EBETAXEL

Main information

  • Trade name:
  • EBETAXEL Concentrate for Soln for Inf 6 Mg/Ml
  • Dosage:
  • 6 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EBETAXEL Concentrate for Soln for Inf 6 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/014/001
  • Authorization date:
  • 27-04-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ebetaxel6mg/mlconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each1mlofconcentrateforsolutionforinfusioncontains6mgpaclitaxel

Avialof5mlcontains30mgpaclitaxel

Avialof16.7mlcontains100mgpaclitaxel

Avialof25mlcontains150mgpaclitaxel

Avialof50mlcontains300mgpaclitaxel

Excipients:Polyoxylcastoroil(macrogolglycerolricinoleate)(522.4mg/ml),ethanolanhydrous(401.7mg/ml)(see

4.4).

Forafulllistofexcipients,see6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Clear,lightyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ovariancarcinoma:Inthefirst-linechemotherapyofovariancancer,paclitaxelisindicatedforthetreatmentof

patientswithadvancedcarcinomaoftheovaryorwithresidualdisease( >

1cm)afterinitiallaparotomy,in

combinationwithcisplatin.

Inthesecond-linechemotherapyofovariancancer,paclitaxelisindicatedforthetreatmentofmetastaticcarcinomaof

theovaryafterfailureofstandard,platinumcontainingtherapy.

Breastcarcinoma:Intheadjuvantsetting,paclitaxelisindicatedforthetreatmentofpatientswithnode-positivebreast

carcinomafollowinganthracyclineandcyclophosphamide(AC)therapy.Adjuvanttreatmentwithpaclitaxelshouldbe

regardedasanalternativetoextendedACtherapy.

Paclitaxelisindicatedfortheinitialtreatmentoflocallyadvancedormetastaticbreastcancereitherincombination

withananthracyclineinpatientsforwhomanthracyclinetherapyissuitable,orincombinationwithtrastuzumab,in

patientswhoover-expressHER-2ata3+levelasdeterminedbyimmunohistochemistryandforwhomananthracycline

isnotsuitable(see4.4and5.1).

Asasingleagent,paclitaxelisindicatedforthetreatmentofmetastaticcarcinomaofthebreastinpatientswhohave

failed,orarenotcandidatesforstandard,anthracyclinecontainingtherapy.

Advancednon-smallcelllungcarcinoma:Paclitaxel,incombinationwithcisplatin,isindicatedforthetreatmentof

non-smallcelllungcarcinoma(NSCLC)inpatientswhoarenotcandidatesforpotentiallycurativesurgeryand/or

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AIDS-relatedKaposi’ssarcoma:PaclitaxelisindicatedforthetreatmentofpatientswithadvancedAIDS-related

Kaposi’ssarcoma(KS)whohavefailedpriorliposomalanthracyclinetherapy.

Limitedefficacydatasupportsthisindication,asummaryoftherelevantstudiesisshowninsection5.1.

4.2Posologyandmethodofadministration

Allpatientsmustbepre-medicatedwithcorticosteroids,antihistamines,andH

antagonistspriortothetreatmentwith

Ebetaxele.g.:

*8-20mgforKSpatients

**oranequivalentantihistaminee.g.chlorpheniramine

Ebetaxelshouldbeadministeredthroughan“in-line”microporousmembrane,poresize0.22 µ

m(see6.6)

First-linechemotherapyofovariancarcinoma:Althoughotherdosageregimensareunderinvestigation,a

combinationregimenofpaclitaxelandcisplatinisrecommended.Accordingtodurationofinfusion,twodosesof

paclitaxelarerecommended:paclitaxel175mg/m 2

administeredintravenouslyover3hours,followedbycisplatinata

doseof75mg/m 2

everythreeweeksorpaclitaxel135mg/m²,ina24-hourinfusion,followedbycisplatin75mg/m²,

witha3weekintervalbetweencourses(see5.1).

Second-linechemotherapyofovariancarcinoma:Therecommendeddoseofpaclitaxelis175mg/m²administered

overaperiodof3hours,witha3weekintervalbetweencourses.

Adjuvantchemotherapyinbreastcarcinoma:Therecommendeddoseofpaclitaxelis175mg/m²administeredover

aperiodof3hoursevery3weeksforfourcourses,followingACtherapy.

First-linechemotherapyofbreastcarcinoma:Whenusedincombinationwithdoxorubicin(50mg/m²),paclitaxel

shouldbeadministered24hoursafterdoxorubicin.Therecommendeddoseofpaclitaxelis220mg/m²administered

intravenouslyoveraperiodof3hours,witha3-weekintervalbetweencourses(see4.5and5.1).

Whenusedincombinationwithtrastuzumab,therecommendeddoseofpaclitaxelis175mg/m²administered

intravenouslyoveraperiodof3hours,witha3-weekintervalbetweencourses(see5.1).Paclitaxelinfusionmaybe

startedthedayfollowingthefirstdoseoftrastuzumaborimmediatelyafterthesubsequentdosesoftrastuzumabifthe

precedingdoseoftrastuzumabwaswelltolerated(fordetailedtrastuzumabposologyseetheSummaryofProduct

CharacteristicsofHerceptin).

Second-linechemotherapyofbreastcarcinoma:Therecommendeddoseofpaclitaxelis175mg/m²administered

overaperiodof3hours,witha3-weekintervalbetweencourses.

TreatmentofadvancedNSCLC:Therecommendeddoseofpaclitaxelis175mg/m²administeredoveraperiodof

Drug Dose Administrationprior

toPaclitaxel

Dexamethasone

20mgoral*orIV Fororaladministration:

approximately12and

6hoursorforIV

administration:30to60

Diphenhydramine** 50mgi.v. 30to60minutes

Cimetidine

orranitidine 300mgi.v.or

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TreatmentofAIDS-relatedKS:Therecommendeddoseofpaclitaxelis100mg/m2administeredasa3-hour

intravenousinfusioneverytwoweeks.

Subsequentdosesofpaclitaxelshouldbeadministeredaccordingtoindividualpatienttolerance.

Paclitaxelshouldnotbereadministereduntiltheneutrophilcountis 1,500/mm³(1,000/mm³forKSpatients)and

theplateletcountis 100,000/mm³(75,000/mm³forKSpatients).Patientswhoexperiencesevereneutropenia

(neutrophilcount<500/mm³for 7days)orsevereperipheralneuropathyshouldreceiveadosereductionof20%for

subsequentcourses(25%forKSpatients)(see4.4).

