ETOPOPHOS

Main information

  • Trade name:
  • ETOPOPHOS Pdr for Soln for Injection 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Pdr for Soln for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ETOPOPHOS Pdr for Soln for Injection 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0002/064/001
  • Authorization date:
  • 10-10-1996
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Etopophos100mgPowderforSolutionforInjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontainsetoposidephosphateequivalentto100mgetoposiode.

Eachvialalsocontains7.64mg(0.33mmol)sodium.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Powderforsolutionforinjection.

Whitetooff-whitelyophilisedpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Etopophosisananti-neoplasticdrugforintravenoususe,whichcanbeusedaloneorincombinationwithother

cytotoxicdrugs.

PresentdataindicatethatEtopophosisapplicableinthetherapyof:smallcelllungcancer,resistantnon-seminomatous

testicularcarcinoma.

4.2Posologyandmethodofadministration

Etopophosshouldbeadministeredintravenously.Theusualdoseforetoposideis50to100mg/m2/day,days1to5or

100mg/m2,days1,3,and5every3to4weeksincombinationwithotherdrugsindicatedinthediseasetobetreated.

Dosageshouldbemodifiedtotakeintoaccountthemyelosuppressiveeffectsofotherdrugsinthecombinationorthe

effectsofpriorradiationtherapyorchemotherapy,whichmayhavecompromisedbonemarrowreserve.Etopophos

maybeinfusedover5minutesto3.5hours.

Inpatientswithimpairedrenalfunction,thefollowinginitialdosemodificationshouldbeconsideredbasedon

measuredcreatinineclearance:

Subsequentdosingshouldbebasedonpatienttoleranceandclinicaleffect.Dataarenotavailableinpatientswith

creatinineclearance<15ml/minandfurtherdosereductionsshouldbeconsideredinthesepatients.

Aswithotherpotentiallytoxiccompounds,cautionshouldbeexercisedinhandlingandpreparingthesolutionof

Etopophos.SkinreactionsassociatewithaccidentalexposuretoEtopophosmayoccur.Theuseofglovesis

recommended.IfEtopophossolutioncontactstheskinormucosa,immediatelywashtheskinwithsoapandwaterand

flushthemucosawithwater.Proceduresforproperhandlinganddisposalofanti-cancerdrugsshouldbefollowed.(See

MeasuredCreatinineClearance DoseofEtoposidePhosphate

>50ml/min 100%ofdose

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Forpreparationforintravenousadministration(Seesection6.6,InstructionsforUseandHandling).

Parenteraldrugproductsshouldbeinspectedvisuallyforparticulatematteranddiscolorationpriortoadministration

wheneversolutionandcontainerpermit.

Careshouldbetakentoavoidextravasation.

Elderly:

Nodosageadjustmentisnecessary.

Paediatricuse:

Safetyandeffectivenessinchildrenhavenotbeenestablished.

4.3Contraindications

Etopophosiscontra-indicatedinpatientswithseverehepaticdysfunctionorinthosepatientswhohavedemonstrated

hypersensitivitytoetoposide,etoposidephosphateoranyothercomponentoftheformulation.

4.4Specialwarningsandprecautionsforuse

Sinceetoposidephosphateisrapidlyandcompletelyconvertedtoetoposide,theWARNINGSandPRECAUTIONS

thatareconsideredwhenprescribingetoposideshouldbeconsideredwhenprescribingEtopophos.

Etopophosshouldbeadministeredbyindividualsexperiencedintheuseofanti-neoplastictherapy.

Careshouldbetakentoavoidextravasation.

Fatalmyelosuppressionhasbeenreportedfollowingetoposideadministration.PatientsbeingtreatedwithEtopophos

mustbeobservedformyelosuppressioncarefullyandfrequentlybothduringandaftertherapy.Doselimitingbone

marrowsuppressionisthemostsignificanttoxicityassociatedwithEtopophostherapy.Thefollowingstudiesshouldbe

obtainedatthestartoftherapyandpriortoeachsubsequentdoseofEtopophos:plateletcount,haemoglobin,white

bloodcellcountanddifferential.Theoccurrenceofaplateletcountbelow50,000/mm3oranabsoluteneutrophilcount

below500cells/mm3isanindicationtowithholdfurthertherapyuntilthebloodcountshavesufficientlyrecovered.

