ETOPOSID "EBEWE"

Main information

  • Trade name:
  • ETOPOSID "EBEWE"
  • Dosage:
  • 20
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ETOPOSID "EBEWE"
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/013/001
  • Authorization date:
  • 25-02-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Etoposide”Ebewe”20mg/ml–Concentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlofconcentrateforsolutionforinfusioncontains20mgofetoposide.

1,5,or10vialsof2.5mlconcentrateforsolutionforinfusioncontains50mgetoposide.

1,5,or10vialsof5mlconcentrateforsolutionforinfusioncontains100mgetoposide.

1,5,or10vialsof10mlconcentrateforsolutionforinfusioncontains200mgetoposide.

1,5,or10vialsof20mlconcentrateforsolutionforinfusioncontains400mgetoposide.

1,5,or10vialsof50mlconcentrateforsolutionforinfusioncontains1000mgetoposide.

Excipients:Benzylalcohol,ethanol.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Clear,lightyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Etoposideisaantineoplasticagentforintravenoususe.Itcanbeusedaloneorincombinationwithotheroncolytic

agents.

Availabledatashowthatetoposidemaybeusedintreatmentofsmall-celledlungcancer,resistantnon-seminomatous

testicularcarcinoma,acutemyelomonocyticandmyelocyticleukaemia(AML,FABsubtypeM4orM5)aspartof

combinationtherapyafterfailureofinductionchemotherapy.

4.2Posologyandmethodofadministration

Etoposideshouldbeadministeredonlybyorunderthedirectsupervisionofaqualifiedphysicianwhoisexperiencedin

theuseofcancerchemotherapeuticagents.

Pregnantpersonnelshouldnothandlechemotherapeuticagents.

Etoposideshouldbeadministeredbyslowintravenousinfusiononly(seebelow).

Etoposideconcentrateforsolutionforinfusionmustbedilutedbeforeuse(seesection6.6;Instructionsforuseand

handling).Immediatelybeforeadministration,therequireddoseofEtoposid"Ebewe"mustbedilutedinglucose5%or

0.9%salinesolutionforinjectiontogiveaconcentrationrangefrom0.2to0.4mg/ml,usuallynotmorethan0.25mg/ml

forthefinalconcentration.Itshouldthenbegivenbyintravenousinfusionoveraperiodofnotlessthan30minutes.

Adults:TherecommendeddoseofEtoposideis60-120mg/m 2

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 1

myelosuppression,thecourseoftreatmentmustnotberepeatedmoreoftenthan10-20dayintervals.Fornon-

haematologicalindicationscoursesmaynotberepeatedmorefrequentlythanat21dayintervals.Inanycaserepeated

coursesofEtoposidemustnotbegivenuntilthebloodpictureshowsnosignsofmyelosuppressionandfound

satisfactory.

Overall,adosagescheduleof100mg/m²for5daysor120mg/m²everyotherdayondays1,3,and5isusedmost

frequently.

Careshouldbetakentoavoidextravasation.

Childrenandadolescents:Safetyandefficacyinchildrenhasnotbeenestablished.

Elderly:Doseadjustmentisnotnecessary.

Renalimpairment:Inpatientswithrenalimpairmentbutwithnormalhepaticfunction,thedoseofetoposidemustbe

reducedandhaematologicalminimumvaluesandrenalfunctionmustbemonitored.

Recommendeddoseregimenonthebasisofcreatinineclearanceisasfollows:

Forinstructionsonuse/handlinganddisposalseeSection6.6.

4.3Contraindications

Etoposideiscontraindicatedin:

Patientswhohaveshownhypersensitivitytoetoposideortoanyoftheexcipients.

Patientswithseverehepaticimpairment.

Patientswithsevererenalimpairment(creatininclearance<15ml/min,seesection4.2Posologyandmodeof

administration)

Patientswithseveremyelosuppression.

Byintra-arterialorbyintra-cavitaryinjection.

Lactation.

4.4Specialwarningsandprecautionsforuse

Etoposideshouldonlybeadministeredbyhealthprofessionalsexperiencedintheuseofantineoplastictreatment.