Patientswithhepaticimpairment:Inadequatedataareavailabletorecommenddosagealterationsinpatientswith

mildtomoderatehepaticimpairments(see4.4and5.2).Patientswithseverehepaticimpairmentshouldnotbetreated

withpaclitaxel.

4.3Contraindications

Paclitaxeliscontraindicatedinpatientswhohaveahistoryofseverehypersensitivityreactionstopaclitaxelorany

otherofthecomponentsparticularlypolyethoxylcastoroil(macrogolglycerolricinoleate)(see4.4).

Paclitaxeliscontraindicatedduringpregnancyandlactation.

Paclitaxelshouldnotbeusedinpatientswithbaselineneutrophils<1,500/mm³(<1,000{mm³forKSpatients).

InKS,paclitaxelisalsocontraindicatedinpatientswithconcurrent,serious,uncontrolledinfections.

4.4Specialwarningsandprecautionsforuse

Paclitaxelshouldbeadministeredunderthesupervisionofaphysicianexperiencedintheuseofcancer

chemotherapeuticagents.Sincesignificanthypersensitivityreactionsmayoccur,appropriatesupportiveequipment

shouldbeavailable.

Patientsmustbepretreatedwithcorticosteroids,antihistaminesandH

antagonists(see4.2).

Paclitaxelshouldbegivenbeforecisplatinwhenusedincombination(see4.5).

Significanthypersensitivityreactionscharacterisedbydyspnoeaandhypotensionrequiringtreatment,angioedemaand

generalisedurticariahaveoccurredin<1%ofpatientsreceivingpaclitaxelafteradequatepremedication.These

reactionsareprobablyhistamine-mediated.Inthecaseofseverehypersensitivityreactions,paclitaxelinfusionshould

bediscontinuedimmediately,symptomatictherapyshouldbeinitiatedandthepatientshouldnotberechallengedwith

thedrug.

Bonemarrowsuppression(primarilyneutropenia)isthedose-limitingtoxicity.Frequentmonitoringofbloodcounts

shouldbeinstituted.Patientsshouldnotberetreateduntilneutrophilsrecoverto 1,500/mm³(1,000/mm³forKS

patients)andplateletsrecoverto 100,000/mm³(75,000/mm³forKSpatients).IntheKSclinicalstudy,themajority

ofpatientswerereceivinggranulocytecolonystimulatingfactor(G-CSF).

Severecardiacconductionabnormalitieshavebeenreportedrarelywithsingleagentpaclitaxel.Ifpatientsdevelop

significantconductionabnormalities(e.g.atrioventricularconductionblock,ventriculartachycardia)duringpaclitaxel

administration,appropriatetherapyshouldbeadministeredandcontinuouscardiacmonitoringshouldbeperformed

duringsubsequenttherapywithpaclitaxel.Hypotension,hypertension,andbradycardiahavebeenobservedduring

paclitaxeladministration;patientsareusuallyasymptomaticandgenerallydonotrequiretreatment.Frequentvitalsign

monitoring,particularlyduringthefirsthourofpaclitaxelinfusion,isrecommended.Severecardiovasculareventswere

observedmorefrequentlyinpatientswithNSCLCthanbreastorovariancarcinoma.Asinglecaseofheartfailure

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Whenpaclitaxelisusedincombinationwithdoxorubucinortrastuzumabforinitialtreatmentofmetastaticbreast

cancer,attentionshouldbeplacedonthemonitoringofcardiacfunction.Whenpatientsarecandidatesfortreatment

withpaclitaxelinthesecombinations,theyshouldundergobaselinecardiacassessmentincludinghistory,physical

examination,ECG,echocardiogram,and/orMUGAscan.Cardiacfunctionshouldbefurthermonitoredduring

treatment(e.g.everythreemonths).Monitoringmayhelptoidentifypatientswhodevelopcardiacdysfunctionand

treatingphysiciansshouldcarefullyassessthecumulativedose(mg/m2)ofanthracyclineadministeredwhenmaking

decisionsregardingfrequencyofventricularfunctionassessment.Whentestingindicatesdeteriorationincardiac

function,evenasymptomatic,treatingphysiciansshouldcarefullyassesstheclinicalbenefitsoffurthertherapyagainst

thepotentialforproducingcardiacdamage,includingpotentiallyirreversibledamage.Iffurthertreatmentis

administered,monitoringofcardiacfunctionshouldbemorefrequent(e.g.every1-2cycles).Formoredetailssee

SummaryofProductCharacteristicsofHerceptinordoxorubicin.

Althoughtheoccurrenceofperipheralneuropathyisfrequent,thedevelopmentofseveresymptomsisrare.Insevere

cases,adosereductionof20%(25%forKSpatients)forallsubsequentcoursesofpaclitaxelisrecommended.In

NSCLCpatientsandinovariancancerpatientstreatedinthefirst-linesetting,theadministrationofpaclitaxelasathree

hourinfusionincombinationwithcisplatin,resultedinagreaterincidenceofsevereneurotoxicitythanbothsingle

agentpaclitaxelandcyclophosphamidefollowedbycisplatin.

Patientswithhepaticimpairmentmaybeatincreasedriskoftoxicity,particularlygradeIII-IVmyelosuppression.

Thereisnoevidencethatthetoxicityofpaclitaxelisincreasedwhengivenasa3-hourinfusiontopatientswithmildly

abnormalliverfunction.Whenpaclitaxelisgivenasalongerinfusion,increasedmyelosuppressionmaybeseenin

patientswithmoderatetoseverehepaticimpairment.Patientsshouldbemonitoredcloselyforthedevelopmentof

profoundmyelosuppression(see4.2).Inadequatedataareavailabletorecommenddosagealterationsinpatientswith

mildtomoderatehepaticimpairments(see5.2).

Nodataareavailableforpatientswithseverebaselinecholestasis.Patientswithseverehepaticimpairmentshouldnot

betreatedwithpaclitaxel.

SinceEbetaxelcontainsethanol(401.7mg/ml),considerationshouldbegiventopossibleCNSandothereffects.

Specialcareshouldbetakentoavoidintra-arterialapplicationofpaclitaxel,sinceinanimalstudiestestingforlocal

toleranceseveretissuereactionswereobservedafterintra-arterialapplication.

