ENDOXANA

Main information

  • Trade name:
  • ENDOXANA 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:
  • ENDOXANA Pdr for Soln for Injection 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0705/001/001
  • Authorization date:
  • 10-08-1990
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0705/001/001

CaseNo:2048244

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

AstaMedicaLtd

168CowleyRoad,CambridgeCB44DL,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EndoxanaInjection100mgPowderforSolutionforInjection

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom19/05/2008until09/08/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 22/05/2008 CRN 2048244 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EndoxanaInjection100mgPowderforSolutionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontainscyclophosphamidemonohydrateequivalentto100mganhydrouscyclophosphamide.

Whenreconstitutedasdirected,thesolutioncontains20mgcyclophosphamideperml.

3PHARMACEUTICALFORM

Powderforsolutionforinjection

Awhitecrystallinepowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Endoxanaisacytotoxicdrugforthetreatmentofmalignantdiseaseinadults.Asasingleagent,ithassuccessfully

producedanobjectiveremissioninawiderangeofmalignantconditions.Endoxanaisalsofrequentlyusedin

combinationwithothercytotoxicdrugs,radiotherapyorsurgery.

4.2Posologyandmethodofadministration

EndoxanaInjectionisforintravenousadministration.

Endoxanashouldonlybeusedbycliniciansexperiencedintheuseofcancerchemotherapy.Endoxanashouldonlybe

administeredwheretherearefacilitiesforregularmonitoringofclinical,biochemicalandhaematologicalparameters

before,during,andafteradministrationandunderthedirectionofaspecialistoncologyservice.

Dosage

Thedose,routeofadministrationandfrequencyofadministrationshouldbedeterminedbythetumourtype,tumour

stage,generalconditionofthepatientandwhetherotherchemotherapyorradiotherapyistobeadministered

concurrently.

Aguidetothedosageregimensusedformostindicationsisgivenbelow.

Thistreatmentshouldbecontinueduntilaclearremissionorimprovementisseenorbeinterruptedwhentheextentof

leucopeniabecomesunacceptable.

Conventional: 80-300mg/m²dailyassinglei.v.doseordailydividedoraldoses.

300-600mg/m²asasinglei.v.doseweekly.

Highdose: 600-1500mg/m²asasinglei.v.doseorshortinfusiongivenat10-20dayintervals.

Elderly:Nospecificinformationontheuseofthisproductintheelderlyisavailable.Clinicaltrialshaveincluded

patientsover65yearsandnoadversereactionsspecifictothisagegrouphavebeenreported.

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Administration

Endoxanaisinertuntilactivatedbyenzymesintheliver.However,aswithallcytotoxics,itissuggestedthat

reconstitutionshouldbeperformedbytrainedpersonnel,inadesignatedarea.

Thosehandlingthepreparationshouldwearprotectivegloves.Careshouldbetakentoavoidsplashingmaterialintothe

eyes.Thematerialshouldnotbehandledbywomenwhoarepregnantorwhoarebreast-feeding.

Forintravenoususe,thecontentsofthevialshouldbedissolvedinphysiologicalsaline(0.9%w/vsodiumchloride)

priortoadministration.ThepHofanaqueoussolutionisbetween4and6.Endoxanaisusuallygivendirectlyintothe

tubingofafastrunningi.v.infusionwiththepatientsupine.Careshouldbetakenthatextravasationdoesnottake

place,however,shoulditoccur,nospecificmeasuresneedtobetaken.

Aminimumurineoutputof100ml/hourshouldbemaintainedduringtherapywithconventionaldosestoavoidcystitis.

Ifthelargerdosesareused,anoutputofatleastthislevelshouldbemaintainedfor24hoursfollowingadministration,

ifnecessarybyaforceddiuresis.

Alkalisationoftheurineisnotrecommended.Endoxanashouldbegivenearlyinthedayandthebladdervoided

frequently.Thepatientshouldbewellhydratedandmaintainedinfluidbalance.