Whenetoposideisgivenintravenously,careisadvisedinordertoavoidestravasation.

Ifradiationand/orchemotherapyisgivenbeforeinitiationofetoposidetreatment,anappropriateintervalmustbe

made,toletthebonemarrowregenerate.

Peripheralbloodcountsandhepaticfunctionmustbemonitored.(Seesection4.8Undesirableeffects).Iftheleukocyte

levelfallsbelow2,000/mm 3

ortheabsoluteneutrophillevelbelow500/mm 3

ortheplateletcountisbelow

50,000/mm 3

,thetreatmentmustbediscontinueduntilthebloodcounthasrecoveredtoacceptablelevels(platelets

above100,000/mm 3

,leukocytesabove4,000/mm 3

).Dependingonwhetheretoposideisusedaloneorascombination

treatment,thebloodlevelsregeneratetypicallywithin21days.

Creatinineclearance(ml/min) Recommendeddailydose(%ofstandarddose)

>50 100

15-50 75

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 2

Bacterialinfectionsmustbebroughtundercontrolbeforeinitiationoftreatmentwithetoposide.

Anaphylacticreactionsasflush,tachycardia,bronchospasmandhypotensionmayoccur(seesection4.8Undesirable

effects).

Theinfusionshouldbegivenslowly,during30to60minutes,toavoidhypotensionorbronchospasm.

Nauseaandvomitingoccurinapproximately30-40%ofthepatients.Antiemeticsarebeneficialincontrolofthis

adverseeffect.

Etoposideshouldbestoredoutofchildren'sreach.

Etoposideshouldnotbemixedwithotherdrugs.

Allpersonsexposedtocontactwithetoposideshouldwearglovesandeyeprotectionsinceskinreactionsarepossible

andthereisariskwhenetoposidecomesintocontactwiththeeyes.

Intheeventofcontactwithetoposide,skinandmucosaeshouldbeabundantlywashedwithwater.

Etoposideismutagenicandcarcinogenic(seesection5.3Preclinicalsafetydata).Thisshouldbetakeninto

considerationwhendesigninglong-termtherapy.

Etoposidemayhavegenotoxiceffects(seesection5.3preclinicalsafetydata).Mentreatedwithetoposidearetherefore

advisednottofatherachildduringtreatmentandforupto6monthsaftertreatment.

Thereisapossibilityofirreversibleinfertility,thereforemenareadvisedtoseekcounsellingonspermpreservation

beforestartingthetreatment.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Etoposidemaypotentiatethecytotoxicandmyelosuppressiveeffectofotherdrugs(e.g.ciclosporin).High-dose

ciclosporintherapywasfoundtoincreasetheexposuretoetoposide,andtoreduceetoposideclearance.

Theeffectoforalanticoagulantsmaybeincreased.

Phenylbutazone,sodiumsalicylateandacetylsalicylicacidmayaffecttheproteinbindingofetoposide.

Therearenodataaboutadministrationofetoposidewithdrugsthatareknowntoinhibitphosphataseactivity(e.g.

levamisolhydrochloride).

Vaccinationofpatientsimmunocompromisedbyachemotherapeuticagentwithliveattenuatedvaccinesmayresultin

severeandfatalinfections.

Potentiallybeneficialinteractions

Etoposideisusuallyusedtogetherwithothercytotoxicdrugsandhasbeenfoundtobetherapeuticsynergisticwitha

rangeofcytotoxicdrugs(e.g.methotrexateandcisplatin).

4.6Pregnancyandlactation

Etoposideissuspectedtocauseseriousbirthdefectswhenadministeredduringpregnancy.Etoposideshouldnotbe

usedduringpregnancyunlessclearlynecessary.Womenofchild-bearingpotentialmustuseeffectivecontraception

duringtreatmentwithetoposide.

Ifpregnancyoccursduringtreatmentappropriateprenatalcounsellingshouldbeprovidedandthebenefitoftreatment

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 3

Itisnotknownifetoposideissecretedinhumanbreastmilk.Arisktothesucklingchildcannotbeexcluded.Etoposide

isstrictlycontraindicatedduringlactationandbreast-feedingshouldbeinterruptedduringtreatment(see4.3

Contraindications).