Pseudomembranouscolitishasbeenrarelyreportedincludingcasesinpatientswhohavenotbeenconcomitantly

treatedwithantibiotics.Thisreactionshouldbeconsideredinthedifferentialdiagnosisofcasesofsevereorpersistent

diarrhoeaoccurringduringorshortlyaftertreatmentwithpaclitaxel.

Paclitaxelincombinationwithradiationofthelung,irrespectiveoftheirchronologicalorder,maycontributetothe

developmentofinterstitialpneumonitis.

InKSpatients,severemucositisisrare.Ifseverereactionsoccur,thepaclitaxeldoseshouldbereducedby25%.

AsEbetaxelcontainspolyethoxylcastoroil(macrogolglycerolricinoleate)itmaycausesevereallergicreactions.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Paclitaxelclearanceisnotaffectedbycimetidinepremedication.

Therecommendedregimenofpaclitaxeladministrationforthefirst-linechemotherapyofovariancarcinomaisfor

paclitaxeltobegivenbeforecisplatin.Whenpaclitaxelisgivenbeforecisplatin,thesafetyprofileofpaclitaxelis

consistentwiththatreportedforsingle-agentuse.Whenpaclitaxelwasgivenaftercisplatin,patientsshowedamore

profoundmyelosuppressionandanapproximately20%decreaseinpaclitaxelclearance.Patientstreatedwithpaclitaxel

andcisplatinmayhaveanincreasedriskofrenalfailureascomparedtocisplatinaloneingynecologicalcancers.

Sincetheeliminationofdoxorubicinanditsactivemetabolitescanbereducedwhenpaclitaxelanddoxorubicinare

givencloserintime,paclitaxelforinitialtreatmentofmetastaticbreastcancershouldbeadministered24hoursafter

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Themetabolismofpaclitaxeliscatalysed,inpart,bycytochromeP450isoenzymesCYP2C8and3A4(see5.2).

ClinicalstudieshavedemonstratedthatCYP2C8-mediatedmetabolismofpaclitaxel,to6-hydroxypaclitaxel,isthe

majormetabolicpathwayinhumans.Concurrentadministrationofketoconazole,aknownpotentinhibitorofCYP3A4,

doesnotinhibittheeliminationofpaclitaxelinpatients;thus,bothmedicinalproductsmaybeadministeredtogether

withoutdosageadjustment.FurtherdataonthepotentialofdruginteractionsbetweenpaclitaxelandotherCYP3A4

substrates/inhibitorsarelimited.Therefore,cautionshouldbeexercisedwhenadministeringpaclitaxelconcomitantly

withmedicinesknowntoinhibit(e.g.erythromycin,fluoxetine,gemfibrozil)orinduce(e.g.rifampicin,carbamazepine,

phenytoin,phenobarbital,efavirenz,nevirapine)eitherCYP2C8or3A4.

StudiesinKSpatients,whoweretakingmultipleconcomitantmedications,suggestthatthesystemicclearanceof

paclitaxelwassignificantlylowerinthepresenceofnelfinavirandritonavir,butnotwithindinavir.Insufficient

informationisavailableoninteractionswithotherproteaseinhibitors.Consequently,paclitaxelshouldbeadministered

withcautioninpatientsreceivingproteaseinhibitorsasconcomitanttherapy.

4.6Fertility,pregnancyandlactation

Paclitaxelhasbeenshowntobebothembryotoxicandfetotoxicinrabbitsandtodecreasefertilityinrats.

Thereisnoinformationontheuseofpaclitaxelinpregnantwomen.Aswithothercytostaticagentspaclitaxelmay

possiblycausefoetaldamageduringtreatmentofpregnantwomen.Paclitaxeliscontra-indicatedduringpregnancy.

Womenmustbeadvisedtoavoidpregnancyduringtherapywithpaclitaxelandtoinformthetreatingphysician

immediatelyshouldpregnancyoccur.

Itisnotknownwhetherpaclitaxelisexcretedinhumanbreastmilk.Paclitaxeliscontraindicatedduringlactation.

Breastfeedingshouldbediscontinuedduringpaclitaxeltherapy.

Bothsexuallyactivemenandwomenshoulduseeffectivemethodsofcontraceptionduringtreatment.

4.7Effectsonabilitytodriveandusemachines

Paclitaxelhasnotbeendemonstratedtointerferewiththisability.However,itshouldbenotedthatpaclitaxeldoes

containalcohol(see4.4and6.1).

4.8Undesirableeffects

Unlessotherwisenoted,thefollowingdiscussionreferstotheoverallsafetydatabaseof812patientswithsolidtumors

treatedwithsingle-agentpaclitaxelinclinicalstudies.AstheKSpopulationisveryspecific,aspecialchapterbasedon

aclinicalstudywith107patients,ispresentedattheendofthissection.

Thefrequencyandseverityofundesirableeffects,unlessotherwisementioned,aregenerallysimilarbetweenpatients

receivingpaclitaxelforthetreatmentofovariancarcinoma,breastcarcinoma,orNSCLC.Noneoftheobserved

toxicitieswereclearlyinfluencedbyage.

Themostfrequentsignificantundesirableeffectwasbonemarrowsuppression.Severeneutropenia( <

500cells/mm³)

occurredin28%ofpatients,butwasnotassociatedwithfebrileepisodes.Only1%ofpatientsexperiencedsevere

neutropeniafor 7days.Thrombocytopeniawasreportedin11%ofpatients.Threepercentofpatientshadaplatelet

countnadir <

50,000/mm³atleastoncewhileonstudy.Anaemiawasobservedin64%ofpatients,butwassevere(Hb

<

5mmol/l)inonly6%ofpatients.Incidenceandseverityofanaemiaisrelatedtobaselinehaemoglobinstatus.

Neurotoxicity,mainlyperipheralneuropathy,appearedtobemorefrequentandseverewitha175mg/m 2

3-hour

infusion(85%neurotoxicity,15%severe)thanwitha135mg/m 2

24-hourinfusion(25%peripheralneuropathy,3%

severe)whenpaclitaxelwascombinedwithcisplatin.InNSCLCpatientsandinovariancancerpatientstreatedwith

paclitaxelover3hoursfollowedbycisplatin,thereisanapparentincreaseintheincidenceofsevereneurotoxicity.