Mesna(Uromitexan)canbeusedconcurrentlytoreduceurotoxiceffects(seeUromitexanSPC).Ifmesna(Uromitexan)

isusedtoreduceurothelialtoxicity,frequentemptyingofthebladdershouldbeavoided.Anti-emeticsgivenbefore

andduringtherapymayreducenauseaandvomiting.

Urineshouldbesentforlaboratoryanalysisbeforeandattheendofeachcourseoftreatmentandthepatientshouldbe

monitoredforevidenceofhaematuriaatregularintervalsthroughoutthetreatmentperiod.Thepatientshouldbe

instructedtoreportanysignsorsymptomsofcystitis.

EndoxanaInjectionshouldbeavoidedinpatientswithcystitisfromanycauseuntilithasbeentreated.

Iftheleukocytecountisbelow4x10 9

/Land/ortheplateletcountisbelow100x10 9

/L,treatmentwithEndoxana

shouldbetemporarilywithhelduntilthebloodcountreturnstonormallevels.

4.3Contraindications

Endoxanaiscontra-indicatedinpatientswithknownhypersensitivitytocyclophosphamide,withacuteinfections,with

bone-marrowaplasia,urinarytractinfectionorwithacuteurothelialtoxicityfromcytotoxicchemotherapyorradiation

therapy.

Endoxanashouldnotbeusedinthemanagementofnon-malignantdisease,exceptforimmuno-suppressioninlife-

threateningsituations.

Endoxanaiscontra-indicatedduringpregnancy.

4.4Specialwarningsandprecautionsforuse

Endoxanashouldonlybeadministeredunderthedirectionofaspecialistoncologyservicehavingthefacilitiesfor

regularmonitoringofclinical,biochemicalandhaematologicaleffectsduringandafteradministration.

Careshouldbeexercisedinpatientswhoareelderly,debilitated,havediabetesmellitusorevidenceof

myelosuppression,orwhohaverecentlyreceived,orarereceiving,concurrenttreatmentwithradiotherapyorcytotoxic

agents.

Cardiotoxicitymaybeinducedinpatientswhohavehad,orarereceiving,mediastinalirradiation,doxorubicinor

pentostatin.Ithasalsobeenreportedwithhighdosesofcyclophosphamide.Insuchinstancescyclophosphamide

therapyshouldbestoppedandappropriatetreatmentinstituted.

Endoxanaisnotrecommendedinpatientswithplasmacreatininegreaterthan120micromol/L(1.5mg/100ml),

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thenormalvalue.

Endoxanamayhaveanadverseeffectonthegonadsandamenorrheoaandazoospermiaoftenoccurwhichmaybe

irreversible.Appropriatecounsellingshouldbegiven.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Increasedmyelosuppressionmaybeseenfollowingconcurrentadministrationofothermarrowdepressantdrugs.

Endoxanapotentiatesthehypoglycaemiceffectsofthesulphonylureacompounds.Otherclinicallysignificant

interactionsareofcyclophosphamidewithallopurinol(increasedincidenceofbonemarrowdepression)and

suxamethonium(prolongedapnoea).

4.6Pregnancyandlactation

Endoxanashouldnotbeusedinpregnancy,especiallythefirsttrimester,unlesstheexpectedbenefitisthoughtto

outweighthesubstantialrisktothefoetus.Endoxanahasbeenshowntobeteratogenic.Mothersshouldnotbreast-feed

whilebeingtreatedwithEndoxana.

4.7Effectsonabilitytodriveandusemachines

Apatient’sabilitytodriveoroperatemachinerymaybeaffectedbythepossiblesideeffectsofcyclophosphamide

administration,e.g.nausea,vomiting.

4.8Undesirableeffects

Anorexia,nauseaandvomitingandmucosalulcerationcanoccur.Thismaybereducedbytheprioradministrationof

ananti-emeticagent.Rarelyrenalandhepaticdysfunction(includingjaundiceandincreasedliverenzymes)havebeen

reported.