4.7Effectsonabilitytodriveandusemachines

Adversereactionssuchassomnolence,fatigueandtransientcorticalblindnessindicatethatcardrivingoroperating

machinescannotberecommendedshortlyaftertreatmentwithetoposide.

4.8Undesirableeffects

Infectionsandinfestations

Rare(>1/10000and<1/1000):

Feverhasbeenreportedinrarecasesduringuseofetoposideandsepsishasrarelybeenreported.

Neoplasmsbenignandmalignant:

Rare(>1/10000and<1/1000):

Theoccurrenceofacuteleukemia,whichmayoccurwithorwithoutapreleukemicphase,hasrarelybeenreportedin

patientstreatedwithetoposideincombinationwithotheranti-neoplasticdrugs.

Ananomalyofthe11q23chromosomehasbeenobservedincertaincasesofsecondaryleukaemiaamongstpatients

thathavetakenepipodophyllotoxinsandinthecasesofleukaemiareturningagain.Afurthercharacteristicof

secondaryleukaemiaamongpatientsthathavetakenepipodophyllotoxinsistheirshortlatencyperiodandtheaverage

timefortheleukaemiatodevelopisapproximately32months.

Bloodandthelymphaticsystemdisorders:

Verycommon(>1/10):

Thedoselimitingtoxicityofetoposideismyelosuppression.Thewhitebloodcellnadirusuallyoccurs5to15days

(granulocytes7to14days)afterdrugadministration.Leukopeniagenerallyoccursmoreoftenthanthrombocytopenia

andismorefrequentlymoderatetosevere(WHOgrade3or4).Haematologicalrecoveryisusuallycomplete24to28

daysafterthelastdoseandcumulativetoxicityhasnotbeenobservedwithetoposidealone.Decreaseinhaemoglobine

(inapproximately40%).

Thenadirofthegranulocytecountusuallyoccurs7to14daysafteradose,withrecoverybyabout21days.

Common(>1/100and<1/10):

Infectionsandhaemorrhagefollowingseveremyelosuppression.

Rare(>1/10000and<1/1000):

Anaemia.

Immunesystemdisorders:

Uncommon(>1/1000and<1/100):

Anaphylacticreactionscharacterisedbychills,flush,tachycardia,dyspnoea,bronchospasmandhypotensionhavebeen

reportedafteradministrationofetoposide.Ahigherfrequencyofanaphylacticreactionsinchildrenwhoreceived

infusionsathigherthanrecommendedconcentrations,hasbeenreported.Theroletheconcentrationoftheinfusion(or

theinfusionrate)playsindevelopmentofanaphylacticreactions,isuncertain.

Thesereactionshaveusuallyrespondedtodiscontinuationoftreatmentandadministrationofpressoragentse.g.

adrenaline(epinephrine),corticosteroids,antihistaminesorvolumeexpandersasappropriate.

Veryrare(<1/10000includingisolatedcases):

Toxicepidermalnecrolysis(1fatalcase).

Rare(>1/10000and<1/1000):

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 4

Metabolismandnutritiondisorders:

Rare(>1/10000and<1/1000):

Hyperuricaemiahasbeenreportedinrarecasesduringuseofetoposide

Nervoussystemdisorders:

Common(>1/100and<1/10):

Peripheralneuropathyhasbeenobservedin0.7to2.0%ofcases.Effectofthecentralnervoussystem(10-3%).

Uncommon(>1/1000and<1/100):

Convulsion.

Rare(>1/10000and<1/1000):

Confusion,hyperkinesias,akinesia,somnolence,dizziness,fatigue,aftertasteandtransientcorticalblindness.

Eyedisorders:

Uncommon(>1/1000and<1/100):

Opticusneuritis.

Cardiacdisorders:

Veryrare(<1/10000includingisolatedcases):

Myocardialinfarctionandrhythmdisturbanceshavebeenreportedafteruseofetoposide.

Vasculardisorders:

Common(>1/100and<1/10):

Hypotensionmayoccuraftertoorapidinfusionandmaybereversedbyloweringtheinfusionrate.