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Peripheralneuropathywasthecauseofpaclitaxeldiscontinuationinafewcases.Sensorysymptomshaveusually

improvedorresolvedwithinseveralmonthsofpaclitaxeldiscontinuation.Pre-existingneuropathiesresultingfrom

priortherapiesarenotacontraindicationforpaclitaxeltherapy.

Arthralgiaormyalgiaaffected60%ofpatientsandwasseverein13%ofpatients.

Asignificanthypersensitivityreactionwithpossiblefataloutcome(definedashypotensionrequiringtherapy,

angioedema,respiratorydistressrequiringbronchodilatortherapy,orgeneralisedurticaria)occurredintwo( <

1%)of

patients.Thirty-fourpercentofpatients(17%ofallcourses)experiencedminorhypersensitivityreactions.Theseminor

reactions,mainlyflushingandrash,didnotrequiretherapeuticinterventionnordidtheypreventcontinuationof

paclitaxeltherapy.

Injectionsitereactionsduringintravenousadministrationmayleadtolocalisedoedema,pain,erythema,and

induration;onoccasion,extravasationcanresultincellulitis.Skinsloughingand/orpeelinghasbeenreported,

sometimesrelatedtoextravasation.Skindiscolorationmayalsooccur.Recurrenceofskinreactionsatasiteofprevious

extravasationfollowingadministrationofpaclitaxelatadifferentsite,i.e.“recall”,hasbeenreportedrarely.Aspecific

treatmentforextravasationreactionsisunknownatthistime.

Thetablebelowlistsundesirableeffectsregardlessofseverityassociatedwiththeadministrationofsingleagent

paclitaxeladministeredasathreehourinfusioninthemetastaticsetting(812patientstreatedinclinicalstudies)andas

reportedinthepostmarketingsurveillance*ofpaclitaxel.

Thefrequencyofundesirableeffectslistedbelowisdefinedusingthefollowingconvention:

verycommon(³1/10);common(³1/100,<1/10);uncommon(³1/1,000,<1/100);rare(³1/10,000,<1/1,000);veryrare

(<1/10,000).

Infectionsandinfestations: Verycommon:infection(mainlyurinarytractand

upperrespiratorytractinfections),withreported

casesoffataloutcome

Uncommon:septicshock

Rare*:pneumonia,peritonitis,sepsis

Bloodandthelymphaticsystem

disorders: Verycommon:myelosuppression,neutropenia,

anaemia,thrombocytopenia,leucopenia,bleeding

Rare*:febrileneutropenia

Veryrare*:acutemyeloidleukaemia,

myelodysplasticsyndrome

Immunesystemdisorders: Verycommon:minorhypersensitivityreactions

(mainlyflushingandrash)

Uncommon:significanthypersensitivityreactions

requiringtherapy(e.g.,hypotension,

angioneuroticoedema,respiratorydistress,

generalisedurticaria,chills,backpain,chestpain,

tachycardia,abdominalpain,paininextremities,

diaphoresisandhypertension)

Rare*:anaphylacticreactions

Veryrare*:anaphylaticshock

Metabolismandnutritiondisorders: Veryrare*:anorexia

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Nervoussystemdisorders: Verycommon:neurotoxicity(mainly:peripheral

neuropathy)

Rare*:motorneuropathy(withresultantminor

distalweakness)

Veryrare*:autonomicneuropathy(resultingin

paralyticileusandorthostatichypotension),grand

malseizures,convulsions,encephalopathy,

dizziness,headache,ataxia

Eyedisorders: Veryrare*:opticnerveand/orvisualdisturbances

(scintillatingscotomata),particularlyinpatients

whohavereceivedhigherdosesthan

recommended

Earandlabyrinthdisorders: Veryrare*:ototoxicity,hearingloss,tinnitus,

vertigo

Cardiacdisorders: Common:bradycardia

Uncommon:cardiomyopathy,asymptomatic

ventriculartachycardia,tachycardiawith

bigeminy,AVblockandsyncope,myocardial

infarction

Veryrare*:atrialfibrillation,supraventricular

tachycardia

Vasculardisorders: Verycommon:hypotension

Uncommon:hypertension,thrombosis,

thrombophlebitis

Veryrare*:shock

Respiratory,thoracicandmediastinal

disorders: Rare*:dyspnoea,pleuraleffusion,interstitial

pneumonia,lungfibrosis,pulmonaryembolism,

respiratoryfailure

Veryrare*:cough

Gastrointestinaldisorders: Verycommon:nausea,vomiting,diarrhoea,

mucosalinflammation

Rare*:bowelobstruction,bowelperforation,

ischaemiccolitis,pancreatitis

Veryrare*:mesentericthrombosis,

pseudomembranouscolitis,oesophagitis,

constipation,ascites,neutropeniccolitis

Hepato-biliarydisorders: Veryrare*:hepaticnecrosis,hepatic

encephalopathy(bothwithreportedcasesoffatal

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BreastcancerpatientswhoreceivedpaclitaxelintheadjuvantsettingfollowingACexperiencedmoreneurosensory

toxicity,hypersensitivityreactions,arthralgia/myalgia,anaemia,infection,fever,nausea/vomitinganddiarrhoeathan

patientswhoreceivedACalone.However,thefrequencyoftheseeventswasconsistentwiththeuseofsingleagent

paclitaxel,asreportedabove.

Combinationtreatment

Thefollowingdiscussionreferstotwomajortrialsforthefirst-linechemotherapyofovariancarcinoma(paclitaxel+

cisplatin:over1050patients);twophaseIIItrialsinthefirstlinetreatmentofmetastaticbreastcancer:one

investigatingthecombinationwithdoxorubicin(paclitaxel+doxorubicin:267patients),anotheroneinvestigatingthe

combinationwithtrastuzumab(plannedsubgroupanalysispaclitaxel+trastuzumab:188patients)andtwophaseIII

trialsforthetreatmentofadvancedNSCLC(paclitaxel+cisplatin:over360patients)(see5.1).

Whenadministeredasathreehourinfusionforthefirst-linechemotherapyofovariancancer,neurotoxicity,

arthralgia/myalgia,andhypersensitivitywerereportedasmorefrequentandseverebypatientstreatedwithpaclitaxel

followedbycisplatinthanpatientstreatedwithcyclophosphamidefollowedbycisplatin.Myelosuppressionappearedto

belessfrequentandseverewithpaclitaxelasathreehourinfusionfollowedbycisplatincomparedwith

cyclophosphamidefollowedbycisplatin.