Alopeciaoccurstosomedegreeinabout20%ofpatientsreceivingover100mgdailyandisinevitablefollowinghigh

doses.Epilationcommencesusuallyafterthefirstthreeweeksoftreatment,butregrowthisevidentafterthreemonths

inmostpatientseventhoughtheyremainontreatment.

Thereticulo-endothelialsystemisdepressed,granulopoiesisandlymphopoiesisbeingmoreaffectedthan

thrombopoiesisanderythropoiesis,butthisdepressionisreversible.Whenasingledoseisgiven,thefallinthe

peripheralwhitecellcountreachesitsnadirwithin5-10days.Recoveryisseenat10-14daysfollowingadministration,

withfullrecoveryinmostcasesby21-28days.Thefallintheperipheralcountandthetimetakentorecovermay

increasewithincreasingdosesofEndoxana.

AnalterationincarbohydratemetabolismmaybeseeninpatientsonEndoxana.Hyperglycaemiahasbeenreported.

Azoospermiaoftenoccursinmenandisdosedependent.Spontaneousrecoveryoffertilitymayoccur,andisalso

dependentondose.Menstruationinwomencommonlyceasesduringtherapy,andmaybepermanent,particularlyin

olderwomen.Endoxanamayhaveanadverseeffectonprepubertalgonads.

Cardiotoxicitymaybeinducedinpatientswhohavehadorarereceivingmediastinalirradiationordoxorubicin.Ithas

alsobeenreportedwithhighdosesofcyclophosphamide.Thismainlyoccursasatachyarrhythmiaandmayprogressin

severecasestointractableheartfailure.Followinglargedoses,ECGchangesandelevationofLDH(lactate

dehydrogenase),AST(aspartateaminotransferase)andCPK(creatinephosphokinase)havebeenreportedinsome

patients.

HaematuriamayoccurduringoraftertherapywithEndoxana.Wheremesna(Uromitexan)isnotgiveninconjunction

withEndoxana,acutesterilehaemorrhagiccystitismayoccurinupto10%ofpatients.Latesequelaeofthiscystitisare

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Endoxanahasbeenshowntobemutagenic,teratogenic,andcarcinogenicincertainlaboratorytestsand,aswithother

cytotoxicagents,therehavebeenreportsofpossibledrug-inducedneoplasia.Thereisanexcessiveriskofacute

leukaemiaandbladdercancerfollowingcyclophosphamidetherapy.

Cyclophosphamidetherapymayleadtoinappropriatesecretionofanti-diuretichormonewithfluidretentionand

hyponatraemia,andsubsequentwaterintoxication.

Inveryrarecases,pneumonitisorinterstitialpneumoniaextendingtochronicinterstitialpulmonaryfibrosismay

develop.Inparticular,alateonsetofpulmonaryfibrosismaybeirreversibleandresultinafataloutcome.

Otherside-effects,suchaspancreatitis,pigmentation,macrocytosis,andinductionofhyperglycaemiaor

hypoglycaemiahavebeenreported.

Note:

Therearecertaincomplications,suchasveno-occlusivedisease,thromboembolism,DIC(disseminatedintravascular

coagulation)orhaemolyticuraemicsyndrome,thatmayalsobeinducedbytheunderlyingdisease,butwhichmight

occurwithanincreasedfrequencyduringchemotherapythatincludesEndoxana.

Side-effectshaveoccasionallyoccurredaftercessationoftreatment.

4.9Overdose

Themostseriousconsequencesofoverdosagearemyelosuppression,haemorrhagiccystitisandcardiotoxicityinthe

formofarrhythmiasandsevereheartfailure.Myelosuppressionusuallyrecoversspontaneously,butuntilitdoes,

administrationofabroad-spectrumantibioticmaybeadvisable.Transfusionofwhole-blood,plateletsorwhitecellsis

rarelynecessary.