Thereisthepossibleoccurrenceofanaphylacticreactionsmanifestedbychills,fever,tachycardia,bronchospasm,

dyspnoea,andhypotension,whichcanbefatal.Treatmentissymptomatic.Theinfusionshouldbeterminated

immediately,followedbytheadministrationofpressoragents,corticosteroids,antihistamines,orvolumeexpandersat

thediscretionofthephysician(Seesection4.8,Undesirableeffects).

Peripheralbloodcountsandliverfunctionshouldbemonitored.(Seesection4.8,Undesirableeffects).Bacterial

infectionsshouldbebroughtundercontrolbeforetreatmentwithEtopophoscommences.

InallinstanceswheretheuseofEtopophosisconsideredforchemotherapy,thephysicianmustevaluatetheneedand

usefulnessofthedrugagainsttheriskofadversereactions.Mostsuchadversereactionsarereversibleifdetectedearly.

Ifseverereactionsoccur,thedoseofEtopophosshouldbereducedoritshouldbediscontinuedandappropriate

correctivemeasuresshouldbetakenaccordingtotheclinicaljudgmentofthephysician.ReinstitutionofEtopophos

therapyshouldbecarriedoutwithcaution,andwithadequateconsiderationofthefurtherneedforthedrug.Close

attentionshouldbepaidtothepossiblerecurrenceoftoxicity.Patientswithlowserumalbuminmaybeatincreased

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Givenitsmechanismofaction,Etopophosshouldbeconsideredapossiblemutagenandcarcinogeninhumans.

Theoccurrenceofacuteleukaemia,whichcanoccurwithorwithoutpreleukaemiaphasehasbeenreportedrarelyin

patientstreatedwithetoposideinassociationwithotheranti-neoplasticdrugs.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

CautionshouldbeexercisedwhenadministeringEtopophoswithdrugsthatareknowntoinhibitphosphataseactivities

(e.g.,levamisolehydrochloride).Highdosecyclosporin(resultinginconcentrations>2000ng/ml)administeredwith

oraletoposidehasledtoan80%increaseinetoposideexposure(AUC)witha38%decreaseintotalbodyclearanceof

etoposide,comparedtoetoposidealone.

4.6Pregnancyandlactation

Etopophoscancausefoetalharmwhenadministeredtopregnantwomen.Etoposideisteratogenicinratsandmiceat

doselevelsequivalenttothoseemployedclinicallyanditisthereforeassumedthatEtopophosisalsoteratogenicin

humans.Therearenoadequateandwell-controlledstudiesinpregnantwomen.

Womenofchildbearingpotentialshouldbeadvisedtouseaneffectiveformofcontraceptiontoavoidbecoming

pregnant.IfEtopophosisusedduringpregnancy,orifthepatientbecomespregnantwhilereceivingthisproduct,the

patientshouldbeappraisedofthepotentialhazardtothefoetus.

Etopophosshouldnotbeadministeredduringpregnancyunlessconsideredessentialbytheclinicianforanindividual

patient.

Theinfluenceofetoposideonhumanreproductionhasnotbeendetermined.

ItisnotknownwhetherEtopophosisexcretedinhumanmilk.Becausemanydrugsareexcretedinhumanmilkand

becauseofthepotentialforseriousadversereactionsinnursinginfantsfromEtopophos,adecisionshouldbemade

whethertodiscontinuenursingortodiscontinueEtopophos,takingintoaccounttheimportanceofEtopophostothe

mother.

4.7Effectsonabilitytodriveandusemachines

None.

4.8Undesirableeffects

Etoposidephosphate:

InclinicalstudieswithEtopophosadministeredasasingleagent,themostfrequentclinicallysignificantadverse

experienceswereleucopeniaandneutropenia.Thrombocytopeniaandanaemiawerealsoreported.Gastrointestinal

adverseeventswereusuallymildtomoderate.Nauseaand/orvomiting,anorexia,mucositis,constipation,abdominal

pain,diarrhoeaandtastealterationwerereported.Astheniaormalaiseaffectedaboutathirdofthepatients.