Forthefirstlinechemotherapyofmetastaticbreastcancer,neutropenia,anaemia,peripheralneuropathy,

arthralgia/myalgia,asthenia,fever,anddiarrhoeawerereportedmorefrequentlyandwithgreaterseveritywhen

paclitaxel(220mg/m²)wasadministeredasa3-hourinfusion24hoursfollowingdoxorubicin(50mg/m²)when

comparedtostandardFACtherapy(5-FU500mg/m²,doxorubicin50mg/m²,cyclophosphamide500mg/m²).Nausea

andvomitingappearedtobelessfrequentandseverewiththepaclitaxel(220mg/m²)/doxorubicin(50mg/m²)

regimenascomparedtothestandardFACregimen.Theuseofcorticosteroidsmayhavecontributedtothelower

Skinandsubcutaneoustissue

disorders: Verycommon:alopecia

Common:transientandmildnailandskinchanges

Rare*:pruritus,rash,erythema

Veryrare*:Stevens-Johnsonsyndrome,epidermal

necrolysis,erythemamultiforme,exfoliative

dermatitis,urticaria,onycholysis(patientson

therapyshouldwearsunprotectiononhandsand

feet)

Musculoskeletal,connectivetissueand

bonedisorders: Verycommon:arthralgia,myalgia

Generaldisordersandadministration

siteconditions: Common:injectionsitereactions(including

localisedoedema,pain,erythema,

induration,onoccasionextravasationcanresultin

cellulitis,skinfibrosisandskinnecrosis)

Rare*:asthenia,pyrexia,dehydration,oedema,

malaise

Investigations: Common:severeelevationinAST(SGOT),

severeelevationinalkalinephosphatase

Uncommon:severeelevationinbilirubin

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Whenpaclitaxelwasadministeredasa3-hourinfusionincombinationwithtrastuzumabforthefirstlinetreatmentof

patientswithmetastaticbreastcancer,thefollowingevents(regardlessofrelationshiptopaclitaxelortrastuzumab)

werereportedmorefrequentlythanwithsingleagentpaclitaxel:heartfailure(8%vs1%),infection(46%vs27%),

chills(42%vs4%),fever(47%vs23%),cough(42%vs22%),rash(39%vs18%),arthralgia(37%vs21%),

tachycardia(12%vs4%),diarrhoea(45%vs30%),hypertonia(11%vs3%),epistaxis(18%vs4%),acne(11%vs

3%),herpessimplex(12%vs3%),accidentalinjury(13%vs3%),insomnia(25%vs13%),rhinitis(22%vs5%),

sinusitis(21%vs7%),andinjectionsitereaction(7%vs1%).

Someofthesefrequencydifferencesmaybeduetotheincreasednumberanddurationoftreatmentswith

paclitaxel/trastuzumabcombinationvssingleagentpaclitaxel.Severeeventswerereportedatsimilarratesfor

paclitaxel/trastuzumabandsingleagentpaclitaxel.

Whendoxorubicinwasadministeredincombinationwithpaclitaxelinmetastaticbreastcancer,cardiaccontraction

abnormalities(20%reductionofleftventricularejectionfraction)wereobservedin15%ofpatientsvs.10%with

standardFACregimen.Congestiveheartfailurewasobservedin <

1%inbothpaclitaxel/doxorubicinandstandard

FACarms.Administrationoftrastuzumabincombinationwithpaclitaxelinpatientspreviouslytreatedwith

anthracyclinesresultedinanincreasedfrequencyandseverityofcardiacdysfunctionincomparisonwithpatients

treatedwithpaclitaxelsingleagent(NYHAClassI/II10%vs.0%;NYHAClassIII/IV2%vs.1%)andrarelyhasbeen

associatedwithdeath(seetrastuzumabSummaryofProductCharacteristics).Inallbuttheserarecases,patients

respondedtoappropriatemedicaltreatment.

Radiationpneumonitishasbeenreportedinpatientsreceivingconcurrentradiotherapy.

AIDS-relatedKaposi’ssarcoma

Exceptforhaematologicandhepaticundesirableeffects(seebelow),thefrequencyandseverityofundesirableeffects

aregenerallysimilarbetweenKSpatientsandpatientstreatedwithpaclitaxelmonotherapyforothersolidtumours,

basedonaclinicalstudyincluding107patients.

Bloodandthelymphaticsystemdisorders:bonemarrowsuppressionwasthemajordose-limitingtoxicity.

Neutropeniaisthemostimportanthaematologicaltoxicity.Duringthefirstcourseoftreatment,severeneutropenia(<

500cells/mm 3

)occurredin20%ofpatients.Duringtheentiretreatmentperiod,severeneutropeniawasobservedin

39%ofpatients.Neutropeniawaspresentfor>7daysin41%andfor30-35daysin8%ofpatients.Itresolvedwithin

35daysinallpatientswhowerefollowed.TheincidenceofGrade4neutropenialasting 7dayswas22%.

Neutropenicfeverrelatedtopaclitaxelwasreportedin14%ofpatientsandin1.3%oftreatmentcycles.Therewere3

septicepisodes(2.8%)duringpaclitaxeladministrationrelatedtothemedicinalproductthatprovedfatal.

Thrombocytopeniawasobservedin50%ofpatients,andwassevere(<50,000cells/mm 3

)in9%.Only14%

experiencedadropintheirplateletcount<75,000cells/mm 3

,atleastoncewhileontreatment.Bleedingepisodes

relatedtopaclitaxelwerereportedin<3%ofpatients,butthehaemorrhagicepisodeswerelocalised.

Anaemia(Hb<11g/dL)wasobservedin61%ofpatientsandwassevere(Hb<8g/dL)in10%.Redcelltransfusions

wererequiredin21%ofpatients.

Hepato-biliarydisorders:Amongpatients(>50%onproteaseinhibitors)withnormalbaselineliverfunction,28%,

43%and44%hadelevationsinbilirubin,alkalinephosphataseandAST(SGOT),respectively.Foreachofthese

parameters,theincreaseswereseverein1%ofcases.

4.9Overdose

Thereisnoknownantidoteforpaclitaxeloverdosage.Theprimaryanticipatedcomplicationsofoverdosagewould

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup/ATCcode:cytostaticagent,L01CD01.