Iftheoverdoseisrecognisedwithinthefirst24hours,andpossiblyupto48hours,i.v.Mesnamaybebeneficialin

amelioratingdamagetotheurinarysystem.Normalsupportivemeasures,suchasanalgesicsandmaintenanceoffluid

balance,shouldbeinstituted.If,despitethesemeasures,thecystitisdoesnotresolve,moreintensivetreatmentmaybe

necessaryandaurologicalopinionshouldbesought.Nofurthercoursesshouldbegivenuntilthepatienthasfully

recovered.

Endoxanaisdialyzable.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Cyclophosphamideisanantineoplasticagentwhichhasbeendemonstratedtohaveacytostaticeffectinmanytumour

types.TheactivemetabolitesofcyclophosphamidearealkylatingagentswhichtransferalkylgroupstoDNAduring

theprocessofcelldivision,thuspreventingnormalsynthesisofDNA.

5.2Pharmacokineticproperties

Cyclophosphamideiswellabsorbedfollowinganoraldosewithameanhalf-lifeof4-8hoursforbothoraland

parenteraladministration.

Itisaninactiveprodrugwithalkylatingmetabolitesproducedbyhepaticmetabolism,reachingpeaklevels4-6hours

afterani.v.injection.Hepaticenzymesmaybeinduced.Theparentcompoundbindspoorlytoplasmaproteinbutthe

activemetabolitesaresignificantlyprotein-bound.Thedrugiswidelydistributedandcrossestheblood-brainbarrier,

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5.3Preclinicalsafetydata

Therearenopre-clinicaldataofrelevancetotheprescriberwhichareadditionaltotheinformationalreadystatedin

othersectionsoftheSummaryofProductCharacteristics.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

None.

6.2Incompatibilities

Benzylalcoholincreasesthedegradationofcyclophosphamide.

6.3ShelfLife

Unopened:3years.

Afterreconstitutionforintravenousadministration:

Chemicalandphysicalin-usestabilityhasbeendemonstrated(inaqueous,sodiumchloride,andglucosesolutions)for

48hoursat2–8°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2-

8°C,unlessreconstitutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keepcontainerintheoutercarton.

Afterreconstitutionstoreat2-8°Candprotectfromlight.

6.5Natureandcontentsofcontainer

20mltypeIortypeIIIglassvialwithbutylrubberclosuresandplasticandaluminiumcaps.

Packsize:1vial.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Forintravenousadministration

Priortoadministrationthecontentsofavialshouldbedissolvedin5mlSodiumChloride0.9%w/vbyintroducingthe

salineintothevialandshakingvigorouslyuntilthepowderiscompletelydissolved.Reconstitutionresultsinaclear

solutionwithpHofbetween4and6.

Forsingleuseonly.Discardanyremainingcontents.

EndoxanaInjectioniscompatiblewiththefollowinginfusionsolutions:sodiumchloride,glucosesolution,sodium

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Generalinstructions

Ifvialsarestoredabovetherecommendedtemperaturethiscancausedegradationoftheactiveingredient,identifiable

byayellowmeltedappearancetothevialcontents.Vialscontainingmeltedmaterialshouldnotbeused.

Cyclophosphamideisacytotoxicagentandshouldbetreatedaccordingly.Protectiveglovesandappropriateequipment

toprotectagainstcontactwitheyesshouldbewornwhenhandlingtheproduct.Thematerialshouldnotbehandledby

womenwhoarepregnantorwhoarebreast-feeding.

Adequatecareandprecautionsshouldbetakeninthedisposalofemptyvialsanditems(syringes,needles,etc)usedin

reconstitutionandadministration.

7MARKETINGAUTHORISATIONHOLDER

ASTAMedicaLimited

168CowleyRoad

Cambridge

CB40DL

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA705/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10August1990

Dateoflastrenewal:10August2005

10DATEOFREVISIONOFTHETEXT

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