Reversiblealopecia,sometimesprogressingtototalbaldness,wasalsoobservedinathirdofthepatients.Chillsand/or

fever,dizzinessandextravasation/phlebitishasalsobeenreported.

Haematological:

MyelosuppressionafterEtopophosadministrationisdoserelatedanddoselimitingwiththeleukocytenadircounts

occurringbetweenday15andday22afterinitiationofdrugtherapy,granulocytenadircountsoccurringbetweenday

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Bonemarrowrecoveryusuallyoccursbyday21butmaybedelayed,andnocumulativetoxicityhasbeenreported.

Feverandinfectionhavealsobeenreportedinpatientswithneutropenia.Deathassociatedwithmyelosuppressionhas

beenreportedfollowingetoposideadministration.(seesection4.4,Specialwarningsandprecautionsforuse)

Gastrointestinal:

Nauseaandvomitingarethemajorgastrointestinaltoxicitiesandoccurinoverone-thirdofpatients.Theseverityof

suchisgenerallymildtomoderate,withtreatmentdiscontinuationrequiredin1%ofpatients.Nauseaandvomitingcan

usuallybecontrolledwithstandardantiemetictherapy.

Bloodpressurechanges:

InclinicalstudiesinvolvingEtopophos,151patientsweretreatedwithEtopophosinfusionstimesrangingform30

minutesto3.5hours,and63patientsreceivedEtopophosasa5-minutebolusinjection.Fourpatientsexperiencedone

ormoreepisodesofhypertension,and8patientsexperiencedoneormoreepisodesofhypotensionwhichmayormay

notbedrugrelated.Onlyoneoftheepisodesofhypotensionwasreportedamongthepatientsreceivingthe5-minute

bolusinjection.Ifclinicallysignificanthyper-orhypotensionoccursinpatientsreceivingEtopophos,appropriate

supportivetherapyshouldbeinitiated.Myocardialinfarctionandrhythmdisordershavebeenreportedinfrequently.

Anaphylactoidreactions:

Anaphylactoidreactions(characterisedbychills,rigors,tachycardia,bronchospasm,dyspnoea,diaphoresis,fever,

pruritus,hypertensionorhypotension,lossofconsciousness,nausea,andvomiting)havebeenreportedfollowing

administrationofEtopophos.Facialflushingandskinrashhavealsobeenreported.Thesereactionshaveusually

respondedtocessationoftherapyandadministrationofpressoragents,corticosteroids,antihistaminesorvolume

expandersasappropriate;however,thereactionscanbefatal.Bloodpressureusuallyreturnstonormalwithinafew

hoursaftercessationoftheinfusion.

Anaphylactic-likereactionshaveoccurredduringtheinitialinfusionofEtopophos.Facial/tongueswelling,coughing,

diaphoresis,cyanosis,tightnessinthroat,laryngospasm,backpain,and/orlossofconsciousnesshavesometimes

occurredinassociationwiththesereactions.Inaddition,anapparenthypersensitivity-associatedapnoeahasbeen

reportedrarely.Higherratesofanaphylactoidreactionshavebeenreportedinchildrenwhoreceivedinfusionsat

concentrationshigherthanthoserecommended.

Rash,urticaria,and/orpruritushaveinfrequentlybeenreportedatrecommendeddoses.Atinvestigationaldoses,a

generalizedpruriticerythematosusmaculopapularrash,consistentwithperivasculitis,hasbeenreported.

Othertoxicities:

Aftertaste,dysphagia,transientcorticalblindness,interstitialpneumonitis/pulmonaryfibrosis,opticneuritis,

pigmentation,seizure,Stevens-JohnsonSyndrome,toxicepidermalnecrolysis,andasinglecaseofradiationrecall

dermatitishavealsobeeninfrequentlyreportedfollowingtheadministrationofetoposide.Rarely,hepatictoxicitymay

beseen.

Theuseofetoposidehasbeenreportedinfrequentlytocauseperipheralneuropathy.

Etoposidehasbeenshowntoreachhighconcentrationsintheliverandkidney,thuspresentingapotentialfor

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Etoposide:

Sinceetoposidephosphateisrapidlyconvertedtoetoposideinthebody,theadverseexperiencesreportedbelowthat

areassociatedwithetoposidemayoccurwithEtopophos.Thefollowingdataonadversereactionsarebasedonboth

oralandintravenousadministrationofetoposide:

Somnolence,fatigue,andoesophagitishavealsobeenreportedfollowingetoposideuse.Higherratesofanaphylactoid

reactionshavebeenreportedinchildrenwhoreceivedinfusionsatconcentrationshigherthanthoserecommended.