Paclitaxelisanovelantimicrotubuleagentthatpromotestheassemblyofmicrotubulesfromtubulindimersand

stabilisesmicrotubulesbypreventingdepolymerization.Thisstabilityresultsintheinhibitionofthenormaldynamic

reorganisationofthemicrotubulenetworkthatisessentialforvitalinterphaseandmitoticcellularfunctions.

Inaddition,paclitaxelinducesabnormalarraysorbundlesofmicrotubulesthroughoutthecellcycleandmultipleasters

ofmicrotubulesduringmitosis.

Inthefirst-linechemotherapyofovariancarcinoma,thesafetyandefficacyofpaclitaxelwereevaluatedintwomajor,

randomised,controlled(vs.cyclophosphamide750mg/m 2

/cisplatin75mg/m 2

)trials.IntheIntergrouptrial(BMS

CA139-209),over650patientswithstageII

,IIIorIVprimaryovariancancerreceivedamaximumof9treatment

coursesofpaclitaxel(175mg/m 2

over3hr)followedbycisplatin(75mg/m 2

)orcontrol.Thesecondmajortrial

(GOG-111/BMSCA139-022)evaluatedamaximumof6coursesofeitherpaclitaxel(135mg/m²over24hrs)followed

bycisplatin(75mg/m²)orcontrolinover400patientswithstageIII/IVprimaryovariancancer,witha>1cmresidual

diseaseafterstaginglaparotomy,orwithdistantmetastases.Whilethetwodifferentpaclitaxelposologieswerenot

comparedwitheachotherdirectly,inbothtrialspatientstreatedwithpaclitaxelincombinationwithcisplatinhada

significantlyhigherresponserate,longertimetoprogression,andlongersurvivaltimewhencomparedwithstandard

therapy.Increasedneurotoxicity,arthralgia/myalgiabutreducedmyelosuppressionwereobservedinadvancedovarian

cancerpatientsadministered3-hourinfusionpaclitaxel/cisplatinascomparedtopatientswhoreceived

cyclophosphamide/cisplatin.

Intheadjuvanttreatmentofbreastcarcinoma,3121patientswithnodepositivebreastcarcinomaweretreatedwith

adjuvantpaclitaxeltherapyornochemotherapyfollowingfourcoursesofdoxorubicinandcyclophosphamide(CALGB

9344,BMSCA139-223).Medianfollow-upwas69months.Overall,paclitaxelpatientshadasignificantreductionof

18%intheriskofdiseaserecurrencerelativetopatientsreceivingACalone(p=0.0014),andasignificantreductionof

19%intheriskofdeath(p=0.0044)relativetopatientsreceivingACalone.Retrospectiveanalysesshowbenefitinall

patientsubsets.Inpatientswithhormonereceptornegative/unknowntumors,reductioninriskofdiseaserecurrence

was28%(95%CI:0.59-0.86).Inthepatientsubgroupwithhormonereceptorpositivetumors,theriskreductionof

diseaserecurrencewas9%(95%CI:0.78-1.07).However,thedesignofthestudydidnotinvestigatetheeffectof

extendedACtherapybeyond4cycles.Itcannotbeexcludedonthebasisofthisstudyalonethattheobservedeffects

couldbepartlyduetothedifferenceindurationofchemotherapybetweenthetwoarms(AC4cycles;AC+paclitaxel

8cycles).Therefore,adjuvanttreatmentwithpaclitaxelshouldberegardedasanalternativetoextendedACtherapy.

Inasecondlargeclinicalstudyinadjuvantnodepositivebreastcancerwithasimilardesign,3060patientswere

randomizedtoreceiveornotfourcoursesofpaclitaxelatahigherdoseof225mg/m²followingfourcoursesofAC

(NSABPB-28,BMSCA139-270).Atamedianfollow-upof64months,paclitaxelpatientshadasignificantreduction

of17%intheriskofdiseaserecurrencerelativetopatientswhoreceivedACalone(p=0.006);paclitaxeltreatment

wasassociatedwithareductionintheriskofdeathof7%(95%CI:0.78-1.12).Allsubsetanalysesfavoredthe

paclitaxelarm.Inthisstudypatientswithhormonereceptorpositivetumorhadareductionintheriskofdisease

recurrenceof23%(95%CI:0.6-0.92);inthepatientsubgroupwithhormonereceptornegativetumortheriskreduction

ofdiseaserecurrencewas10%(95%CI:0.7-1.11).

Inthefirst-linetreatmentofmetastaticbreastcancer,theefficacyandsafetyofpaclitaxelwereevaluatedintwopivotal,

phaseIII,randomised,controlledopen-labeltrials.Inthefirststudy(BMSCA139-278),thecombinationofbolus

doxorubicin(50mg/m²)followedafter24hoursbypaclitaxel(220mg/m²by3-hourinfusion)(AT),wascompared

versusstandardFACregimen(5-FU500mg/m²,doxorubicin50mg/m²,cyclophosphamide500mg/m²),both

administeredeverythreeweeksforeightcourses.Inthisrandomisedstudy,267patientswithmetastaticbreastcancer,

whohadeitherreceivednopriorchemotherapyoronlynon-anthracyclinechemotherapyintheadjuvantsetting,were

enrolled.ResultsshowedasignificantdifferenceintimetoprogressionforpatientsreceivingATcomparedtothose

receivingFAC(8.2vs.6.2months;p=0.029).Themediansurvivalwasinfavourofpaclitaxel/doxorubicinvs.FAC

(23.0vs.18.3months;p=0.004).IntheATandFACtreatmentarm44%and48%respectivelyreceivedfollow-up

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TheoverallresponseratewasalsosignificantlyhigherintheATarmcomparedtotheFACarm(68%vs.55%).

Completeresponseswereseenin19%ofthepaclitaxel/doxorubicinarmpatientsvs.8%oftheFACarmpatients.All

efficacyresultshavebeensubsequentlyconfirmedbyablindedindependentreview.

InthesecondpivotalstudytheefficacyandsafetyofthepaclitaxelandHerceptincombinationwasevaluatedina

plannedsubgroupanalysis(metastaticbreastcancerpatientswhoformerlyreceivedadjuvantanthracyclines)ofthe

studyHO648g.TheefficacyofHerceptin incombinationwithpaclitaxelinpatientswhodidnotreceiveprior

adjuvantanthracyclineshasnotbeenproven.