Uncommon(>1/1000and<1/100):

Hypertensionand/orflushhavealsobeenreported.Thebloodpressureusuallyreturnstonormallevelwithinafew

hoursafterdiscontinuationofinfusion.

Phlebitis.

Respiratorydisorders:

Uncommon(>1/1000and<1/100):

Apnoeawithspontaneousresumptionofbreathingafterdiscontinuationofetoposidetreatment,hasbeenreported.

Sudden,fatalreactionsassociatedwithbronchospasmshavebeenreported.

Cough,laryngospasmandcyanosis.Interstitialpneumonitis/pulmonaryfibrosis.

Rare(>1/10000and<1/1000):

Pneumoniahasrarelybeenreported.

Gastrointestinaldisorders:

Verycommon(>1/10):

Nauseaandvomitingarethemostcommongastrointestinaltoxicitiesandoccurinapproximately30-40%ofthe

patients(seesection4.4Specialwarningsandprecautionsforuse).Diarrhoea(1-13%)andanorexia(10-13%).

Common(>1/100and<1/10):

Stomatitis(1-6%).

Rare(>1/10000and<1/1000):

Abdominalpain,constipationandoesophagitisoccurrarely.

Hepato-biliarydisorders:

Etoposidehasbeenshowntoreachhighconcentrationsinliverandthereforethereisapossibilityofaccumulationin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 5

Uncommon(>1/1000and<1/100):

Afterhighdosesofetoposide,anincreaseinliverenzymeshasbeenreported.

Skinandsubcutaneoustissuedisorders:

Verycommon(>1/10):

Reversiblealopeciawhichmayresultintotalbaldnesshasoccurredinapproximately66%ofthepatients.

Uncommon(>1/1000and<1/100):

Oedemaofthefaceandtongue,sweating.

Rare(>1/10000and<1/1000):

Rash,urticaria,pigmentationandpruritushavebeenreportedinrarecasesafteradministrationofetoposide.

Veryrare(<1/10000includingisolatedcases):

TwocasesofStevens-Johnsonsyndromehavebeendescribedintheliterature;aconnectionwithetoposideisnot

proven.

Asinglecaseofradiationrecalldermatitishasalsobeenreported.

Etoposidehasbeenshowntoreachhighconcentrationsinthekidneysandthereforethereisapossibilityof

accumulationincasesofimpairedfunction.

Reproductivesystemandbreastdisorders:

Ammenorrhea,anovulatorycycles,decreasedfertilityandhypomenorrhea.

4.9Overdose

Totaldosesof2.4to3.5g/m 2

administeredintraveneously.over3dayshaveresultedinseveremucositisand

myelotoxicity.Metabolicacidosisandcasesofseverehepatotoxicityhavebeenreportedinpatientsreceivinghigher

dosesofetoposidethanrecommended.

Provenantidotesagainstetoposideoverdosagehavenotbeenestablished.Symptomaticandsupportivetreatmentmust

begiven.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagents/podophyllotoxinderivatives,

ATC-code:L01CB01.

Etoposideisasemisyntheticderivativeofpodophyllotoxinwithasignificantcytotoxicactivityanddosage-scheme-

dependentproperties.EtoposideaffectsthefunctionoftopoisomeraseII(DNAopeningenzyme)andinhibitsDNA-

synthesisintheterminalphase.ThisresultsincleavageofsingleanddoublestrandedDNA.Celldeathoccursin

relationtotheconcentrationofetoposideanddurationofexposure.EtoposideisphasespecificwithcellstopinSand

earlyG

-phasesofthecellcyclebutdiffersfromotherknownpodophyllcompoundsthroughthefactthatitdoesn't

causeaccumulationinthemetaphase,butpreventsthecellfrommitosisordestroyscellsthatpreparemitosis.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesofetoposidearesubjecttosubstantialinterindividualvariation.Itisrapidlydistributed

andapproximately94%boundtoplasmaproteins.Plasmadecaykineticsfollowabi-exponentialcurveandcorrespond

toatwocompartmentmodelwithadistributionhalf-lifeabout1.5hoursandaterminaleliminationrangingfrom4to

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 6

thedoseoverarange100–600mg/m².OverthesamedosagerangeAUCandCmaxincreaselinearlywithdose.