4.9Overdose

Totaletoposidedosesof2.4g/m 2

to3.5g/m 2

administeredintravenouslyoverthreedayshaveresultedinsevere

mucositisandmyelotoxicity.

Metabolicacidosisandcasesofserioushepatictoxicityhavebeenreportedinpatientsreceivinghigherthan

recommendeddosesofetoposide.

NoprovenantidoteshavebeenestablishedforEtopophosoverdosage.Treatmentshouldthereforebesymptomaticand

supportive.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Etoposidephosphateisconvertedinvivototheactivemoiety,etoposide,bydephosphorylation.Themechanismof

actionofetoposidephosphateisbelievedtobethesameasthatofetoposide.

Etoposideisasemi-syntheticderivativeofpodophyllotoxin.Experimentaldataindicatethatetoposidearreststhecell

cycleintheG 2

phase.Etoposidediffersfromthevincaalkaloidsinthatitdoesnotcauseanaccumulationofcellsin

metaphase,butpreventscellsfromenteringmitosisordestroyscellsintheG 2

phase.Theincorporationofthymidine

AdverseDrugEffectsObservedwithSingle-Agent

Etoposide Percentage

Rangeof

Patients

HaematologicToxicity

Leukopenia(<1000/mm 3

3-17

Leukopenia(<4000/mm 3

60-91

Thrombocytopenia(<50,000/mm 3

1-20

Thrombocytopenia(<100,000/mm 3

22-41

Anemia 0-33

GastrointestinalToxicity

Nauseaandvomiting 31-43

Abdominalpain 0-2

Anorexia 10-13

Diarrhoea 1-13

Stomatitis 1-6

Hepatic 0-3

Alopecia 8-66

Peripheralneurotoxicity1-2 1-2

Hypotension1-2 1-2

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5.2Pharmacokineticproperties

FollowingintravenousadministrationofEtopophos,etoposidephosphateisrapidlyandcompletelyconvertedto

etoposideinplasma.Adirectcomparisonofthepharmacokineticparameters(AUCandC

)ofetoposidefollowing

intravenousadministrationofmolarequivalentdosesofEtopophosandetoposidewasmadeintworandomisedcross-

overstudiesinpatients.ResultsfrombothstudiesdemonstratednostatisticallysignificantdifferencesintheAUCand

foretoposidewhenadministeredasEtopophosoretoposide.Inaddition,therewerenostatisticallysignificant

differencesinthepharmacodynamicparameters(haematologictoxicity)afteradministrationofEtopophosor

etoposide.BecauseofthepharmacokineticandpharmacodynamicbioequeivalenceofEtopophostoetoposide,the

followinginformationonetoposideshouldbeconsidered.

Invitro,etoposideishighlyproteinbound(97%)tohumanplasmaproteins.Inastudyoftheeffectsofother

therapeuticagentsoninvitrobindingof14Cetoposidetohumanserumproteins,onlysodiumsalicylate,andaspirin

displacedprotein-boundetoposideatconcentrationsgenerallyachievedinvivo.Plasmadecaykineticsfollowabi-

exponentialcurveandcorrespondtoatwocompartmentalmodel.Themeanvolumeofdistributionisapproximately

32%ofbodyweight.Etoposidedemonstratesrelativelypoorpenetrationintothecerebrospinalfluid.Urinaryexcretion

isapproximately45%ofanadministereddose,29%beingexcretedunchangedin72hours.

Etoposideisclearedbybothrenalmetabolismandbiliaryexcretion.Patientswithimpairedrenalfunctionreceiving

etoposidehaveexhibitedreducedtotalbodyclearance,increasedAUCandlowersteadystatevolumeofdistribution.

Concomitantcisplatintherapyisassociatedwithreducedtotalbodyclearanceofetoposide.Inchildren,elevatedSGPT

levelsareassociatedwithreduceddrugtotalbodyclearance.Prioruseofcisplatinmayalsoresultinadecreaseof

etoposidetotalbodyclearanceinchildren.