Thecombinationoftrastuzumab(4mg/kgloadingdosethen2mg/kgweekly)andpaclitaxel(175mg/m²)3-hour

infusion,everythreeweekswascomparedtosingle-agentpaclitaxel(175mg/m²)3-hourinfusion,everythreeweeksin

188patientswithmetastaticbreastcanceroverexpressingHER2(2+or3+asmeasuredbyimmunohistochemistry),

whohadpreviouslybeentreatedwithanthracyclines.Paclitaxelwasadministeredeverythreeweeksforatleastsix

courseswhiletrastuzumabwasgivenweeklyuntildiseaseprogression.Thestudyshowedasignificantbenefitforthe

paclitaxel/trastuzumabcombinationintermsoftimetoprogression(6.9vs.3.0months),responserate(41%vs.17%),

anddurationofresponse(10.5vs.4.5months)whencomparedtopaclitaxelalone.Themostsignificanttoxicity

observedwiththepaclitaxel/trastuzumabcombinationwascardiacdysfunction(see4.8).

InthetreatmentofadvancedNSCLC,paclitaxel175mg/m²followedbycisplatin80mg/m²hasbeenevaluatedintwo

phaseIIItrials(367patientsonpaclitaxelcontainingregimens).Bothwererandomisedtrials,onecomparedto

treatmentwithcisplatin100mg/m²,theotherusedteniposide100mg/m²followedbycisplatin80mg/m²ascomparator

(367patientsoncomparator).Resultsineachtrialweresimilar.Fortheprimaryoutcomeofmortality,therewasno

significantdifferencebetweenthepaclitaxelcontainingregimenandthecomparator(mediansurvivaltimes8.1and

9.5monthsonpaclitaxelcontainingregimens,8.6and9.9monthsoncomparators).Similarly,forprogression-free

survivaltherewasnosignificantdifferencebetweentreatments.Therewasasignificantbenefitintermsofclinical

responserate.Qualityofliferesultsaresuggestiveofabenefitonpaclitaxelcontainingregimensintermsofappetite

lossandprovideclearevidenceoftheinferiorityofpaclitaxelcontainingregimensintermsofperipheralneuropathy

(p<0.008).

InthetreatmentofAIDS-relatedKS,theefficacyandsafetyofpaclitaxelwereinvestigatedinanon-comparativestudy

inpatientswithadvancedKS,previouslytreatedwithsystemicchemotherapy.Theprimaryend-pointwasbesttumour

response.Ofthe107patients,63wereconsideredresistanttoliposomalanthracyclines.Thissubgroupisconsideredto

constitutethecoreefficacypopulation.Theoverallsuccessrate(complete/partialresponse)after15cyclesoftreatment

was57%(CI44-70%)inliposomalanthracycline-resistantpatients.Over50%oftheresponseswereapparentafter

thefirst3cycles.Inliposomalanthracycline-resistantpatients,theresponserateswerecomparableforpatientswhohad

neverreceivedaproteaseinhibitor(55.6%)andthosewhoreceivedoneatleast2monthspriortotreatmentwith

paclitaxel(60.9%).Themediantimetoprogressioninthecorepopulationwas468days(95%CI257-NE).Median

survivalcouldnotbecomputed,butthelower95%boundwas617daysincorepatients.

5.2Pharmacokineticproperties

Followingintravenousadministration,paclitaxelexhibitsabiphasicdeclineinplasmaconcentrations.

Thepharmacokineticsofpaclitaxelweredeterminedfollowing3and24hourinfusionsatdosesof135and175mg/m².

Meanterminalhalf-lifeestimatesrangedfrom3.0to52.7hours,andmean,non-compartmentallyderived,valuesfor

totalbodyclearancerangedfrom11.6to24.0l/hr/m²;totalbodyclearanceappearedtodecreasewithhigherplasma

concentrationsofpaclitaxel.Meansteady-statevolumeofdistributionrangedfrom198to688l/m²,indicating

extensiveextravasculardistributionand/ortissuebinding.Withthe3-hourinfusion,increasingdosesresultin

non-linearpharmacokinetics.Forthe30%increaseindosefrom135mg/m²to175mg/m²,theC

andAUC

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Followinganintravenousdoseof100mg/m 2

givenasa3-hourinfusionto19KSpatients,

themeanC

was1,530ng/ml(range761-2,860ng/ml)andthemeanAUC5,619ng.hr/ml(range2,609-9,428

ng.hr/ml).Clearancewas20.6l/h/m2(range11-38)andthevolumeofdistributionwas291l/m2(range121-638).The

terminaleliminationhalf-lifeaveraged23.7hours(range12-33).

Intrapatientvariabilityinsystemicpaclitaxelexposurewasminimal.Therewasnoevidenceforaccumulationof

paclitaxelwithmultipletreatmentcourses.

Invitrostudiesofbindingtohumanserumproteinsindicatethat89-98%ofdrugisbound.Thepresenceofcimetidine,

ranitidine,dexamethasoneordiphenhydraminedidnotaffectproteinbindingofpaclitaxel.

Thedispositionofpaclitaxelhasnotbeenfullyelucidatedinhumans.Meanvaluesforcumulativeurinaryrecoveryof

unchangeddrughaverangedfrom1.3to12.6%ofthedose,indicatingextensivenon-renalclearance.

Hepaticmetabolismandbiliaryclearancemaybetheprincipalmechanismfordispositionofpaclitaxel.Paclitaxel

appearstobemetabolisedprimarilybycytochromeP450enzymes.Followingadministrationofaradiolabelled

paclitaxel,anaverageof26,2and6%oftheradioactivitywasexcretedinthefaecesas6-hydroxypaclitaxel,

3’-p-hydroxypaclitaxel,and6-3’-p-dihydroxy-paclitaxel,respectively.Theformationofthesehydroxylated

metabolitesiscatalysedbyCYP2C8,-3A4,andboth–2C8and–3A4respectively.Theeffectofrenalorhepatic

dysfunctiononthedispositionofpaclitaxelfollowinga3-hourinfusionhasnotbeeninvestigatedformally.

Pharmacokineticparametersobtainedfromonepatientundergoinghaemodialysiswhoreceiveda3-hourinfusionof

paclitaxel135mg/m²werewithintherangeofthosedefinedinnon-dialysispatients.

