygarmentsshouldbeusedbaseduponthetaskbeing

performed(e.g.sleevelets,apron,gauntlets,disposablesuits)toavoidexposedskinsurfacesandinhalationofvapours

anddust.Appropriatetechniquesshouldbeusedtoremovepotentiallycontaminatedclothing.

Severalguidelinesforproperhandlinganddisposalofantineoplasticdrugshavebeenpublishedandshouldbe

considered.Theseguidelinessuggestincinerationorchemicaldeactivation(e.g.,with5%trisodiumphosphate)any

residualorcontaminatedmaterial.

Accidentalcontactmeasures

Shouldaccidentaleyecontactoccur,copiousirrigationforatleast15minuteswithwater,normalsalineorabalanced

saltophthalmicirrigatingsolutionshouldbeinstitutedimmediately,followedbypromptophthalmicconsultation.

Shouldaccidentalskincontactoccur,theaffectedpartmustbeirrigatedimmediatelywithcopiousamountsofwaterfor

atleast15minuteswhileremovingcontaminatedclothingandshoes.Medicalattentionshouldbesoughtimmediately.

Contaminatedclothingshouldbedestroyedandshoescleanedthoroughlybeforereuse(see4.4‘Specialwarningsand

precautionsforuse’).

Careintheadministrationof‘Cosmegen’willreducethechanceofperivenousinfiltration(see4.4‘Specialwarnings

andprecautionsforuse’and4.8‘Undesirableeffects’).Itmayalsodecreasethechanceoflocalreactionssuchas

urticariaanderythematousstreaking.Onintravenousadministrationof‘Cosmegen’,extravasationmayoccurwithor

withoutanaccompanyingburningorstingingsensation,evenifbloodreturnswellonaspirationoftheinfusionneedle.

Ifanysignsorsymptomsofextravasationhaveoccurred,theinjectionorinfusionshouldbeterminatedandrestartedin

anothervein.Ifextravasationissuspected,intermittentapplicationoficetothesitefor15minutes4timesdailyfor3

daysmaybeuseful.Thebenefitoflocaladministrationofdrugshasnotbeenclearlyestablished.Becauseofthe

progressivenatureofextravasationreactions,closeobservationandplasticsurgeryconsultationisrecommended.

Blistering,ulcerationand/orpersistentpainareindicationsforwideexcisionsurgery,followedbysplit-thicknessskin

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7MARKETINGAUTHORISATIONHOLDER

LundbeckPharmaceuticalsIrelandLimited

14LowerPembrokeStreet,

Dublin2

8MARKETINGAUTHORISATIONNUMBER

PA1301/3/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:01April1979

Dateoflastrenewal:01April2009

10DATEOFREVISIONOFTHETEXT

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