5.3Preclinicalsafetydata

ThecarcinogenicpotentialofEtopophoshasnotbeenstudied.However,baseduponitspharmacodynamicmechanism

ofaction,Etopophosisapotentialcarcinogenicandgenotoxicagent.Etoposidehasbeenshowntobemutagenicin

mammaliancellsandEtopophosisexpectedtohavesimilarmutageniceffects.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Dextran40

SodiumCitrate

6.2Incompatibilities

Etopophosshouldnotbephysicallymixedwithanyotherdrug.

6.3ShelfLife

18months.

Chemicalandin-usestabilityhasbeendemonstratedfor7daysat2-8°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan7daysat2-8°

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Whenreconstitutedasdirected,Etopophossolutionscanbestoredinglassorplasticcontainersunderrefrigeration(2-

8°C)for7days;atcontrolledroomtemperature20-25°Cfor24hoursfollowingreconstitutionwithSterileWaterfor

Injection,USP,5%DextroseInjection,USP,or0.9%SodiumChlorideInjection,USP;oratcontrolledroom

temperature20-25°Cfor48hoursfollowingreconstitutionwithBacteriostaticWaterforInjectionwithBenzylAlcohol

orBacteriostaticSodiumChlorideforInjectionwithBenzylAlcohol.Etopophossolutionsfurtherdilutedasdirected

canbestoredunderrefrigeration(2-8°C)oratcontrolledroomtemperature20-25°Cfor24hours.

6.4Specialprecautionsforstorage

Storebetween2-8°C.

Keepthevialintheoutercarton.

6.5Natureandcontentsofcontainer

20mlflintglasstypeIvialwithabutylrubberstopperandflip-offaluminiumseal,packedasasinglevial.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

SolutionsofEtopophosshouldbepreparedinanasepticmanner.Immediatelypriortoadministration,thecontentof

eachvialmustbereconstitutedwitheither5mlor10mlWaterforInjectionB.P.,5%GlucoseIntravenousInfusion

B.P.or0.9%SodiumChlorideIntravenousInfusionB.P.toaconcentrationequivalentto20mg/mlor10mg/ml

etoposiderespectively.Thisproducesaclearcolourlesstopaleyellowsolution.

Followingreconstitutionthesolutionmaybeadministeredwithoutfurtherdilutionoritcanbefurtherdilutedto

concentrationsaslowas0.1mg/mletoposidewitheither5%GlucoseIntravenousInfusionB.P.or0.9%Sodium

ChlorideIntravenousInfusionB.P.

Forin-usestoragetimepleaserefertosection6.3,Shelflife.

Etopophosshouldnotbephysicallymixedwithanyotherdrug.Etopophosisforsingleuse

only.Discardanyremainingcontentsafteruse.

Guidelinesforthesafehandlingofanti-neoplasticagents:

Trainedpersonnelshouldreconstitutethedrug.

Thisshouldbeperformedinadesignatedarea.

Adequateprotectiveglovesshouldbeworn.

Precautionsshouldbetakentoavoidthedrugaccidentallycomingintocontactwiththeeyes.Intheeventof

contactwiththeeyes,irrigatewithlargeamountsofwaterand/orsaline.

Thecytotoxicpreparationshouldnotbehandledbypregnantstaff.

Adequatecareandprecautionsshouldbetakeninthedisposalofitems(syringes,needlesetc)usedto

reconstitutecytotoxicdrugs.Excessmaterialandbodywastemaybedisposedofbyplacingindoublesealed

polythenebagsandincineratingatatemperatureof1,000°C.Liquidwastemaybeflushedwithcopiousamounts

ofwater.

Theworksurfaceshouldbecoveredwithdisposableplasticbackedabsorbentpaper.

UseLuer-Lockfittingsonallsyringesandsets.Largeboreneedlesarerecommendedtominimizepressureand

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7MARKETINGAUTHORISATIONHOLDER

Bristol-MyersSquibbPharmaceuticalsLimited

Swords,

CountyDublin.

8MARKETINGAUTHORISATIONNUMBER

PA0002/064/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 10October1996

Dateoflastrenewal: 10October2006

10DATEOFREVISIONOFTHETEXT

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