Inclinicaltrialswherepaclitaxelanddoxorubicinwereadministeredconcomitantly,thedistributionandeliminationof

doxorubicinanditsmetaboliteswereprolonged.Totalplasmaexposuretodoxorubicinwas30%higherwhen

paclitaxelimmediatelyfolloweddoxorubicinthanwhentherewasa24-hourintervalbetweendrugs.

Foruseofpaclitaxelincombinationwithothertherapies,pleaseconsulttheSummaryofProductCharacteristicsof

cisplatin,doxorubicinortrastuzumabforinformationontheuseofthesemedicinalproducts.

5.3Preclinicalsafetydata

Thecarcinogenicpotentialofpaclitaxelhasnotbeenstudied.However,paclitaxelmaybeapotentialcarcinogenicand

genotoxicagent,duetoitspharmacodynamicmechanismofaction.

Paclitaxelhasdemonstratedtobemutagenicinbothinvitroandinvivomammaliantestsystems.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Polyoxylcastoroil(macrogolglycerolricinoleate)

Ethanol,anhydrous

6.2Incompatibilities

ThepolyethoxylatedcastoroilmayresultinDEHP[di(2-ethylhexyl)phthalate]leachingfromplasticised

polyvinylchloride(PVC)containersatlevelswhichincreasewithtimeandconcentration.Consequently,the

preparation,storageandadministrationofdilutedPaclitaxelshouldbecarriedoutusingnon-PVC-containing

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6.3Shelflife

Vialbeforeopening

3years

Afteropeningbeforedilution

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor28daysbelow25°Cfollowingmultipleneedleentries

andproductwithdrawal.

Fromamicrobiologicalpointofview,onceopenedtheproductmaybestoredforamaximumof28daysbelow25°C.

Otherin-usestoragetimesandconditionsaretheresponsibilityoftheuser.

Afterdilution

Chemicalandphysicalstabilityafterdilutionisdocumentedfor48hoursbelow25ºCand2-8ºC.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Storeinoriginalcontainertoprotectfromlight.

Forstorageofthedilutedmedicinalproductseesection6.3.

6.5Natureandcontentsofcontainer

Type1glassvials(withbutylrubberstopper)containing5ml,16.7ml,25mlor50mlofsolution.

The1,5or10vialsarepackagedwithorwithoutprotectiveplasticoverwrap(ONCO-SAFE)inacarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Handling:

Aswithallantineoplasticagents,cautionshouldbeexercisedwhenhandlingpaclitaxel.

Pregnantwomenorwomenofchildbearingpotentialmustbewarnedtoavoidhandlingcytotoxicagents.

Dilutionshouldbecarriedoutunderasepticconditionsbytrainedpersonnelinadesignatedarea.Adequateprotective

glovesshouldbeworn.Contactwithskinandmucousmembranesshouldbeavoided.Incaseofcontactwithskin,the

skinshouldbewashedwithsoapandwater.Followingtopicalexposure,tingling,burningandrednesshavebeen

observed.Incaseofcontactwiththemucousmembranes,theseshouldbeflushedthoroughlywithwater.Upon

inhalation,dyspnoea,chestpain,burningthroatandnauseahavebeenreported.

Ifunopenedvialsarerefrigerated,aprecipitatemayformthatredissolveswithlittleornoagitationuponreachingroom

temperature.Productqualityisnotaffected.Ifthesolutionremainscloudyorifaninsolubleprecipitateisnoted,the

vialshouldbediscarded.

Followingmultipleneedleentriesandproductwithdrawals,thevialsmaintainmicrobial,chemicalandphysical

stabilityforupto28daysat25°C.Otherin-usestoragetimesandconditionsaretheresponsibilityoftheuser.

PreparationforIVadministration:Priortoinfusion,paclitaxelmustbedilutedusingaseptictechniquesin0.9%

SodiumChlorideInjection,or5%DextroseInjection,or5%Dextroseand0.9%SodiumChlorideInjectiontoafinal

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Chemicalandphysicalin-usestabilityofthesolutionpreparedforinfusionhasbeendemonstratedat5°Candat25°C

for48hourswhendilutedin5%Dextrosesolution,andfor48hourswhendilutedin0.9%SodiumChlorideInjection.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

Afterdilutionthesolutionisforsingleuseonly.

Uponpreparation,solutionsmayshowhaziness,whichisattributedtotheformulationvehicle,andisnotremovedby

filtration.Paclitaxelshouldbeadministeredthroughanin-linefilterwithamicroporousmembrane 0.22 µ

m.No

significantlossesinpotencyhavebeennotedfollowingsimulateddeliveryofthesolutionthroughIVtubingcontaining

anin-linefilter.

Therehavebeenrarereportsofprecipitationduringpaclitaxelinfusions,usuallytowardstheendofa24hourinfusion

period.Althoughthecauseofthisprecipitationhasnotbeenelucidated,itisprobablylinkedtothesupersaturationof

thedilutedsolution.Toreducetheprecipitationrisk,paclitaxelshouldbeusedassoonaspossibleafterdilution,and

excessiveagitation,vibrationorshakingshouldbeavoided.Theinfusionsetsshouldbeflushedthoroughlybeforeuse.

Duringinfusion,theappearanceofthesolutionshouldberegularlyinspectedandtheinfusionshouldbestoppedif

precipitationispresent.

TominimisepatientexposuretoDEHP,whichmaybeleachedfromplasticisedPVCinfusionbags,sets,orother

medicalinstruments,dilutedPaclitaxelsolutionsshouldbestoredinbottleswithoutPVC(glass,polypropylene)or

plasticbags(polypropylene,polyolefin)andadministeredthroughpolyethylene-linedadministrationsets.Useoffilter

deviceswhichincorporateshortinletand/oroutletplasticisedPVCtubinghasnotresultedinsignificantleachingof

DEHP.

Disposal:

Allitemsusedforpreparation,administrationorotherwisecomingintocontactwithpaclitaxelshouldundergodisposal

accordingtolocalguidelinesforthehandlingofcytotoxiccompounds.

7MARKETINGAUTHORISATIONHOLDER

EbewePharmaGes.mb.HNfg.KG

Mondseestrasse11

4866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA789/14/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27 th

April2007

Dateoflastrenewal:23 rd

August2009

10DATEOFREVISIONOFTHETEXT

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