Theaveragevolumeofdistributionisapproximately32%ofbodyweight.Etoposideshowsarelativelypoor

penetrationpropertyintocerebospinalfluid.Approximately45%ofanadministereddoseisexcretedintheurine,about

onethirdisexcretedwithin72hours.Only6%orlessofanintravenousdoseisrecoveredinthebileasetoposide.

Phenylbutazone,sodiumsalicylateandacetylsalicylicacidmayaffecttheproteinbindingofetoposide.

5.3Preclinicalsafetydata

Reproductiontoxicity:Etoposideisteratogenicinratsatalevellowerthanthatusedclinicallyonanapplieddose

basis.

Mutagenicity:Positiveresultsfrominvitroandinvivogenetictoxicityandchromosomalaberrationstudiesindicate

thatetoposideismutagenic.

Carcinogenicity:Animaltrialstodeterminecarcinogenicityofetoposidehavenotbeenperformed.

However,basedontheDNAdamagingeffectandthemutagenicpotential,etoposideshouldbeconsideredas

potentiallycarcinogenicinhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzylalcohol(20mg/ml)

Ethanol96%(v/v)(260,60mg/ml)

Anhydrouscitricacid

Macrogol300

Polysorbate80

6.2Incompatibilities

Etoposideshouldnotbephysicallymixedwithanyotherdrugexceptforthemedicinalproductsdeclaredinsection6.6

Instructionsforuseandhandling.

PlasticdevicesmadeofacrylicorABSpolymershavebeenreportedtocrackwhenusedwithundilutedEtoposid

"Ebewe",concentrateforsolutionforinfusion20mg/ml.Thiseffecthasnotbeenreportedwithetoposideafterdilution

oftheconcentrateforsolutionforinfusionaccordingtoinstructions.

6.3ShelfLife

Packagedforsale:3years(beforereconstitution).

Dilutedsolutions:24hours

6.4Specialprecautionsforstorage

Nospecialprecautionsforstoragefortheconcentrate.

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursatroomtemperature.Froma

microbiologicalpointofview,thedilutedmedicinalproductshouldbeusedimmediately.Ifnotusedimmediately,in-

usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24

hoursat2to8 o

C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.Seesection6.6

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 7

6.5Natureandcontentsofcontainer

1,5or10ambervialsofTypeIglassaccordingtoPh.Eur.withanominalcapacityof5ml(50mg/2.5ml,100mg/5ml),

10ml(200mg/10ml),20ml(400mg/20ml)and50ml(1000mg/50ml)withorwithoutaprotectiveplasticoverwrap

(ONKO-SAFE).

Thevialsareclosedwithfluoropolymer-coatedchlorobutylrubberstoppersaccordingtoPh.Eur.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Handleaccordingtoguidelinesforcytotoxics.

Concentrateforsolutionforinfusionmustnotbeusedundiluted.

Shouldonlybedilutedwithisotonicsodiumchlorideorisotonicglucoseinfusionsolutions.Theconcentrationof

etoposideinthereconstitutedsolutionforinfusionshouldnotexceed0.4mg/mlduetotheriskofprecipitation.

Aswithotherpotentiallycytotoxiccompoundscautionshouldbeexercisedwhenhandlingetoposide(gloves,mask,

overall).Contactwithskinandmucousmembranesshouldbeavoided.

Ifetoposidecomesintocontactwithskinwashwithwater.

Onlyforintravenoususe.

Singleuseonly.

Unusedsolutionshouldbediscarded.

Syringes,containers,absorbentmaterials,solutionandanyothercontaminatedmaterialshouldbeplacedina

designatedimperviouscontainerandincinerated,inaccordancewithlocalprocedures.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

Onlyclearsolutionspracticallyfreefromparticlesshouldbeused.

Cytotoxicsshouldnotbehandledbypregnantpersonnel.

7MARKETINGAUTHORISATIONHOLDER

EbewePharmaGesm.b.H.Nfg.KG

A-4866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA0789/013/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25February2005

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 8

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 31/05/2010 CRN 2079614 page number: 9